Reproductive Endocrinology PDF

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Table of contents Reproductive

1. The Menstrual Cycle
2. Puberty and Its Disorders

12. Reproductive Endocrinology Diagnostic
Imaging Endocrinology
and Infertility
13. An Overview of Female Infertility
Reproductive Endocrinology and Infertility

3. Amenorrhea
14. Surgical Treatment of Female Infertility
4. Dysfunctional Uterine Bleeding
15. Ovulation Induction
5. Diagnosis and Management of Polycystic
Ovary Syndrome 16. Assisted Reproductive Technology
6. Obesity: Recognition and Treatment in 17. Alternative Medicine and Female Infertility
Women
18. Male Infertility
7. Hormonal Contraception
19. Your Environment; Your Fertility—Is There
8. Endometriosis a Link?
9. Hyperprolactinemia
10. Premenstrual Syndrome
11. Treatment of the Menopausal Woman
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9 7 8 15 7 0 5 97 0 2 2
v a d e m e c u m
Reproductive Endocrinology
and Infertility
Vivian Lewis, M.D.

Department of Obstetrics and Gynecology
Division of Reproductive Endocrinology
University of Rochester School of Medicine and Dentistry
Rochester, New York, U.S.A.
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Copyright ©2007 Landes Bioscience

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Library of Congress Cataloging-in-Publication Data
Reproductive endocrinology and infertility / [edited by] Vivian Lewis.

p. ; cm. -- (Vademecum)
Includes bibliographical references and index.
ISBN-13: 978-1-57059-702-2 (alk. paper)
1. Endocrine gynecology . 2. Infertility, Female--Endocrine aspects. I. Lewis, Vivian,
M.D. II. Series.
[DNLM: 1. Genital Diseases, Female. 2. Endocrine System Diseases. 3. Infertility,
Female. WP 140 R4247 2007]
RG159.R452 2007
618.1--dc22
2007001376
While the authors, editors, sponsor and publisher believe that drug selection and dosage and
the specifications and usage of equipment and devices, as set forth in this book, are in accord
with current recommendations and practice at the time of publication, they make no
warranty, expressed or implied, with respect to material described in this book. In view of the
ongoing research, equipment development, changes in governmental regulations and the
rapid accumulation of information relating to the biomedical sciences, the reader is urged to
carefully review and evaluate the information provided herein.
Dedication
I would like dedicate this book to my family whose love, support and
patience have made it possible for me to pursue a career in academic medi-
cine. My parents, Oswald Lewis and Vivian Lewis, encouraged and nur-
tured a love of learning. My brothers and sister were crucial in providing
an intellectually stimulating environment as I grew up. My husband,
Rustam Tahir, and sons, Darius and Jason, have been understanding and
supportive while I put in the long hours necessary to complete this project.
I am grateful to you all.
Contents
Preface ......................................................................... xv
Acknowledgements ..................................................... xvi
Part I: Reproductive Endocrinology
1. The Menstrual Cycle ...................................................... 3
John T. Queenan, Jr.
GnRH .................................................................................................... 3
Follicular Phase ....................................................................................... 4
Luteal Phase ............................................................................................ 7
The Endometrium: Proliferative and Secretory Phases ............................ 8
2. Puberty and Its Disorders ............................................ 10
Adelina M. Emmi and Lawrence C. Layman
Normal Puberty Physiology .................................................................. 10
Somatic Changes ............................................................................. 10
Endocrinology of Puberty ................................................................ 10
Abnormalities of Puberty ...................................................................... 12
Precocious Puberty .......................................................................... 12
Delayed Puberty .............................................................................. 15
3. Amenorrhea ................................................................. 23
Michael Wittenberger and Alicia Armstrong
Evaluation ............................................................................................. 23
Eugonadism, Uterus Present ............................................................ 25
Hypogonadism (Prior Estrogen Exposure),
Uterus Present ......................................................................... 25
Eugonadism, Uterus Absent ............................................................ 28
Hypogonadism, Uterus Present ....................................................... 29
Diagnoses ............................................................................................. 29
Eugonadotropic Amenorrhea
(Normal FSH and LH) ............................................................ 29
Hypogonadotropic Amenorrhea ...................................................... 32
Hypergonadotropic Amenorrhea ..................................................... 33
Treatment ............................................................................................. 34
4. Dysfunctional Uterine Bleeding ................................... 36
William R. Phipps
Differential Diagnosis and Mechanisms of Bleeding ............................. 37
History ................................................................................................. 39
Physical Examination ............................................................................ 40
Laboratory, Imaging and Other Diagnostic Studies ............................... 40
Treatment ............................................................................................. 43
Ovary Syndrome .......................................................... 47
Kathleen M. Hoeger
Diagnosis .............................................................................................. 47
Epidemiology ........................................................................................ 47
Clinical Features ................................................................................... 47
Pathophysiology .................................................................................... 48
Endocrine Evaluation ............................................................................ 49
Impact of Obesity ................................................................................. 50
Metabolic Complications ...................................................................... 51
Treatment Options ............................................................................... 51
Oral Contraceptives and Progestins ................................................. 53
Anti-Androgens ............................................................................... 53
Insulin Sensitizing Agents ................................................................ 54
Lifestyle Modification ...................................................................... 54
6. Obesity: Recognition and Treatment in Women .......... 56
Erin E. Flaherty and Richard S. Legro
Assessment ............................................................................................ 57
Metabolic Syndrome ....................................................................... 57
Treatment ............................................................................................. 58
Diet and Exercise ............................................................................. 58
Pharmacotherapy ............................................................................. 58
Categories of Weight Loss Drugs ..................................................... 59
Other Medications and Herbal Supplements ................................... 60
Surgery ................................................................................................. 61
7. Hormonal Contraception ............................................ 65
Sarah Prager and Jody Steinauer
Background .......................................................................................... 65
Assessing Evidence about Contraception ............................................... 65
Combination Hormonal Contraception ............................................... 67
Combination Oral Contraception ................................................... 67
Extended Use Combined Oral Contraception ................................. 70
Transdermal Contraceptive System .................................................. 72
Combined Contraceptive Vaginal Ring ........................................... 73
Injectable Combined Hormonal Contraception .............................. 74
Progestin Only Contraceptive Methods ................................................ 74
Progestin Only Pills ......................................................................... 74
Progestin Only Intramuscular Injection ........................................... 76
Implantable Progestin Contraception .............................................. 77
Levonorgestrel Intrauterine System ....................................................... 78
Emergency Contraception .................................................................... 79
8. Endometriosis .............................................................. 84
Sireesha Reddy
Definition and Epidemiology ............................................................... 84
Pathogenesis .......................................................................................... 84
Diagnosis .............................................................................................. 84
Medical Treatment ................................................................................ 85
Oral Contraceptives ......................................................................... 85
Progestins ........................................................................................ 86
Gonadotropin Releasing Hormone Analogs ..................................... 86
New Therapies ................................................................................ 87
Surgical Treatment ................................................................................ 87
9. Hyperprolactinemia ..................................................... 89
Ghassan Haddad and Michael A. Thomas
Biochemistry ......................................................................................... 89
Etiology ................................................................................................ 89
Physiologic ...................................................................................... 89
Pharmacologic ................................................................................. 90
Pathologic ....................................................................................... 91
Prolactinomas ....................................................................................... 91
Evaluation ............................................................................................. 92
Galactorrhea ......................................................................................... 92
Treatment ............................................................................................. 93
Observation ..................................................................................... 93
Medical Treatment ........................................................................... 93
Surgery ............................................................................................ 94
Radiotherapy ................................................................................... 94
Pregnancy Considerations ..................................................................... 94
10. Premenstrual Syndrome ............................................... 96
Stephanie A.M. Giannandrea, Linda H. Chaudron
and Tana A. Grady-Weliky
Risk Factors .......................................................................................... 96
Clinical Symptoms and History ............................................................ 97
Differential Diagnosis ........................................................................... 98
Etiology ................................................................................................ 99
Treatment ............................................................................................. 99
Lifestyle Interventions ................................................................... 100
Nutritional, Vitamin and Alternative/Complementary
Treatment Strategies .............................................................. 100
Psychoeducation ............................................................................ 101
Cognitive Behavioral Therapy (CBT) ............................................ 101
Pharmacologic Interventions ............................................................... 101
Antidepressants .............................................................................. 101
Anxiolytics ..................................................................................... 104
Hormonal Treatments ................................................................... 104
11. Treatment of the Menopausal Woman ....................... 107
Ghassan Haddad and Daniel B. Williams
The Menopause .................................................................................. 107
The Transition ............................................................................... 107
Symptoms of Menopause .................................................................... 108
Vasomotor Symptoms ................................................................... 108
Regimens for Hormone Replacement ................................................. 109
Alternative Treatments for Hot Flashes .......................................... 110
Alternative Medicine ..................................................................... 111
Genitourinary ..................................................................................... 112
Local Therapy (Vaginal or Topical Administration) ....................... 112
Osteoporosis ....................................................................................... 113
Pathophysiology ............................................................................ 113
Risk Factors and Diagnosis ............................................................ 113
Cardiovascular Disease ........................................................................ 115
HERS Study and Secondary Prevention
of Cardiovascular Disease ...................................................... 116
WHI Study and Primary Prevention of Cardiovascular Disease ..... 116
Alzheimer’s Disease ............................................................................. 116
Risks of Homone Replacement ........................................................... 117
Estrogen Replacement Therapy and Breast Cancer ........................ 117
Estrogen Replacement Therapy and Endometrial Cancer .............. 117
Venous Thromboembolic Events ................................................... 117
Benefits of Hormone Replacement ..................................................... 118
12. Reproductive Endocrinology Diagnostic Imaging ..... 120
Peter Klatsky and Victor Y. Fujimoto
Principles of Ultrasound and Magnetic Resonance Imaging (MRI) ..... 120
Ambiguous Genitalia .......................................................................... 120
Amenorrhea ........................................................................................ 121
Secondary Amenorrhea .................................................................. 125
Infertility ............................................................................................ 126
Anatomic and Tubal Factor Infertility ............................................ 126
MR-Hysterosalpingography ........................................................... 135
Recurrent Pregnancy Loss ................................................................... 135
Ovulatory Disorders ...................................................................... 136
Diminished Ovarian Reserve ......................................................... 137
Endometriosis ..................................................................................... 139
Fibroids .............................................................................................. 141
Part II: Infertility

13. An Overview of Female Infertility .............................. 145
Sandra L. Torrente and Valerie Montgomery Rice
Overview ............................................................................................ 145
Tubal Disorders .................................................................................. 149
Treatment ...................................................................................... 150
Endometriosis ............................................................................... 150
Uterine Disorders .......................................................................... 150
Cervical Disorders ......................................................................... 150
Unexplained Infertility .................................................................. 151
14. Surgical Treatment of Female Infertility .................... 153
Mohammed Al-Sunaidi and Togas Tulandi
Diagnostic Laparoscopy ...................................................................... 153
Laparoscopy Promoting Fertility ......................................................... 154
Adhesiolysis ................................................................................... 154
Treatment of Endometriosis .......................................................... 154
Treatment of Distal Tubal Occlusion ............................................. 156
Treatment of Proximal Tubal Occlusion ......................................... 158
Treatment of Mid-Tubal Occlusion ............................................... 159
Laparoscopic Treatment of Polycystic Ovary Syndrome (PCOS) ... 159
Hysteroscopy in Infertility .................................................................. 161
Diagnostic Hysteroscopy ............................................................... 161
Operative Hysteroscopy ................................................................. 162
15. Ovulation Induction .................................................. 165
Jon C. Havelock and Karen D. Bradshaw
Testing Prior to Ovulation Induction .................................................. 165
Ovulation Induction Monitoring ........................................................ 167
Complications of Ovulation Induction ............................................... 167
Multiple Pregnancy ....................................................................... 167
Ovarian Hyperstimulation Syndrome (OHSS) .............................. 168
Methods of Ovulation Induction ........................................................ 168
Weight Loss ................................................................................... 168
Clomiphene Citrate ....................................................................... 168
Metformin ..................................................................................... 170
Aromatase Inhibitors ..................................................................... 170
Laparoscopic Ovarian Diathermy .................................................. 171
Glucocorticoids ............................................................................. 171
Pulsatile Gonadotropin Releasing Hormone .................................. 171
Dopamine Agonists ....................................................................... 171
Gonadotropins for Ovulation Induction ............................................. 172
Background ................................................................................... 172
Follicular Maturation with hCG—The Terminal Act
in Ovulation Induction ......................................................... 173
Gonadotropin Ovulation Induction in PCOS ............................... 174
Ovulation in Hypogonadotropic Hypogonadism ........................... 175
Gonadotropins in Controlled Ovarian
Hyperstimulation (COH) ...................................................... 176
COH with Gonadotropins in in Vitro Fertilization (IVF) ............. 176
16. Assisted Reproductive Technology ............................. 178
Tiffany Von Wald and Kim Thornton
Definitions ......................................................................................... 178
Infertility History and Evaluation ....................................................... 179
Indications for ART ............................................................................ 181
Tubal Disease ................................................................................ 182
Endometriosis ............................................................................... 182
Male Factor Infertility ................................................................... 183
Unexplained Infertility .................................................................. 184
Diminished Ovarian Reserve ......................................................... 184
Other Indications for ART ............................................................ 184
Success Rates ...................................................................................... 184
Complications .................................................................................... 185
Multiple Gestation ........................................................................ 185
Ovarian Hyperstimulation Syndrome (OHSS) .............................. 186
Ectopic Pregnancy ......................................................................... 186
Other Risks ................................................................................... 187
Fetal Risks ..................................................................................... 187
17. Alternative Medicine and Female Infertility ............... 189
Hey-Joo Kang, Pak Chung and Raymond Chang
Acupuncture ....................................................................................... 189
Herbal Treatments .............................................................................. 191
Vitamins and Dietary Supplements ..................................................... 191
Mind/Body Techniques ....................................................................... 192
18. Male Infertility ........................................................... 194
Stephanya Shear and Jeanne O’Brien
Epidemiology ...................................................................................... 194
Physiology .......................................................................................... 194
Differential Diagnosis ......................................................................... 195
Evaluation ........................................................................................... 196
History and Physical ...................................................................... 196
Laboratory Studies ......................................................................... 197
Radiologic Studies ......................................................................... 198
Management ....................................................................................... 199
Post Evaluation—Follow Up Care ................................................. 199
Other Surgical and Medical Treatments for Infertility .................... 200
19. Your Environment; Your Fertility—Is There a Link? .. 201
Shanna H. Swan
The Environment and Reproductive Factors in the Male .................... 202
The Environment and Reproductive Factors in the Female ................. 203
Factors That May Alter a Couples’ Fertility ......................................... 208
Web-Based Resources .......................................................................... 209
Index .......................................................................... 213
Editor
Vivian Lewis, M.D.
Department of Obstetrics and Gynecology
Division of Reproductive Endocrinology
University of Rochester School of Medicine and Dentistry
Contributors
Mohammed Al-Sunaidi, M.D. Linda H. Chaudron, M.D., M.S.
Department of Obstetrics Departments of Psychiatry,
and Gynecology Pediatrics, and Obstetrics
McGill University and Gynecology
Montreal, Quebec, Canada University of Rochester
Chapter 14 Medical Center
Alicia Armstrong, M.D. Chapter 10
Reproductive Biology
and Medicine Branch Pak Chung, M.D.
National Institute of Child Health Department of Obstetrics
and Human Development and Gynecology
Bethesda, Maryland, U.S.A. Center for Reproductive Medicine
Chapter 3 and Fertility
Weill Medical College
Karen D. Bradshaw, M.D. of Cornell University
Department of Obstetrics New York, New York, U.S.A.
and Gynecology Chapter 17
Division of Reproductive
Endocrinology Adelina M. Emmi, M.D.
University of Texas Section of Reproductive
Southwestern Medical Center Endocrinology, Infertility
Dallas, Texas, U.S.A. and Genetics
Chapter 15 Department of Obstetrics
and Gynecology
Raymond Chang, M.D. Medical College of Georgia
Department of Internal Medicine Augusta, Georgia, U.S.A.
Institute of East-West Medicine Chapter 2
New York, New York, U.S.A.
Chapter 17
Erin E. Flaherty, D.O. Kathleen M. Hoeger, M.D.
Department of Obstetrics Department of Obstetrics
and Gynecology and Gynecology
Pennsylvania State University University of Rochester
College of Medicine Medical Center
Hershey, Pennsylvania, U.S.A. Rochester, New York, U.S.A.
Chapter 6 Chapter 5
Victor Y. Fujimoto, M.D. Hey-Joo Kang, M.D.

Department of Obstetrics, Center for Reproductive Medicine
Gynecology and Reproductive and Fertility
Sciences Weill Medical College
UCSF Women’s Health, of Cornell University
Mount Zion New York, New York, U.S.A.
San Francisco, California, U.S.A. Chapter 17
Chapter 12
Peter Klatsky, M.D.
Stephanie A.M. Giannandrea, B.A. Department of Obstetrics,
University of Rochester Gynecology and Reproductive
Medical Center Sciences
Rochester, New York, U.S.A. University of California,
Chapter 10 San Francisco
San Francisco, California, U.S.A.
Tana A. Grady-Weliky, M.D. Chapter 12
Department of Psychiatry
University of Rochester Lawrence C. Layman, M.D.
School of Medicine and Dentistry Neurodevelopmental Biology
Rochester, New York, U.S.A. Program
Chapter 10 Institute of Molecular Medicine
and Genetics
Ghassan Haddad, M.D. Medical College of Georgia
Department of Obstetrics Augusta, Georgia, U.S.A.
and Gynecology Chapter 2
Endocrinology Richard S. Legro, M.D.
University of Cincinnati Department of Obstetrics
College of Medicine and Gynecology
Cincinnati, Ohio, U.S.A. Pennsylvania State University
Chapters 9, 11 College of Medicine
Hershey, Pennsylvania, U.S.A.
Jon C. Havelock, M.D. Chapter 6
Pacific Centre for Reproductive
Medicine
Burnaby, BC, Canada
Chapter 15
Jeanne O’Brien, M.D. Stephanya Shear, M.D.
Department of Urology Department of Urology
University of Rochester University of Rochester
Medical Center Medical Center
Rochester, New York, U.S.A. Rochester, New York, U.S.A.
Chapter 18 Chapter 18
William R. Phipps, M.D. Jody Steinauer, M.D., M.A.S.

Department of Obstetrics Department of Obstetrics,
and Gynecology Gynecology and Reproductive
University of Rochester Sciences
Rochester, New York, U.S.A. University of California,
Chapter 4 San Francisco
San Francisco, California, U.S.A.
Sarah Prager, M.D. Chapter 7
Department of Obstetrics
and Gynecology Shanna H. Swan, Ph.D.
University of Washington Department of Obstetrics
Seattle Washington, U.S.A. and Gynecology
Chapter 7 University of Rochester School
of Medicine and Dentistry
John T. Queenan, Jr, M.D. Rochester, New York, U.S.A.
Department of Obstetrics Chapter 19
and Gynecology
University of Rochester Michael A. Thomas, M.D.
Medical Center Department of Obstetrics
Rochester, New York, U.S.A. and Gynecology
Chapter 1 Division of Reproductive
Endocrinology
Sireesha Reddy, M.D. University of Cincinnati
Department of Obstetrics College of Medicine
and Gynecology Cincinnati, Ohio, U.S.A.
University of Rochester Chapter 9
Medical Center
Rochester, New York, U.S.A. Kim Thornton, M.D.
Chapter 8 Division of Reproductive
Endocrinology and Infertility
Valerie Montgomery Rice, M.D. Beth Israel Deaconess Medical Center
Department of Obstetrics and
and Gynecology Boston IVF
School of Medicine Harvard Medical School
Meharry Medical College Waltham, Massachusetts, U.S.A.
Nashville, Tennessee, U.S.A. Chapter 16
Chapter 13
Sandra L. Torrente, M.D. Daniel B. Williams, M.D.
Department of Obstetrics Department of Obstetrics
and Gynecology and Gynecology
School of Medicine Division of Reproductive
Meharry Medical College Endocrinology
Nashville, Tennessee, U.S.A. University of Cincinnati
Chapter 13 College of Medicine
Cincinnati, Ohio, U.S.A.
Togas Tulandi, M.D. Chapter 11
Department of Obstetrics
and Gynecology Michael Wittenberger, M.D.
McGill University National Institute of Child Health
Montreal, Quebec, Canada and Human Development
Chapter 14 Bethesda, Maryland, U.S.A.
Chapter 3
Tiffany Von Wald, M.D.
Endocrinology and Infertility
Beth Israel Deaconess Medical Center
Harvard Medical School
Boston, Massachusetts, U.S.A.
Chapter 16
Preface
Reproductive Endocrinology and Infertility provides an overview of the most

frequently encountered clinical challenges faced by medical students and
residents. Part I begins with chapters on reproductive hormonal physiology
and development to provide a basis for understanding the management of
the most common reproductive clinical problems that confront obstetri-
cian-gynecologists and other practitioners in women’s health. Several of the
chapters, including obesity, premenstrual syndrome, menopause and imag-
ing, provide a cross-disciplinary approach to endocrine related problems
common among reproductive aged women. Part II includes chapters on the
evaluation of infertility, as well as surgical and medical approaches to treat-
ing infertility in men and women. The chapter on alternative medicine pro-
vides a basis for understanding the increasingly popular use of therapies such
as acupuncture and herbal treatments. The last chapter discusses the influ-
ence of environmental factors on fertility, an important field that is often
ignored in the traditional approach to infertility.
This text is meant to be used as a portable reference with readily acces-
sible information including a summary of key points in each chapter. All
of the contributors are involved in residency training programs and under-
stand the kinds of patient management questions that are encountered in
a busy practice. Our goal with this book is to provide information that will
support solid patient management and hopefully pique the appetite to
learn more.
Vivian Lewis, M.D.

Acknowledgements
I wish to extend many thanks to all of the contributors for their hard
work. I am especially grateful to the authors who are current or recent train-
ees as their perspective is closest to the main target audience for this book. I
would also like to thank Ron Landes and the staff at Landes Publication for
their help and responsiveness. Finally, Anne Tedrow’s organizational skills
were invaluable in helping to compile the submissions of the 33 authors
featured in this volume.
Part I
Reproductive Endocrinology
Chapter 1
The Menstrual Cycle

John T. Queenan, Jr.
Once a month the human endometrium exhibits a well-orchestrated, repeating
cycle of proliferation, differentiation, death and renewal. Remarkably, the same cells
programmed to slough within two weeks in the absence of a blastocyst are also able
to nurture a gestation, if present, for 40 weeks. For implantation to occur, synchro-
nization between the age of the embryo and the developmental stage of the en-
dometrium is an absolute requirement. When functioning properly, the
hypothalamic-pituitary-ovarian axis will coordinate the recruitment and selection
of a dominant follicle while ordering endometrial preparation.
Reproductive cycles begin at puberty as the hypothalamic pulse generator is ac-
tivated and GnRH is secreted. Menstrual cycles are the most irregular during the 2
years after menarche and during the 3 years before menopause. Once a cyclic pat-
tern is established, the menstrual cycle serves as a highly sensitive indicator of an
intact hypothalamic pituitary ovarian (H-P-O) axis. To the clinician, the monthly
cycle of endometrial degeneration and regeneration provides confirmation that the
infertile patient has ovulatory cycles.
Hypothalamic secretion of GnRH guides pituitary secretion of FSH and LH.
The hypothalamus receives an enormous variety of signals and information. The
interplay between the follicle and the CNS depends upon the ability of estrogen to
transmit messages of positive and negative feedback. There are highly sensitive re-
gions within the hypothalamus where estrogen can elicit feedback. Progesterone
also exerts profound negative feedback on the hypothalamus. CNS neurotransmit-
ters can exert their influence independent of sex steroids. Norepinephrine is stimu-
latory whereas dopamine, B-endorphins and other opioid peptides are inhibitory to
the release of GnRH. The convergence of signals within the hypothalamus culmi-
nates in a pattern of pulsatile GnRH secretion.
GnRH
Gonadotropin releasing hormone (GnRH) is a 10 amino acid peptide that is
synthesized in the neuronal bodies of the arcuate nucleus of the medial basal hypo-
thalamus and transported to the median eminence by neuroendocrine cell termi-
nals. GnRH effluxes into capillaries and is transported from the hypothalamus to
the pituitary through the portal circulation. GnRH binds to its receptor on the cell
surface of the gonadotrophs. There, it activates adenylate cyclase and stimulates
gonadotropin release. GnRH can stimulate the synthesis and release of both FSH
and LH from the same cell. The variation in pulse frequency alters the ratio of FSH
to LH.
GnRH is secreted in a pulsatile manner; the amplitude and frequency of secre-
tion vary throughout the cycle. In cell culture, pulsatile, rhythmic activity is an
intrinsic property of individual GnRH neurons. A single or small group of GnRH
Reproductive Endocrinology and Infertility, edited by Vivian Lewis. ©2007 Landes Bioscience.
4 Reproductive Endocrinology and Infertility
neurons may initiate a pulse and entrain other participating cells resulting in a neu-
roendocrine cascade. In the hypothalamus, the population of these neurons is termed
1 the GnRH pulse generator.
If the frequency of GnRH pulses increases, there will be slight dominance of
FSH over LH. This small, incremental FSH rise in the early follicular phase is suffi-
cient to elicit follicular recruitment. One pulse every hour is typical of the follicular
phase while one pulse every 2-3 hours is typical of the luteal phase.
Normal gonadotropin secretion requires pulsatile GnRH discharge within a critical
frequency and amplitude. Adequate FSH levels and LH pulses at approximately
60-90 minutes stimulate the normal growth of ovarian follicles. A slower frequency
results in anovulation and amenorrhea. Follicles do not develop when the LH pulses
decline to intervals of less than 2-3 hours. High, prolonged GnRH exposure satu-
rates the GnRH receptors causing anovulation by down-regulation of the GnRH
receptor and abolition of the gonadotropin response.
Follicular Phase
Although the process of menstruation represents the endpoint of a previous cycle
of endometrial changes, the first day of menstruation is the most recognizable point
and is usually taken to mark the first day of an idealized 28 day menstrual cycle.
On cycle day 1 menstruation arrives and a new cycle begins. During the follicu-
lar phase an orderly sequence of events takes place that ensures that the proper
number of follicles is ready for ovulation. Folliculogenesis is a process that is initi-
ated well prior to the arrival of menstruation. Once a primary follicle leaves the
resting state it will take 85 days, or three complete menstrual cycles, to reach the
point of ovulation. The follicle destined to ovulate is recruited in the first few days
of the third cycle. It will measure 1-2 mm on cycle day 1. The first morphological
evidence of maturation is differentiation of the granulosa cell layer and enlargement
of the oocyte. Follicular recruitment will be driven by FSH secretion that started at
the end of the luteal phase in the previous cycle.
The demise of the corpus luteum at the end of the preceding cycle results in an
abrupt decline in levels of progesterone, estrogen, and inhibin. FSH secretion is
suppressed in the luteal phase by negative feedback from estrogen and progesterone.
The sharp decline in these factors abolishes the negative feedback and allows FSH to
rise shortly before and during menses. The increase in FSH at the luteal-follicular
transition is responsible for follicle recruitment and initiation of steroidogenesis.
Ovarian follicles may be found in four conditions: resting, growing, preovula-
tory or atretic. Once follicles leave the resting state, there are only two possible
outcomes—ovulation or atresia—with atresia accounting for more than 99%.
The primary oocyte, formed in fetal life, persists in prophase of the first meiotic
division until the time of ovulation. Oocytes are stored in primordial follicles and
protected for later use. This nongrowing group of follicles is termed the resting pool.
Within the primordial follicle, the oocyte is sequestered in an immuno-privileged
site. There are several layers of protection. Granulosa cells secrete the zona pellucida
inward placing a mucopolysaccharide layer around the oocyte. Numerous cytoplas-
mic processes of the granulosa cells penetrate the zona pellucida presumably for
respiration and nutrient exchange. A basal lamina separates the granulosa cells from
the theca cells. Inflammatory cells are found within the ovarian cortex and stroma;
however the oocyte is shielded from the influence of infection or hormones while it
lies behind this barrier.
The Menstrual Cycle 5
Oocytes residing in the resting pool are probably under inhibitory control from
autocrine factors. It is well documented that when oocytes are removed from resting
follicles, they can spontaneously undergo nuclear maturation in vitro. This suggests 1
a release from local inhibitory factors. Such a strategy makes sense, as the limited
supply of female gametes would be protected from influences that would render
them unsuitable for future cycles.
Folliculogenesis is continuous throughout life. Each day a cohort of follicles
reaches 2-5 mm size and is either available to be further recruited by FSH or will
undergo atresia. Thus, a cohort is always ready and continuously available for a
response to FSH. Even without gonadotropin stimulation, some primordial follicles
will leave the resting pool and develop into preantral follicles. This process occurs
during times of anovulation (i.e., childhood, pregnancy, and OCP use) as well as
during ovulatory cycles. The initial steps of follicular growth are independent of
stimulation by pituitary hormones. Therefore the rate is unaffected by changes in
the circulating gonadotropin or sex steroid hormone levels. The absence of gonado-
tropin stimulation will not prolong the total lifespan of oocytes, nor will excessive
gonadotropin stimulation prematurely exhaust the oocyte supply.
Primordial follicles are continuously undergoing an initial phase of growth and
development that, in the vast majority of circumstances, will end in atresia. The
gross wastage of follicles may be the necessary consequence of maintaining a con-
stant supply of gonadotropin-sensitive follicles throughout each day of a woman’s
reproductive life. This general pattern is interrupted when a group of follicles re-
sponds to a rise in FSH at cycle start and is propelled to further growth. Once they
leave the resting pool they will establish contact with the circulatory system.
Under the influence of FSH, the number of granulosa cells increases. As the
FSH concentration rises there is a concomitant rise in estradiol receptors within the
granulosa cells. Increasing estradiol levels within the follicle stimulate mitotic activ-
ity and increase the sensitivity to FSH. One of the major actions of FSH is the
induction of granulosa cell aromatase activity. Little or no estrogen can be produced
by FSH unprimed granulosa cells. FSH induces its own receptors and also increases
activin, inhibin, and LH receptors. Activin is a potent FSH stimulator that will
account for more FSH than does GnRH. Once the follicle acquires LH receptors
and aromatase activity, ovarian androgens produced by the theca will be converted
to estradiol. High local concentrations of estradiol enhance the follicular response to
LH by working synergistically with FSH to induce LH receptors. Ovarian steroido-
genesis is usually LH dependent.
Folliculogenesis is thought to occur in four phases: recruitment, selection, domi-
nance and ovulation. Recruitment takes place during cycle days 2, 3, and 4. The
term recruitment indicates a cohort of quasi-synchronous follicles has entered a
gonadotropin-dependent rapid growth phase. Overt connection of the follicular
apparatus to the peripheral blood stream is coincident with onset of gonadotropin-
dependent follicular growth. By cycle day 5 both menstrual flow and follicular re-
cruitment end.
In women, spontaneous multiple ovulation is atypical. Selection refers to the
reduction of the cohort size down to the species-specific ovulatory quota. The domi-
nant follicle is selected early when it develops LH receptors. LH stimulates andro-
gen production in the theca. The dominant follicle uses androgen as a substrate and
further accelerates estrogen output. Fluid accumulates amid the granulosa cell mass.
The antrum is formed as the oocyte is displaced to one side by this process. Follicles
at this stage measure 4-6 mm from the secretion of mucopolysaccharides by the

granulosa layer, and the transudation of plasma proteins from the newly acquired
1 theca layer. By day 6 rising levels of estrogen in the bloodstream begin to cause
peripheral effects. Estrogen first induces the lining of the uterus to proliferate and
later promotes the secretion of thin, watery cervical mucus.
The follicle destined to become dominant secretes the greatest amount of estra-
diol, which, in turn, increases the density of FSH receptors on the granulosa cell
membrane. Rising peripheral estradiol levels result in negative feedback on FSH
secretion. This withdraws the stimulus to the smaller follicles that have fewer FSH
receptors. The nondominant follicles cease development and then become atretic.
Selection marks the time when the influence of a single follicle creates an environ-
ment in which only it can adequately mature and reach ovulation.
Peripheral levels of estradiol rise significantly by day 7 shortly after the process of
selection of the dominant follicle has occurred. LH receptors are present on theca
cells at all stages of the cycle and on granulosa cells after the follicle matures. While
directing a decline in FSH levels the midfollicular rise in estradiol exerts a positive
influence on LH. During the late follicular phase LH levels rise steadily stimulating
androgen production in the theca.
Usually one follicle reaches maturity and is ovulated while the remainder un-
dergo atresia before the point of ovulation. The primary purpose of the other fol-
licles is to deliver androgen substrate. Aromatase activity is highest in the preovulatory
follicle thereby maintaining a high concentration of estradiol and a low concentra-
tion of androstenedione. In contrast the other follicles are FSH and aromatase defi-
cient with a resultant predominance of androstenedione. After having served the
purpose of acting as an endocrine gland, these follicles ultimately undergo atresia.
By Day 8 selection ends and maturation begins.
Normally, only one ovary sponsors recruitment. Once a dominant follicle is
present, the opposite ovary could be removed without effect on the ensuing ovula-
tion. This means that there is unambiguous ovarian asymmetry once the dominant
follicle has been selected. The dominant ovarian follicle is the sole follicle destined
to ovulate and somehow it continues to thrive in a milieu that it has helped to make
inhospitable to others within its cohort. As the level of circulating estradiol rises, the
plasma FSH falls back to basal levels (through negative feedback). The follicle reaches
a state of gonadotropin independence. It is now self-sustaining and could continue
to mature under the influence of only interfollicular FSH and estradiol.
At this point in the cycle, rising levels of estradiol have induced endometrial
proliferation. The lining which started at 1 mm will grow to a thickness of 8-10
mm. Ovarian hormones produce cyclic changes in all other parts of the female re-
productive system. In the proliferative phase rising levels of estrogen promote secre-
tion of thin watery mucus that permits the passage of spermatozoa into the uterus
around the time of ovulation.
By Day 11 estradiol is near its peak, and the lining has grown to maximal thick-
ness. The follicle is near mature size at 16-20 mm. The final steps of oocyte matura-
tion steps are completed on day 12. Having risen rapidly, estrogen levels reach a
peak 24-36 hours before ovulation.
The LH surge is preceded by an accelerated increase in serum estradiol levels. At
nearly all times in the menstrual cycle, estradiol exerts a negative feedback effect.
However, when estrogen levels exceed a critical threshold for a period of 2-3 days a
change in the functional capacity of the gonadotrope occurs. There is a marked
increase in sensitivity to GnRH and large amounts of gonadotropins are releasable
from a reserve pool. Only at this time can an LH surge occur. The process of
self-priming means the LH response to the second GnRH pulse is much greater
than to the first. The rising progesterone levels seen at the late follicular phase fur- 1
ther augment the LH surge as well as initiating a small surge in FSH.
The LH surge leads to resumption of oocyte maturation, luteinization of granu-
losa cells and the production of progesterone and prostaglandins. Shortly before
ovulation the preovulatory follicle reaches a diameter of 20-25 mm. Elevation of a
conical stigma on the surface of the protruding follicle precedes rupture. Proteolytic
enzymes and prostaglandin participate in degradation of the follicular wall. The
oocyte, zona pellucida and corona radiata will detach from the follicular wall and
float in the antral fluid. As ovulation approaches, the blood supply to the ovary
increases and the ligaments contract pulling the ovary closer to the fallopian tube.
The late follicular increase in serum estradiol levels will elicit an abundance of clear
fertile mucus secreted by the cervix.
Prior to ovulation the oocyte enters telophase of the first meiotic division. Chromo-
somal reduction occurs by migration of one half of the oocyte chromosomes into the
periphery of the cytoplasm. There the chromosomes are packaged into the first polar
body and extruded from the cytoplasm. After expulsion of the first polar body the
oocyte enters second meiotic division. It arrests at metaphase until fertilization occurs.
Ovulation occurs 10-12 hours after the LH peak and 36 hours after the estradiol
peak. The most reliable indicator for the timing of ovulation is the onset of the LH
surge, which begins 28-32 hours before ovulation. When the mature follicle rup-
tures, the oocyte, zona pellucida, and corona radiata are expelled into the peritoneal
cavity near the entrance to the tube. The second meiotic division of the oocyte is not
completed until after penetration of the ovum by a spermatozoon.
Luteal Phase
Fertilization takes place within the ampullary portion of the tube. Over the next
two to three days the ovum remains unattached within the lumen as it is propelled
toward the endometrial cavity by the ciliary action of the tubal epithelium. Movement
of the ovum down the tube is aided by a current of fluid propelled by the action of the
ciliated epithelium lining the tube. There is also propulsion from the gentle peristaltic
action of the longitudinal and circular smooth muscle layers of the tube.
The cervical mucus becomes highly viscid after ovulation and forms a plug that
inhibits ascending entry of microorganisms from the vagina. The cervix functions
to admit spermatozoa to the upper genital tract at a time when fertilization is oppor-
tune, but at other times, including pregnancy, to protect the normally sterile uterus
and upper tract from bacterial invasion. These cyclic changes form the basis for the
“natural’ forms of contraception that identify “the fertile period.”
Immediately following ovulation, the ruptured follicle collapses, leaving behind a
collapsed cyst lined by a thick layer of granulosa cells. It usually fills with a blood clot
and redistends. With a sufficient number of LH receptors on the granulosa cells, LH
acts directly on the granulosa cells to cause luteinization (formation of the corpus
luteum) and the production of progesterone. The granulosa cells enlarge and increase
their lipid content. Penetration of the basement membrane by blood vessels provides
the LDL cholesterol that serves as the substrate for corpus luteum (CL) progesterone
production. Large deposits of cholesterol arise from circulating lipoproteins (i.e., the
yellow color) and support the high quantities of progesterone production. The blood
clot and luteinized thecal and granulosa layers are invaded by capillaries to form a rich
vascular network. The thecal layer acquires a blood supply that it did not contain
during the entire follicular phase. This facilitates the massive progesterone secretion.
The corpus luteum is the most active steroidogenic tissue in humans, but in the ab-
1 sence of pregnancy it has a finite lifespan of 12-16 days.
After ovulation the GnRH pulse generator is slowed for the luteal phase. LH,
FSH and estradiol levels fall but some LH is essential to maintain CL function. The
accumulation of LH receptors during the follicular phase sets the stage for the ex-
tent of luteinization and the functional capacity of the corpus luteum. Normal luteal
function requires optimal preovulatory follicular development and continued tonic
LH stimulation. A defective luteal phase can contribute to infertility and early preg-
nancy wastage. Maintenance of the corpus luteum is normally dependent on pulsa-
tile gonadotropin secretion, but endogenous (from a pregnancy) or exogenous hCG
can serve the same purpose.
The onset of the LH surge (28-32 h prior to ovulation) is the most reliable
clinical indicator for the timing of ovulation. Progesterone is thermogenic so core
body temperature rises by about 0.6˚F until 2 days before the next period in
nonconception cycles.
If implantation does not occur, LH and FSH return to basal levels and their recep-
tor numbers are reduced leading to a marked decline in the progesterone and estradiol
synthesis. Without the continued stimulus of LH, the corpus luteum cannot be main-
tained and 12-14 days after ovulation it regresses to form the functionless corpus albicans.
Regression of the corpus luteum appears to involve the luteolytic action of its own
estrogen production, mediated by an alteration in local prostaglandin production.
Initiation of a new cycle is dependent on regression of the corpus luteum. Reac-
tivation of the GnRH system results from the withdrawal of the inhibitory effects of
corpus luteum steroids and inhibin. Released from the negative feedback effects, the
GnRH pulses begin to accelerate leading to a rise in FSH levels that occurs two days
before the onset of menses.
The Endometrium: Proliferative and Secretory Phases
After menses the endometrium consists of simple tubular glands set within a
vascular, cellular stroma. During the proliferative phase of the menstrual cycle, the
glands are small, straight and round when seen in cross section. The endometrium is
the primary target (organ) for ovarian steroids. Under the influence of estrogen, the
glands multiply and their epithelium becomes taller and pseudostratified, during
the follicular phase of the cycle.
After ovulation, the onset of the secretory phase is signaled by the appearance of
subnuclear vacuoles of glycogen which are evident in the endometrial glands by day
16. These start to migrate toward the lumen by day 17 although the majority are
still subnuclear. By day 19 glycogen vacuoles are being extruded from the luminal
edge of the cell. Meanwhile, after 2-3 days of tubal transport, the embryo enters the
uterine cavity on day 17. It will not attach to the uterine epithelium for 2 to 3 days.
On day 18-19, it hatches from the zona pellucida in preparation for attachment.
There is a narrow window of receptivity to blastocyst implantation that corre-
sponds to the period between cycle days 20 and 24 in a 28 day cycle. Peak levels of
progesterone are seen at 8-9 days after ovulation, which approximates the time of
implantation of the embryo. At that time, the endometrium has sufficient depth,
vascularity, and nutritional richness to sustain placentation. While the endometrium
is acquiring its receptivity, the embryo is acquiring its invasiveness.
On day 21 the embryo attaches to the uterine epithelium. The peak of
interglandular glycogen secretion coincides with the time of implantation of the free
blastocyst. Day 22 marks the peak in estradiol and progesterone levels for the luteal
phase. The embryo has initiated invasion into the lining. A portion of the cytotro-
phoblast population differentiates into a syncytiotrophoblast that synthesizes large 1
amounts of hCG. HCG serves to “rescue” the corpus luteum and maintains luteal
function with secretion of progesterone until placental steroidogenesis is established.
By midsecretory phase, progesterone is abundant and intraglandular glycogen
secretion reaches a peak. Stromal edema and spiral artery development reach a peak
on day 22 or 23 in response to progesterone. Decidualization is seen as nuclei en-
large, and cytoplasm becomes very eosinophilic. It begins as a periarteriolar blush of
cuffing around the spiral arterioles on day 23. By day 24 the embryo has completely
penetrated the endometrial lining and by Day 25 syncytiotrophoblast cells are se-
creting HCG in amounts that stimulate the corpus luteum to continue to produce
progesterone. The wave of decidualization proliferates and will reach a state of
confluence by day 26. Decidualization occurs only when the endometrium is se-
quentially exposed to estrogenic priming followed by progesterone stimulation.
Without embryo implantation, decreasing steroid levels lead to increased coiling
and constriction of the spiral arteries which supply the upper 2/3 of the functional
endometrium. The decreased blood flow to the functional portion of the en-
dometrium furthers the process of ischemia and degradation. Fibrin thrombi begin
to occupy endometrial capillaries of premenstrual endometrium. Obstructed vessels
lead to increases in hydrostatic pressure. By day 28, the endometrium contains tor-
tuous glands that are fragmented. The stroma consists of dark necrotic fragments.
Free hemorrhage is present throughout the tissue. Menstrual bleeding is controlled
by vasoconstriction of the ruptured basal arteries in the denuded basal layer. The
basalis layer remains intact after menstruation and a new lining is regenerated from
this layer. Within 2 days of the onset of menses the surface epithelium begins to
regenerate under the influence of estrogen and continues this process while the en-
dometrium is still shedding.
Key Points
Events from hypothalamus, pituitary ovary and uterus are integrated via the
interaction among GnRH, gonadotropins, HCG and the sex steroids. Embryonic
implantation is the culmination of a highly complex sequence of tightly regulated
events. Estrogen and progesterone have a central role in directing the changes that
facilitate implantation. Embryo quality and endometrial development are the two
main determinants of successful nidation. The HPO axis is structured to enable
these two determinants to function synchronously. In the absence of pregnancy, the
cycle is programmed to slough the endometrium and begin anew.
Suggested Reading
1. Queenan Jr JT, Fazleabas A. Embryo-uterine interactions during implantation. In:
Seibel MM, ed. Infertility: A Comprehensive Text. Stamford: Appleton and Lange,
1997:671-685.
2. Mutter GL, Ferenczy A. Anatomy and histology of the uterine corpus. In: Kurman RJ,
ed. Blaustein’s Pathology of the Female Genital Tract. 5th ed. New York City:
Springer-Verlag, 2002:383-420.
3. Bulun SE, Adashi EY. The physiology and pathology of the female reproductive axis.
In: Larsen PR et al, eds. Williams Textbook of Endocrinology. Philadelphia: WB
Saunders, 2003:587-663.
4. Clement PB. Anatomy and histology of the ovary. In: Kurman RJ, ed. Blaustein’s Pa-
thology of the Female Genital Tract. 5th ed. New York City: Springer-Verlag,
2002:649-674.
Chapter 2
Puberty and Its Disorders

Adelina M. Emmi and Lawrence C. Layman
Normal Puberty Physiology
Somatic Changes
Normal puberty is a progression of events in both girls and boys that is gener-
ally complete in 3-4 years. In females, thelarche (breast buds) is usually the first
sign of estrogen production and occurs at an average age of 10.5 years, while
pubarche (pubic hair growth) generally occurs about 6 months later. In 10-20%
of girls, pubarche is the first event. These are estimates; thelarche varies slightly
among different racial groups (white: 10.4 years; black: 9.5 years; Mexican/Ameri-
can: 9.8 years). Tanner Stages are used to classify the stages of puberty in both
boys and girls (Table 2.1). Tanner Stage 1 is prepubertal, while Stage 5 is the fully
mature adult status. Peak growth rate for girls generally is seen at Tanner Stage 3
breast development.
Adrenarche is the result of adrenal androgen production (androstenedione,
DHEA, and particularly DHEAS), which begins prior to changes in gonadotro-
pin secretion at 6-8 years of age and continues through the mid-teens. During
female puberty, growth in height occurs at a rate of 4-5 cm/year in early puberty.
As estrogen production increases, growth hormone increases, resulting in increased
IGF-1 and IGFBP-3, which mediates skeletal growth. Maximal growth velocity
occurs in girls at age 12 and usually results in about a 9 cm increase in height.
Menarche (initiation of menses) occurs on the downward arm of the growth curve
at a median age of 12.5 years (white: 12.6 years; black: 12.15 years; Mexican/
American: 12.3 years). A variety of additional factors affect pubertal onset, such as
weight, stress, and extreme physical activity. Some authors have noted a younger
age of onset of breast development and possibly menarche in African-American
girls that may be attributable to a greater BMI.
In boys the initial pubertal event is testicular growth, which begins at about
10.5 years of age. When the testes exceed 2.5 cm in any dimension, the onset of
puberty is approaching. Pubarche frequently starts simultaneously with testicular
development. Axillary hair growth occurs at about the time of peak height veloc-
ity (about age 14 years in boys and 12 in girls) (Table 2.2).
Endocrinology of Puberty
The GnRH pulse generator is the principal regulator of puberty through its
control of pituitary gonadotropins and is active early in life. As a result, gona-
dotropin levels change throughout fetal development, childhood, puberty and
adulthood. Gonadotropins begin to rise at 10 weeks gestation, peak at
Puberty and Its Disorders 11
Table 2.1. Tanner staging in females with approximate ages

in parentheses
Tanner Stages Breast Pubic Hair 2
Stage 1 nipple elevation only no pubic hair
(prepubertal)
Stage 2 breast budding (9.5) sparse growth, most on labia
majora (10.5)
Stage 3 increases in gland tissue, coarser, spread to mons (11.5)
no separation of breast
from areola (11)
Stage 4 areola forms separate adult type-limited growth (12)
mound from breast (12)
Stage 5 areola recedes to single adult type-extends to medial
breast contour (14) thigh (13.5)
mid-gestation and decline at term because of negative feedback from placental

steroids. At birth, there is a withdrawal of gestational steroids, which leads to a
rise in FSH and LH with a subsequent decline which is sex specific. Girls tend
to have a higher FSH to LH ratio at all times compared to boys, and their gona-
dotropin levels decline over a 2 to 4 year period. This early neonatal gonadotro-
pin elevation may be significant enough to cause estradiol production and
transient breast development in girls or result in testosterone production in boys.
Thereafter, gonadotropin levels decline over about a 6-month period in boys.
During childhood gonadotropins remain low in both sexes until puberty. Typi-
cally, prepubertal gonadotropins tend to exhibit a ratio of LH/FSH that is less
than one.
Gonadotropins begin to rise by age 9 years, first FSH, then LH. These in-
creases are a reflection of the increasing pulse frequency of GnRH from the pulse
generator. The exact central inhibitor of GnRH until this age is unclear. Slower
GnRH pulse frequency tends to lead to the preferential secretion of FSH, while
faster pulse frequency favors LH secretion. Initially LH pulses are nocturnal, but
then become apparent throughout the day and result in gonadal steroid produc-
tion. Maturation of the hypothalamic-pituitary-gonadal (H-P-G) axis with posi-
tive and negative feedback by gonadal steroids and inhibition by inhibin occurs
around midpuberty and culminates in menstruation. However, a fully mature
H-P-G axis in the female is usually operative within the first two years of me-
narche with regular ovulatory cycles.
Table 2.2. Usual order of pubertal events in males and females

Females Males
Thelarche Testicular growth
Pubarche Pubarche
Maximal growth velocity Maximal growth velocity
Menarche
Adult pubic hair
Adult breast
In boys, two Sertoli cell proteins, inhibin B and antimullerian hormone (AMH)/
mullerian inhibiting substance (MIS), are produced in the early neonatal period.
Inhibin B (human males have minimal inhibin A) increases soon after birth and
2 peaks at 4-12 months of age, declines to low levels by ages 3-9, and then increases
again with the onset of puberty (at lower levels than the neonate). AMH/MIS is
evident in the first month of life and peaks about 6 months of age, drops during
childhood, and becomes very low with puberty, probably secondary to increased
testosterone inhibition. These hormones are useful markers of testicular function in
early childhood.
Abnormalities of Puberty
Precocious Puberty
Definitions and Etiology
Precocious puberty is defined as the onset of puberty before the age of 8 in girls
and age 9 in boys. These ages are 2.5 standard deviations below the mean age of
puberty in North American children. This disorder is five times more common in
girls than boys. It is classified as either central (GnRH-dependent) or peripheral
(GnRH-independent) depending on whether the inciting event has activated the
H-P-G axis. In central precocious puberty (CPP), activation of the hypothalamic-
pituitary axis occurs, leading to premature sexual development that typically follows
the normal pattern of puberty except that it is early. In peripheral precocious
puberty (PPP), steroid production is independent of activation of the central axis, as
is the case in gonadal or adrenal tumors or McCune-Albright syndrome. Precocious
puberty is often idiopathic, especially in girls, however, a work-up is indicated in
order to rule out significant pathology. If left untreated, final adult height will be
compromised because of steroid-induced premature closure of the epiphyses. These
children have normal reproductive function and do not appear to be at risk for
premature menopause. Psychosocial issues should also be addressed because other
aspects of development correspond with chronological age. In addition, more
benign variants, premature thelarche and premature pubarche, may also occur.
Diagnosis of Precocious Puberty
Precocious puberty may result in a decrease of final adult height; so arresting the
growth is an important objective. The history and physical exam are extremely im-
portant as are growth charts. A skeletal film of the hand for bone age is very impor-
tant in assessing the severity of the disorder and need for treatment (Fig. 2.1).
Premature thelarche may occur in girls 1-2 years old because of the GnRH pulse
generator activity. Normally, this will not result in advanced growth and the bone
age is consistent with chronologic age. No treatment is necessary, even though some
girls may have follicular activity on ultrasound. Premature adrenarche without other
signs of puberty is also a benign process, and if the bone age is normal, these patients
can be followed expectantly. Patients with premature adrenarche tend to be taller
and heavier than other children their age. These patients may be at risk for polycys-
tic ovary syndrome in the future. If they have hirsutism, serum levels of total test-
osterone, DHEAS, and 17-hydroxyprogesterone may be indicated. If markedly
elevated androgens are present or there is evidence of virilization, adrenal or ovarian
neoplasms and congenital adrenal hyperplasia should be excluded as in peripheral
precocious puberty (Fig. 2.1).
Figure 2.1. An algorithm that can be used as a guide in the diagnosis of preco-
cious puberty (PP). T, testosterone; DHEAS, dehydroepiandrosterone sulfate; 17OHP,
17-hydroxyprogesterone; US, ultrasound; MAS, McCune-Albright syndrome.
For children who develop breasts and have pubic hair suggesting precocious pu-
berty, the history and physical examination including height, weight, Tanner stag-
ing, signs of virilization and estrogenization, thyroid exam, and a thorough
neurological exam should be performed. A bone age will demonstrate accelerated
growth compared to chronological age (for example, if the bone age for a 5-year
old is 8 years). A CT or MRI is usually necessary to exclude a CNS tumor in
patients with central or peripheral precocious puberty. In particular, patients with
precocious puberty who have a rapid course of progression or who have CNS signs
should have an MRI of the brain to exclude a tumor. A “GnRH stimulation test” is
useful to determine if CPP or PPP is present. A LH response greater than FSH
response indicates a central cause, while a primarily FSH response suggests a periph-
eral, or GnRH-independent cause. Since native GnRH is not available for these
tests, a GnRH-agonist such as leuprolide acetate can be used at a dose of 20 μg/kg
S.Q. FSH and LH levels should be drawn at baseline (before agonist administra-
tion) and every 15 minutes for 1 hour thereafter. If the LH/FSH ratio exceeds 1 or
the maximum level of LH exceeds ~7 mIU/mL (cutoff value should be determined
for your own lab), then the etiology is central (mediated through the H-P-G axis). It
has also been suggested that if an immunofluorometric LH assay is used, a single
unstimulated LH value >0.6 mIU/mL may eliminate the need for a “GnRH stimu-
lation test” (remember there is lab variability and this cutoff level should be deter-
mined in your lab). Ovarian volume may also be increased in patients with CPP.
In patients who do not have evidence of a central cause, ovarian ultrasound or

adrenal CT may be helpful to evaluate the presence of a neoplasm. For boys, tes-
ticular palpation may indicate a mass needing biopsy. Thyroid studies (TSH and
2 total T4), prolactin, estradiol, DHEAS, testosterone, estradiol, and hCG levels
should be considered.
Causes and Treatment of Precocious Puberty
Central Precocious Puberty
A number of factors can activate the hypothalamic production of GnRH, lead-
ing to stimulation of pituitary gonadotrophs and gonadal steroid production. Tu-
mors can impinge on inhibitory neurons causing increased secretion of GnRH. A
suspected malignancy should be followed by biopsy for identification. Benign tu-
mors, such as hamartomas (hyperplastic malformations of the tuber cinerum which
elaborate GnRH), can be successfully treated with GnRH agonist therapy. Long
standing hypothyroidism can cause central precocity (usually associated with re-
tarded bone age). Treatment will curtail symptoms. A careful history may illicit a
previous history of an infectious process (i.e., meningitis), trauma, radiation, or
developmental abnormalities (hydrocephalus). Ectopic gonadotropin production by
tumors accounts for less than 0.5% of the causes of central precocity. The most
common of these tumors include chorioepithelioma, dysgerminoma, and
hepatoblastomas.
Therapy is directed toward arresting further sexual development and skeletal
growth. GnRH agonist therapy has become the standard for children with central
precocious puberty. The depot form of leuprolide acetate is given at a dose of 300
μg/kg every four weeks. Be aware that 7.5 mg or more may be necessary for treat-
ment in some children rather than the standard 3.75 mg dose. Therapy with
leuprolide is continued until an age agreed upon by the patient, family, and the
physician, usually 11-12 years of age. Adequate suppression of the H-P-G axis
should be assessed by drawing an LH level by a standard GnRH agonist test or by
a single LH value 2 hours after a dose of GnRH agonist. The maximal LH should
be suppressed to less than 2-5 mIU/mL depending upon the assay used, although
most suggest <2 mIU/mL. Follow-up visits should be scheduled every 3 months
to assess growth velocity and every 6 months to assess Tanner staging and bone-age
at least initially, and then less often.
Peripheral Precocious Puberty
Peripheral precocity can be caused by a number of disorders. A careful history
will eliminate rare iatrogenic causes such as hormone containing lotions or meat
from animals fed steroids. Gonadal neoplasms occur in about 10% of both boys and
girls diagnosed with precocious puberty. The most common cause of precocity from
gonadal estrogen production in girls is a follicular cyst. Careful follow up (including
ultrasound to document ovarian size) and observation is appropriate. Surgery should
be avoided because it might lead to an unnecessary oophorectomy. The most com-
mon malignant tumor that causes peripheral precocity is the granulosa-theca cell
tumor, although these are very rare. They are almost always unilateral and diagnosed
at an early stage,. In boys, tumors that produce hCG can cause precocious puberty.
Treatment is usually surgical, and if malignant, adjuvant therapy may be indicated.
Hepatoblastomas and hepatomas usually present with bilateral testicular enlarge-
ment and have a poor prognosis.
Mc Cune-Albright syndrome is associated with precocity and is five times more

common in girls than in boys. The diagnosis is made with the findings of café-au-lait
spots, precocious puberty and polyostotic fibrous dysplasia. The order of pubertal
development is sometimes completely haphazard. Skeletal fractures may occur in 2
the regions of polyostotic fibrous dysplasia because fibrous tissue replaces normal
bone. The femur and skull are the most frequent fracture sites. The risk of fractures
usually does not persist into adulthood. Hearing loss may occur if there is involve-
ment of the temporal bone. McCune-Albright syndrome is caused by a somatic cell
mutation of the Gsα gene, which encodes for a G-protein. Abnormal activation of
other organs utilizing cAMP can occur so these patients should be screened for
hypercortisolism, hyperthyroidism, and growth hormone excess. Testolactone, an
aromatase inhibitor, at a dose of 20-40 mg/kg/day in four divided doses has been
used successfully. Newer aromatase inhibitors have been used as well, but there is
much more experience with testolactone. Adult height is not compromised and
these adults have normal reproductive function.
An important cause of PPP in boys is familial male precocious puberty (FMPP),
previously known as testotoxicosis. This often presents at age 2-3 and occurs via an
activating mutation of the luteinizing hormone receptor (LHR) gene that results in
increased testosterone production without an increase in the LH ligand. These pa-
tients have prepubertal levels of gonadotropins, but adult-sized testes and adult lev-
els of testosterone. It is inherited in an autosomal dominant mode, but interestingly,
does not affect females. This can be treated by ketoconazole, a P450 cytochrome
inhibitor of adrenal and gonadal steroidogenesis at doses of 400-600 mg/day. Liver
enzymes must be followed to avoid hepatotoxicity. Antiandrogens such as flutamide
may be added, but may also be hepatotoxic.
Less common causes of peripheral precocious puberty include adrenal tumors
(virilizing in boys; feminizing in girls), such as adrenal adenomas and cancer. Adre-
nal cancer has a poor prognosis.
Delayed Puberty
Diagnosis
Delayed puberty is defined as no signs of puberty by age 14 in boys. In girls, it is
defined as either the absence of thelarche by age 13 or menarche by age 15. These
are 2.5 standard deviations above the mean for North American children. In boys,
delayed puberty signifies that there is a hypogonadal state. In girls, the differential
diagnosis is complex and may include a hypogonadal state, anatomic abnormalities,
such as absence or obstruction of the outflow tract, and certain disorders with ongo-
ing estrogen production most commonly polycystic ovary syndrome (PCOS). An
algorithm is shown in Figure 2.2. Note that the evaluation and diagnostic categories
are similar for males with the exception of an obstructed genital tract.
All patients with delayed puberty should have a TSH, total T4 (more robust
assay than the problematic free T4), and serum prolactin, and detailed psychosocial
history. Hypothyroidism (central, rather than primary) hyperprolactinemia, and
hypothalamic disorders (eating disorders/stress/exercise) may occur in patients who
are eugonadal or hypogonadal depending upon the duration of the process.
A careful history and physical exam of the patient with delayed puberty are
extremely important to ascertain if there are any initial signs of puberty and estro-
gen production. If there are no signs of breast development, the patient clearly has
Figure 2.2. An algorithm that can be used as a guide in the diagnosis of delayed
puberty. AIS, androgen insensitivity syndrome.
hypogonadism. If she has breast development, she has evidence of at least previous
estrogen production, but her estrogen status must be determined at the time of pre-
sentation (she could now be hypogonadal). One of two tests is recommended: a
vaginal maturation index or a progestin challenge test. Estradiol levels are not very
helpful since it may be difficult to discriminate between low and low-normal. A
vaginal smear (or vaginal maturation index) can be performed using a Q-tip to swab
the vagina. The swab is gently rolled onto a slide and set with Urine Sedi-Stain or
another quick prep stain. The ratio of parabasal, intermediate, and superficial (P/I/S)
cells is reported, usually in that sequence. A predominance of parabasal cells (such as
70/30/0) indicates that the patient is probably hypogonadal (hypoestrogenic). If there
are superficial cells present (as in 0/30/70), the patient is probably making estrogen
or is eugonadal. The second screening test for the eugonadal state is the progestin
challenge test. It is usually performed by administering medroxyprogesterone acetate
10 mg for 5-10 days (after a negative pregnancy test, if the patient has normal breast
development). If the patient is hypogonadal, she may spot, but will not have a men-
strual bleed after the medication is completed. This test can be repeated if negative
the first time. The progestin challenge test does not need to be performed in patients
with no breast development or who have a vaginal smear indicating no estrogen
production (predominant parabasal cells).
Hypogonadism
If hypogonadism is suspected on the basis of physical exam (Tanner 1 breasts),
vaginal maturation index, or negative progestin withdrawal, serum gonadotropins
should be obtained. If elevated, they should be repeated in several weeks for confir-
mation because of the pulsatile secretion of gonadotropins. When gonadotropins
are persistently elevated, gonadal failure, also known as hypergonadotropic hypogo-
nadism, is present. A karyotype should be performed in all children with elevated 2
gonadotropins to rule out a chromosomal abnormality (see below). If gonadotro-
pins are low or normal (in the face of hypogonadism), the patient has
hypogonadotropic hypogonadism due to hypothalamic or pituitary disease. Since
sex steroids are necessary for growth, performing a bone age should be considered in
hypogonadal patients. These patients can have delayed bone age compared to chro-
nological age. They do not usually have a bone age beyond 11-12 years, however, if
bone age is markedly delayed, growth hormone deficiency and/or hypothyroidism
should be strongly considered.
Hypergonadotropic Hypogonadism
Females
Patients with hypergonadotropic hypogonadism will either have a normal fe-
male karyotype (46,XX), a normal male karyotype of 46,XY (Swyer syndrome) or
an abnormal karyotype. About half of females with gonadal failure and amenor-
rhea will have an abnormal karyotype as compared to only 10-15% of boys with
delayed puberty due to hypergonadotropic hypogonadism. In females with a chro-
mosome abnormality, about half are found to have a 45,X cell line and the re-
mainder possess a 45,X cell line plus a second mosaic cell line. The second cell line
can be a 46,XX, 47,XXX, 46,XY, 46,X, i(Xq) or a number of structural abnor-
malities of the X chromosome including deletions. Turner stigmata may or may
not be present. The most common feature is short stature (usually <5 feet), while
absent puberty occurs in 90-95%. Cardiac anomalies (coarctation, dilated aortic
root, bicuspid aortic valve) occur in ~50% of patients and renal anomalies in
30%. Therefore, patients should be evaluated for these abnormalities with a car-
diac echo and an IVP or renal ultrasound. A cardiac echo has been suggested to be
performed every three years for the rest of her life since patients may develop a
dilated aortic root that is prone to rupture.
It should also be kept in mind that about 10% of patients with a 45,X cell line
will have some menstrual function, even if short-lived. It is therefore wise to karyo-
type all women who develop hypergonadotropic hypogonadism with short stat-
ure (<5’3”). Patients who have 45,X/46,XY karyotype can have a phenotype that
ranges from completely absent sexual development to normal appearing male ex-
ternal genitalia depending on whether streak gonads or testes are present. Girls
with a 46,XY cell line are at increased risk of developing gonadal tumors, such as
gonadoblastomas or germ cell tumors like dysgerminomas. These tumors occur in
about 15% of patients with a 45,X/46,XY cell line and in 20-25% of those with a
pure 46,XY cell line (Swyer syndrome or 46,XY gonadal dysgenesis), and there-
fore, removal of the gonads is indicated when the diagnosis is made. Most patients
with gonadal dysgenesis and a Y cell line, including Swyer syndrome, are pheno-
typic females with normal vagina, uterus, and cervix since their nonfunctioning
testes (streak gonads) do not make AMH/MIS. They are not short as are the pa-
tients with a 45,X cell line. Regular follow up of patients with ovarian failure due
to gonadal dysgenesis should also include thyroid studies, as there is an increased
risk of developing disease.
Women with hypergonadotropic hypogonadism and normal female chromo-

somes (46, XX) are phenotypic females with or without breast development. They
can present with completely absent puberty (sexual infantilism), or with secondary
2 sexual development and amenorrhea, or they may have normal sexual development
and abbreviated reproductive capacity. This disorder is termed 46,XX gonadal dys-
genesis, premature ovarian failure, or hypergonadotropic amenorrhea. These pa-
tients have normal female internal and external genitalia as well as normal female
height. Autoimmune disorders are present in about 20% of these patients, most
frequently hypothyroidism and Addison’s disease. It is therefore reasonable to ob-
tain a TSH, T4 and 8 AM cortisol level. The cortisol level should be 17-20 μg/dL to
rule out Addison’s disease, and should be followed up with an ACTH stimulation
test if low. A serum calcium, phosphorus and antinuclear antibody are also reason-
able, although autoimmune parathyroid disease is less common. Premature ovarian
failure can be associated with a number of genetic abnormalities. It is therefore
important to get a good genetic history. Fragile X syndrome carrier status may be
observed in ~3-4% of women with sporadic 46,XX ovarian failure, but in up to
10-15% of patients if two or more women in the family are affected with gonadal
failure. It is reasonable to determine if there is a family history of mental retardation,
which increases the likelihood for Fragile X syndrome. Fragile X syndrome may be
tested by DNA (not cytogenetics) for the permutation allele. Although a patient
with ovarian failure is unlikely to get pregnant spontaneously, there could be a risk
for other family members to have a child with Fragile X syndrome.
In patients with hypergonadotropic hypogonadism who do not have breast de-
velopment, a pelvic exam should be performed to determine if a vagina is present
(Fig. 2.2). Rarely, 17-hydroxylase deficiency (17-OHase) may be observed in fe-
males (who will have a uterus/vagina) or in males (who will have a blind vaginal
pouch). It is a wise precaution to draw an 8 AM cortisol to exclude adrenal failure
secondary to 17-OHase deficiency. Also, rare inactivating mutations in the LHR
gene should be considered in a patient with gonadal failure, no breast development,
and no vagina.
Treatment of Gonadal Failure
Estrogen can be used to initiate breast development in these patients. Unop-
posed conjugated estrogens are usually administered in a dose of 0.3 mg/day for a
few months and then increased to 0.625, 0.9, then 1.25 mg/day until breast devel-
opment is adequate. Initial low dose administration may allow for a more normal
looking breast with early treatment. Low doses of ethinyl estradiol can be used be-
ginning at 1 μg/day and gradually increased. Alternatively, estradiol 0.5 mg may be
started and increased by 0.5 mg increments. Once breast development is achieved,
progestins should be added. Medroxyprogesterone acetate 5-10 mg/day for 10-12
days/month is added for endometrial protection. The patient can then be switched
to oral contraceptives. Pregnancy is extremely unlikely in these patients even with
ovulation induction or estrogen withdrawal. The chances are not zero since ovarian
function may wax or wane in those with a 46,XX karyotype. In vitro fertilization
with oocyte donation allows many of these patients the chance to reproduce. Care
must be taken in patients with a 45,X cell line because their risk of death due to
aortic rupture in pregnancy is 1-2%. For patients with a 45,X cell line, treatment
with recombinant growth hormone may also be considered. Although there is sig-
nificant cost associated with its use, some evidence indicates that height gains of 2-3
inches may occur with long term treatment.
Males
The most common karyotype of males with gonadal failure is a normal 46,XY.
However, 10-15% may have a 47,XXY (Klinefelter syndrome) or 46,XX karyotype
(sex-reversed male). Patients with a 47,XXY karyotype are usually in the 50th per- 2
centile for normal male height and eunuchoid due to lack of epiphyseal closure
(decreased upper to lower body ratio). Puberty is often initiated, but the tempo is
disrupted and they become hypogonadal. The most consistent finding in this syn-
drome is testicular fibrosis which leads to azoospermia in >95% of pure 47,XXY
males. If mosacism is present, about half of these males will have azoospermia. Gy-
necomastia occurs in about one-third to one-half of patients and frequently does
not respond to hormonal therapy. Medical care should include evaluation for diabe-
tes mellitus, breast cancer, leukemias, lymphomas, and germ cell tumors. Males
with a 46,XX karyotype have a normal male phenotype since they have the sex
determining region of the Y chromosome (SRY) initially, but they commonly de-
velop gonadal failure and are azoospermic.
Treatment for males with hypergonadotropic hypogonadism (regardless of karyo-
type) is comprised of replacing androgens to induce secondary sexual characteristics
and normal sexual function and to prevent osteoporosis. When diagnosed in the
newborn period, treatment with testosterone cypionate 25 mg IM is given several
times to induce penile growth. If treatment is initiated at puberty, testosterone
enanthate 50-100 mg IM should be given every 2-4 weeks. The usual adult dose for
maintenance is 200 mg administered every two weeks. Topical testosterone gel or
patches can also be utilized.
Similar to females with gonadal failure, fertility is highly unlikely and donor
insemination generally offers the best chance for pregnancy. In some circumstances,
if a testicular biopsy or epididymal aspiration demonstrates mature sperm, IVF with
ICSI may be an option.
Hypogonadotropic Hypogonadism
When the patient is hypogonadal (absent breast development, without an es-
trogen withdrawal bleed, or a negative progestin challenge) and serum gonadotro-
pins are low or normal (“normal” is inappropriate given the hypogonadism), the
diagnosis is hypogonadotropic hypogonadism (HH). An MRI of the brain is nec-
essary to exclude a pituitary tumor, most commonly a prolactinoma or
craniopharygioma. If a tumor is present, it is usually treated medically (dopamine
agonist for a prolactinoma), but surgery may be required for a craniopharyngioma,
which may be malignant. If a tumor is not present, the cause is generally hypotha-
lamic by exclusion. Although it is possible to perform a triple test (insulin induced
hypoglycemia, GnRH, and TRH stimulation and check baseline and hormone
levels every 15 minutes for 1-2 hours—TSH, prolactin, cortisol, LH, FSH, and
GH), the cost is great and the yield is very low except in patients who have extreme
short stature, which could suggest pituitary failure. If the patient has a height be-
low the 5th percentile, particularly if there is a family history of pituitary failure,
then combined pituitary hormone deficiency (CPHD) should be considered. Ge-
netic counseling and testing for mutations in genes such as PIT1, PROP1, HESX1,
or LHX3 should be considered.
In the absence of a tumor, strong consideration must be given to the history and
physical exam with particular attention to BMI, eating and exercise patterns, and
stress. Eating disorders such as anorexia nervosa or bulimia must be sought because
of the significant morbidity and mortality. A history of extreme exercise such as
prolonged running or ballet must also be elicited, as should a history of stress. Morning
cortisol levels are elevated in patients with eating disorders, and reverse T3 levels
may be elevated (preferential conversion of T4 to rT3 instead of the more active
2 T3). Correction of the underlying problem with an increase in weight, reducing the
exercise, or trying to relieve the stress will often lead to menstruation.
For patients with hypogonadotropic hypogonadism who have no pituitary tu-
mor and are of normal weight, two diagnoses must be considered. They may have
constitutional delay of puberty (CDP) if they initiate puberty spontaneously before
age 17 in girls and age 18 in boys (CDP is more common in boys). If they are older
than 17 for girls and 18 for boys, the diagnosis is idiopathic or isolated
hypogonadotropic hypogonadism (IHH). A history should be sought for anosmia/
hyposmia, midline facial defects, associated neurologic deficits such as synkinesia
(tested by raising both arms for example when asked to raise one-corticospinal tract
abnormality), hearing loss, or visual abnormalities. When IHH is combined with
anosmia/hyposmia, the patient has Kallmann syndrome. Mutations in the KAL1
gene on the X chromosome account for about 5-10% of the causes in males (not
females since it is X-linked recessive). Males with mutations in the KAL1 gene may
also have unilateral renal agenesis (50% in one series), which should be tested. Mu-
tations in the FGFR1 (KAL2) gene occur in about 10% of patients (male and fe-
male) with Kallmann syndrome. This autosomal dominant form of Kallmann
syndrome can lead to individuals with mutations who are not affected (reduced
penetrance), which can complicate the diagnosis. Midline facial defects and dental
agenesis may occur in patients with FGFR1 mutations.
For patients with normosmia, mutations in the gonadotrophin releasing hor-
mone receptor (GNRHR) comprise approximately 5-10% of the cases and are in-
herited in an autosomal recessive fashion. Although mutations in other genes have
been reported, they are thought to be rare. Testing for deletions of KAL1 may be
performed commercially, but testing FGFR1 and GNRHR are generally performed
only by research laboratories.
Treatment for patients with hypogonadotropic hypogonadism involves adminis-
tration of estrogen for girls (testosterone for boys) as described above. In contrast to
patients with gonadal failure, patients with IHH can be given S.Q. FSH and LH
(see ovulation induction chapter) for ovulation induction in females and cycle fe-
cundity is similar for age-matched fertile women. For men who have testes larger
than prepubertal size (≥4 mL by Prader orhidometer), 2000-3000 IU of hCG may
be given S.Q. three times/weekly. If there is little or no response, recombinant FSH
150 IU may be added to this regimen. Most males will have evidence of spermato-
genesis and fertility although it may take 6-12 months and their semen analysis
parameters are often lower than what would be considered normal.
Eugonadism (in Females)
If breast development is normal and amenorrhea is present, the exam will deter-
mine if there is an outflow tract obstruction. The exam may identify an anatomic
abnormality, such as absence of the uterus and vagina with either complete androgen
insensitivity syndrome (CAIS) or mullerian aplasia (Mayer-Rokitansky-Kuster-Hauser
syndrome) or obstruction of the outflow tract. A karyotype will serve to distinguish
CAIS (46,XY) vs mullerian aplasia (46,XX), as will a testosterone (normal male levels
in CAIS and normal female levels in mullerian aplasia). However, this is often not
necessary. CAIS patients usually have absent pubic hair because of an X-linked reces-
sive mutation in the androgen receptor gene, while females with mullerian aplasia are
normal appearing females and should have pubic hair, since the defect involves uter-
ine, renal, vaginal, and skeletal development. Remember that about 1/3 of women
with mullerian aplasia will have unilateral renal agenesis and may have skeletal spinal
fusion defects (Klippel Fiel syndrome) and need some form of evaluation for this. 2
Treatment is usually successfully accomplished with progressive vaginal dilation initi-
ated when the patient is sexually mature and interested in intercourse (usually later
teenage years or early 20s). Typically, lubricated, increasing sized vaginal dilators are
used for 20-30 minutes/day over a period of 3-6 months until achievement of the final
desired vaginal depth and size. Surgical creation of a neovagina, such as the McIndoe
procedure, may also be utilized, but patients should understand that wearing a vaginal
mold for 6-9 months postoperatively may still be necessary.
Other obstructive causes such as a transverse vaginal septum or imperforate hy-
men will present as cyclic, worsening pelvic pain since uterine contents collect in the
vagina (hematocolpos) and in the uterus (hematometra). These disorders present
urgently or emergently. If an imperforate hymen is present, a hymenectomy may be
performed, which is a relatively straightforward procedure in which the hymen is
excised. A transverse vaginal septum presents a much more challenging operative
procedure since the septum may be much thicker and higher in the vagina than
appreciated; however, the septum must be opened and removed. A vaginal mold is
also necessary postoperatively with this procedure.
If no outflow obstruction is observed in a eugonadal patient and thyroid studies
and prolactin are normal, the patient very likely has polycystic ovary syndrome
(PCOS) as the cause of amenorrhea. These patients are at risk for diabetes and
endometrial hyperplasia so treatment with oral contraceptives or acyclic progester-
one, such as medroxyprogesterone acetate, if pregnancy is not desired. Ovulation
induction is indicated for attempting pregnancy.
Key Points
1. The onset of puberty should occur over a three to four year period, with the
usual first sign of puberty being breast budding (thelarche).
2. Sexual development prior to the age of 8 years in girls and 9 years in boys is
considered early, and mandates an evaluation. It is often idiopathic and is
five times more common in girls than boys.
3. Precocious puberty can be classified as being central (activation of the
hypothalamic-pituitary-gonadal axis), which may be treated with GnRH
agonists, or peripheral, which will not respond to GnRH agonists. If preco-
cious puberty is not treated, final adult height may be compromised.
4. Delayed puberty is defined as absent puberty by age 14 in boys (no testicu-
lar development). For girls, no thelarche by age 13 or no menarche by age
15 is considered delayed.
5. All patients with delayed puberty should have a TSH, T4, prolactin, and
girls should have a test for the presence of estrogen (a progestin withdrawal
test or vaginal maturation index).
6. If a delayed puberty patient has evidence of estrogen, a pelvic exam will distin-
guish if there is an outflow tract abnormality vs. polycystic ovary syndrome.
7. In hypoestrogenic girls with delayed puberty, it is necessary to obtain FSH
and LH levels. If gonadotropins are elevated, ovarian failure is present and a
karyotype is warranted to exclude the presence of a Y chromosome. If gona-
dotropins are low or normal, a central (hypothalamic or pituitary) etiology
is present, and an MRI is necessary to exclude a tumor.
Suggested Reading
1. Grumbach MM. The neuroendocrinology of human puberty revisited. Horm Res 2002;
57(Suppl 2):2-14.
2 2. Grumbach MM. A window of opportunity: The diagnosis of gonadotropin deficiency
in the male infant. J Clin Endocrinol Metab 2005; 90(5):3122-7.
3. Hayes FJ, Crowley Jr WF. Gonadotropin pulsations across development. Horm Res
1998; 49(3-4):163-8.
4. Layman LC, Reindollar RH. Diagnosis and treatment of pubertal disorders. Adolesc
Med 1994; 5(1):37-56.
5. Layman LC. Genetics of human hypogonadotropic hypogonadism. Am J Med Genet
1999; 89(4):240-8.
6. Layman LC. Mutations in human gonadotropin genes and their physiologic signifi-
cance in puberty and reproduction. Fertil Steril 1999; 71(2):201-18.
7. Layman LC. Human gene mutations causing infertility. J Med Genet 2002;
39(3):153-61.
8. Lee PA. The effects of manipulation of puberty on growth. Horm Res 2003; 60(Suppl
1):60-7.
9. Reindollar RH, Byrd JR, McDonough PG. Delayed sexual development: A study of
252 patients. Am J Obstet Gynecol 1981; 140(4):371-80.
10. Reiter EO, Lee PA. Delayed puberty. Adolesc Med 2002; 13(1):101-18, (vii).
11. Sun SS, Schubert CM, Chumlea WC et al. National estimates of the timing of sexual
maturation and racial differences among US children. Pediatrics 2002; 110(5):911-9.
Chapter 3
Amenorrhea
Michael Wittenberger and Alicia Armstrong
Introduction
Amenorrhea is a common gynecologic complaint that generates consternation
in patients and clinicians alike. Patients are concerned because cyclic menstrual pe-
riods are considered to be a sign of health, and conversely, the absence of menstrual
periods are a sign of disease. Additionally, the broad differential diagnosis, perceived
complexity of the work up and the ramifications of the diagnoses often intimidate
clinicians. The purpose of this chapter is to provide a framework to systematically
evaluate and treat primary and secondary amenorrhea.
Many clinicians consider primary and secondary amenorrhea to be the same
diagnosis. Although there is a great deal of overlap, a subset of patients with primary
amenorrhea differ markedly from those with secondary amenorrhea relative to the
possibility of restoration of menses and conception. Traditionally, primary amenor-
rhea is defined as no menarche by 14 years of age in the absence of secondary sexual
characteristics or absence of menses by 16 years of age in the presence of normal
growth and secondary sexual characteristics. This definition has remained unchanged
despite a shift towards earlier menarche. Secondary amenorrhea occurs in a woman
with prior menses, and represents the absence of menses for a duration equal to at
least three of her previous cycle intervals or six months. These definitions provide an
initial framework to identify amenorrhea; however, the timelines described should
not be strictly adhered to particularly in the presence of anatomic abnormalities and
obvious pathology.
Evaluation
Using the patient’s history and physical exam to guide the ordering of addi-
tional tests, the evaluation of amenorrhea can be both time efficient and cost
effective. One such diagnostic approach is depicted in Figures 3.1-3.5. This man-
agement algorithm classifies patients by physical evidence of estrogen secretion
and the absence of a Y chromosome. Because steroidogenesis is one of the basic
functions of the intact gonad, the absence of breast development strongly suggests
hypoestrogenemia; and therefore, hypogonadism. However, the presence of breasts
does not confirm normal estrogen levels or eugonadism. Breast development is
only a marker for past exposure to estrogen. To obtain information on a patient’s
current estrogen status, it is necessary to evaluate the patient’s reproductive or-
gans. Upon speculum examination of the patient’s vagina and cervix, a
well-estrogenized vagina is characterized by pink, moist mucosa with multiple
rugations and the presence of mucous discharge from the cervix. The presence of
superficial cells on vaginal cytology is also characteristic of the well-estrogenized
state. Conversely, thin, pale appearing vaginal mucosa without cervical discharge
Figure 3.1. Evaluation of amenorrhea.

Amenorrhea 25
is suggestive of hypoestrogenism and hypogonadism. In addition to assisting in

classifying the patient as eugonadal (normal serum estrogen) versus hypogonadal
(hypoestrogenic), examination of the reproductive organs allows many anatomi-
cal abnormalities to be discovered, and specifically, perhaps most importantly, the
presence of a uterus can be documented. These two features: hypogonadism ver- 3
sus eugonadism and presence or absence of a uterus will provide the direction for
subsequent tests.
Eugonadism, Uterus Present
Amenorrheic patients with evidence of estrogen production and an intact
uterus require further evaluation to determine the etiology of their amenorrhea
(Fig. 3.2). Pregnancy, even in a patient with primary infertility, always needs to
be considered and eliminated as an etiology of amenorrhea. Thyroid disorders
and hyperprolactinemia are common disorders associated with amenorrhea, there-
fore thyroid stimulating hormone and prolactin levels should be assessed. It is
useful to perform a progestin challenge test in these individuals to assess the
amount of estrogen production and the competency of the uterine outflow tract.
A progestin challenge test takes advantage of endogenous estradiol and usually
causes withdrawal bleeding within 2 to 7 days after cessation of progestins. Mul-
tiple formulations of progestins can be used (Table 3.1), and any amount of
bleeding is considered a positive test. Lack of withdrawal bleeding should be
further evaluated with another progestin challenge test after providing additional
estrogen priming (1.25 mg conjugated estrogens or 2 mg estradiol for 21 days).
Failure to bleed after this regimen may occur in several situations. First, when
there is a lack of functional endometrium or an outflow tract obstruction. Alter-
natively, the patient may have elevated serum androgen levels that resulted in
decidualization of the endometrial lining. In some instances withdrawal bleeding
can occur in the presence of gonadal failure. Patients with vasomotor symptoms
and a positive withdrawal bleed should have their follicle stimulating hormone
(FSH) level assessed.
Hypogonadism (Prior Estrogen Exposure), Uterus Present
Patients with vasomotor symptoms may be transitioning to our next class of
amenorrheic patients—those with previous estrogen exposure and intact uteri who
present with hypogonadism (Fig. 3.3). Measurement of serum FSH is critical in
this group of patients to determine whether the deficiency in estrogen is second-
ary to a central versus a peripheral abnormality (e.g., hypothalamus and pituitary
versus ovary). Low FSH levels indicate central dysregulation. A normal FSH level
in the presence of hypoestrogenemia is also abnormal and should be interpreted
as a possible central cause of amenorrhea. These patients have increased amounts
of sialic acid in the carbohydrate portion of the FSH molecule rendering it bio-
logically inactive. Antibodies in the immunoassay are still able to recognize the
Table 3.1. Progestin challenge test

Parenteral 200 mg progesterone in oil
Oral micronized progesterone 300 mg qhs for 5 days
Oral medroxyprogesterone acetate 10 mg for 5 days
Figure 3.2. Eugonadism with uterus.

Amenorrhea
Figure 3.3. Hypogonadism with uterus present and prior estrogen exposure.
27
3
Table 3.2. Gonadotropin levels

FSH LH
Normal adult female levels 5-20 IU/L 5-20 IU/L
3 Ovulatory peak levels twice basal twice basal
Hypogonadotropic state <5 IU/L <5 IU/L
Hypergonadotropic state >20 IU/L >40 IU/L
Adapted from: Speroff L, Fritz MA, eds. Clinical Gynecologic Endocrinology
and Infertility, 7th ed. Lippincott Williams & Wilkins, 2004.
molecules, indicating that immunoreactivity does not always equal bioactivity. Since
there are many possible etiologies associated with hypogonadotropic amenorrhea,
information from the patient’s history and physical should be used to direct further
tests. Multiple endocrinopathies, CNS tumors, systemic illnesses, excessive exercise
and eating disorders should all be considered and the appropriate endocrine screen-
ing tests and imaging studies ordered. For patients with elevated FSH levels
(hypergonadotropic amenorrhea) who are less than 30 years old, a karyotype should
be ordered because of the higher likelihood of finding a chromosomal abnormality.
If a normal karyotype is discovered, a transvaginal ultrasound may be helpful in
further differentiating between the remaining patients. If an abnormal karyotype is
discovered an ultrasound may identify the presence of testicular tissue.
Eugonadism, Uterus Absent
Eugonadal patients who do not have evidence of a cervix on examination (Fig.
3.4) should undergo imaging studies for confirmation. If an absent uterus is con-
firmed, a karyotype should be obtained to rule out the presence of a Y chromo-
some. Testosterone levels are often useful in the differential diagnosis of patients
with a 46 XY karyotype.
Figure 3.4. Eugonadism without a uterus.

Amenorrhea 29
Table 3.3. Causes of primary amenorrhea

Cause Frequency
Ovarian failure 48.5%
Congenital absence of the uterus and vagina 16.2% 3
GnRH deficiency 8.3%
Constitutional delay of puberty 6.0%
Adapted from: Timmreck LS, Reindollar RH. Contemporary issues in primary
amenorrhea. Obstet Gynecol Clin North Am 2003; 30:287-302.
Hypogonadism, Uterus Present

Patients with a uterus without any evidence of prior estrogen exposure (Fig. 3.5)
require a work up similar to those patients with evidence of prior estrogen exposure
(Fig. 3.3). However, since they are presenting with primary amenorrhea, several
additional diagnoses, discussed in the next section, need to be considered.
Diagnoses
To summarize, the evaluation of primary or secondary amenorrhea leads to a
differential diagnosis that includes both eugonadal and hypogonadal states. Hy-
pogonadism can be further classified by FSH levels: hypogonadotropic (low FSH)
and hypergonadotropic (high FSH) hypogonadism. Tables 3.3 and 3.4 summarize
common causes of both primary and secondary amenorrhea.
Eugonadotropic Amenorrhea (Normal FSH and LH)
Eugonadal amenorrhea covers a spectrum of disorders ranging from common to
extremely rare conditions. Polycystic ovary syndrome (PCOS), a very common gy-
necologic condition, can lead to both primary and secondary amenorrhea. It is char-
acterized by oligo-ovulation or anovulation, clinical or biochemical evidence of
Table 3.4. Causes of secondary amenorrhea

Cause Frequency
Anovulation 28%
Ovarian Failure – abnormal karyotype 0.5%
– normal karyotype 10%
Hypothalamic suppression 10%
Weight loss/anorexia 10%
Prolactinoma 7.5%
Asherman’s syndrome 7%
Hypothyroidism 1%
Adapted from: Reindollar RH, Novak M, Tho SP et al. Adult-onset amenorrhea: A

study of 262 patients. Am J Obstet Gynecol 1986; 155:531-543.
Figure 3.5. Hypogonadism with a uterus.

Amenorrhea 31
hyperandrogenemia, and polycystic appearing ovaries. According to the 2003

Rotterdam criteria, two out of three of these features must be present for this diag-
nosis. In addition to amenorrhea, patients with PCOS frequently have problems
with infertility and insulin resistance. They are also at increased risk for developing
metabolic syndrome, endometrial hyperplasia and endometrial cancer. 3
In addition to PCOS, several anatomic abnormalities can result in amenorrhea
in the presence of normal estradiol levels. Congenital absence of the uterus and
vagina, also known as Mayer-Rokitansky-Kuster-Hauser syndrome, is an example
of eugonadal amenorrhea. Failure of the undifferentiated mullerian system to fuse
properly results in varying degrees of uterine and vaginal agenesis in these women.
Patients often have a short vaginal pouch or absent vagina. The uterus and fallopian
tubes are frequently absent or if present consist of small uterine remnants attached
to normal fallopian tubes and ovaries. Thirty percent of these patients have renal
anomalies such as unilateral renal agenesis and twelve percent have skeletal anoma-
lies. Because ovarian function is normal, ovarian steroidogenesis is intact, puberty is
normal, but menstruation fails to occur. Other less common congenital anomalies
resulting in amenorrhea include: absence of the endometrial cavity or endometrium,
cervical atresia, transverse vaginal septum and imperforate hymen. Absence of the
endometrium is exceedingly rare. Cervical atresia may present as hematometria or
hematoperitoneum. Patients with transverse septae, resulting from failure of the
lower third of the vagina to canalize, may present with hematocolpos and urinary
frequency. A vaginal septum may be associated with abnormalities of the fallopian
tubes or unilateral absence of the ovary and fallopian tube. Imperforate hymen may
be distinguished from a transverse vaginal septum by physical examination. Patients
with an imperforate hymen will demonstrate distention of the introitus by the he-
matocolpos when they perform a valsalva maneuver. Asherman’s syndrome, an ac-
quired cause of amenorrhea, results from partial or complete destruction of the
endometrium, often as a complication of a surgical procedure. Asherman’s syndrome,
or uterine synechiae, may result from overzealous postpartum curettage, uterine
surgery (cesarean section, metroplasty or myomectomy), uterine artery emboliza-
tion, and infection. Rare infectious causes of Asherman’s syndrome include tubercu-
losis and uterine schistosomiasis.
Various types of male pseudo-hermaphrodism can cause primary amenorrhea.
The most common of these conditions, androgen insensitivity syndrome (AIS) occurs
when an abnormal androgen receptor fails to initiate a signal in response to testoster-
one due to mutations in either the androgen binding or DNA binding sites. In its
classical form, patients have a 46 XY karyotype and testes which produce both test-
osterone and Mullerian inhibitory substance (MIS). MIS causes regression of the
Mullerian system and the absence of internal female genitalia. These individuals are
unable to respond to testosterone with masculinization of the external genitalia and
the default, an external female phenotype and formation of a short vaginal pouch, is
seen in these patients. At puberty, peripheral aromatase converts testosterone to estra-
diol and breast development ensues. These patients also have very little pubic hair and
are usually tall due to the presence of the Y chromosome. Partially descended testicles
may result in the finding of bilateral inguinal hernias in childhood. In addition to the
classical form of AIS, incomplete androgen insensitivity may present with amenor-
rhea; however, these phenotypic females may undergo varying degrees of virilization
with puberty. Another form of male pseudo-hermaphrodism is caused by a deficiency
in 17-ketoreductase. Instead of a defect in the androgen receptor, these patients have
impaired testosterone production and present with clinical findings that are similar to
incomplete androgen insensitivity.
Hypogonadism comprises the remainder of the causes of amenorrhea. Hypogo-
nadism may result when defects occur at the level of the hypothalamus and pituitary
3 or at the level of the ovary. Evaluation of gonadotropin levels can readily distinguish
between the two. Hypogonadotropic hypogonadism represents a central nervous
system abnormality and hypergonadotropic hypogonadism is indicative of a process
occurring in the ovary. The first of these, hypogonadotropic hypogonadism, may be
subdivided into the following categories: congenital abnormalities, acquired lesions,
endocrinopathies, systemic illnesses, maladaptive behaviors, constitutional delay of
puberty, and idiopathic hypothalamic hypogonadism.
Hypogonadotropic Amenorrhea
The most common congenital cause of hypogonadotropic hypogonadism is
Kallmann syndrome. Kallmann syndrome is characterized by isolated GnRH defi-
ciency resulting in primary amenorrhea and sexual infantilism. Patients also have
anosmia or hyposmia, midline facial defects and occasionally renal agenesis. Con-
sistent with hyposmia/anosmia, imaging studies demonstrate absent or hypoplastic
olfactory bulbs. It may be inherited in a X-linked and autosomal dominant or
recessive fashion. The X-linked recessive gene (KAL gene) encodes for an adhesion
protein. Lack of this protein prevents GnRH producing neurons from migrating to
their normal position in the hypothalamus adjacent to the anterior pituitary. Other
conditions leading to hypogonadotropic amenorrhea include: autosomal recessive
GnRH receptor mutations, X-linked adrenal hypoplasia, mutations in the FSH β
gene, and Prader-Willi and Laurence-Moon-Biedl syndromes.
Acquired lesions in the CNS may also result in amenorrhea. Malignant and
nonneoplastic intrasellar masses, such as nonfunctioning pituitary adenomas, cran-
iopharyngiomas, cysts, fat deposits, tuberculosis, and sarcoidosis can lead to pitu-
itary compression and hypogonadotropic amenorrhea. Nonfunctioning pituitary
tumors comprise approximately 30-40% of all pituitary adenomas and may secrete
biologically inactive FSH, α subunit, and rarely LH. Craniopharyngiomas usually
develop between ages 6 to 14 years. These calcified-appearing tumors on radiologi-
cal imaging may invade and destroy the pituitary and suprasellar regions. Lesions
such as internal carotid aneurysms and obstruction of the aqueduct of Sylvius may
produce hypogonadotropic amenorrhea. Other pituitary tumors may lead to endo-
crinopathies that secondarily lead to amenorrhea. Over 50% of pituitary tumors
detected at autopsy secrete prolactin, which can inhibit pulsatile secretion of GnRH.
Prolactinomas typically develop after puberty has started. Increased ovarian estro-
gen production leads to increased prolactin production via increased mRNA. About
one third of patients with a prolactinoma present clinically with galactorrhea. Other
endocrine tumors, such as Cushing’s syndrome and acromegaly usually produce
amenorrhea prior to their full clinical expression. Deficiencies in hormones may
also produce or accompany hypogonadotropic amenorrhea. Hypothyroidism is re-
sponsible for a small fraction of patients with amenorrhea, but is readily treatable
and normal menstruation is quickly restored. Sheehan’s syndrome, pituitary insuffi-
ciency due to ischemia or infarction after an obstetric hemorrhage, is characterized
by pan-hypopituitarism resulting in amenorrhea among other problems.
In addition to congenital and acquired lesions of the CNS, all manners of stress
may affect the hypothalamus and result in hypogonadotropic amenorrhea. Systemic
Amenorrhea 33
illness such as poorly controlled diabetes, childhood rheumatoid arthritis and

malabsorptive bowel disease may affect gonadotropin production and result in de-
layed menarche. Starvation as seen in eating disorders is a profound stress to the
body. Anorexia nervosa usually presents after menarche and represents a significant
life-threatening condition that may initially be noticed secondary to amenorrhea. 3
Neuropeptide Y, a peptide produced in the arcuate nucleus, normally stimulates
feeding behavior; however, when elevated in anorexia nervosa, it inhibits GnRH
secretion. Weight gain restores gonadotropin production, but normal menses do
not always ensue. Similar to anorexia, extreme exercise especially prior to menarche
may delay puberty. A reduction in body fat below a critical level and an increase in
energy expenditure trigger a decrease in leptin levels. Lower leptin levels can sup-
press reproductive and thyroid functions and increase adrenal activity. Both patients
with anorexia and exercise-induced amenorrhea have low FSH/LH and elevated
cortisol and may be difficult to distinguish clinically. However, they differ subtly in
other endocrine markers. Patients with anorexia have normal TSH and thyroxine
(T4), but low T3 and elevated reverse T3; whereas, patients with exercise-induced
amenorrhea have reductions in all thyroid hormones (T4, T3, rT3) and elevated
growth hormone, testosterone, prolactin and endorphins.
Another potential cause of delayed menarche associated with decreased FSH is
constitutional delay of puberty. These girls usually present from families with similar
histories of delayed menarche. They are shorter than their peers, and bone age lags
behind their chronological age. If given GnRH, they will respond with a pubertal
pattern of gonadotropin release (LH>FSH). When their bone age reaches 9 to 11
years, they usually spontaneously enter puberty.
When all other identifiable causes of hypogonadotropic amenorrhea are ruled
out, the remaining patients with low or normal gonadotropin levels, normal prolac-
tin, and normal imaging studies are labeled as having idiopathic hypothalamic amen-
orrhea. However, many of these will have increased cortisol secretion and may
represent another class of stress-induced amenorrhea.
Hypergonadotropic Amenorrhea
In contrast to hypogonadotropic hypogonadism, hypergonadotropic hypogo-
nadism is often the result of primary ovarian hypofunction. Hypergonadotropic
amenorrhea includes a variety of clinical entities including: Turner’s syndrome, ova-
rian failure, and pseudo-ovarian failure.
Turner’s syndrome results from a missing sex chromosome in all or a portion of
the cells. The resulting karyotype, 45 X, indicates they have a single copy of an X
chromosome (monosomy X). Absence of key ovarian genes on the other X chromo-
some results in premature loss of germ cells. During fetal life, Turner’s syndrome
patients have a normal number of germ cells at midgestation; however, an acceler-
ated loss of germ cells occurs thereafter. Due to this accelerated loss of follicles, less
than 15% of women with Turner’s syndrome will enter spontaneous puberty. Fur-
thermore, less than 5% will achieve a spontaneous pregnancy before developing
ovarian failure. Mosaicism, in which all of the cell lines are not monosomy X, ex-
plains why some patients are able to initiate puberty and even achieve pregnancy.
Approximately 5% of Turner’s syndrome patients have Y chromosome material that
is evident on karyotyping. This number doubles when specific Y chromosome DNA
probes are used in the evaluation. However, only mosaic Turner’s syndrome patients
with the presence of a Y cell line on karyotype are at increased risk for gonadoblastoma.
In addition to premature ovarian failure, other stigmata of Turner’s syndrome may

be observed which include: cardiovascular abnormalities that may cause complica-
tions in pregnancy; wide spaced nipples (shield chest); renal anomalies (horseshoe
kidney); high arched palate; low hairline; webbed neck; multiple pigmented nevi;
3 short fourth metacarpal digits; increased carrying angle of the arms; lymphedema;
and short stature with height usually less than 63 inches/160 cm. Turner’s syndrome
patients also have an increased prevalence of autoimmune disorders—Hashimoto’s
thyroiditis and diabetes mellitus.
Hypergonadotropic patients with a normal complement of chromosomes may
develop amenorrhea secondary to, or as a transition to ovarian failure. Multiple
causes of 46 XX ovarian failure have been elucidated. Acquired causes include: ra-
diation; chemotherapy; and possibly infectious elements like childhood viruses. Au-
toimmune ovarian failure has been commonly described. Therefore, a careful look
for other autoimmune disorders is imperative. Other autoimmune disorders include:
Hashimoto’s thyroiditis; pernicious anemia; vitiligo; diabetes mellitus; hypoparathy-
roidism; and, importantly, adrenal insufficiency. Adrenal insufficiency is a poten-
tially lethal condition that may present with subtle findings of hyperpigmentation,
weakness, lethargy, anorexia, nausea, vomiting, and orthostatic hypotension. Ge-
netic causes of ovarian failure include: mutations occurring in the POF1 and 2
regions of the X chromosome; expansion of CGG repeats between 55-200 in the
FMR1 gene as seen in the Fragile X syndrome premutation; blepharosphimosis/
ptosis/epicanthus inversus syndrome; ataxia telangectasia; myotonic dystrophy; and
galactosemia. Patients with 46 XY gonadal dysgenesis (Swyer syndrome) also have a
normal, though unexpected, complement of chromosomes. They have mutations in
or in proximity to the SRY gene that results in impaired testicular development.
Streak gonads rather than normal testes form, MIS is not produced and normal
internal female genitalia develop. In the absence of normal testosterone production,
normal external female genitalia also develop. Because gonadal steroidogenesis is
not normal, puberty and menses do not occur. The presence of a Y chromosome
also places these patients at increased risk for germ cell tumors.
Patients with resistant ovary syndrome (Savage syndrome) also have
hypergonadotropic hypogonadism, but they have normal ovarian germ cell re-
serve as evidenced by normal antral follicle counts. Instead, they have FSH recep-
tor gene mutations or post-receptor signaling defects. Since they do not have ovarian
failure despite the absence of menses, they are termed pseudo-ovarian failure.
Aromatase enzyme deficiencies, 17-hydroxylase gene mutations and LH receptor
gene mutations may also present with elevated gonadotropins and normal ovarian
germ cell reserve.
Treatment
Once a diagnosis is established, appropriate treatment can be implemented. Treat-
ment of these diverse disorders often requires consultation with other specialists.
The treatment of primary and secondary amenorrhea may involve medical manage-
ment, surgical management, and patient specific counseling.
Medical management should be directed at treating the underlying condition,
preventing undesirable complications, and addressing reproductive concerns. Pa-
tients with hypothyroidism or hyperprolactinemia are two groups of amenorrheic
patients readily treated medically. Thyroid hormone replacement rapidly corrects
amenorrhea associated with hypothyroidism. Likewise, prolactinomas are usually
Amenorrhea 35
slow growing and respond well to dopamine agonists such as bromocriptine or

cabergoline. Patients with PCOS have amenorrhea secondary to anovulation. Lack
of luteal progesterone and unopposed estrogen places them at risk for endometrial
hyperplasia and carcinoma. Therefore, cyclic progestin administration may be nec-
essary to prevent these complications. Alternatively, ovulation induction may be 3
desirable if pregnancy is wanted. In addition, PCOS patients often have insulin
resistance and are at risk for diabetes and metabolic syndrome. Beginning an
insulin-sensitizing agent to potentially prevent these complications may be consid-
ered, but this recommendation is still under active investigation. All hypogonadal
patients are by definition estrogen deficient and therefore subject to increased risk of
premature osteopenia and osteoporosis. Again, treatment should be considered to
prevent this unwarranted complication. Finally, many patients are concerned with
reproductive options. For those patients with diagnoses amenable to potential con-
ception, ovulation induction versus contraception should be offered. Other patients
with ovarian failure or mullerian anomalies often require referral for assisted repro-
ductive technologies in order to conceive.
For those patients with diagnoses requiring surgical intervention, appropriate
referral is imperative. Surgery is necessary to restore anatomy, remove tumors, or to
prevent the malignant transformation of Y chromosome containing gonads. Uter-
ine outflow tract abnormalities and Asherman’s syndrome should be corrected by an
appropriately trained gynecologist or reproductive endocrinologist. Neurosurgical
intervention may be required for other tumors of the CNS. Lastly, any patient diag-
nosed with a Y chromosome by karyotype requires a gonadectomy to prevent the
development of germ cell tumors. In patients with AIS, the gonads are allowed to
remain in situ until after puberty to facilitate more normal breast formation.
Counseling is an important aspect of treatment of amenorrhea. Patients are of-
ten concerned that amenorrhea is a sign of a significant problem. Some patients are
given information that may have devastating implications for their future fertility
and self-identity and others may learn about some undesirable health effects associ-
ated with their diagnosis. Therefore, it is critical to provide supportive counseling
and carefully discuss all the ramifications of the diagnosis. Finally, counseling may
provide a primarily therapeutic role in treating anorexia and encouraging weight
gain and exercise reduction.
Suggested Reading
1. Timmreck LS, Reindollar RH. Contemporary issues in primary amenorrhea. Obstet
Gynecol Clin North Am 2003; 30:287-302.
2. Reindollar RH, Novak M, Tho SP et al. Adult-onset amenorrhea: A study of 262
patients. Am J Obstet Gynecol 1986; 155:531-543.
3. Apgar BS. Diagnosis and management of amenorrhea. Clinics in Family Medicine
2002.
4. Speroff L, Fritz MA. Clinical Gynecologic Endocrinology and Infertility, 7th ed. Phila-
delphia: Lippincott Williams & Wilkins, 2004.
Chapter 4
Dysfunctional Uterine Bleeding

William R. Phipps
Introduction
Abnormal vaginal bleeding is a common complaint encountered by physicians.
Such bleeding may be secondary to a wide array of specific underlying problems,
but in many cases a diagnosis of dysfunctional uterine bleeding (DUB) is ultimately
made. The term DUB refers to abnormal uterine bleeding that is not a consequence
of structural or systemic disease. Usually DUB is related to anovulatory menstrual
cycles, a condition specifically referred to here as anovulatory DUB. Women with
ovulatory cycles may also have DUB, specifically referred to here as ovulatory DUB.
Other terms used to describe abnormal bleeding patterns include oligomenorrhea
and polymenorrhea, traditionally used to designate patterns of bleeding episodes
with intervals greater than 35 and less than 24 days, respectively. The term menor-
rhagia refers to episodes of excessive flow and/or duration occurring at regular nor-
mal intervals, and metrorrhagia to such episodes occurring at irregular intervals.
Still another term, used increasingly in recent years, is heavy menstrual bleeding,
and is generally used to describe abnormal uterine bleeding on the basis of either
anovulatory or ovulatory DUB.
Any vaginal bleeding not occurring on the basis of regular ovulatory menstrual
cycles can be considered abnormal, and thus the characteristics of normal menses as
shown in Table 4.1 are pertinent. However, many women without clinically signifi-
cant abnormalities have menstrual patterns that fall outside these norms, and natu-
rally a patient is most likely to consult her physician when she detects a pattern that
she considers abnormal for herself. In this same vein, a woman with a clinically
significant abnormality may not recognize that anything is wrong. In any event, the
decision to intervene should be governed by the individual circumstances present,
and not the presence or absence of a specific pattern.
Table 4.1. Normal menses: Characteristics

Mean Normal Range
Menarche 12-13 years 8-16 years
Interval 28-30 days 24-35 days
Duration 4-6 days 2-7 days
Amount of flow 30-45 ml 20-80 ml
Menopause 50-52 years 40-60 years
Dysfunctional Uterine Bleeding 37
Differential Diagnosis and Mechanisms of Bleeding

Table 4.2 lists a number of conditions that may present with abnormal vaginal
bleeding. Although many if not most patients with abnormal bleeding will ulti-
mately be diagnosed as having DUB, it is important that the other entities shown be
4
Table 4.2. Causes of abnormal vaginal bleeding
Dysfunctional Uterine Bleeding
Anovulatory DUB
Ovulatory DUB
Pregnancy-Related Bleeding
Threatened, missed, or incomplete abortion
Ectopic pregnancy
Molar pregnancy
Third trimester or puerperal bleeding
Benign Anatomic Lesions
Endometrial hyperplasia
Uterine myoma(s)
Adenomyosis
Endometrial or endocervical polyp(s)
Cervical or vaginal endometriosis
Vaginal adenosis
Müllerian anomalies associated with partial outflow obstruction
Uterine arteriovenous malformation
Cesarean delivery scar
Malignancies
Endometrial adenocarcinoma
Uterine sarcoma
Cervical or vaginal carcinoma
Gestational trophoblastic neoplasia
Disorders of Hemostasis
Thrombocytopenia
von Willebrand disease
Other platelet disorders
Factor deficiencies
Anticoagulation therapy
Severe hepatic disease
Inflammatory Processes
Endometritis, cervicitis
Infectious or atrophic vaginitis
Miscellaneous
Pelvic lacerations/trauma
Intrauterine device
Intravaginal foreign body
Drug-related (including hormonally active agents)
Hypothyroidism
Uterine sarcoidosis
Modified from: Phipps WR. Abnormal vaginal bleeding. In: Leppert PC, Peipert JF,
eds. Primary Care for Women, 2nd Ed. Philadelphia: Lippincott Williams & Wilkins,
2004:136.
excluded with reasonable certainty prior to treatment. Accordingly, the diagnosis of

either anovulatory or ovulatory DUB is one of exclusion.
The pathophysiology and optimal treatment of anovulatory DUB are best un-
derstood by comparison to the bleeding that occurs as part of the normal menstrual
cycle. In the follicular or proliferative phase of the cycle, estradiol produced by the
enlarging dominant follicle causes endometrial glands and stroma to proliferate.
4 After ovulation, during the luteal or secretory phase, the corpus luteum produces
large amounts of progesterone in addition to estrogen, resulting in secretory changes
in the endometrium. In the absence of pregnancy and the secretion of human chori-
onic gonadotropin, regression of the corpus luteum is associated with the with-
drawal of progesterone and estrogen. The result is a normal menses, an orderly and
self-limited event that involves desquamation of the entire endometrium.
The initiation of normal menstruation involves enzymatic degradation of the
functional layer of the endometrium and associated breakdown of blood vessels.
Subsequent hemostasis is provided first by normal coagulation mechanisms and
then by arterial vasoconstriction and reepithelialization. The normal coagulation
mechanisms include the formation of platelet plugs, involving von Willebrand fac-
tor (VWF), as well as thrombin-induced fibrin generation. Typically, clots are not
passed because of endometrial fibrinolytic proteins that promote clot liquefaction.
Unlike normal menstrual bleeding, anovulatory DUB involves exposure of the
endometrium to estrogen unopposed by progesterone for relatively long time peri-
ods. This leads to abnormally high and structurally unstable endometrium. The
tissue is delicate and undergoes essentially spontaneous breakdown with associated
bleeding related to the presence of increased numbers of often dilated, irregular, and
fragile venous capillaries. The process is not an orderly one, may go on more or less
indefinitely, and involves different portions of the endometrium at different times.
Additionally, clot passage may occur on the basis of an exhaustion of endometrial
fibrinolytic proteins.
Ovulatory DUB differs from anovulatory DUB in that ovulation occurs on a
regular basis, and thus the abnormal bleeding usually has a regular pattern. The
heavy nature of ovulatory DUB is thought in part to be a consequence of abnormal
arachidonic acid metabolism on endometrial function with excess production of
vasodilatory as opposed to vasoconstrictive prostaglandins. As well, women with
ovulatory DUB have been shown to have abnormally increased levels of endome-
trial fibrinolysis.
As for other causes of abnormal vaginal bleeding, pregnancy-related bleeding
may occur in both abnormal and essentially normal pregnancies, and thus the pos-
sibility of pregnancy must always be considered prior to intervention. In particular
it is important to make a diagnosis of an ectopic pregnancy as early as possible,
allowing for early medical or surgical treatment. The abnormal bleeding that occurs
vaginally during a tubal pregnancy is nearly always a consequence of endometrial
shedding secondary to abnormal corpus luteum function. This bleeding often pre-
cedes pelvic pain symptoms which are generally a consequence of tubal rupture and/
or intrapelvic bleeding.
The possibilities of a disorder of hemostasis or both benign and malignant
anatomic lesions should also be considered in all patients presenting with abnor-
mal vaginal bleeding. In particular platelet disorders often present as menor-
rhagia, especially in adolescents. In older patients, malignancies are relatively
more common, and it is especially important to rule out endometrial hyperplasia
and adenocarcinoma. In this same vein, cancer always needs to be ruled out in
the presence of any bleeding that occurs in a postmenopausal woman who is not
taking hormone replacement therapy. The mechanisms by which heavy abnor-
mal bleeding occurs in conditions such as uterine myomas and endometrial can-
cer are not well understood, but in many cases large and fragile surface blood
vessels are present, seemingly related to the release of angiogenic factors pro-
4
duced by the tumors themselves.
History
A careful history is of course essential to the management of any patient present-
ing with abnormal bleeding. The date of onset of the presenting episode and her
prior menstrual history need to be determined along with the presence of concomi-
tant symptoms of any kind. Also important are the patient’s general obstetrical and
gynecologic history, including her pregnancy and infertility history, prior pelvic sur-
geries, abnormalities noted on prior exams, Pap smear results, and contraceptive
method. A history of any significant medical problems should be noted, and inquir-
ies made about symptoms suggestive of endocrine and bleeding disorders and about
family members having similar problems.
The typical history in cases of anovulatory DUB is one of irregular episodes of
often painless bleeding occurring in an unpredictable fashion with episodes ranging
from a day of spotting to several weeks of continuous, heavy bleeding, often with
passage of clots vaginally. Long periods of amenorrhea may or may not be inter-
spersed among bleeding episodes. The cyclic symptoms of mittelschmerz and pre-
menstrual molimina are absent. Patients particularly at risk include postmenarchal
teenagers, women with polycystic ovarian syndrome or obesity-related ovulatory
dysfunction, and perimenopausal women, up to 50% of whom report episodes of
heavy abnormal bleeding.
Women with ovulatory DUB in general present with menorrhagia. Monthly blood
loss greater than 80 ml is considered abnormal and often associated with iron-deficiency
anemia. As a practical matter, it is difficult to precisely quantify blood loss, and thus
decisions about both investigating and treating a patient for menorrhagia largely hinge
on her subjective complaints. If a more objective assessment is desired for whatever
reason, however, the quantity of flow can be assessed by using a pictorial blood flow
chart developed by Higham et al. Less accurately, the number of standard tampons or
pads used by a patient during her menses can be counted, with each standard tampon
or pad corresponding very roughly to 5 ml of blood loss.
A history of mucocutaneous bleeding, such as epistaxis, gingival bleeding, or
easy bruising, may suggest von Willebrand disease (VWD), idiopathic thrombocy-
topenia purpura, or another bleeding diathesis. In particular patients with VWD,
the most common bleeding disorder of hemostasis, often have a history of excessive
menstrual bleeding since menarche, postpartum hemorrhage, bleeding associated
with surgery or dental procedures, or anemia. Von Willebrand disease is an
autosomal-dominant condition with considerable molecular and clinical heteroge-
neity. It has an overall prevalence of about 1%, and in particular should be consid-
ered when an adolescent patient presents with abnormal uterine bleeding. The family
history may not always be helpful, because of the variable penetrance associated
with mild to moderate VWD (type 1), and because males especially may not be
symptomatic. Of note, individuals with blood type O have on average 25% lower
von Willebrand factor (VWF) levels, and on this basis many women have what can
considered to be a relatively mild nongenetic form of VWD, as opposed to having

an inherited mutation involving the von Willebrand protein gene. Furthermore,
hypothyroidism can result in an acquired form of VWD, which resolves with thy-
roid replacement.
The history will also often provide diagnostic clues when a benign or malignant
anatomic lesion is the cause of abnormal bleeding. An enlarging submucosal myoma
4 in a patient with regular menstrual cycles will often present with a regular bleeding
pattern associated with a gradually increasing amount and/or duration of bleeding
over time, and perhaps increasing dysmenorrhea. Ovulatory women with bleeding
from an endometrial or endocervical polyp may present with a pattern of erratic
bleeding episodes essentially superimposed on a normal menstrual cycle pattern.
Women with endometrial hyperplasia or adenocarcinoma will often have a long
history of obvious anovulation and symptoms consistent with polycystic ovarian
syndrome.
It is also important to note that some women with conditions usually associated
with menorrhagia, such as ovulatory DUB, a submucosal myoma, or a bleeding
diathesis, may be oligo-ovulatory. Accordingly such women would be expected to
present with irregular and heavy menses, mimicking the usual pattern encountered
with anovulatory DUB. Other combinations of causes may also be present, and
thus in general the identification of one cause should not necessarily preclude a
search for others that may be contributing to an individual patient’s abnormal bleeding
symptoms.
Physical Examination
In cases of abnormal vaginal bleeding, a careful physical exam may reveal find-
ings pointing towards a specific diagnosis. Obviously the patient’s vital signs are
important, especially in the presence of acute or substantial bleeding, or when an
abnormal pregnancy may be present, situations in which immediate surgical or
medical intervention may be in order. The presence of a goiter may suggest hy-
pothyroidism, and acne and hirsutism may suggest polycystic ovarian syndrome
(PCOS), often associated with anovulatory DUB. The pelvic exam is particularly
important. The vagina and cervix should be thoroughly inspected for lesions, and
the amount of ongoing bleeding noted. Bimanual exam may reveal evidence for an
intrauterine or ectopic pregnancy, uterine myomas or adenomyosis, a Müllerian
anomaly with partial outflow obstruction, or an ongoing pelvic infection.
Laboratory, Imaging and Other Diagnostic Studies
Decisions about what diagnostic studies should be performed in cases of abnor-
mal vaginal bleeding need to be individualized. Table 4.3 provides a list of evaluative
measures that should be considered, and most patients should at least have a com-
plete blood cell count (CBC) that includes platelets if not done recently. In general,
it is mandatory to rule out pregnancy with a serum or sensitive urine pregnancy test
in anyone that could possibly be pregnant, regardless of contraceptive method or
the specific bleeding pattern present. If pregnancy is not present, most premeno-
pausal women should have their ovulatory status established. This may involve basal
body temperature charting, serum progesterone determinations, or endometrial sam-
pling. Given the high prevalence of autoimmune thyroid disease in women, the
concentration of thyroid-stimulating hormone (TSH) should also be routinely as-
sessed, even in the absence of more specific evidence for thyroid disease.
Table 4.3. Diagnostic studies in cases of abnormal vaginal bleeding

Study Rationale, Comments
CBC To assess for anemia and to rule out thrombocytopenic
bleeding.
Iron profile (serum About two thirds of patients with menorrhagia are 4
iron, total iron binding iron-deficient.
capacity, ferritin)
Serum or sensitive Mandatory whenever the possibility of pregnancy
urine pregnancy test is present.
Pictorial blood May be particularly useful in of ovulatory DUB when the
assessment charting diagnosis is unclear and for monitoring treatment results.
TSH Women with hypothyroidism may have DUB
on the basis of ovulatory dysfunction and acquired VWD.
Other endocrine Progesterone levels may be used to assess for either
studies regular or irregular ovulation. Other hormonal testing
may be needed to delineate the nature of ovulatory
dysfunction (e.g., PCOS, impending menopause,
or hyperprolactinemia).
Ivy BT and/or Either test can be used to screen for platelet dysfunction.
PFA-100 closure time The PFA-100 closure time is more reproducible and is
substantially more sensitive than the BT for VWD but
is still often normal in mild cases of VWD.
PT, aPTT, VWF In cases of an inherited procoagulant deficiency, or
antigen, ristocedin bleeding due to chronic liver disease or vitamin K
cofactor assay of deficiency, the PT or aPTT is generally abnormal, but
VWF, factor VIII these tests frequently do not identify several common
disorders of hemostasis. Patients with VWD generally
have abnormal VWF antigen, ristocedin cofactor assay
of VWF, and factor VIII results.
ABO typing Individuals with blood type O have decreased VWF
and factor VIII levels.
Transvaginal In general, not reliable to exclude endometrial
ultrasonography polyps or submucosal myomas in premenopausal
women; endometrial thickness <5 mm in postmeno-
pausal women makes endometrial cancer very unlikely.
Saline Sensitivity for detecting intracavitary lesions similar to
sonohysterogram that of hysteroscopy.
Hysterosalpingogram Less sensitive for detection of intracavitary lesions than
SSH or hysteroscopy, but may be warranted when a less
common Müllerian anomaly is suspected or in infertilty
patients when tubal status is also a concern.
Pelvic MRI Particularly helpful when adenomyosis is suspected and
other testing is nondiagnostic.
Hysteroscopy Miniaturized instrumentation may allow for coupling of
diagnostic and therapeutic procedures in the office setting.
Endometrial sampling Critically important if concern about hyperplasia,
adenocarcinoma, or endometritis.
Especially younger patients should usually be assessed for the presence of disor-
ders of hemostasis. When such a disorder is suspected, in addition to a CBC, testing
should include a prothrombin time (PT), an activated partial thromboplastin time
(aPTT), an Ivy bleeding time (BT) and/or platelet function analyzer-100 (PFA-100)
closure time, as well as studies more specific for VWD, namely the ristocetin cofac-
tor assay of VWF, quantification of VWF antigen, and a factor VIII assay. In this
4 context both the BT and the PFA-100 closure time serve to screen nonspecifically
for platelet dysfunction, but these tests, especially the BT, have relatively poor sensi-
tivity for VWD. Furthermore, even if the more specific tests to assess for VWD are
done, its diagnosis can still be problematic as the results can be ambiguous. Consul-
tation with a hematologist may be in order in such cases, as well as in cases with
negative results but nonetheless a high level of suspicion for a bleeding diathesis. In
both of these situations, additional testing, especially platelet aggregation and re-
lease studies, may be warranted, but the determination of what testing is appropri-
ate is best left to the consulting hematologist.
Particularly when there is a distinct possibility of an anatomic lesion, a variety of
imaging studies may be of use, but again the specific studies warranted depend on
the individual circumstances. Transvaginal ultrasonography may immediately reveal
obvious lesions such as submucosal or intramural myomas, adenomyosis, or polyps,
but especially in premenopausal women both polyps and myomas associated with
cavity distortion are frequently missed. Thus in many cases the instillation of saline
solution into the uterus coupled with real-time ultrasonography, or a saline
sonohysterogram (SSH), should be performed. This allows for much better delinea-
tion of intracavitary mass lesions, with sensitivity very similar to that of hysteros-
copy. Transvaginal ultrasonography by itself, however, can be particularly helpful in
cases of younger obviously anovulatory patients when there is concern about the
possibility of endometrial hyperplasia or adenocarcinoma. In such cases, a thicker
endometrial lining (greater than 10-11 mm) as measured by ultrasound should lower
the threshold for performing an endometrial biopsy. Transvaginal ultrasonography
by itself is also useful in cases of postmenopausal bleeding in that an endometrial
thickness measurement of less than 4-5 mm makes endometrial cancer very un-
likely, thus obviating the need for an endometrial biopsy.
Another option to evaluate the anatomy of the uterine cavity is of course the
hysterosalpingogram (HSG), which has the additional benefit of assessing for tubal
disease in cases of abnormal bleeding in which infertility is also an issue. However,
the HSG has inferior sensitivity and specificity as compared to SSH for detecting
intracavitary mass lesions and should not be done routinely in cases of abnormal
bleeding. An exception is situations in which an unusual Müllerian anomaly is sus-
pected, for example uterus didelphys in combination with an obstructed hemivagina
in which partial outflow obstruction can occur and result in an abnormal bleeding
pattern. Pelvic magnetic resonance imaging (MRI) may also occasionally be war-
ranted, especially in cases in which other imaging studies are inconclusive and an
unusual Müllerian anomaly or adenomyosis is suspected.
Hysteroscopy is another diagnostic measure that should be considered early on,
particularly if this can be done in an office setting using a flexible instrument with a
small outer diameter. Hysteroscopy is better for assessing for focal lesions such as
polyps or submucosal myomas than for diffuse lesions such as endometrial hyper-
plasia, but is still considered to be highly accurate for the detection of frank en-
dometrial adenocarcinoma. One advantage of office hysteroscopy over SSH is the
increasingly available option of performing directed biopsies or removing focal le-

sions such as small endometrial or endocervical polyps.
When a tentative diagnosis of anovulatory DUB is made, the decision about
whether or not to perform endometrial sampling depends primarily on the risk for
endometrial hyperplasia or adenocarcinoma, two conditions that also occur as a
consequence of chronic anovulation. Most women older than 35 and virtually all
4
women older than 40 who present with apparent anovulatory bleeding should un-
dergo endometrial sampling, as should many younger women with a long history of
anovulation, particularly if obesity, hyperinsulinemia, or a thick endometrial stripe
by ultrasound is present. Such sampling can usually be accomplished easily in the
office setting using a Pipelle endometrial suction curette or similar device. From a
diagnostic standpoint, there is little if any place for traditional dilatation and curet-
tage, except in conjunction with hysteroscopy.
Treatment
Once a diagnosis of either anovulatory or ovulatory DUB is made, either tenta-
tively or more definitively, treatment is tailored to the individual circumstances of
the case. These include a host of factors, including the degree of ongoing bleeding
and the presence or absence of hemodynamic stability, whether or not causes of
bleeding other than DUB are also present, and future fertility considerations. The
focus of the treatment modalities discussed here is those for DUB, but many of
these same modalities may be indicated for other causes of abnormal bleeding. For
example, many of the treatments effective in cases of ovulatory DUB can also be
applied successfully in cases of VWD.
For women with apparent anovulatory DUB, following initial diagnostic mea-
sures, the first goal of therapy is to stop the acute bleeding episode. This can nearly
always be accomplished without surgical intervention. If uterine curettage is per-
formed, this by itself does provide a substantial acute therapeutic effect, although in
general there is no reason not to start medical therapy immediately after endome-
trial sampling of any kind. In most cases of anovulatory DUB, the bleeding can be
stopped with the administration of a progestin. A typical progestin regimen is
medroxyprogesterone acetate (MPA), 10-20 mg orally once daily for 10 days. This
will usually stop the bleeding during the time it is being administered followed by
more or less orderly withdrawal bleeding starting immediately after the MPA is
discontinued. This sequence of events is similar to that of the secretory phase of the
normal cycle. It is important to advise the patient at risk for pregnancy that occa-
sionally ovulation will occur as a result of progestin administration and that she
should expect to have bleeding after it has been stopped.
Another therapeutic option useful in stopping acute anovulatory DUB in-
volves oral contraceptives (OCs), each containing 30-35 μg of ethinyl estradiol
and a progestin. A variety of regimens may be used, including, for example, hav-
ing the patient take 2-4 pills daily for five days, which will often bring the bleed-
ing to a halt within one or two days, followed by another 21 days of one pill daily,
after which withdrawal bleeding can be expected. For the patient who has been
bleeding heavily for a prolonged period of time, with little residual endometrial
tissue, it may be best to initially use high-dose estrogen therapy, for example con-
jugated estrogens (Premarin), 25 mg by intravenous bolus every 4 hours for two
or three doses. The immediate improvement with such therapy is due more to a
pharmacologic effect of estrogen on small vessel hemostasis than to estrogen’s ability
to cause proliferation and healing of endometrial tissue. Once the bleeding has
stopped in response to such treatment, in general an OC regimen should be started.
Patients diagnosed as having anovulatory DUB, but not responsive to the regi-
mens outlined above, require additional evaluation. This may include endometrial
sampling if not previously performed, SSH, or hysteroscopy.
Once the acute episode of anovulatory DUB has been treated, attention is di-
4 rected towards the possible need for long-term treatment. For the patient who is
usually ovulatory, for whom it is thought that the bleeding episode just treated is
unlikely to recur, a period of observation may be all that is necessary. On the other
hand, some form of chronic therapy is indicated for patients whose anovulatory
state responsible for the DUB is unlikely to abate spontaneously. The goals of this
long-term therapy, which must include a progestin component, are to prevent re-
currences of the unpredictable bleeding episodes, prevent endometrial hyperplasia,
and lower the patient’s risk for endometrial cancer. Iron supplementation should be
started at this time, if indicated.
Long-term treatment with OCs in the usual cyclic fashion is the best treatment
for most patients with anovulatory DUB, although some patients may prefer
extended-cycle OCs. Treatment with OCs is particularly useful for those women
who occasionally undergo spontaneous ovulation and need birth control, as well as
those with polycystic ovarian syndrome, because of amelioration of the associated
hyperandrogenism. Patients who are not candidates for OC use may be treated with
cyclic progestin treatment, for example, MPA, 10 mg orally once daily the first
10-14 days of each month, or even every second or third month. Anovulatory women
with DUB who desire pregnancy should of course have an appropriate hormonal
evaluation followed by initiation of ovulation induction therapy.
Patients diagnosed as having ovulatory DUB can be treated successfully with
several different regimens, both hormonal and nonhormonal in nature. These in-
clude OCs or a nonsteroidal anti-inflammatory drug (NSAID) regimen, such as
ibuprofen, 400 mg orally every 6 hours, starting on cycle day 1 and continuing
through cessation of menses. Both of these treatments not only decrease the amount
of bleeding, but also address the often associated problem of dysmenorrhea. The
mechanism by which NSAIDs work is not entirely clear, but appears to involve a
disproportionate reduction in the uterine concentrations of vasodilatory prostaglan-
dins as compared to that of the prostaglandin F2α, a potent vasoconstrictor.
Another possible treatment modality for ovulatory DUB is an antifibrinolytic
agent, such as epsilon aminocaproic acid. In particular, there is strong evidence that
the antifibrinolytic agent tranexamic acid is very effective, but unfortunately this
agent is not generally available in the United States. Still another option is danazol,
for example, 200 mg orally daily. Most patients taking such a dose continue to
experience regular menses, and androgenic side effects may be a problem. Further-
more, barrier contraception is needed if the patient is sexually active.
An option for ovulatory DUB that may be underutilized in the United States is
the Mirena levonorgestrel-releasing intrauterine system (LNG-IUS). The LNG-IUS
is an intrauterine device designed to release 20 μg of the progestin levonorgestrel
daily over a period of 5 years. Although only approved in this country as a birth
control measure, many studies have shown the LNG-IUS to be highly effectively for
ovulatory DUB, with large reductions (greater than 80%) of blood loss, and overall
outcomes comparable to those achieved with endometrial ablation. The effects seen
are primarily on the basis of local endometrial effects, as a substantial majority of
ovulatory women using the LNG-IUS continue to ovulate regularly. Interestingly,

despite continued ovulation, women with endometriosis and ovulatory DUB have
reduced dysmenorrhea symptoms after LNG-IUS insertion. Furthermore, women
with abnormal bleeding attributed to myomas also experience decreased bleeding
after LNG-IUS insertion, and the device provides effective treatment for endome-
trial hyperplasia. For women with ovulatory DUB, the most common side effect is
4
breakthrough bleeding, and there is an increased risk of functional cyst formation.
At times, patients with either anovulatory or ovulatory DUB have a consistently
poor response to the long-term medical options described, or unacceptable side
effects. In that situation, consideration may be given to treatment with a long-acting
gonadotropin releasing hormone (GnRH) agonist, such as leuprolide acetate, to
induce a menopause-like state. Long-term treatment with a GnRH agonist for most
patients is problematic, however, because of the adverse effects on bone density as
well as vasomotor symptoms. Thus in general, a patient with DUB failing to re-
spond to the regimens described is best treated surgically, particularly if the patient
is older and future fertility is not a concern.
Long-term surgical options for DUB include hysterectomy and endometrial ab-
lation. Both can be performed using several different approaches. Hysterectomy is
clearly the most definitive treatment for DUB and can be done by laparotomy,
laparoscopically, or vaginally, with the best approach for a given patient determined
by the individual circumstances involved. The ovaries may be preserved. In general,
hysterectomy is associated with more complications than ablation procedures but
also higher long-term patient satisfaction rates and substantially lower rates of the
need for repeat surgery. Furthermore women at increased risk for endometrial hy-
perplasia or adenocarcinoma are not good candidates for ablation.
For many patients, however, despite the advantages of hysterectomy, endome-
trial ablation may be a better choice, particularly if the goal is not amenorrhea. This
may be because of medical reasons, such as surgical risks for hysterectomy, or per-
sonal preference, such as the desire to avoid a more major surgery. Generally about
40% of women experience amenorrhea after ablation, and a similar proportion ex-
perience significantly reduced bleeding. There are now many options available for
ablation, both hysteroscopic and nonhysteroscopic, as recently reviewed by Shirk. If
a nonhysteroscopic approach is used, in general a diagnostic hysteroscopy should be
done beforehand. This primarily has to do with not missing lesions such as carcino-
mas or submucosal myomas.
Summary and Key Points
1. Many women with abnormal vaginal bleeding have either anovulatory or
ovulatory DUB. The diagnosis of DUB is one of exclusion.
2. Diagnostic studies in cases of abnormal bleeding need to be tailored to the
individual circumstances present. It is important to rule out pregnancy in
any woman presenting with abnormal bleeding. The possibility of a disor-
der of hemostasis should also always be considered.
3. Transvaginal ultrasonography, SSH, hysteroscopy, and endometrial biopsy
are all measures that should be considered early in the evaluation of a woman
with abnormal uterine bleeding.
4. Most cases of DUB can be managed medically, both in the short and long
run. Consideration should be given to placement of a LNG-IUS before sur-
gical interventions such as hysterectomy or endometrial ablation.
Suggested Reading
1. Breitkopf DM, Frederickson RA, Snyder RR. Detection of benign endometrial masses
by endometrial stripe measurement in premenopausal women. Obstet Gynecol 2004;
104:120-5, [In this retropective study, premenopausal women with abnormal bleed-
ing and intracavitary lesions often had endometrial thickness measurement less that 5
mm by ultrasound, highlighting the relatively poor sensitivity of transvaginal ultra-
4 sonography in such cases].
2. Clark TJ. Outpatient hysteroscopy and ultrasonography in the management of en-
dometrial disease. Curr Opin Obstet Gynecol 2004; 16:305-11, [This review provides
a good discussion of the relative merits of transvaginal ultrasonography, SSH, and
outpatient hysteroscopy in cases of abnormal uterine bleeding].
3. Ferenczy A. Pathophysiology of endometrial bleeding. Maturitas 2003; 45:1-14, [This
review of the mechanisms involved in abnormal uterine bleeding focuses on the un-
derlying histology].
4. Hatasaka H. The evaluation of abnormal uterine bleeding. Clin Obstet Gynecol 2005;
48:258-73, [This review presents a well balanced approach to evaluating women with
abnormal uterine bleeding].
5. Higham JM, O’Brien PM, Shaw RW. Assessment of menstrual blood loss using a
pictorial chart. Br J Obstet Gynaecol 1990; 97:734-9, [This paper describes a rela-
tively simple and objective pictorial chart method for quantifying menstrual blood
loss].
6. Hurskainen R, Paavonen J. Levonorgestrel-releasing intrauterine system in the treat-
ment of heavy menstrual bleeding. Curr Opin Obstet Gynecol 2004; 16:487-90, [This
review provides a short but useful overview on the use of the LNG-IUS in cases of
abnormal uterine bleeding].
7. Kouides PA. von Willebrand disease and other disorders of hemostasis in the patient
with menorrhagia. Women’s Health 2005; 1:231-44, [Perhaps 10 or 15% of all women
who present with abnormal uterine bleeding have VWD. This review helps the clini-
cian understand what should be done when VWD is either suspected or diagnosed].
8. Lethaby A, Shepperd S, Cooke I et al. Endometrial resection and ablation versus hys-
terectomy for heavy menstrual bleeding. Cochrane Database Syst Rev 2000; CD000329,
[This Cochrane review compared hysterectomy to endometrial ablation for the man-
agement of heavy menstrual bleeding].
9. Marsh F, Duffy S. The technique and overview of flexible hysteroscopy. Obstet Gynecol
Clin North Am 2004; 31:655-68, [This paper provides a useful overview of the use of
office flexible hysteroscopy in cases of abnormal uterine bleeding].
10. Shirk GJ. Minimally invasive surgery for ablation of the endometrium. Clin Obstet
Gynecol 2005; 48:325-36, [This review provides the clinician with an update in the
rapidly changing area of endometrial ablation techniques].
11. Speroff L, Fritz MA. Regulation of the menstrual cycle. Clinical Gynecologic Endocri-
nology and Infertility. 7th ed. Philadelphia: Lippincott Williams & Wilkins,
2005:187-231, [This chapter in the latest version of a classic textbook provides the
reader with a good understanding of the normal menstrual cycle, allowing for an in-
formed approach to the patient whose cycle is not normal].
12. Speroff L, Fritz MA. Dysfunctional uterine bleeding. Clinical Gynecologic Endocri-
nology and Infertility. 7th ed. Philadelphia: Lippincott Williams and Wilkins,
2005:547-71, [This chapter provides a broad and updated overview of all aspects of
DUB].
Chapter 5
Diagnosis and Management of Polycystic

Ovary Syndrome
Kathleen M. Hoeger
Diagnosis
Polycystic ovary syndrome (PCOS) is a heterogeneous condition associated with
irregular menstrual cycles and androgen excess. Additional terminologies used to
describe the syndrome include Stein-Leventhal syndrome, named for the authors of
the first published description in 1935, or sclerocystic ovarian disease. An interna-
tional consensus conference has proposed that the syndrome can be diagnosed if at
least two of the following features are present: irregular or absent ovulation, elevated
androgens or clinical androgen excess, and polycystic ovaries on ultrasound (Fig.
5.1). The finding of polycystic ovaries on ultrasound is neither solely diagnostic nor
necessary for diagnosis of PCOS. Additionally, the syndrome can only be diagnosed
after exclusion of other medical conditions.
Differential diagnosis of PCOS includes nonclassic adrenal hyperplasia due to
21-hydroxylase deficiency, Cushing’s syndrome, hyperprolactinemia, hypothyroid-
ism, acromegaly or virilization due to an adrenal or ovarian neoplasm. The history
alone may serve to distinguish the features of PCOS which is often perimenarchal in
onset. However, a panel of endocrine tests is generally indicated to fully exclude the
other causes of anovulation and/or hirsutism (see Endocrine Evaluation).
Epidemiology
The prevalence of PCOS varies by ethnic group and geographic area studied.
However, the best population based studies suggest the prevalence is approximately
6-7% in reproductive aged women. As such it is recognized as one of the most
common endocrine disorders in women and the most frequent cause of ovulatory
dysfunction. In women presenting with hirsutism approximately 74% will be found
to have PCOS.
There is evidence that PCOS is a heritable condition. So far there have been
unsuccessful attempts to define a specific gene mutation, but studies of the sisters of
PCOS women suggest an autosomal dominant pattern with approximately 50% of
sisters demonstrating features of PCOS. Current understanding is that this is a
multi-genetic disorder.
Clinical Features
The key physical features of PCOS are listed in Table 5.1. In general the diagno-
sis of PCOS is based on clinical history. Typically women with PCOS present with
irregular, infrequent menses or amenorrhea. This is typically present at menarche
with onset of irregular menses from the outset, or delayed onset of menarche. Less
Table 5.1. Physical features of PCOS

Hyperandrogenism
Acne
Alopecia
Male pattern hair growth (Hirsutism) Locations:
5 Chin
Sideburn
Upper lip
Chest/peri-areolar
Lower abdomen
Inner thighs
Sacral
Insulin Resistance (associated but not required for diagnosis)
Acanthosis nigricans Darkening of skin on back of neck/
underarms
Central adiposity Increased waist circumference
compared to hip
Skin tags
typical is onset of menstrual irregularity at a later age. It is now recognized however

that the condition of PCOS can exist in women with regular menses.
The most distinctive feature is that of clinical androgen excess. Hirsutism is
usually present and can range from mild to severe. Usually hair growth is present on
the face and chin as well as the lower abdomen. It is also not uncommon to see
frontal hair loss and thinning of scalp hair.
Acanthosis nigricans, a dark thickening of the skin, is often present. It can be
found at the base of the neck, the axilla and under the breast. Acne is also often
present from adolescence but by itself may not be a distinguishing feature of PCOS.
Pathophysiology
No single etiologic factor fully explains all the features of PCOS. Excess an-
drogen production is primarily from the ovary. Increased testosterone produc-
tion by theca cells of polycystic ovaries has been demonstrated. Increased LH
secretion by the pituitary gland is consistently demonstrated. It is not clear if this
is a primary defect in the GnRH pulse generator or if this is a secondary phenom-
ena. Increased LH stimulation to the theca cells drives increased androgen pro-
duction.
It is also recognized that women with PCOS, independent of body weight,
demonstrate insulin resistance. When carefully studied, most women with PCOS
demonstrate hyperinsulinemia. Increased insulin resistance is associated with wors-
ening of the clinical manifestations of PCOS. Insulin acts, along with increased
LH secretion, to enhance androgen production from the ovary. Insulin also inhib-
its hepatic production of sex-hormone binding globulin (SHBG). SHBG is the
principle binding protein for testosterone, and decreased SHBG results in in-
creases in the proportion of unbound or free testosterone.
Diagnosis and Management of Polycystic Ovary Syndrome 49
Table 5.2. Endocrine evaluation for PCOS

Hyperandrogenism
Total testosterone
SHBG or free testosterone Free testosterone assays are highly variable and
often have poor reproducibility depending on lab.
Free androgen index (FAI) can be calculated with 5
SHBG-total testosterone/SHBG (both in nmol/L).
DHEAS
17-hydroxyprogesterone ACTH stimulation test for value >2 ng/mL.
24 hour urinary free cortisol If Cushing’s disease suspected.
2 hour oral glucose Screen for glucose intolerance or diabetes.

tolerance test Use a 75 gm glucose load with a fasting
and 2 hour glucose.
Oligo-Amenorrhea
TSH
Prolactin
FSH
LH LH is usually higher than FSH in PCOS, but this is
not always seen particularly in the obese patient.
Imaging Studies
Pelvic ultrasound Not necessary for diagnosis but can be confirm-
atory. If very elevated testosterone, can screen
for ovarian tumor.
Adrenal imaging If very elevated adrenal androgens.
Endocrine Evaluation
As PCOS is diagnosed after exclusion of other endocrine disorders, a work-up
to assess for these other conditions is indicated. Table 5.2 summarizes the primary
endocrine evaluation. Key to the differential diagnosis is to rule out late onset
congenital adrenal hyperplasia due to 21-hydroxylase deficiency. This disorder
mimics PCOS as it also presents at menarche and is associated with
hyperandrogenism. Unlike PCOS the increased androgens in congenital adrenal
hyperplasia are primarily from adrenal origin. A morning blood sample for
17-hydroxyprogesterone is a good screening test for congenital adrenal hyperpla-
sia due to 21-hydroxylase deficiency. Samples should be drawn in the follicular
phase if the patient is cycling. Generally levels less than 2 ng/mL are not consis-
tent with late onset 21-hydroxylase deficiency. Borderline values should be fol-
lowed by an ACTH stimulation test. Androgen evaluation should include a serum
total testosterone and DHEAS. Hormonal assays for free testosterone are highly
variable with poor reproducibility. Perhaps a better way to estimate free testoster-
one is to use SHBG to calculate a free testosterone index (ratio of total testoster-
one to SHBG—both measured in nmol/L, also called free androgen index [FAI]).
Figure 5.1. Ultrasound of polycystic ovary. Note increased numbers of follicles in

peripheral pattern and hyperechoic stroma.
This has been shown to be more reliable as a screen for free hormone. In general
values of FAI that are greater than 4.0 are suggestive of androgen excess although
there is a large overlap in the normal range.
Menstrual irregularity should prompt evaluation of TSH and prolactin. For men-
strual irregularity or amenorrhea in the absence of hirsutism, an FSH value can be
helpful to eliminate premature ovarian failure as a cause. Although typically LH
levels are higher than FSH in PCOS, the ratio of LH to FSH is not diagnostic of
PCOS. LH secretion is modified by obesity which is a common finding in PCOS.
Imaging studies are indicated for extremely high values of testosterone (>200 ng/
dL) or DHEAS (>2 times the upper limits of the assay) to assess for ovarian or
adrenal virilizing neoplasm; however these conditions are exceedingly rare. Usually
the clinical picture suggesting tumors is one of rapid onset of androgen excess and
virilization. Cushing’s syndrome is also a rare cause of androgen excess. The clinical
picture in this case would likely include hypertension, abdominal striae and easy
bruising. Round facial appearance with facial plethora, buffalo hump fat distribu-
tion, and centripetal obesity are also features of the syndrome.
Ovarian ultrasound to assess for polycystic morphology of the ovaries is neither
necessary nor conclusive for diagnosis, but can be confirmatory if the clinical pic-
ture is supportive (see Fig. 5.1).
Impact of Obesity
It is generally recognized that obesity, although not a defining feature of the
syndrome, is highly prevalent in PCOS. Most studies in the United States report
higher incidences of obesity (upward of 50%) than those of other countries. There is
variable ethnic distribution of obesity in PCOS as well.
Obesity is overall highly prevalent in most developed countries, and the rate of
obesity is growing rapidly. Insulin resistance, a feature seen independently of body
weight in PCOS, is almost universally noted with obesity. As noted previously, insu-
lin resistance, in association with obesity, will worsen the clinical presentation of
PCOS. Numerous studies demonstrate worse androgen profile and more severe
menstrual disturbances in obese subjects with PCOS compared to their lean coun-
terparts. Response to treatment may also be adversely impacted by obesity.
5
Metabolic Complications
Although PCOS often presents in the early reproductive years, it is now recog-
nized that the consequences of PCOS extend beyond the reproductive axis and the
reproductive years. Women with PCOS appear to be at substantial risk of develop-
ing diabetes and cardiovascular disease. Several studies indicate that the risk of meta-
bolic syndrome in PCOS is approximately 50% in young adulthood. Metabolic
syndrome is a constellation of metabolic risk factors that increase the risk of cardio-
vascular events 2-fold. For women, these include increased abdominal waist circum-
ference (>88 cm), elevated triglycerides (≥ 150 mg/dL), reduced HDL (<50 mg/
dL), elevated blood pressure (≥ 130 mm Hg systolic or ≥ 85 mm Hg diastolic or
drug treatment for hypertension), and elevated fasting glucose (≥ 100 mg/dL).
Many women with PCOS develop impaired glucose tolerance or frank diabetes.
In studies of obese women with PCOS 30-40% will have previously undiagnosed
impaired glucose tolerance and as many as 10% will have frank type 2 diabetes. This
increased risk of impaired glucose tolerance and diabetes is also seen in young ado-
lescent women with PCOS who are obese. Therefore assessment of women with
diagnosis of PCOS should include an assessment of glucose tolerance. This is best
accomplished through the use of an oral glucose tolerance test.
Vascular endothelial dysfunction has been described in women of all ages with
PCOS and appears to be associated with insulin resistance. Hypertension may de-
velop during the reproductive years although this has not been consistently demon-
strated. Coronary artery calcification and increased carotid intima media thickness
has also been shown to be significantly more prevalent in women with PCOS com-
pared to control women.
Several recent studies have associated obstructive sleep apnea with insulin resis-
tance. Increased BMI alone did not show the same association. The prevalence of
sleep apnea in women with PCOS is higher than in non-PCOS women and may be
linked primarily to increased insulin resistance.
Given the prevalence of increased metabolic abnormalities in women with PCOS,
careful attention to assessment of the metabolic state is recommended. This in-
cludes assessment of glucose tolerance and lipid profiles even in young women with
PCOS particularly if they are obese. Inquiry into symptoms of sleep apnea is also
recommended.
Treatment Options
Many women present to their physician for management of symptoms of andro-
gen excess and/or menstrual irregularity. In general medical treatment is designed to
lower serum androgens and thereby improve symptoms. There are several pharma-
ceutical agents that are used for PCOS although there is no specific FDA-approved
medication for the treatment of PCOS. Table 5.3 summarizes the main clinical
treatments in PCOS.
5
52
Table 5.3. Treatment options for PCOS

Presumed Mechanism
Treatment of Action Impact Possible Disadvantages
Combination oral Decreases LH secretion Cyclic menses Possible adverse impact on lipids
contraceptives Suppresses ovarian testosterone production Reduced serum testosterone Hypertension
Increases SHBG Improved acne/hirsutism Increased coagulability
Variable progestin component with variable
androgen impact
Cyclic progestins Endometrial stabilization and induces Induction of menses No androgenic improvements
secretory changes
Spironolactone Reduces 17-hydroxylase Reduced acne Menstrual irregularity
Inhibits DHT binding to receptor Reduced hirsutism Pregnancy Category C
Flutamide Blocks action of DHT on receptor Reduced hirsutism Hepatocellular dysfunction
Possible teratogen
Finasteride Inhibits 5-α reductase Reduced hirsutism No impact on alopecia
Possible teratogen
Eflornithine Inhibits ornithine decarboxylase Topical cream that slows rate Does not prevent new hair growth
hydrochloride of facial hair growth Does not impact androgens
Metformin Reduces hepatic glucose output Improved ovulatory rates Gastrointestinal side effects common
Decreases insulin levels Improved menstrual cycles
Decreased androgens
Pioglitazone/ Improves skeletal and Improved ovulatory rates Possible weight gain
Rosiglitazone hepatic insulin sensitivity Effective insulin sensitizer Pregnancy category C
Oral Contraceptives and Progestins

One first line agent that is used for the control of menstrual irregularity is also
the predominant treatment for androgen suppression. Use of combination oral con-
traceptives will significantly reduce circulating free testosterone. Oral contraceptives
contain ethinyl estradiol which will suppress LH secretion from the pituitary and
decrease LH-driven production of testosterone from the ovary. Additionally, estro-
genic compounds increase SHBG production in the liver which will reduce the
circulating component of free testosterone. The progestin component of the oral
5
contraceptive will also contribute to LH suppression. The type of progestin varies in
different combination oral contraceptives. Progestins can have variable androgenic
activity as they are derived from an androgenic base. Drosperinone, an analog of
spironolactone with unique anti-androgenic activity, also has progestin activity and
is now available in an oral contraceptive. At this time, it has not yet been studied for
its effects to reduce androgenic symptoms more than other oral contraceptive for-
mulations, but it is a promising agent in the treatment of androgen excess disorders.
Cycle control is significantly enhanced when using oral contraceptives. Most
women with PCOS are oligo-ovulatory at best, and continuous estrogenic exposure
of the endometrium without exposure to progesterone enhances the potential for
erratic breakthrough bleeding which can be heavy, as well as increasing the risk for
development of endometrial hyperplasia and cancer of the endometrium. The proges-
tin component in oral contraceptives will significantly reduce this risk.
Cycle control with intermittent use of oral progestins such as medroxyprogesterone
acetate will also result in regular withdrawal bleeding. Used on a regular basis this
will also decrease endometrial hyperplasia and cancer risks. However, oral progestins
alone will not significantly reduce androgenic symptoms and are often inadequate
as a single agent for the control of all the symptoms of PCOS.
The metabolic effects of oral contraceptives have raised some concerns about the
use of these agents in insulin resistant women. Some but not all studies indicate
worsening of insulin resistance in PCOS women on oral contraceptives. They have
not, however, been shown to increase the rate of type 2 diabetes. Effects of oral
contraceptives on vascular reactivity and inflammation in PCOS are yet not well
studied, and it should be recognized that there may be potential adverse effects
when considering these agents for PCOS treatment.
Anti-Androgens
Spironolactone is an anti-mineralocorticoid agent that also acts as an
anti-androgen. It is a potassium sparing diuretic that in high doses (100-200 mg/
day) demonstrates significant anti-androgenic properties. Spironolactone interferes
with testosterone biosynthesis by reducing 17-hydroxylase activity and thus lowers
plasma testosterone. It also inhibits dihydrotestosterone’s binding to the androgen
receptor. It is not FDA-approved for treatment of androgenic symptoms but in
many studies has been shown to be an effective agent in this regard. It is often
combined with oral contraceptives to reduce testosterone action and production.
Menstrual cycle irregularity can be seen with the use of spironolactone alone.
Typically it is combined with oral contraceptives, thereby reducing this concern.
Additionally it is a pregnancy category C drug so should be used with contraception
to avoid pregnancy while taking it.
Flutamine and finasteride can improve androgenic symptoms in PCOS. In gen-
eral potential serious side-effects have limited their use in the United States. Flutamide
is a nonsteroidal, nonhormonal antiandrogenic drug, which has been demonstrated

to block the action of dihydrotestosterone (DHT) on androgen receptors. It has
been associated with hepatocellular dysfunction. Finasteride is a 4-aza analog of
testosterone and is a competitive inhibitor of both tissue and hepatic 5-alpha reduc-
tase. This results in inhibition of the conversion of testosterone to dihydrotestosterone.
In small mostly uncontrolled studies it has been shown to be effective in the treat-
ment of hirsutism. It does not seem to treat androgenic alopecia in women however,
5 unlike the effect seen in male pattern baldness in men.
Eflornithine hydrochloride is an inhibitor of ornithine decarboxylase in skin. It
is available as a topical cream that can slow the rate of hair growth and has been
shown to have some effect in the treatment of facial hirsutism.
Insulin Sensitizing Agents
Given the prevalence of insulin resistance seen in PCOS, a number of
insulin-sensitizing agents have been studied in the treatment of symptoms. Cur-
rently metformin, a biguanide, and pioglitazone and rosiglitazone, thiazolidinediones,
are available clinically, and all have been studied in PCOS. The single most com-
mon agent for use in PCOS is metformin. Metformin appears to work by reducing
hepatic glucose output thereby reducing the demand for insulin. A meta-analysis of
thirteen studies of metformin in PCOS concluded that metformin significantly en-
hanced the rate of ovulation. There was also evidence for improved insulin levels
and reduced cholesterol. There is conflicting evidence that metformin’s effects are
partially mediated through weight reduction. Metformin has been noted in several
studies to be associated with weight reduction in the initial phase of treatment, but
this is not consistently seen. The effects of metformin on pregnancy loss and gesta-
tional diabetes have been studied only in small uncontrolled trials. Current evidence
is not sufficient to conclude a consistent positive effect.
The thiazolidinedione therapies are associated with improved insulin action at
the level of skeletal muscle and liver. The largest available study involved troglitazone,
which is no longer on the market due to hepatotoxicity. However, significant im-
provements in ovulation were noted in a 48-week trial. Both pioglitazone and
rosiglitazone have been shown to improve ovulatory rates in PCOS in small trials.
Both are pregnancy category C agents and have not been studied in pregnancy. No
association with weight reduction is noted with these agents. Several studies indi-
cate slight increases in weight with use although metabolic improvements are noted.
Lifestyle Modification
Weight reduction, of as little as 3-5%, has been associated with improvements in
ovulation rates in PCOS women who are overweight or obese. Although studies are
consistent in this regard, no large scale controlled trials are available to assess im-
provements in pregnancy rates. There are no specific dietary regimens that target
PCOS and effective weight reduction has been demonstrated with a wide variety of
approaches.
Achieving and maintaining permanent weight reduction is a challenge that is
often met with repeated failures and relapse. Severely restrictive diets have not been
shown to improve outcomes over modest changes in diet that result in slow weight
reduction. Metabolic parameters are also consistently improved with lifestyle modi-
fication that includes weight reduction. Exercise, although not a significant tool in
initial weight reduction, is associated with better maintenance of weight reduction
over time and should be encouraged. Significant support is needed to encourage

women with PCOS who are overweight or obese to consider lifestyle modification
as the first line of therapy.
Key Points
PCOS is a common reproductive disorder in women and is primarily manifest
with symptoms of androgen excess and menstrual irregularity. Although identified
as a disorder of reproduction, the pathophysiology of PCOS includes insulin resis- 5
tance, and therefore metabolic abnormalities are common. Treatment of PCOS should
address both the endocrine and metabolic aspects of the disease. Attention should
be particularly paid to glucose tolerance in overweight and obese women at diagno-
sis and followed closely. Newer treatments with insulin sensitizing agents have shown
promise in the management of PCOS over the long-term, but additional trials are
needed.
Suggested Reading
1. Rotterdam/ESHRE/ASRM sponsored PCOS Consensus Working Group. Revised 2003
consensus on diagnostic criteria and long-term health risks related to polycystic ovary
syndrome. Fertil Steril 2004; 81(1):19-25.
2. Azziz R, Woods KS, Reyna R et al. The prevalence and features of the polycystic ovary
syndrome in an unselected population. J Clin Endocrinol Metab 2004; 89(6):2745-9.
3. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005; 352(12):1223-36.
4. Dunaif A. Finegood DT. Beta-cell dysfunction independent of obesity and glucose
intolerance in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996;
81(3):942-7.
5. Lord JM, Flight IH, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone,
rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane
Database of Systematic Reviews 2003; (3):CD003053.
6. Legro RS, Kunselman AR, Dodson WC et al. Prevalence and predictors of risk for type
2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: A
prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 1999;
84(1):165-9.
7. Knowler WC, Barrett-Connor E, Fowler SE et al. Diabetes prevention program re-
search group. Reduction in the incidence of type 2 diabetes with lifestyle intervention
or metformin. N Engl J Med 2002; 346(6):393-403.
Chapter 6
Obesity: Recognition and Treatment in Women

Erin E. Flaherty and Richard S. Legro
Introduction
The increasing prevalence of obesity in the United States over the last decade
makes the assessment and treatment of obesity a paramount issue and a challenge
for medical professionals. According to clinical experts obesity is quickly reaching
epidemic proportions, with 64% of the U.S. adult population being considered
obese, or overweight, and 5% of this group is categorized as “extreme obesity”, with
a BMI of >40. In clinical terms, a BMI >40 correlates to being overweight by 100
lbs in men and 80 lbs in women. Looking to the future, the number of teenagers
(age 12-19) classified as overweight increased from 10.5% to 15.5% from 1999-2000,
according to the CDC. This trend reinforces the need for obesity to be treated as a
public health issue.
The increased health risks of obesity include hypertension, elevated serum cho-
lesterol and death related to cardiovascular diseases as well as diabetes, gallbladder
disease, osteoarthritis, carpal tunnel, sleep apnea, respiratory problems and endome-
trial, breast and colon cancers. Specific to the obstetrician/gynecologist, obesity is
associated with both increased gynecological and obstetrical morbidity. Major gyne-
cological problems include abnormal uterine bleeding, ovulatory dysfunction and
endometrial cancer. Adult weight gain is associated with increased risk for breast
cancer in postmenopausal women. An overweight individual undergoing surgery
has an increased risk of excess blood loss, increased operating time and longer expo-
sure to anesthesia and infection. Obesity in pregnancy increases the risk of gesta-
tional hypertension, preeclampsia gestational diabetes, fetal macrosomia and cesarean
delivery. Obesity is an independent risk factor for spontaneous abortion and preg-
nancy loss among women who undergo infertility treatment, as well as among natu-
ral conceptions. Thus, weight should be assessed at every annual gynecologic exam
and during reproductive health counseling.
It is estimated that 300,000 US adults die of obesity-related causes and the direct
cost of obesity and physical inactivity have been estimated at 9.4% of the U.S.
healthcare expenditures. Thus as a major cause of preventable death, obesity is a
significant public health challenge. The U.S. Preventative Services Task Force issued
recommendation of screening for obesity in 2003. The recommendations were to
screen all adult patients for obesity and offer intensive counseling and behavioral
intervention to promote sustained weight loss for obese adults. Obesity needs to be
recognized as a chronic disease, and the patient, as well as practitioner, need to
understand that successful treatment requires a lifelong effort.
Obesity: Recognition and Treatment in Women 57
Assessment
The diagnosis and classification of obesity has come to focus on the evaluation
of the body mass index, (BMI). BMI is a practical approach for assessing body fat in
a clinical setting. The BMI provides a more accurate measurement of total body fat
compared with assessment by weight alone. However, the BMI can be an overesti-
mation of adiposity in persons of short stature or who are very muscular, and an
underestimation in persons who have lost muscle mass. BMI disregards gender, age,
and ethnicity, but these factors do not markedly influence the validity of BMI for
classifying individuals into broad categories of overweight and obesity. Overweight 6
is categorized by a BMI of 25-29.9 kg/m2 and obesity as BMI ≥ 30 kg/m2. The BMI
can quickly be determined by using a BMI table or calculated by multiplying weight
in lbs. by 703 and dividing by height in inches, squared, which gives a BMI as kg/
m2. There are two physical classifications of body fat distribution; gynecoid and
android. Gynecoid is usually seen in women of reproductive age and has a more
favorable prognosis. Gynecoid describes a “pear-shaped” distribution where the fat
is concentrated on the hips and buttocks. Android type is more common in meno-
pausal women as fat is redistributed to the trunk and abdomen, “apple-shaped”.
The waist: hip ratio is >0.8. The android type is associated with increased complica-
tions from obesity.
Assessment of associated risk for obesity-related diseases and mortality includes
determination of degree of obesity and overall health status. Three factors are in-
volved in assessment.
1. BMI
2. Waist circumference. Waist circumference has been found to be an indepen-
dent risk factor for disease and is a good evaluation of those categorized as
normal or overweight. A waist circumference >40 in for men and 35 in for
women is associated with an increased risk of diabetes, dyslipidemia and
cardiovascular disease secondary to excess abdominal fat.
3. Overall medical risk. High absolute risk of mortality occurs when there is
coexisting heart disease or other atherosclerotic disease, type 2 diabetes mel-
litus, sleep apnea, hypertension, cigarette smoking, high LDL cholesterol,
impaired fasting glucose (>110-125), family history of early cardiovascular
disease or age ≥55 in women, or postmenopausal status. Obesity is also
associated with a greater risk of several non-lethal conditions including: os-
teoarthritis, gallstones, stress incontinence and menstrual disturbances.
Metabolic Syndrome
Metabolic syndrome is a clustering of risk factors for cardiovascular disease. The
Expert Panel on the Detection, Evaluation, and Treatment on High Blood Choles-
terol in Adults (Adult Treatment Panel III) defines the syndrome as three or more of
the following criteria:
1. Abdominal obesity: waist circumference >102 cm in men and >88 cm in
women;
2. Hypertriglyceridemia: ≥150 mg/dl;
3. Decreased high-density lipoprotein (HDL) cholesterol: <40 mg/dl in men
and <50 mg/dl in women;
4. High blood pressure: ≥130/85 mm Hg;
5. High fasting glucose: ≥110 mg/dL.
Obesity is a component of metabolic syndrome, but it is not absolutely required

to make the diagnosis if other criteria are present. Diagnosis of metabolic syndrome
is important to alert the clinician of increased risk of diabetes and cardiovascular
disease. The prevalence of US adults having the metabolic syndrome is 22%, and it
is even more common among high risk groups such as women with polycystic ovary
syndrome with about a third of women affected.
Treatment
6
Diet and Excercise
The first step towards treating obesity includes nutrition counseling, dietary
modification and exercise. A reasonable initial weight loss goal is 10% reduction
of one’s current weight, with a timeline of 6 months of therapy. To achieve a
weight loss of 1-2 pounds per week, the patient should follow a diet that consists
of 500-1000 fewer calories per day but still meets nutritional needs. This would
translate into a 1000-1200 kcal/day diet for most women and 1200-1600 kcal/
day for men. If this level of intake leaves the patient hungry, the total kcal/day can
be increased by 100-200 kcal. The patient needs to undergo nutrition education
to include:
1. Energy value of different foods
2. Food composition—fats, carbohydrates, and proteins
3. Evaluation of nutrition labels to determine calorie content and food com-
position
4. Food preparation—avoidance of high calorie ingredients
5. Avoidance of high caloric foods
6. Adequate water intake
7. Reduced portion sizes
8. Limiting alcohol consumption
To maintain the weight loss individuals need to follow a balanced, low calorie
diet and sustained physical activity. Most weight loss occurs because of decreased
caloric intake, but sustained physical activity can help prevent weight regain. An
exercise regimen should be started with the goal of exercising at least 30 minutes 3-4
times/week and then gradually increased in frequency and duration. Increased physical
activity is important in efforts to lose weight because it increases energy expenditure
and plays an integral role in weight maintenance. Exercise can also help prevent the
decrease in muscle mass often found during weight loss. The long-term goal is to
develop the habit of exercising 30 minutes of moderate intensity activity on most
days of the week.
Behavior therapy can also play a significant role in providing tools for overcom-
ing barriers to compliance with dietary therapy and/or increased physical activity.
Specific strategies include self-monitoring of both eating habits and physical activ-
ity, stress management, stimulus control, problem solving, contingency manage-
ment, cognitive restructuring and social support. In regards to children, intensive,
family-based behavioral treatment programs have a favorable effect on children’s
weight for as long as ten years.
Pharmacotherapy
Pharmacotherapy can supplement dietary changes and exercise to promote weight
loss. Pharmacotherapy can be utilized after 6 months of combined intervention of
diet and increased physical activity in patients with a BMI >30 with no concomitant
obesity-related risk factors for diseases, and in patients with a BMI >27 with con-
comitant obesity-related risk factors or diseases. The amount of extra weight loss
attributed to these agents is less than 5 kilograms at 1 year evaluation. Thus, the
major role of medications is to help the patient comply with their diet and physical
activity plans while losing weight. The use of long term medication to aid in the
treatment of obesity may be indicated for carefully selected patients to prevent the
weight regain often seen after weight loss, but there are no guidelines for how long a
weight loss drug should be continued. Initially, if a patient has not lost 2 kg after 4 6
weeks on a medication, it is not likely that the patient will benefit from the drug.
Categories of Weight Loss Drugs
Appetite Suppressants
These agents decrease food intake by reducing appetite or increasing satiety. The
mechanisms of action are to increase secretion of dopamine, norepinephrine, or
serotonin into the synaptic neural cleft, to inhibit the reuptake of these neurotrans-
mitters into the neuron or a combination of the two effects. There are three classes
of anorexiant drugs, and all affect neurotransmitters in the brain.
1. Affect catecholamines: dopamine and norepinephrine. These noradrenergic
agents are useful for short term treatment and include the drugs
phenteremine, diethylpropion, phendimetrazine and benzphetamine. Stimu-
lants act via catecholamine neurotransmitters, such as amphetamines and
phenylpropanolamine. Phenylpropanolamine, which was an over-the-counter
medication, was removed secondary to an association with hemorrhagic
stroke. Side effects of this class of medications include insomnia, dry mouth,
constipation, euphoria, palpitations and hypertension.
2. Affect serotonergic: Fenfluramine and dexfenfluramine are included in this
class. These medications have been associated with valvular heart disease
and pulmonary hypertension. In 1997, the “Phen/fen” combination was
withdrawn from the market after reports of valvopathy after as little as one
month’s use of this medication. The mechanism apparently involves seroto-
nin stimulation of fibroblast growth and fibrogenesis.
3. Affect more than one neurotransmitter. Sibutramine (Meridia) is an appe-
tite suppressant that works via norepi and serotonergic mechanisms in the
brain (Fig. 6.1). Side effects include tachycardia and hypertension.
The newly discovered endocannabinoid (EC) system and cannabinoid CB1 re-
ceptor play an important role in appetite and energy regulation and offer a novel
target for a new class of anti-obesity drugs. Rimonabant, the first specific CB1-receptor
blocker to enter clinical development, has been shown to reduce food intake and
body weight in treated animals, and there are also beneficial effects in the adipocyte.
The results of phase 3 studies involving obese patients have shown that rimonabant
induces significant weight loss and improves metabolic risk factors for diabetes and
cardiovascular disease. It is anticipated that this drug will be available in the near
future for the treatment of obesity in the U.S. Common side effects in preclinical
studies included depression, anxiety, and nausea.
Certainly, close monitoring for side effects with any weight loss medication is
necessary. Several randomized controlled studies of weight loss medications have
been performed, but questions remain concerning long-term effects on health, the
Figure 6.1. Mechanisms of action of sibtramine. Adapted from: Yanovski SZ,

Yanovski JA. Obesity. N Engl J Med 2002; 346(8):591-602.
optimal duration of treatment, and the use of combination regimens including poly-
pharmacy and combination with lifestyle interventions.
Decrease Nutrient Absorption
Orlistat (Xenical) binds GI lipases in the lumen of gut, which prevents hydroly-
sis of dietary fat (triglycerides) into absorbable free fatty acids and monoacylglycerols
(Fig. 6.2). Orlistat is an irreversible lipase inhibitor and thus decreases the amount
of ingested dietary fat that is absorbed Side effects of this medication include de-
creased absorption of fat-soluble vitamins and nutrients, flatulence, fecal urgency
and incontinence, steatorrhea, oily spotting and increased frequency of defecation.
Other Medications and Herbal Supplements
Many agents have as an unintended side effect weight loss. These include
metformin, a biguanide used to treat type 2 diabetes, acarbose, an alpha-glucosidase
inhibitor also used to treat type 2 diabetes, and topiramate an anti-epileptic drug. It
should be noted that these agents do not have an FDA indication for the treatment
of obesity and trials, including those specifically in some cases designed as weight
loss trials have shown a lack of efficacy or an unfavorable risk benefit ratio. There-
fore their use can not be routinely recommended.
Dietary supplements and herbal preparations are not prospectively reviewed by
the FDA for safety or efficacy. These agents are only reviewed if they are shown to
present a “significant or unreasonable risk”, as has been the case with ephedra supple-
ments. Herbals and supplements include chitosan, chromium picolinate, conjugated
linoleic acid, ephedra alkaloids (ma huang) and garcinia cambogia. There is insuffi-
cient data on these agents except for ephedra alkaloids and caffeine, which do have
randomized, controlled trials that indicate efficacy in promoting weight loss. Chro-
mium picolinate, an essential trace mineral and cofactor to insulin, which improves
insulin action and is available as an over the counter supplement. A meta-analysis of
10 double-blind randomized clinical trials with this supplement found a relatively
small weight reduction of 1.1-1.2 kg (0.08-0.2 kg/wk) compared with placebo dur-
ing a treatment period of 6-14 wk in patients with an average BMI of 28-33, without
any appreciable side effects. Thus the risk benefit ratio for weight loss appears as
favorable, if not more so, than with other herbal or pharmacologic medications.
Figure 6.2. Mechanisms of action of orlistat. Adapted from: Yanovski SZ, Yanovski
JA. Obesity. N Engl J Med 2002; 346(8):591-602.
Surgery
Bariatric surgery is currently the most successful approach to rescuing patients
with severe obesity and reversing or preventing the development of several diseases
associated with obesity. There are an increasing number of surgeries being performed
for the treatment of obesity. This rise in procedures can be attributed to the in-
creased population of “extreme obesity” as well as the failure of diet, exercise and
medical therapies. Another factor could be the ability to perform the surgery
laproscopically. Surgery can be an additional treatment option for patients with a
BMI >40 who failed lifestyle changes with or without medication supplementation
and have obesity-related comorbid conditions. Surgery alone will not correct any
underlying psychological eating disorders. Additionally, reduction of cardiovascular
morbidity and mortality does not occur due to weight loss through surgery alone.
The Swedish Obese Subjects (SOS) Study, which was an observational study, did
show that the average long term weight loss for the surgical patient is 20 kg, versus,
no change for those using medical treatment. The SOS study was also able to dem-
onstrate improvements in or prevention of comorbid conditions associated with
obesity when compared with similar patients undergoing medical therapy. In a

24-month follow-up evaluation, there was a decreased incidence in hypertension,
diabetes and lipid abnormalities, but by 8 years, only a decrease in diabetes was
noted. Another notable finding was a decreased caloric intake and greater physical
activity in surgery vs. control patients throughout the follow-up period.
Different surgical procedures are available to treat obesity (Fig. 6.3), and have
evolved since the first bariatric surgery performed in the 1950s with the introduc-
tion of the jejunoileal bypass and subsequently the gastric bypass in 1967.
6 1. Roux-en-Y gastric bypass (RYGB) limits gastric capacity and causes mild
malabsorption. This procedure involves the construction of a proximal gas-
tric pouch whose outlet is a Y-shaped limb of small bowel of varying lengths.
The proximal stomach is separated from the remaining portion of the stom-
ach with staples.
2. Biliopancreatic bypass combines a limited gastrectomy with a long Roux
limb intestinal bypass, works primarily through malabsorption.
3. Laparoscopic adjustable gastric band is placed around the upper-most por-
tion of the stomach and restricts capacity, usually less than 30 ml in volume.
There is restricted passage to the subsequent part of the stomach, leading to
weight loss by decreased dietary intake. The band can be adjusted by the
infusion of saline through a subcutaneous port.
4. Vertical banded gastroplasty involves stapling the upper stomach to limit
gastric capacity.
There is a larger weight loss after gastric bypass compared with other types of
surgery, and this may be related to altered gut-to-brain signaling.
Surgery is not without risks however. Among surgeons, there is a learning curve in
which those with fewer than 20 procedures had a 5% mortality rate, as compared with
greater than 50 had a near zero mortality. The length of surgery also stabilized after
150 cases. Complications also decreased from 12.5% for fewer than 100 cases, to 3%
after 150 cases. Such complications include anastomotic leak, subphrenic abscess,
splenic injury, pulmonary embolism, wound infection and stoma stenosis. Perioperative
mortality is influenced by age; in a young patient with a BMI <50, there was a 1%
mortality rate in comparison to a patient with a BMI >60 and comorbidities such as
diabetes, hypertension, or cardiovascular disease, the mortality jumped to 2-4%.
Women of reproductive age who have undergone bariatric surgery require coun-
seling and management of subsequent pregnancies. Patients with adjustable gastric
banding should be advised that they are at risk of becoming pregnant unexpectedly
after weight loss following surgery. All patients are advised to delay pregnancy for
12-18 months after surgery to avoid pregnancy during the rapid weight loss phase
in order to avoid malnutrition and small-for-dates features in the neonate. After
restrictive procedures (where iron containing foods such as red meat may be poorly
tolerated) increased iron is needed. After gastric bypass procedures (in which the
duodenum—where most iron is absorbed—is bypassed) increased iron must be taken
during pregnancy to allow adequate absorption in the proximal jejunum. Further-
more, adequate calcium intake or supplementation should be verified. Women with
a gastric band should be monitored by their general surgeons during pregnancy
because adjustment of the band may be necessary. Women who have undergone
bypass surgery do not appear to be at undue risk for adverse pregnancy outcomes,
and initial results from larger case series have been promising.
Figure 6.3. Types of bariatric surgical procedures.
Key Points
Obesity is a serious and prevalent disorder whose effective management re-
quires ongoing care and a lifetime commitment. The increased prevalence of
obesity in children and adolescents indicates the urgent need to implement effec-
tive preventative interventions, beginning early in life, to improve dietary habits
and increase physical activity. Medications can be an adjunct only for those at
substantial medical risk and in whom nonpharmacologic treatment has not re-
sulted in sufficient weight loss to improve health or prevent regain. Surgery is
becoming a viable option for the long-term success of maintained weight loss but
still requires a commitment to behavioral changes and nutrition education.
Acknowledgements
This work was supported by PHS K24 HD01476, a GCRC grant MO1 RR
10732 to Pennsylvania State University and K24 HD01476.
6
Suggested Reading
1. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002; 346(8):591-602, [This is an
excellent review article of the treatment of obesity].
2. Mokdad AH, Ford ES, Bowman BA et al. Prevalence of obesity, diabetes, and
obesity-related health risk factors, 2001. JAMA 2003; 289(1):76-9.
3. North American Association for the Study of Obesity and the National Heart, Lung,
and Blood Institute. The practical guide: Identification, evaluation, and treatment
of overweight and obesity in adults. Bethesda, MD: National Institutes of Health,
2000, (Report No.: 00-4084), [This is an evidence based and very practical guide for
the diagnosis and management of obesity and was central to the preparation of this
chapter].
4. Hu FB. Overweight and obesity in women: Health risks and consequences. J Womens
Health 2003; 12(2):163-72.
5. Colditz GA. Economic costs of obesity and inactivity. Med Sci Sports Exerc 1999;
31(11 Suppl):S663-7.
6. McTigue KM, Harris R, Hemphill B et al. Screening and interventions for obesity in
adults: Summary of the evidence for the U.S. Preventive Services Task Force. Ann
Intern Med 2003; 139(11):933-49.
7. Executive summary of the third report of the national cholesterol education program
(ncep) expert panel on detection, evaluation, and treatment of high blood cholesterol
in adults (adult treatment panel iii). JAMA 2001; 285(19):2486-97.
8. Ehrmann DA, Liljenquist DR, Kasza K et al. Prevalence and predictors of the meta-
bolic syndrome in women with polycystic ovary syndrome (PCOS). J Clin Endocrinol
Metab 2005.
9. Epstein LH, Valoski A, Wing RR et al. Ten-year outcomes of behavioral family-based
treatment for childhood obesity. Health Psychology 1994; 13(5):373-83.
10. Snow V, Barry P, Fitterman N et al. Pharmacologic and surgical management of obe-
sity in primary care: A clinical practice guideline from the American College of Physi-
cians. Ann Intern Med 2005; 142(7):525-31.
11. Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in
overweight patients with dyslipidemia. N Engl J Med 2005; 353(20):2121-34.
12. Li Z, Maglione M, Tu W et al. Meta-analysis: Pharmacologic treatment of obesity.
Ann Intern Med 2005; 142(7):532-46.
13. Pittler MH, Stevinson C, Ernst E. Chromium picolinate for reducing body weight:
Meta-analysis of randomized trials. Int J Obes Relat Metab Disord 2003; 27(4):522-9.
14. Sjostrom L, Lindroos AK, Peltonen M et al. Lifestyle, diabetes, and cardiovascular risk
factors 10 years after bariatric surgery. N Engl J Med 2004; 351(26):2683-93, [This is
the best and longest longitudinal study of a cohort of obese patients, some receiving
bariatric surgery and some medical therapy. The long term outcomes for medical therapy
are poor compared to bariatric surgery].
15. Buchwald H, Avidor Y, Braunwald E et al. Bariatric surgery: A systematic review and
meta-analysis. Jama 2004; 292(14):1724-37.
Chapter 7
Hormonal Contraception
Sarah Prager and Jody Steinauer
Background
There are 6.3 million pregnancies annually in the United States, and almost
half of them are unplanned. Approximately 50% of the women who become preg-
nant unintentionally are using some form of contraception at the time of concep-
tion. In the United States, unintended pregnancy, especially among women under
age 25, is more of a problem than in other Western nations, with teen pregnancy
rates in five northern European countries and Canada ranging from 5-53% of the
U.S. rate. This is thought to be due, at least in part, to the fact that adolescent
women in the U.S. are less likely than their European counterparts to use contra-
ception of any kind; most specifically, hormonal contraceptives.
Contraceptive failures occur for a variety of reasons. Most failures are partially
due to imperfect use. Some women may not understand how best to use their
method or how to handle common mistakes like missed pills or late placement of
a contraceptive patch. Providers can help women determine which method will be
safest and most effective, given the individual’s particular medical and social situ-
ation. By understanding each method’s mechanism, side effects, and
contraindications, providers can help women to contracept safely and effectively.
Each contraceptive method has characteristics that are more or less beneficial
for an individual woman, such as efficacy, cost, frequency of intervention, protec-
tion against sexually transmitted infections (STIs), and other health benefits (Tables
7.1 and 7.2). In general, efficacy of a method increases with decreased frequency
of intervention (i.e., placing an IUD once every 5-10 years as opposed to taking a
contraceptive pill daily). This chapter will deal exclusively with hormonal meth-
ods of contraception though other methods (abstinence, lactational amenorrhea,
natural family planning, male and female condoms, diaphragms, cervical caps,
and copper intrauterine devices) exist and are used effectively by many women
(Tables 7.1 and 7.2).
Assessing Evidence about Contraception
As we describe each of the contraindications to individual methods, we will
be using Medical Eligibility Criteria for Contraceptive Use, a guide produced by
the World Health Organization that can be purchased and is available on their
Web site. This easy-to-use resource summarizes the evidence for dozens of po-
tential contraindications for contraceptive use and provides guidelines for safety
in prescribing every contraceptive method. The guideline ascribes one of four
categories to each potential contraindication and method: (1) indicates that the
benefits clearly outweigh the risks and the method is safe to be used in any
circumstance; (2) indicates that the benefits generally outweigh the risks, and
7
66
Table 7.1. Comparison of contraceptive methods

Frequency Failure Rate Protection Other
Contraceptive of Perfect Typical Average against Health
Method Intervention Use Use Cost STDs/AIDS Benefits Comments
No method None 85% 85% $0 No No
Barrier methods Each act of 2-6% 15-21% $0.25-3 Yes No Condoms and female
intercourse condoms
Combined Daily 0.3% 8% $20-50 No Yes
hormonal pills
Progestin only pills Daily 0.3% 8% $30-50 No Yes
Transdermal patch Weekly 0.3% 8% $38-45 No Yes
Vaginal ring Monthly 0.3% 8% $30-38 No Yes Specific prescribing
precautions: organ prolapse;
chronic vaginitis, constipation.
1-Month injection Monthly 0.05% 3% $35 No Yes Not currently available
3-Month injection Every 3 months 0.3% 3% $45-60 No Yes Requires clinician visit
Implants Every 3 years 0.05% 0.05% $450-750 No Yes Requires clinician visit
Levonorgestrel Every 5-7 years 0.1% 0.1% $300-400 No Yes Requires clinician visit
intrauterine system
Copper IUD Every 10-12 years 0.8% 0.6% $250-300 No No Requires clinician visit
Note that the column STDs/HIV protection means acquisition of the infection. All hormonal methods decrease risk of pelvic inflammatory disease.
Modified with permission from: Steinauer J. A new era of contraception. Johns Hopkins Advanced Studies in Medicine 2005; 5(6):285-293.
Hormonal Contraception 67
one may almost always use the method; (3) indicates that the risks generally
outweigh the benefits and use of the method is usually not recommended unless
other more appropriate methods are not available or acceptable; and (4) indi-
cates that the risks always outweigh the benefits, and the method should not be
used in any circumstance. For each method described we provide the
evidence-based WHO contraindications, and in some cases, these may differ
from the product label as approved by the U.S. Food and Drug Administration
(FDA).
Combination Hormonal Contraception 7
Combination Oral Contraception
Oral contraceptive pills are the most common method of birth control used by
women in the United States, with approximately 11.7 million current users (30.6%
of the sexually active population). (<http://www.alanguttmacherinstitute.org/pubs/
fb_contr_use.html>) Over 80% of women born in the United States since 1945
have used oral contraceptive pills at some time in their lives, and this method is
currently used by more than 100 million women worldwide.
Combination oral contraceptives (COCs) contain an estrogen and a progestin.
Ethinyl estradiol (EE) is the most commonly used estrogen, and there are at least
seven different progestins commonly used in the U.S. COCs are available in
monophasic and multi-phasic (bi- and triphasic) formulations. Monophasic formu-
lations contain the same amount of hormones in each active pill, whereas multiphasic
preparations contain varying amounts of estrogen/progestin (usually progestin) in
each hormonally active pill. Typically, COCs are packaged with 21 active pills and 7
placebo pills, although in the US there are two exceptions: Mircette with 21 active
pills, 5 pills containing EE only and 2 placebo pills, and Seasonale with 84 active
and 7 placebo pills.
The primary mechanism of action for COCs is ovulation suppression (90-95%).
Secondary mechanisms include thickened cervical mucus (which can limit sperm
penetration), thinned endometrium (which can limit implantation) and decreased
tubal motility. These secondary effects are mostly due to the progestin component
of COCs.
Combined oral contraceptives have the potential to be a highly effective method
of contraception; however actual user failure rates (8%) are higher than perfect
user rates (0.3%). Many women have difficulty taking a pill every day, but other
obstacles contribute to the failure rate. Insurance limitations on number of packs
of pills prescribed, or state limitations on contraception coverage for poor women
are also obstacles to using birth control appropriately. As well, many practitioners
mistakenly believe that a pelvic examination and pap smear are required before
refilling or initiating a prescription for combined hormonal contraception. In ac-
tuality, only a blood pressure measurement is required prior to initiating a com-
bined hormonal method. Thus patient and provider education, and policy changes,
are necessary to promote maximally effective use of COCs. It is partially because
of the high failure rate of COCs that longer term methods of contraception have
been developed and are gaining popularity.
In addition to its contraceptive effect, women using COCs may benefit from the
side effect of decreased menstrual bleeding and more predictable menses. COCs
decrease the incidence of anemia and menstrual cramping.
7
68
Table 7.2. Major methods of contraception and some related safety concerns, side effects and noncontraceptive benefits
Method Noncontraceptive Benefits Side Effects Complications
Combined pills, • Less dysmenorrhea and blood loss • Nausea, vomiting • VTEs
injection, patch, • Less PMS • Headaches • Myocardial infarction (MI)
and ring • Protects against PID • Dizziness • Hypertension
• Decreased ovarian and endometrial cancers • Mastalgia • Severe depression
• Fewer benign breast masses, ovarian cysts • Chloasma • Hepatic adenoma
• Fewer ectopic pregnancies • Vaginal spotting and bleeding • Cervcial adenocarcinoma
• Reduces acne • Mood changes
Progestin-only pills • Lactation not affected • Spotting, bleeding • None
• Decreased menstrual pain and blood loss • Amenorrhea
• Mood changes
• Headaches
• Hot flashes
Progestin-only implants • Lactation not affected • Menstrual changes • Infection at implant site
• Less blood loss • Mood changes • Anesthesic reaction
• Fewer ectopic pregnancies • Weight gain or loss • Complicated removal
• Headaches • Depression
• Hair loss
Progestin-only • Lactation not affected • Menstrual changes • Allergic reaction
injections • Reduced risk of endometrial • Weight gain • Excessive weight gain
and ovarian cancers • Headaches • Glucose intolerance
• Fewer ovarian cysts • Hair loss • Depression
• Less mittelschmerz • Adverse impact on lipids
• Fewer sickle cell crises • Mood changes
• May reduce risk of PID, seizures
• Can be used with anti-convulsants
continued on next page

Table 7.2. Continued
Method Noncontraceptive Benefits Side Effects Complications
IUD • Lactation not affected • Copper-IUD increases menstrual • PID following insertion
• Copper T and LNG IUDs reduce risk blood loss, cramping • Uterine perforation
for ectopic pregnancy • LNG IUD may cause irregular • Bleeding with expulsion
• LNG IUD reduces cramping and blood loss bleeding or amenorrhea
Sterilization • Women: reduced risk of endometrial or • Pain at surgical site • Surgical complications:
Hormonal Contraception
ovarian cancer, ectopic pregnancy, PID • Pelvic adhesions hemorrhage, infection, organ
• Men: none known • Subsequent regret damage, anesthetic
complications, pain
• Ectopic pregnancy
Abstinence • Prevents most STIs, cervical dysplasia • None excerpt possible • None known
• Enhanced self-image possible peer pressure
• Partner may seek sex elsewhere
Male latex condom • Reduces risk of STIs and cervical dysplasia • Loss of sensation or spontaneity • Rare anaphylactic reaction
• Allergic reaction to latex to latex (use polyurethane
• Skin irritation condoms)
Female condom • May reduce STI and cervical • Difficult to use • Potentially,Toxic shock
dysplasia risk • Vaginal and bladder infections syndrome (TSS)—no cases
reported
Diaphragm/cervical • Reduces risk of cervical STIs, PID and • Vaginal and bladder infections • TSS
cap possibly cervical dysplasia • Vaginal erosions from poorly • Anaphylactic reaction to latex
fitted device
• allergy to spermicide/latex
Reproduced from: Hatcher R, Zieman M et al. A Pocket Guide to Managing Contraception. Tiger: Bridging the Gap Foundation, 2005.
69
7
Combined oral contraceptive use provides protection against many cancers. COC
use for 5 years provides a 50% reduction in risk of ovarian cancer, and use for 10 years
reduces risk by 80%. This protection extends for 30 years after discontinuation of
COCs, and also applies to women carrying BRCA mutations. COCs containing at
least 30 μg of estrogen provide protection against endometrial cancer. This is espe-
cially important among high-risk groups such as women with polycystic ovarian syn-
drome, obesity and perimenopausal women. Women who have taken COCs have a
reduced risk of death from colorectal cancer. After more than 50 studies about the
effect of COCs on risk of breast cancer, the consensus is that COCs have minimal to
7 no effect and may actually protect against metastatic disease.
Though COCs appear to be protective for many cancers, their use is associated
with a 60% increased risk of adenocarcinoma of the cervix, which is a rare cancer
with an annual incidence of 0.5/100,000 women. COCs containing 50 μg or more
of estrogen have been associated with an increased risk of hepatocellular adenoma
but no increased risk of hepatic carcinoma.
Hormonal contraception is not for everyone, and some women have bothersome
side effects of COCs. These include physical symptoms such as nausea and vomiting
(approximately 12%), especially in the first few cycles, breast tenderness or pain, and
headaches. Some women are bothered by intermenstrual spotting, (commonly occurs
in the first few cycles) and the uncommon development of amenorrhea. Rarely, women
note decreased libido or anorgasmia. Mood changes, depression, anxiety, irritability
and fatigue have been reported by women taking COCs, though placebo-controlled
studies have demonstrated no increased risk of these side effects. Finally, some women
simply don’t like the stress of having to remember to take a pill everyday.
Contraindications for all combined hormonal methods, which fall into WHO
categories 3 and 4, are listed in Table 7.3. COCs should be used with caution, if at
all, in women with these conditions. In particular, pay close attention to the guide-
lines when considering prescribing COCs to a woman with hypertension, a per-
sonal or family history of blood clots or venous thromboembolic events (VTEs), or
other types of vascular compromise.
Extended Use Combined Oral Contraception
The primary reason for COC failure is forgetting to start the next cycle of con-
traception at the appropriate time. By the end of the placebo week, up to 25% of
women have developed an ovarian follicle large enough to ovulate unless immedi-
ately suppressed by hormones. Since the beginning of each pack is a high-risk time
to miss pills, a few modifications of the COC regimen might improve efficacy. One
method is to shorten the number of placebo days per cycle. Two such pills in Europe
continue estrogen and progestin into the fourth week, leaving fewer days for pla-
cebo, and in the U.S., Mircette® (desogestrel/ethinyl estradiol [EE]) continues es-
trogen for 5 days into the fourth week and leaves 2 placebo days. While physiologically
it makes sense that shortening the placebo period might increase efficacy, no studies
have tested this hypothesis.
Another modification to the traditional COC regimen is to reduce the number of
“starts” by cycling women for longer than the typical 28-day period. Seasonale®
(levonorgestrel/EE), an extended cycle pill approved by the FDA, does this by ad-
ministering 12 weeks (84 days) of active hormone followed by 7 days of placebo. A
woman taking Seasonale® will have only four withdrawal bleeds per year. A large,
randomized, multicenter trial found that Seasonale® had a failure rate of 0.60 per
Table 7.3. When risks outweigh benefits in initiating combined

hormonal contraception
WHO
Medical Condition Category
Breastfeeding <6 weeks postpartum 4
Postpartum nonbreastfeeding, and breastfeeding >6 weeks to ≤6 months 3
Smoking <15 cigs/day and age ≥35 years 3
Smoking ≥15 cigs/day and age ≥35 years 4
Current or past DVT or PE 4 7
Major surgery with prolonged immobilization 4
Controlled hypertension or elevated BP in range of 140-159/90-99 3
Uncontrolled hypertension 4
Vascular disease 4
Multiple risk factors for arterial cardiovascular disease (CVD) 3
Current and h/o ischemic heart disease 4
Stroke 4
Known thrombogenic mutations 4
Valvular heart disease with thrombogenic complications 4
Diabetes with vascular involvement or of >20 years duration 3
Migraine with aura, at any age 4
Migraine without aura and age ≥35 years 3/4*
Headache without aura and age <35 years 2/3
Current breast cancer 4
H/o breast cancer and no evidence of disease 3
Active hepatitis or severe cirrhosis 4
Benign or malignant liver tumors 4
*This indicates that initiation of COCs is a category 3, but initiation of COCs after
development of migraines is a category 4. Modified from: WHO Medical Eligibility
Criteria for Contraceptive Use. 3rd ed. Geneva: Reproductive Health and Research
World Health Organization, 2004.
100 woman-years, based on Pearl Index calculations. This compares favorably to a

traditional regimen pill of the same hormonal doses, Nordette® 28 (levonorgestrel/
EE), which has a failure rate of 1.78 per 100 woman-years in studies. Studies have
shown continuous COC use for up to one year without a placebo period to be safe
and acceptable, and products with more extended regimens are undergoing FDA
consideration. It is also possible to prescribe extended cycle regimens using tradition-
ally packaged COCs in an off-label manner, which gives women the option of cy-
cling every 6, 8 or 12 weeks, or not at all. However, this may mean that women have
to pay out of pocket for extra pills because of insurance limits on number of packs per
year, and it may be difficult for some women to follow directions when not packaged
for this purpose. Studies of extended cycle COC regimens have demonstrated com-
parable efficacy and side effect profiles to traditional regimens although continuous
users may experience more frequent spotting in the first three cycles than cyclic users.
No study has demonstrated superior contraceptive efficacy; however, studies were
not large enough to have the statistical power to test this hypothesis.
Women who might especially benefit from extended cycles are those who have
symptoms exacerbated by their menses. This might include women with seizure
disorders, endometriosis, menstrual headaches, premenstrual dysphoric disorder,
menorrhagia or dysmenorrhea. By limiting the number of times a woman menstru-
ates, one can also reduce the amount of suffering due to these conditions.
Transdermal Contraceptive System
The Ortho Evra® (norelgestromin/EE) transdermal system, or “patch,” is a com-
bination hormonal contraceptive method that was introduced in 2002. This is a
7 1.75 x 1.75 inch patch that administers estrogen and progestin through skin ab-
sorption. In the FDA-approved regimen it is applied weekly for three weeks, fol-
lowed by a patch-free week, during which time a woman will have a withdrawal
bleed. It can be worn on any part of the body except the breasts. It should be placed
on the first day of menses, and if this is done, no backup initial contraception is
needed. If the patch is initiated after the first day of menses, a backup method
should be used for one week.
The patch releases 150 μg of norelgestromin (the primary active metabolite of
norgestimate) and 20 μg of EE per day. The hormones are absorbed through the
skin, avoid first pass metabolism through the liver, and achieve a constant serum
level of hormones. Patch users have a 60% higher average serum estrogen level than
users of a 35 μg COC, though the peak level reached daily in COC users is 25%
higher than that of patch users. This may have implications on the risk of rare ad-
verse effects related to estrogen such as VTE, though currently there are not data to
suggest whether the risk is increased compared with COC use, and no specific pre-
scribing restrictions are currently recommended.
The patch works by the same mechanism as COCs and has a comparable failure
rate (0.88 pregnancies per 100 woman-years). However, in the initial efficacy trials,
the failure rate was higher in women who weighed more than 198 pounds (90 kg).
The lower efficacy of the patch in larger women may apply to other low-dose com-
bined hormonal methods as well; most efficacy studies did not include women whose
body weight exceeded 198 pounds, and secondary data analyses of this question are
ongoing. Women who are overweight should therefore be counseled that the patch
(and possibly other low-dose, combined hormonal methods) may offer them less
protection against pregnancy than other methods.
There is evidence that women find it easier to adhere to weekly patch use than to
daily COC use. In one study, 88% of women using the patch were perfectly compli-
ant (no missed or late patches) compared with 78% of perfectly compliant women
using COCs. There are no data to indicate whether this improved adherence will
lead to reduced failures.
Certain adverse events are specific to the patch, such as local skin reactions in 20%
of women, of which only 2.6% are treatment-limiting. Partial and complete patch
detachment also occurs in 2.8% and 1.8% of women respectively. When this happens,
a woman should place another patch immediately, and go to her provider or pharmacy
for a replacement patch. If a woman is late in placing a patch during the first week, i.e.,
has been without a patch for more than 7 days, she should use emergency contracep-
tion (EC) if indicated, place a patch as soon as possible, and use a back-up method for
one week. If she is 1-2 days late with the second or third patch in a cycle, she can
simply replace her patch immediately without EC or a back-up method, but if she is
more than 2 days late, she must take additional precautions (Table 7.4).
Table 7.4. An algorithm for missed or late contraceptive patch

When Patched Missed Management [Patient Instructions]
1st week patch • Use emergency contraception if unprotected
intercourse has occurred.
• Place the patch immediately.
• Use a back-up method for 7 days.
• Change patch each week on the same day
of the week from now on.
2nd-3rd week patch • 1-2 days late: Remove the old patch and place 7
a new one immediately. No back-up method or
emergency contraception is needed.
• >2 days late: Remove the old patch and place a
new one on immediately. Use EC if unprotected
intercourse has occurred (especially if she is 4
days or more late applying her patch).
• Use back-up method for 7 days. Change the
patch each week on the same day of the week.
4th week patch • Remove the patch.
• Place a new patch on the usual day.
• No back-up method or EC is needed.
Reproduced from: Hatcher R, Zieman M et al. A Pocket Guide to Managing
Contraception. Tiger: Bridging the Gap Foundation, 2005.
Research on extended cycle patch use shows results of delayed menses and fewer
bleeding days when compared to cyclic patch use. However there is also concern
that using the patch in a continuous manner may cause an accumulation of EE in
the blood, leading to higher than acceptable levels. Until there are more data, I
would caution against using the patch in a continuous manner.
The side effect profile for the patch is very similar to that of COCs, with the
exception of more common complaints of spotting, breast symptoms and dysmen-
orrhea as compared to COCs. Spotting and breast symptoms typically resolve after
the first two cycles, and dysmenorrhea, though more common with the patch than
with COCs, is not usually a cause of discontinuation. Contraindications for the
patch are the same as for COC (Table 7.3).
Combined Contraceptive Vaginal Ring
NuvaRing® (etonogestrel/EE), introduced in the U.S. in 2001, is another
way to administer combined hormonal contraception. The ring has an outer di-
ameter of almost 2 inches, and a cross-sectional diameter of approximately 1/8
inch. It is self-inserted into the vagina, left in place for three weeks, and then
removed for one ring-free week. If the ring is initially placed on the first day of
menses, no back-up contraception is needed, but if it is placed on day 2-5, a
back-up method should be used for seven days. The ring is meant to be left in
place during intercourse, though it can be removed for up to three hours without
reduced efficacy.
The ring releases approximately 120 μg of etonogestrel and 15 μg EE daily
through the vagina, and serum levels are adequate for 35 days. This method of
administration, similar to transdermal release, avoids first-pass metabolism through
the liver. The mechanism of action for the ring is the same as for COCs and the
patch, but it is unique in that the progestin used in the ring suppresses ovulation
in all users.
Women generally find it easy to use the ring and use it perfectly in 86% of
cycles. The cumulative failure rate is similar to that of COCs (1.18 per 100
woman-years), though among women who use the ring perfectly the cumulative
failure rate is lower (0.77 per 100 woman-years). Overall, the ring is well tolerated;
95% of women find it easy to insert and remove, and 83% deny feeling it during
intercourse.
7 In addition to the side effects known to be associated with COCs (nausea, head-
aches, breast tenderness, etc), ring users experience unique side effects. Fifteen per-
cent of study participants discontinued the ring due to vaginal symptoms including
vaginitis, leukorrhea, “feeling the ring” when it is in place, and, very rarely, expul-
sion. On the other hand, the ring resulted in a more desirable bleeding pattern when
compared with COCs.
Studies of extended cycle vaginal ring use have demonstrated high satisfaction
rates with continuous use of ring for 49- and 91-days as well as year-long continu-
ous use. Unscheduled bleeding was lowest with the traditional 28-day cycle; how-
ever, overall bleeding days were reduced with postponement of withdrawal bleeding.
Because each ring, if left in place, releases adequate serum levels for 35 days, it could
be used as a once-a-month extended cycle regimen (therefore not requiring addi-
tional rings purchased per year).
Most of the contraindications and precautions for the ring are similar as those
for COCs and the patch, and the World Health Organization (WHO) criteria can
be applied (Table 7.3). If a woman removes her ring for more than 3 hours, she
should replace it immediately, use EC if applicable, and use a back-up method for 7
days. If she is late in replacing her ring after the ring-free week, she should do the
same. Contraindications that are specific to the ring include chronic vaginitis, pelvic
organ prolapse and severe constipation.
Injectable Combined Hormonal Contraception
Currently, there is not an injectable form of combined hormonal contraception
available in the United States. Lunelle® (medroxyprogesterone acetate/estradiol
cypionate), a 0.5 ml suspension that is injected intramuscularly into the deltoid or
gluteus maximus every 28-30 days, was taken off the market in 2002. It is still used
some in other countries and may be available in the U.S. in the future.
Progestin Only Contraceptive Methods
Progestin Only Pills
The progestin only pill (POP), also commonly called the mini-pill, contains
only progestin and is taken daily without any pill-free days. The mechanism of
action is identical to the progestin-related mechanisms for COCs. The primary
mechanism is thickening of the cervical mucus (this action is short lived, and re-
quires punctual dosing to be effective). Progestin use also causes decreased tubal
and endometrial motility and thin, atrophic endometrium. Only about 50% of
women will have ovarian suppression with the currently available POP. Because the
major mechanism of action requires punctual dosing to maintain effectiveness,
women must take the POP within one hour of the same time each day. If 27 or
more hours have lapsed since the last dose, a woman should take her POP immedi-
ately, consider using EC (if indicated), and should also use a back-up method for 2
days. If taken correctly, the efficacy of POPs equals that of COCs, with a failure
rate of 0.3%-8%. However, this efficacy may be slightly inflated because most women
using POPs are at reduced risk for pregnancy because of their lactating or
perimenopausal status.
Women using POPs experience many of the same noncontraceptive benefits
of women using COCs, such as improvements in menstrual side effects and de-
creased risk of endometrial cancer. POPs confer no protection against ovarian and 7
colon cancers. The progestin only pill can be safely used in many women for
whom estrogen is contraindicated. These include women with a history of clots or
VTE, hypertension , coronary artery disease or cerebrovascular disease; women
over 35 years who smoke; and recently post-partum or breastfeeding women.
The main disadvantage to POP use is the need for a strict dosing regimen.
Adherence to daily dosing at the same time every day is often prohibitive, and
most women prefer the increased flexibility in timing of administration allowed
with COCs. The only absolute contraindication for progestin use is current breast
cancer, but there are several conditions in which the risks of POP use generally
outweigh the benefits (Table 7.5).
Table 7.5. When risks outweigh benefits in initiating progestin

only pills and Levonorgestrel/Etonogestrel implant
(Implanon)*
WHO
Breast Feeding (<6 weeks postpartum) 3
Current DVT/PE 3
Current and h/o ischemic heart disease 2/3**
Stroke 2/3**
Migraine with aura 2/3**
Unexplained vaginal bleeding (implant only) 3
H/o breast cancer and NED 3
Viral hepatitis (active) 3
Cirrhosis (severe) 3
Liver tumors (benign or malignant) 3
Drugs that affect liver enzymes (rifampicin or certain anticonvulsants) 3
*This table also applies to Implanon, which will be discussed below. **This indicates
that initiation of POPs is a category 2, but continuation of POPs after development of
this condition is a category 3. Reproduced from: WHO Medical Eligibility Criteria
for Contraceptive Use. 3rd ed. Geneva: Reproductive Health and Research World
Health Organization, 2004.
Progestin Only Intramuscular Injection

Depo-Provera® (medroxyprogesterone acetate, 150 mg/ml), is given as an intra-
muscular injection into the deltoid or gluteus maximus every three months (11-13
weeks). It is highly effective, with a failure rate of only 0.3%, and is acceptable to
most women. The need to return to a clinic every 3 months for an injection may be
considered a disadvantage of this method. A new, low-dose formulation of
Depo-Provera was approved in 2005 that can be administered subcutaneously, and
has the potential to be self-administered. This formulation, Depo-subQ-Provera
104™, has equivalent efficacy with no pregnancies noted in 720 women over one
7 year. It is considered to be one of the main reasons for the drop in teen pregnancy in
the 1990s.
The mechanism of action for Depo-Provera differs from other progestin-only
methods. Because the progestin dose is larger, Depo-Provera suppresses ovulation
by inhibiting the LH and FSH surges. The FSH surge is blocked to a lesser degree,
thus women don’t usually suffer from hypoestrogenemia. Depo-Provera also thick-
ens cervical mucus, atrophies the endometrium, and slows tubal and endometrial
motility, but its primary action is ovulation suppression.
Depo-Provera is a good method for women with contraindications to estrogen,
and the reliable ovulation suppression decreases recurrence of ovarian cysts in sus-
ceptible women. Most women with endometriosis also experience improvement in
pain symptoms, and Depo-subQ Provera 104™ has been FDA approved specifi-
cally for the indication of treating pain due to endometriosis. Women experience a
decrease in menstrual bleeding and dysmenorrhea, and a decreased incidence of
anemia. Half of women using Depo Provera become amenorrheic after 1 year of
use. Additionally, women with sickle cell disease experience a reduction in the fre-
quency and severity of crises on Depo-Provera, and in women with epilepsy
Depo-Provera decreases seizure frequency.
There are several undesirable side effects of Depo-Provera. Most women experi-
ence spotting and irregular menses for the first several months of use. After the first
six months, most women experience a significant reduction in, if not absence of,
their menses. These bleeding side effects are the main reasons for dissatisfaction and
discontinuation. Another significant side effect is weight gain. Studies have shown
that women can gain an average of 5.4 pounds in the first year, and 16.5 pounds
after 5 years. Women who are overweight or obese when they initiate Depo-Provera
are at increased risk of significant weight gain. Interestingly, in the only randomized,
placebo-controlled trial to assess weight gain, Depo-Provera was not associated with
weight gain in women of normal weight at baseline.
As opposed to most other forms of hormonal contraception where return to
fertility is immediate, return to fertility in Depo-Provera users is delayed. It takes an
average of 10 months from the last injection to ovulate, but can take as long as 18
months. If a woman plans to conceive within the next 2 years, Depo-Provera may
not be the ideal contraceptive method for her.
Recently there has been much discussion about the effect of Depo-Provera on
bone mineral density (BMD) and a concern about fracture risk. In 2004, the FDA
added a Black Box Warning to Depo-Provera stating that the method should not be
used for longer than 2 years unless it is the only contraceptive option. There is
evidence that BMD is decreased in women using Depo-Provera, but there is also
evidence that this decrease is reversible once Depo-Provera is discontinued, While
concern is appropriate, it is premature to limit use of this contraceptive method to 2
Table 7.6. When risks outweigh benefits in initiating Depo-Provera

WHO
Breastfeeding <6 weeks postpartum 3
Multiple risk factors for cardiovascular disease 3
Systolic BP ≥60 or DBP ≥100 3
Current deep vein thrombosis (DVT) or pulmonary embolism (PE) 3
Vascular disease 3 7
Current and h/o ischemic heart disease 3
Stroke 3
Migraine with aura 2/3
Unexplained vaginal bleeding 3
H/o breast cancer 3
Diabetes with nephropathy/retinopathy/neuropathy 3
DM with vascular involvement or of >20 years duration 3
Active hepatitis or severe cirrhosis 3
Benign or malignant liver tumors 3
Modified from: WHO Medical Eligibility Criteria for Contraceptive Use. 3rd ed.
Geneva: Reproductive Health and Research World Health Organization, 2004.
years, especially in teens who are at very high risk for unintended pregnancy. It is not
likely that the bone mineral density loss associated with Depo-Provera is sufficient
to raise the risk of osteoporosis later in life.
Similar to progestin only pills, Depo-Provera has only one true contraindica-
tion, that of current breast cancer. There are several other conditions for which it
may not be the most appropriate method (Table 7.6). In general, Depo-Provera is
safe and well tolerated and should remain a powerful component of one’s contracep-
tive armamentarium.
Deciding about the appropriate time to initiate Depo-Provera can be a chal-
lenge. It is best to first administer within 5 days of the onset of a woman’s last
menstrual period. If outside of this time frame, or if outside of the repeat dosing
window of 11-13 weeks, certain precautions should be taken (Fig. 7.1).
Implantable Progestin Contraception
Implanon® (etonogestrel) is a single-rod, subdermal implant that slowly releases
etonogestrel—the active metabolite of desogestrel—and provides reliable contra-
ception for up to three years [package insert]. Using a special device, it is inserted
under the skin of the upper arm by a medical professional. This method was ap-
proved in 2006 at the time of publication, but is not yet marketed. Implanon is a
highly effective method with no pregnancies occurring in more than 70,000
woman-cycles in the original studies. Similar to other progestin-only methods, its
main side effect is irregular bleeding, and this is currently the primary reason for
discontinuation.
Figure 7.1. Initial injection or late reinjection (more than 13 weeks since last injec-
tion) of DMPA or switching from DMPA to COCs or another hormonal method.
Reproduced from: Hatcher R, Zieman M et al. A Pocket Guide to Managing Con-
traception. Tiger: Bridging the Gap Foundation, 2005.
Levonorgestrel Intrauterine System

The levonorgestrel intrauterine system (LNG-IUS), Mirena®, is one of two forms
of intrauterine contraception (IUC) currently available in the United States (the
other is the ParaGard®, which is a copper intrauterine device [IUD]). IUC is in-
serted into the uterus by a health care professional. Insertion can occur at any time
during the menstrual cycle and rarely requires local anesthesia. Perforation is very
rare (less than 1 in 1000) and expulsion is also uncommon (2.9%). LNG-IUS is a
highly effective method of contraception, with equivalent efficacy to sterilization
(0.1% failure rate per year for LNG-IUS and 0.8-3.7% for various sterilization
methods). The LNG-IUS releases 20 μg of levonorgestrel daily and results in effec-

tive contraception for up to 7 years (though it is currently only FDA approved for 5
years of use). Its primary mechanism of action is to thicken cervical mucus (the
progestin effect). Its secondary mechanisms include alteration of uterotubal fluid
such that sperm migration is impaired, a weak foreign body reaction that reduces
the receptivity of the endometrium to implantation, and the prevention of ovula-
tion (in 5-15% of cycles).
Many women using the LNG-IUS note spotting during the first 1-6 months.
However, the overall effect of this method is to reduce menstrual blood loss (70-90%)
and at 12 months post-insertion, approximately 20% of women are amenorrheic. 7
IUC is under-utilized in the U.S. compared with other developed nations—only
1% of U.S. women at risk for unintended pregnancy use IUC. Providers and pa-
tients commonly believe that there is a relationship between IUC use and pelvic
inflammatory disease (PID). There is a slight, transient increased risk for PID at the
time of IUC insertion thought to be due to the presence of bacteria in the cervix at
the time of insertion. This risk of transient PID is between 1 and 8 per 1000. For
this reason, any woman at risk for sexually transmitted infections (STIs) should be
screened at or before the time of IUC insertion. If a woman is found to have visible
cervicitis, placement of IUC should be delayed until at least 3 months after treat-
ment. If the IUC is placed on the same day as screening for gonorrhea and chlamy-
dia, and the test returns as a positive, it is safe to treat the patient with appropriate
antibiotic therapy for cervical infection and leave the IUC in place. After the first 20
days, there is no increased risk of PID, and IUC is not associated with an increase in
future tubal infertility. Furthermore, the LNG-IUS may decrease risk of PID sec-
ondary to the barrier provided by the thickened cervical mucus. Though the manu-
facturer has not yet incorporated this information into its package insert, this much
maligned contraceptive method may actually provide protection against PID and
tubal infertility.
Like all methods of contraception, there are certain contraindications or cau-
tions for use of the LNG-IUS (Table 7.7). Overall, this method is well tolerated,
and 81% of LNG-IUS users continue its use for 1 or more years. Its acceptability to
both patients and providers is improving as more data regarding its many benefits
and few adverse side effects become better understood.
Emergency Contraception
The purpose of contraception is to prevent pregnancy, but, it can be difficult to
adhere perfectly to any birth control regimen. When a woman forgets her pills, does
not replace a patch right on time, or is a condom user and experiences a condom
break, she can employ emergency contraception (EC) to decrease her risk of preg-
nancy. It is estimated that 51,000 pregnancies were averted by EC use in 2000, and
it may account for 43% of the decrease in abortion since 1994.
EC specifically refers to methods used to prevent pregnancy after intercourse has
already happened. There are three approaches to providing EC: high doses of com-
bined oral contraceptives, high doses of progestin only pills, or placement of a
copper-T IUD. The copper-T IUD is most effective, and also least commonly used
in the United States. Of the hormonal methods, the progestin-only method is pre-
ferred because of its lower incidence of nausea and vomiting.
The mechanisms of action for EC are multiple: inhibition of ovulation (primary
mechanism); thickening of cervical mucus which traps sperm; inhibition of tubal
Table 7.7. When risks outweigh benefits in initiating intrauterine

contraception
WHO
Pregnancy 4
Postpartum, puerperal sepsis 4
Immediately after septic abortion or pregnancy 4
7 Distorted uterine cavity 4
Current DVT (Only for LNG IUS) 3
Unexplained vaginal bleeding, before evaluation 4
Gestational trophoblastic disease (benign/malignant) 3/4
Cervical, endometrial cancers 4/2
Ovarian cancer 3/2
Breast cancer current (only for LNG IUS) 4
H/O breast cancer and NED (only for LNG IUS) 3
PID current or within last 3 months 4/2
Current sexually transmitted infection 4/2
Increased risk of STI 2-3
Active hepatitis, severe cirrhosis, or liver tumors (Only for LNG IUS) 3
Modified from: WHO Medical Eligibility Criteria for Contraceptive Use. 3rd ed.
Geneva: Reproductive Health and Research World Health Organization, 2004.
transport; disruption of fertilization; early cell division or transport of the embryo;

and disruption of the endometrium to prevent implantation. It is important to note
that none of these mechanisms disrupt a pregnancy once it has been established.
A woman not desiring pregnancy should take EC as soon as she realizes she has
had unprotected intercourse. She can use either of the hormonal methods within 5
days after unprotected intercourse, and the copper-T IUD within 8 days, but sooner
is always better as the efficacy decreases with each hour. The combined hormonal
EC provides a 75% reduction in the incidence of pregnancy, and the progestin only
EC provides an 89% reduction.
Because EC is more effective the sooner it is taken after unprotected intercourse,
some states have made it more accessible to women through policy changes. Practi-
tioners should consider advanced provision of EC either by giving women a pre-
scription or the actual pills as a back-up to their regular contraceptive method. Several
countries and seven states (AK, CA, HI, ME, NH, NM, WA) allow women to
obtain EC directly from a pharmacist without a prescription. The FDA is consider-
ing making EC available over the counter, which would also help improve access
and decrease unintended pregnancy. Advanced provision is associated with an in-
crease in use of EC, more prompt use of EC, no change in baseline contraceptive
use, and no decrease in condom use.
The original method of prescribing EC (the Yuzpe method) involves 2 doses of
COCs given 12 hours apart. The total dose needs to include at least 100 μg of EE,
and either 100 μg norgestrel or 50 μg levonorgestrel. If taken within 12 hours after
Table 7.8. Emergency contraception options using combination

oral contraceptives
Number of Pills to Take
Brand Name of COC with Each Dose*
Ovral®, Ogestrel® 2 white pills
Alesse, Levlite® 5 pink pills
Nordette® 28, Levlen® 4 light-orange pills
Levora®, Lo/Ovral®, Low-Ogestrel® 4 white pills 7
Triphasil®, Tri-Levlen® 4 yellow pills
Trivora® 4 pink pills
*This dose is then repeated after 12 hours. Reproduced from: Steinauer J. A new
era of contraception. Johns Hopkins Advanced Studies in Medicine 2005;
5(6):285-293.
unprotected intercourse, a woman’s risk for pregnancy is 0.5%; If not taken at all,
her risk is 8%. There are a number of brands of COCs that can be used as EC (Table
7.8).
The preferred method of EC is the progestin only method which is more effec-
tive and better tolerated than the combined method. Plan B® is a commercially
available progestin-only EC product that consists of two pills, each with 75 μg
levonorgestrel. The package insert indicates that one pill should be taken as soon as
possible after unprotected intercourse, followed 12 hours later by the second pill
[package insert]. There is evidence that taking both pills at the same time provides
equal protection against pregnancy.
The side effects from EC are primarily nausea and vomiting. These are re-
ported by 50% and 19%, respectively, of women using combined EC, and 23%
and 6%, respectively, of women using progestin only EC. Practitioners should
prescribe anti-emetics if using combined EC or if a patient has previously had
nausea/vomiting with progestin only EC. If a patient vomits within 1 hour of
taking EC, she should repeat the dose. The FDA-approved contraindications for
EC are the same as for COCs and POPs, respectively [package insert]; however
according to the WHO’s, evidence-based guidelines, there are no contraindications
for either method of EC.
It is important to remember that the ultimate goal of EC is prevention of preg-
nancy, and to that end, when approached for an EC prescription, practitioners should
take the opportunity to do contraceptive counseling with the patient. A woman can
safely start any of the above mentioned forms of contraception immediately (i.e., the
next day) following EC use, with the exception of the LNG-IUS. If her period does
not come when expected on the birth control method or within 21 days of taking EC,
she should take a pregnancy test.
Conclusion
The incidence of unintended pregnancy remains high in the US, largely due
to underutilization of highly effective and reliable forms of contraception. Al-
though oral contraceptive pills are the most common hormonal method in the
United States, providers should encourage patient to use methods that require less
frequent interventions and have higher efficacy. With the tools provided in this
chapter, an appropriate method of hormonal contraception can be found for al-
most any woman.
Key Points
1. All methods of combined hormonal contraception (COCs, patch, ring) have
low failure rates if used correctly. However, it may be easier for a woman to
remember to place a patch once a week or a ring once a month than it is to
take a pill every day. Don’t be afraid to prescribe these newer forms of com-
bined hormonal contraception.
7
2. Progestin-only methods (POPs, Depo-Provera, Mirena) should not be re-
served only for women with contraindications to estrogen. The progestin
injection and intrauterine contraceptive have much higher efficacy than
COCs and are highly acceptable to women.
3. Depo-Provera is a very safe method of contraception. Though concerns re-
garding decreases in bone mineral density are warranted, there isn’t evidence
at this point to suggest that Depo-Provera affects long-term bone health or
puts women at risk for development of osteoporosis or fracture.
4. The Mirena LNG-IUS (and the ParaGard IUD) is the most effective method
of contraception currently available in the United States. It is even more
effective at preventing pregnancy than tubal sterilization. Concerns that many
providers and patients have regarding the association between IUC and PID
are unfounded. In fact, there is now evidence to suggest that Mirena may
decrease a woman’s risk of PID and tubal infertility.
5. Emergency contraception is safe and easy to use. Progestin-only EC, like
Plan B, has very few side effects and is typically very well tolerated. While all
women trying to avoid pregnancy should be encouraged to consistently use
an effective method of contraception, advanced and frequent provision of
EC to sexually active women of reproductive age can prevent many un-
planned pregnancies. Ideally, Plan B will be available over the counter, so
women can access it in a more timely and efficacious manner.
Suggested Reading
1. Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect 1998;
30(1):24-29, 46.
2. Speroff L, Darney PD. A Clinical Guide for Contraception. 4th ed. Philadelphia:
Lippincott Williams & Wilkins, 2005.
3. WHO. Medical Eligibility Criteria For Contraceptive Use. 3rd ed. Geneva: Reproduc-
tive Health and Research World Health Organization, 2004.
4. Hatcher RA et al. Contraceptive Technology. 18th ed. New York: Ardent Media INC.,
2004.
5. Hatcher R, Zieman M et al. A Pocket Guide to Managing Contraception. Tiger: Bridg-
ing the Gap Foundation, 2005.
6. Steinauer J. A new era of contraception. Johns Hopkins Advanced Studies in Medicine
2005; 5(6):285-293.
7. Stewart FH, Harper CC, Ellertson CE et al. Clinical breast and pelvic examination
requirements for hormonal contraception: Current practice vs evidence. JAMA 2001;
285(17):2232-2239.
8. American Cancer Society Web site. http://www.cancer.org/docroot/NWS/content/
NWS_1_1x_Slight_Risk_for_Rare_Cancer_Linked_to_Oral_Contraceptives.asp;
Accessed 2005.
9. Anderson FD, Hait H. A multicenter, randomized study of an extended cycle oral

contraceptive. Contraception 2003; 68(2):89-96.
10. Miller L, Hughes JP. Continuous combination oral contraceptive pills to eliminate
withdrawal bleeding: A randomized trial. Obstet Gynecol 2003; 101(4):653-661.
11. Patient Information Sheet Norlegstromin/ethinyl estradiol (marketed as Ortho Evra):
U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research,
2005.
12. Stewart FH, Kaunitz AM, Laguardia KD et al. Extended use of transdermal
norelgestromin/ethinyl estradiol: A randomized trial. Obstet Gynecol 2005;
105(6):1389-1396.
13. Miller L, Verhoeven CH, Hout J. Extended regimens of the contraceptive vaginal ring:
A randomized trial. Obstet Gynecol 2005; 106(3):473-482. 7
14. Guillebaud J. Contraception: Your Questions Answered. 4th ed. Edinburgh, London,
New York, Oxford, Philadelphia, St. Louis, Sydney, Toronto: Churchill Livingstone,
2004.
15. Scholes D, LaCroix AZ, Ichikawa LE et al. Change in bone mineral density among
adolescent women using and discontinuing depot medroxyprogesterone acetate con-
traception. Arch Pediatr Adolesc Med 2005; 159(2):139-144.
16. Hubacher D, Lara-Ricalde R, Taylor DJ et al. Use of copper intrauterine devices and
the risk of tubal infertility among nulligravid women. N Engl J Med 2001;
345(8):561-567.
17. Westhoff C. Clinical practice. Emergency contraception. N Engl J Med 2003;
349(19):1830-1835.
18. Raine TR, Harper CC, Rocca CH et al. Direct access to emergency contraception
through pharmacies and effect on unintended pregnancy and STIs: A randomized
controlled trial. JAMA 2005; 293(1):54-62.
Chapter 8
Endometriosis
Sireesha Reddy
Definition and Epidemiology
Endometriosis is a condition that is characterized by the presence of functional
endometrial glands and stroma outside of the uterine cavity. This condition is found
to be highly prevalent in women of reproductive age. However, the exact prevalence
of endometriosis is unknown. It is believed approximately 20-50% of cases under-
going laparotomy reveal endometriosis at the time of surgery. The median age of
women who have endometriosis is 37. Because 15% of these women are under the
age of 30, endometriosis can also occur in the younger adult women and also in
adolescence especially when there is an association with uterine anomalies. Although
endometriosis is considered an estrogen-dependent disease with treatments focus-
ing on this mechanism, rare cases have been identified in both premenarchal and
postmenopausal females.
Pathogenesis
Two main theories attempt to explain how endometriosis disseminates outside
of the endometrial cavity and at almost all body sites: (1) the retrograde menstrua-
tion theory, whereby, endometrial cells via menstrual flow efflux through the fallo-
pian tubes to implant and develop in ectopic sites; and (2) the metaplastic theory,
whereby peritoneal serosa or the Mullerian remnants spontaneously differentiate
into endometrial tissue in ectopic locations. Endometriosis is a slow and progressing
condition which justifies its classification into three types: (1) superficial endometrio-
sis, which may start as papules that turn red and finally black (2) ovarian endometrio-
mas (3) deeply infiltrating endometriosis. Several factors such as anatomical defects
(uterine anomalies), environmental toxins (dioxin), defects in immune regulatory
cells (diminished clearing by macrophages), elevated inflammatory mediator ex-
pression (elevated prostaglandin levels) and recently, growth mediators (elevated
aromatase expression) may play a role in the initiation of endometriosis.
Diagnosis
Diagnosis of endometriosis is often problematic. Although patients classically
present with pelvic pain, dysmenorrhea, dyspareunia, pelvic mass and infertility,
there are also many patients who are asymptomatic. It has been found that 25% of
all women who experience pelvic pain and 40-50% of infertile women have en-
dometriosis. Most symptoms that women experience are a result of local infiltration
of endometriosis into the pelvis: pelvic pain, dyschezia (painful defecation), ab-
dominal bloating, dyspareunia, back pain, dysuria and suprapubic pain. Menstrua-
tion can greatly accentuate these symptoms.
Endometriosis 85
Because of the poor correlation between these symptoms and the diagnosis of
endometriosis, there should be a careful clinical evaluation in combination with judi-
cious use and critical interpretation of laboratory tests, imaging techniques, and, in
most instances, surgical staging combined with histological examination of excised
lesions. A thorough medical history should be taken focusing on duration and loca-
tion of pain in addition to a precise physical examination noting areas of pain and
tenderness. Family history can reveal female relatives with similar symptoms or even a
diagnosis of endometriosis suggesting a higher risk for developing endometriosis.
Laboratory markers such as serum CA-125 are of limited value. It is usually
elevated only in advanced stages of endometriosis and can also be elevated in other
gynecological conditions; therefore not suitable for routine screening. Transvaginal
ultrasound and magnetic resonance imaging are often helpful, particularly in detec- 8
tion of endometriotic cysts. Recently, transrectal ultrasound and magnetic resonance
imaging were shown to be valuable in detection of deep infiltrating lesions, espe-
cially in the rectovaginal septum. For most clinicians, laparoscopy allows a direct
assessment of the pelvis for endometriotic foci and the ability to make a definitive
diagnosis through appropriate biopsies. Laparoscopy also allows for the possibility
of treatment through resection of endometriotic lesions and endometriomas and
lysis of adhesions. Medical treatment options are effective, as are surgical treatment
options. Complications associated with surgery, however, push the balance in favor
of empiric short term medical therapy whenever possible. Clinicians often choose to
treat women with endometriosis-related complaints with a first-line medical therapy.
If that fails, then a second-line medical therapy is warranted under most conditions.
Laparoscopic surgery is often reserved for patients in whom second-line medical
therapy has failed or is contraindicated by desire to conceive.
Treatment
Goals of treatment should involve addressing patient’s primary complaints as
well as reproductive wishes. The most comprehensive treatment plan will include
relief of symptoms, removal of all endometriotic lesions, and restoration of pelvic
anatomy and delaying progression of the disease. Despite important advances in
treating endometriosis, the optimal therapy has not been yet identified. Medical
and surgical therapies, individually or in combination, may be needed to achieve the
appropriate treatment plan.
Medical Treatment
The mainstay of medical therapy focuses on the principle that endometriosis is
an estrogen-dependent condition. Many clinical observations show that estrogen is
essential for the growth of endometriosis. Endometriosis has been shown to regress
and become inactive in states of amenorrhea and menopause. Therefore, treatment
of endometriosis often relies on drugs that suppress ovarian steroids and induce a
hypoestrogenic state that causes atrophy of ectopic endometrium. The most widely
used agents to achieve this goal are oral contraceptives and GnRH agonists. The
evidence-based support for medical therapy is mostly observational.
Oral Contraceptives
Oral contraceptives (OCs) containing 20-35 μg of ethinyl estradiol can be used
in a conventional regimen with monthly withdrawal bleeds or as a long-cycle regi-
men with continuous administration of OCs for 3 or 6 months followed by a
hormone-free interval of 7 days. This regimen may be used for women who suffer
from dysmenorrhea or pelvic pain. Symptomatic relief can be achieved in 75-100%
of women in observational studies. Continuous use of OCs prevents the cyclic fluc-
tuations of serum levels of ethinyl estradiol and progestogen and, hence, the cyclic
variations of metabolic serum parameters. Although the long-cycle regimen is ini-
tially associated with an elevated rate of irregular bleeding, the total number of
bleeding days that require sanitary product protection is lower than during conven-
tional OC treatment. Many physicians tend to prescribe extended OC cycles for
postponement of menstruation or reduction of frequency of regular bleeding.
Progestins
8 Progestins can cause suppressed gonadotropin levels to induce a hypoestrogenic
state. Because of its direct action on the endometrium resulting in atrophy and
decidualization, it is believed the mechanism of action is similar on endometriosis.
Medroxyprogesterone acetate (150 mg of the Depot product every 3 months) can
be used as a treatment for endometriosis. The side effect of slow return to ovulation
is often seen as an undesirable side effect in women desiring fertility.
Medroxyprogesterone acetate orally at 30 mg continuously for 90 days was shown
to have benefit in women with laparoscopically confirmed mild to moderate en-
dometriosis. After therapy a repeat laparoscopy revealed marked regression of
endometriotic lesions and ovulation returned within two to three weeks of discon-
tinuing treatment. Megestrol acetate at 40 mg per day has been found to provide
symptomatic relief in as much as 85% of treated patients. The side effects of oral
progestins can be breakthrough bleeding and spotting, depression, weight gain and
breast tenderness. Norethindrone acetate has been used successfully in both symp-
tomatic relief as well as resulting in regression of lesions in post-treatment surgical
observation. The dosage should start at 5 mg daily to be gradually titrated to effect
until a maximum of 50 mg maximum daily.
Gonadotropin Releasing Hormone Analogs
Gonadotropin releasing hormone analogs (GnRH) cause a temporaty medical
menopause resulting in hypogonadism and hypoestrogenism by acting on the pitu-
itary to reduce gonadotropin synthesis and secretion. Most of the side effects expe-
rienced occur because of the hypoestrogenic state including hot flashes, vaginal
dryness, mood lability and decreased libido. The GnRH agonists have been shown
to work well in reducing pain symptoms associated with endometriosis such as dys-
menorrhea, dyspareunia, and noncyclic pelvic pain. GnRH agonists are often initi-
ated with the onset of menses, but a more rapid response is observed with mid-luteal
administration. A limit of 6 months per treatment course is required due to loss of
bone mineral density during therapy, but this can be extended via the addition of
‘add-back’ therapy with estrogens. Retreatment with these drugs is supported by
limited data. Several investigators have studied the use of GnRH agonists as surgical
adjuncts. Their use preoperatively has not been shown to be of value. Similarly, 3
months of postoperative administration has failed to enhance treatment. However,
6 months of postoperative GnRH agonists appear to improve the duration of relief
of pain symptoms. Symptoms often recur after discontinuation of therapy, and
hypoestrogen-related side effects limit the long-term use of most medications. Fur-
thermore, these therapies are of limited value in patients with a desire to become
pregnant because they inhibit ovulation.
Endometriosis 87
New Therapies
Mifepristone, an antiprogestogen, is currently being studied. This appealing
therapy to treat endometriosis may work without suppressing ovarian function.
Aromatase inhibitors may have similar characteristics as they can inhibit estrogen
production selectively in endometriotic lesions without affecting ovarian function;
an observational trial in a small group of women who had exhausted all other medi-
cal therapies including GnRH agonists showed reduction in pain symptoms.
Levonorgestrel intrauterine device has proven effective in relieving dysmenorrhea
associated with endometriosis, as well as pain associated with rectovaginal endometrio-
sis. This approach is promising in the long-term management of endometriosis as it
limits systemic absorption of hormones, minimizing side effects. The most current 8
research has targeted anti-inflammatory mechanisms and modulators of the im-
mune system. TNF-binding protein-1 and IL-12 have been shown to be effective in
reducing endometriotic lesions in animal models, while pentoxifylline and INF-alpha
2b have shown encouraging results in clinical studies.
Surgical Treatment
Often surgical treatment is considered when medical therapy has failed. With
advances in laparoscopy, this technique has become the method of choice in the
surgical evaluation and treatment of endometriosis. Laparotomy may still be used in
cases of severe endometriosis which may involve other major organs and if adhesive
disease is suspected. However, in all other cases, laparoscopy offers both diagnostic
and therapeutic capabilities by confirming the presence of endometriosis and then
the option to resect if reasonable. Laparoscopy also has many advantages: (1) being
an outpatient procedure (2) minimizing hospital stay (3) lowering morbidity (4)
smaller incisions and (5) superior visualization of lesions.
Although there is controversy concerning the optimal approach to the treatment
of endometriosis, the general opinion is if surgery is being performed then resecting
as much of the visualized endometriosis as possible should be the goal. Laparoscopic
resection of endometriosis utilizes various energy sources: electrocautery (monopolar
and bipolar) and lasers. Excision of the lesions allows for safer and improved diag-
nostic results especially when evaluating superficial versus deeply infiltrating lesions
in comparison to simple superficial fulguration and coagulation of endometriotic
implants.
Since endometriosis is a progressive disease and the extent of disease varies at
diagnosis, recurrence rates can be also variable. Less than a third of patients experi-
ence recurrence of symptoms within three years after laparoscopy and approximately
50% experience symptom recurrence five years after laparoscopy. In patients who
have mild to moderate endometriosis, 90% will respond with improved symptoms
in the first year. In the remaining 10%, one-third will show disease regression, an-
other third show disease progression and the remainder show no change in disease.
Most patients will obtain relief of symptoms after laparoscopy for at least a year.
Other surgical options exist for patients with ongoing pelvic pain especially mid-
line pain with associated dysmenorrhea. LUNA (laparoscopic uterosacral nerve ab-
lation) and presacral neurectomy (via laparoscopy or laparotomy) have been used
with varying results. Patients who have ongoing symptoms and have completed
childbearing should have the option of proceeding to a total abdominal hysterec-
tomy with or without a bilateral salpingoopherectomy. Even with this last approach,
there is a small risk of recurrence (3%) so there should be long term followup of
these patients.
Key Points
1. Endometriosis is the presence of endometrial glands implanted outside of
the uterine cavity.
2. Endometriosis is a condition that mostly affects women of reproductive age.
3. More common symptoms of endometriosis are pelvic pain and infertility.
Pain does not correlate to the extent of disease.
4. Most common medical therapies are oral contraceptives and GnRH analogs.
5. Laparoscopic resection of endometriosis can result in at least one year of
8 symptom-free interval with a high probability of recurrence in 3-5 years.
Suggested Reading
1. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North
Am 1997; 24:235-258.
2. Valle RF. Endometriosis: Current concepts and therapy. Int J Gynecol Obstet 2002;
78:107-119.
3. Montogomery Rice V. Conventional medical therapies for endometriosis. Ann NY
Acad Sci 2002; 955:343-352.
4. Valle RF, Sciarra JJ. Endometriosis: Treatment strategies. Ann NY Acad Sci 2003;
997:229-239.
Chapter 9
Hyperprolactinemia
Ghassan Haddad and Michael A. Thomas
Introduction
Prolactin (PRL) is a hormone that primarily affects lactation; however, the
clinical effects of hyperprolactinemia extend far beyond the mammary glands and
affect distant organs such as the gonads, bones, as well as the brain in cases of
tumors. Hyperprolactinemia is the most common endocrine disorder of the
hypothalamic-pituitary axis. It is diagnosed when the serum prolactin level is con-
sistently elevated above 25 ng/ml. Prolactin, like other anterior pituitary hormones,
is under constant hypothalamic control. However, its predominant control is
tonic-inhibitory through the action of prolactin inhibitory factors (PIF). The major
PIF is dopamine. Dopamine inhibits PRL secretion via D-2 receptors on the sur-
face of the anterior pituitary lactotroph cells. Some of the weak PRL releasing
factors (PRF) include thyroid releasing hormone, vasoactive intestinal peptide,
angiotensin II, serotonin, and vasopressin. Under normal physiologic conditions,
the role of these weak stimulatory agents is not clear, and therefore the predomi-
nant control of PRL secretion remains the inhibitory effect of dopamine.
Biochemistry
PRL is a glycoprotein hormone secreted primarily by the anterior pituitary
lactotrophs. During pregnancy, the decidua secretes PRL as well, but decidual pro-
lactin does not enter the circulation. It is concentrated in the amniotic fluid with
levels exceeding those in the serum (10-100 fold that in the maternal or fetal se-
rum). During pregnancy, the elevation in serum prolactin is solely due to pituitary
secretion. PRL is secreted in different forms: prolactin (monomer), “big” prolactin
(dimer), and “big big” prolactin, a polymer. Prolactin hormone can also vary in the
size of the glycoprotein moieties attached to the amino acid basic structure. The
three different forms differ in their potency as well: The big big prolactin is less
bioactive than the smaller counterparts.
Etiology
Hyperprolactinemia has several causes which can be divided into three major
categories: physiologic, pharmacologic, and pathologic (Table 9.1).
Physiologic
Physiologic causes include pregnancy, lactation, nipple stimulation, exercise, sleep,
and stress. Except for pregnancy and lactation, the increase in serum PRL levels
from physiologic stimulation is typically modest. In contrast, during pregnancy,
PRL levels rise to a range of 200-400 ng/ml at term. During lactation, basal levels
are elevated (40-50 ng/ml) and increase 2-10 fold with suckling.
Table 9.1. Causes of hyperprolactinemia

Pathological
Pathological Pituitary/
Physiological Pharmacological Nonpituitary Hypothalamic
Pregnancy Phenothiazines Hypothyroidism Prolactinomas
Breast feeding Haloperidol Chest wall lesions Acromegaly

(herpes zoster,
Sleep MAO inhibitors surgery, trauma) Craniopharyn-
giomas
Nipple TCAs Chronic renal
9 stimulation failure Meningiomas
SSRIs
Exercise Liver cirrhosis Other pituitary
Butyrophenones adenomas
Stress Ectopic prolactin
Risperidone secretion Sarcoidosis
affecting the stalk
Thioxanthenes Seizures
Aneurism
α-Methyldopa
Trauma with stalk
Metoclopramide transection
Domperidone
Reserpine
Protease inhibitors
Verapamil
Estrogens (high doses)
Pharmacologic
Since dopamine exerts the main control on PRL secretion, any medication that
affects dopamine action can lead to abnormal PRL secretion. Estrogens in high
doses can inhibit dopamine release and therefore increase PRL. Neuroleptic drugs
such as phenothiazines, butyrophenones, risperidone, thioxanthenes as well as
anti-depressants like tricyclic antidepressants, serotonin reuptake inhibitors (SSRIs)
and monoamine oxidase inhibitors can competitively block the D-2 receptor and
increase PRL. Antiemetics like metoclopramide (Reglan) exert the same action. A
third of patients who take antiemetics will exhibit galactorrhea. Other medications
that deplete the sympathetic mediators (including dopamine) can elevate PRL, such
as alpha methyldopa. Protease inhibitors, used in HIV-positive patients, may also
increase PRL levels, though the exact mechanism for this increase is unknown.
Pharmacologically-induced hyperprolactinemia resolves within 3-6 months after dis-
continuing the medication.
Hyperprolactinemia 91
Pathologic
Diseases that lead to hyperprolactinemia can be broadly categorized into one of
two categories: hypothalamic-pituitary disorders and “peripheral” disorders.
Peripheral Disorders
Chest wall lesions (following chest surgery, herpes zoster, nipple piercing) as well
as prolonged nipple stimulation can increase serum PRL levels as well as cause galac-
torrhea. This occurs via a reduction in hypothalamic dopamine. Notably, routine
breast exams are not associated with increased PRL. Chronic renal failure, due to a
decreased clearance of PRL, can result in hyperprolactinemia. Renal transplant re-
verses it. Forty percent of patients with hypothyroidism have mildly elevated PRL
levels, due to the increase in thyroid releasing hormone, which is also a PRL releas-
ing factor. Some rare causes of ectopic hyperprolactinemia include small cell carci- 9
noma of the lung as well as colorectal cancer. Liver cirrhosis can also cause an elevation
of PRL, possibly secondary to decreased clearance.
Hypothalamic-Pituitary Disease
Pituitary or extra-pituitary lesions can compress the pituitary stalk and conse-
quently cut-off (partially or completely) the inhibitory dopaminergic input from
the hypothalamus to the anterior pituitary. PRL levels are typically less than 100-150
ng/ml. Examples include traumatic stalk transection, craniopharyngiomas, hamar-
tomas, vascular aneurisms, granulomatous diseases such as tuberculosis and sarcoi-
dosis, and nonfunctional pituitary tumors. However, the most common cause of
persistent hyperprolactinemia is a prolactin secreting adenoma or prolactinoma.
Prolactinomas are the most common functional pituitary tumors. About 11% of
autopsies performed on “normal” subjects showed the presence of incidental pitu-
itary adenomas, 44% of which stained positive for prolactin.
Other pituitary conditions that can present with hyperprolactinemia are acrome-
galy and Cushing’s disease. Acromegaly is caused by a growth hormone secreting
adenoma. About 30-40% of such adenomas cosecrete prolactin. This is not a sur-
prise given the common embryologic origin of the somatotrophic cells (GH secret-
ing cells) and the mammotrophic cells (PRL secreting cells) of the anterior pituitary.
The associated hyperprolactinemia partially explains the hypogonadism observed in
acromegalic patients. Cushing’s disease, caused by an ACTH secreting pituitary ad-
enoma, can also be associated with hyperprolactinemia. Although the association is
infrequent, mixed adenomas secreting both ACTH as well as PRL have been re-
ported.
Prolactinomas
Prolactinomas are pituitary adenomas (a monoclonal tumor) that secrete PRL.
Like other pituitary adenomas, they can be classified into microadenomas or
macroadenomas based on their size (less than 10 mm and greater than 10 mm,
respectively). It is important to differentiate between the two because
microadenomas are unlikely to compress the optic chiasm, while macroadenomas
can compress it resulting in visual field damage which can be irreversible. In ad-
dition, macroadenomas, through a mass effect, can compromise other pituitary
cells (such as gonadotrophs, thyrotrophs, and ACTH releasing cells). The over-
whelming majority of prolactinomas are benign tumors, meaning that they do
not metastasize to distant organs. Very few cases of malignant prolactinomas are
reported in the literature; however, prolactinomas can be locally destructive, es-

pecially the macroadenomas. In addition to affecting pituitary function by a local
mass effect, they can invade the optic chiasm as well as the adjacent cavernous
sinus causing cranial nerve neuropathies (CN III, IV, V1, V2, VI). In women, the
slightest elevation in prolactin can cause menstrual disturbances. Men, on the
other hand, tend to present with symptoms of local mass effect. Physiologic ef-
fects of hyperprolactinemia in men (low libido, impotence, and infertility) are
less sensitive to the hyperprolactinemia than symptoms in females (oligomenor-
rhea or amenorrhea).
When to check a PRL level?
• Any patient (male or female) with galactorrhea
• Any male patient with erectile dysfunction
9 • Any female patient with amenorrhea or oligomenorrhea
• Any female patient with symptoms of premenopausal hypogonadism
• Patients with neurological symptoms suggestive of pituitary adenomas (se-
vere headaches, visual field changes)
• Patients with incidental pituitary adenomas discovered while imaging the
brain for unrelated reasons
Evaluation
Although prolactin is secreted in a pulsatile fashion, a random blood test usually
suffices. If the prolactin is mildly elevated on initial evaluation (<40 ng/ml), it is
prudent to repeat it prior to making a diagnosis of hyperprolactinemia. If the mild
prolactin elevation is persistent on subsequent testing or if the initial level is greater
than 40 ng/ml, then a specific cause should be sought. A TSH level should always be
checked to rule out primary hypothyroidism, as this can result in an elevated PRL
level (due to the PRL stimulating effect of TRH). A renal panel should be checked,
as compromised kidney function leads to decreased clearance of PRL. Brain imag-
ing, using gadolinium enhanced MRI (preferred) or CT scanning is mandatory to
rule out hypothalamic-pituitary lesions. Although microadenomas typically pro-
duce serum PRL levels less than 100 ng/ml, while macroadenomas typically show
levels greater than 100 ng/ml, a serum level cannot distinguish between the two. For
example, a macroadenoma can produce very high serum PRL levels (greater than
1000 ng/ml), but due to an intrinsic artifact in the immunoassay (termed “the hook”
effect), the result is read as a value less than 100 ng/ml. Only when the serum is
diluted (1:100 dilution) will the true value of PRL be measured. In addition, other
pituitary tumors (nonfunctioning pituitary macroadenomas and hypothalamic tu-
mors) can cause elevations of PRL with values less than 100 ng/ml (by compressing
the dopaminergic inhibitory fibers from the hypothalamus). Such tumors need to
be accurately diagnosed and differentiated from microprolactinomas because their
treatment is completely different. Therefore, while the initial blood test is helpful in
diagnosing hyperprolactinemia, brain imaging is warranted to accurately identify
the cause.
Galactorrhea
Galactorrhea is defined as the presence of a milky nipple discharge at any time in
men and in women with no recent history of pregnancy or breast-feeding. Evalua-
tion of galactorrhea in the office includes examining the breast discharge on a slide
under a microscope. The finding of fat globules is diagnostic.
Treatment
Observation
Patients with microprolactinomas who are otherwise asymptomatic (no loss of
libido or sexual dysfunction in men, or no menstrual irregularity or infertility in
women) could be expectantly managed with serial PRL determinations. Patients
who have evidence of hypogonadism due to the hyperprolactinemia need to be
treated to avoid the complications of prolonged hypogonadism (the most impor-
tant is osteoporosis).
Medical Treatment
Whenever possible, medical treatment should always be sought first because
of the high response rate and the relatively few complications. This applies to 9
both micro- and macroprolactinomas. Even without therapy, 93% of
microprolactinomas do not enlarge when followed over a period of 4-6 years;
moreover, any increase in size is paralleled by an increase in prolactin serum levels.
Therefore, if the initial brain imaging shows the presence of a microprolactinoma,
follow up as well as response to treatment can be done by periodically checking
serum prolactin levels.
PRL levels should be checked periodically while on medical therapy. Once the
PRL levels have normalized, the dosages could be slowly tapered down to a lower
dose; however, therapy is typically life-long as the tumor tends to grow back once
the drugs are discontinued. Occasionally, the drugs can be discontinued after sev-
eral years and the patient reevaluated. About 20% of patients are able to com-
pletely discontinue the medication and remain normoprolactinemic. The mainstay
of medical treatment is dopamine receptor agonists (D2 agonists).
Bromocriptine (Parlodel)
The first widely used dopaminergic agent used to treat prolactinomas was
bromocriptine. Response rate is over 80-90%. PRL serum levels show a drop as
early as 24 hours after starting therapy. In patients with macroadenomas, improve-
ment in visual symptoms starts a few days to two weeks after therapy is initiated.
Over 80% of patients will have a reduction in tumor size. The most common side
effects are GI related (nausea and vomiting). Other side effects are orthostatic hy-
potension, nasal congestion, and occasionally, psychotic symptoms. Side effects can
be minimized by starting with a lower dose at bedtime and gradually increasing it to
BID dosing. If side effects persist, switch from oral to vaginal administration. Pro-
lactin levels should be checked 4 weeks after starting therapy as well as 4 weeks after
adjusting the dose. In amenorrheic patients who desire pregnancy, bromocriptine is
the drug of choice due to its established fetal safety profile.
Cabergoline (Dostinex)
Cabergoine is another dopamine agonist. Unlike other agonists, cabergoline has
a long half-life and therefore is administered twice weekly. It also appears to have
fewer side effects compared to bromocriptine. Similar to bromocriptine, it can be
given vaginally in the event of intolerable side effects. Due to its lower side effect
profile and long half-life, cabergoline is often used as first line treatment except in
patients who desire pregnancy (more data exist on the safety of bromocriptine expo-
sure during early pregnancy). It is more expensive than bromocriptine.
Other Dopamine Agonists

Pergolide is a dopamine agonist used to treat Parkinson’s disease. It is less com-
monly used than bromocriptine but appears to be as effective. Another dopamine
agonist, not available in the United States, but with efficacy comparable to that of
bromocriptine, is quinagolide.
Surgery
Surgery should not be offered as first line therapy due to lower success rates
compared to medical therapy and a higher complication rate. The surgical cure
rate for microadenomas is in the range of 50-60%, while for macroadenomas it is
about 25%. Complications include visual loss, other cranial nerve injuries (CN
III, IV, V), cerebrospinal fluid rhinorrhea, meningitis, and damage to other pitu-
9 itary cells. Surgical mortality for macroadenomas is about 0.9%, while morbidity
is 6-20%.
Radiotherapy
Radiotherapy is generally considered as third line treatment due to the high
success rates of medical therapy and surgery when indicated.
Pregnancy Considerations (Table 9.2)
For women who desire pregnancy, bromocriptine is the drug of choice to assist
in achieving ovulation. It has a well-established safety profile when used during the
first few weeks of gestation. Fewer data are available on cabergoline.
For patients with microadenomas, bromocriptine can be stopped after concep-
tion. Such patients have a very low incidence of tumor enlargement during preg-
nancy (<5%) and therefore periodic imaging and visual field testing is not routinely
recommended. Nor is it necessary to measure prolactin levels in pregnancy, as there
is no correlation between tumor enlargement and serum prolactin levels.
For patients with macroadenomas, the risk of clinically significant tumor en-
largement during pregnancy is about 26%. There is no clear answer as to the best
therapeutic approach, but three management strategies exist:
1. Stop the bromocriptine (or other dopamine agonist) after conception and
closely follow up the patients (with visual field testing and imaging) for
signs of tumor enlargement
2. Perform a prepregnancy tumor debulking (however, such patients usually
still require bromocriptine to achieve ovulation)
3. Continue bromocriptine for the duration of the pregnancy. The few studies
on bromocriptine exposure during late gestation suggest that this is safe for
the fetus.
Table 9.2. Clinical course of prolactinoma in pregnancy

Symptomatic
Prolactinoma Type Previous Therapy Enlargement
Microadenoma None 1.4%
Macroadenoma None 26.2%
Macroadenoma Yes 3.0%
All pregnant patients with macroadenomas should have monthly visual field
testing.
Key Points
1. Regardless of the prolactin level, newly diagnosed hyperprolactinemia pa-
tients of suspected pituitary origin should have brain imaging performed to
rule out a macroadenoma or other stalk compressing lesions.
2. Females tend to present earlier than males due to menstrual disturbances.
3. The primary therapy for prolactinomas is medical. Second line treatment is
surgical, and third line is radiotherapy.
4. Patients desiring to conceive should preferably be placed on bromocriptine.
Suggested Reading 9
1. Biller BM, Baum HB, Rosenthal DI et al. Progressive trabecular osteopenia in women
with hyperprolactinemic amenorrhea. J Clin Endocrinol Metab 1992; 75(3):692-7.
2. Mah PM, Webster J. Hyperprolactinemia: Etiology, diagnosis, and management. Semin
Reprod Med 2002; 20(4):365-74, [This is a good review article on hyperprolactinemia.
It would serve as an excellent supplement to reading this chapter).
3. Luciano AA. Clinical presentation of hyperprolactinemia. J Reprod Med 1999; 44(12
Suppl):1085-90, [This is worth reading in full. It is a good clinical review of how
patients (both men and women) with elevated prolactin levels typically present to thei
physician].
4. Kletzky OA, Marrs RP, Howard WF et al. Prolactin synthesis and release during preg-
nancy and puerperium. Am J Obstet Gynecol 1980; 136(4):545-50.
5. Pollock A, McLaren EH. Serum prolactin concentration in patients taking neuroleptic
drugs. Clin Endocrinol (Oxf ) 1998; 49(4):513-6.
6. Honbo KS, Van Herle AJ, Kellett KA. Serum prolactin levels in untreated primary
hypothyroidism. Am J Med 1978; 64(5):782-7.
7. Molitch M. Medical management of prolactin secreting pituitary adenomas. Pituitary
2002; 5(2):55-65.
8. Webster J, Piscitelli G, Polli A et al. A comparison of cabergoline and bromocriptine in
the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study
Group. N Engl J Med 1994; 331(14):904-9.
9. Ciric I, Ragin A, Baumgartner C et al. Complications of transsphenoidal surgery:
Results of a national survey, review of the literature, and personal experience. Neuro-
surgery 1997; 40(2):225-36, (discussion 236-7).
10. Rossi AM, Vilska S, Heinonen PK. Outcome of pregnancies in women with treated or
untreated hyperprolactinemia. Eur J Obstet Gynecol Reprod Biol 1995; 63(2):143-6.
Chapter 10
Premenstrual Syndrome
Stephanie A.M. Giannandrea, Linda H. Chaudron
and Tana A. Grady-Weliky
Introduction
Clinical descriptions of premenstrual symptoms have been reported in the
medical literature since the time of Hippocrates. Emotional and physical symp-
toms occurring along a continuum of severity are common during the luteal phase
of the menstrual cycle. Premenstrual syndrome (PMS) is a complex of mild to
moderate emotional and/or physical symptoms, which typically do not interfere
with patients’ usual level of functioning. Up to 75% of reproductive-aged women
have reported premenstrual symptoms at some time during their lives. Premen-
strual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome,
which affects 3-8% of reproductive-aged women. The hallmark of premenstrual
syndrome at all levels of severity is the exclusive occurrence of symptoms during
the luteal phase of the menstrual cycle with remission typically within 3 days of
menses onset.
A diagnosis of premenstrual syndrome (PMS) requires at least one physical or
emotional symptom from the International Classification of Diseases—10th edi-
tion (ICD-10). Premenstrual dysphoric disorder, PMDD, is a more severe condi-
tion in which there is a marked mood change (depression, mood swings, irritability
or anxiety) as well as the presence of other physical and somatic symptoms. Pro-
spective symptom rating for at least two menstrual cycles and disruption in social
and/or occupational functioning are required to fulfill the “research” criteria for
this diagnosis found in the Appendix of the Diagnostic and Statistical Manual—
4th edition-Text Revision (DSM-IV-TR) and listed in Table 10.1. The presence
of the diagnosis of PMDD in the DSM classification has been met with signifi-
cant controversy. The controversy centered on the fact that only women could be
affected by this diagnosis and that it could potentially lead to gender discrimina-
tion. After a period of discussion and debate, it was determined that the diagnos-
tic criteria for PMDD would remain as “research” criteria to improve understanding
of the etiology and to identify the best treatment options.
Risk Factors
Family history of mood disorder, history of severe mood swings or negative
reactions to oral contraceptives, obesity, poor diet, and lack of exercise are among
the factors that increase a woman’s susceptibility to the development of PMS/
PMDD. A history of sexual or physical abuse also appears to put women at greater
risk for PMS.
Premenstrual Syndrome 97
Table 10.1. Premenstrual dysphoric disorder criteria*

A. In most menstrual cycles during the past year, five (or more) of the following
symptoms were present for most of the time during the last week of the luteal
phase, began to remit within a few days after the onset of the follicular phase,
and were absent in the week postmenses, with at least one of the symptoms
being either (1), (2), (3), or (4):
1. Markedly depressed mood, feelings of hopelessness,
or self-deprecating thoughts
2. Marked anxiety, tension, feelings of being “keyed up,” or “on edge”
3. Marked affective lability (e.g., feeling suddenly sad or tearful or increased
sensitivity to rejection)
4. Persistent and marked anger or irritability or increased 10
interpersonal conflicts
5. Decreased interest in usual activities (e.g., work, school, friends, hobbies)
6. Subjective sense of difficulty in concentrating
7. Lethargy, easy fatigability, or marked lack of energy
8. Marked change in appetite, overeating, or specific food cravings
9. Hypersomnia or insomnia
10. A subjective sense of being overwhelmed or out of control
11. Other physical symptoms, such as breast tenderness or swelling,
headaches, joint or muscle pain, a sensation of “bloating,” weight gain
Note: In nonmenstruating females (e.g., those who have had a hysterectomy),
the timing of luteal and follicular phases may require measurement of
circulating reproductive hormones.
B. The disturbance markedly interferes with work or school or with usual social
activities and relationships with others (e.g., avoidance of social activities,
decreased productivity and efficiency at work or school).
C. The disturbance is not merely an exacerbation of the symptoms of another
disorder, such as major depressive disorder, panic disorder, dysthymic
disorder, or a personality disorder (although it may be superimposed on any
of these disorders).
D. Criteria A, B, and C must be confirmed by prospective daily ratings during at
least two consecutive symptomatic cycles. (The diagnosis may be made
provisionally prior to this confirmation.)
*DSM-IV-TR research criteria
Clinical Symptoms and History

Premenstrual syndrome is characterized by mood swings, depressed mood, ir-
ritability and/or anxiety, which may be accompanied by physical symptoms. These
symptoms occur exclusively during the luteal phase of the menstrual cycle. Com-
mon physical symptoms observed in PMS are breast tenderness, abdominal bloat-
ing, headache, and joint and muscle aches. The diagnosis of PMDD requires
marked mood disturbance (depression, irritability, mood swings) as well as the
presence of other emotional and/or physical symptoms. Additionally, a significant
reduction in social and/or occupational functioning is required for the diagnosis

of PMDD. The functional impairment tends to be in social as opposed to occu-
pational domains. Prospective daily recording of the presence and severity of
symptoms for at least two menstrual cycles is used to confirm the diagnosis of
PMDD. Specific diagnostic criteria for premenstrual dysphoric disorder are shown
in Table 10.1.
Differential Diagnosis
A comprehensive history and physical examination are indicated to rule out
other possible causes of the emotional and physical symptoms of PMS. The differ-
ential diagnosis includes premenstrual molimina, hypothyroidism, perimenopause
and major mood or anxiety disorders. Most ovulatory women experience some
physical changes (e.g., breast tenderness, bloating, and food cravings) during the
10 luteal phase. If these physical symptoms do not interfere with normal life func-
tions, the term molimina can be applied. Hypothyroidism can share many of the
same symptoms as PMS; however there should be no cyclic variation. A thyroid
stimulating hormone level is a sufficient screen, if warranted by clinical suspicion.
There is also considerable overlap between the symptoms of perimenopause and
those of PMS. Many women experience symptoms of emotional irritability, cyclic
mastalgia, bloating and hot flashes as part of the perimenopause. It is likely that
similar pathophysiologic factors mediate symptoms in both disorders. In a practi-
cal sense, to document PMS, women should maintain a calendar of symptoms that
can be correlated with the reproductive cycle. For PMDD, women must meet the
DSM-IV-TR diagnostic criteria (Table 10.1).
Distinguishing the emotional symptoms observed in PMS from those present
in other major mood or anxiety disorders (e.g., major depressive disorder, dys-
thymia, panic disorder) is important because of the different treatment strategies.
Women with PMS respond to unique therapeutic interventions, such as calcium
carbonate, gonadotropin releasing hormone agonists and intermittent dosing with
serotonin reuptake inhibitors (SRIs). If patients present with continuous mood or
anxiety symptoms across the menstrual cycle, the diagnosis of PMS cannot be
made. If patients exhibit mood and/or anxiety symptoms across the menstrual
cycle with an increase in severity during the luteal phase, the appropriate diagno-
sis is premenstrual exacerbation (PME) of the underlying condition, not PMS.
Therefore, diagnostic verification of premenstrual syndrome is best accomplished
through prospective daily symptom recording (or “charting”). This prospective
rating is required to make a diagnosis of PMDD.
A number of valid and reliable diagnostic instruments, e.g., Calendar of Pre-
menstrual Experiences (COPE), Premenstrual Symptoms Screening Tool (PSST),
Visual Analogue Scale (VAS), Daily Record of Severity of Problems (DRSP), are
available to document emotional and physical symptoms across the menstrual
cycle. These forms include emotional, physical and functional symptoms that pa-
tients rate or “chart” daily using a Likert-type scale to assess the presence, timing,
and severity of symptoms. The diagnosis of PMS/PMDD is verified if there is: (1)
demonstrated evidence of a relative absence of symptoms during the follicular
phase of the menstrual cycle; (2) significant increase in emotional and/or physical
symptoms during the luteal phase of the menstrual cycle; and (3) functional im-
pairment during the luteal phase of the menstrual cycle (for PMDD).
Etiology
The etiology of PMS is not completely known, but appears to be multi-factorial.
Fluctuating hormones across the menstrual cycle play a role, since PMS is not ob-
served in prepubertal girls or in menopausal women. Recent studies have also sug-
gested a role for serotonin and other neurotransmitters in the etiology of PMS.
Because of the temporal relationship of PMS symptoms to corpus luteum func-
tion, the most obvious explanation for PMS would be the systemic and psychological
effects of sex steroids produced by the corpus luteum. However, multiple studies have
shown no difference between women with PMS and controls with respect to circulat-
ing levels of progesterone and estrogen. Investigators have examined daily steroid lev-
els, peak steroid levels and ratios of progesterone to estradiol, generally with the same
conclusion—no significant difference between women with PMS and controls.
Nonetheless, there is adequate evidence to suggest intrinsic differences in sensitiv-
ity to physiologic levels of estrogen and progesterone. Administration of a gonadotro- 10
pin releasing hormone (GnRH) agonist to women with PMS, which suppresses output
of estrogen and progesterone, can relieve their psychological symptoms, whereas women
without PMS do not show any consistent difference in mood. Allopregnanalone, a
metabolite of progesterone produced in the ovary and the brain, is believed to play an
important role because of its influence on GABA receptors. Recent efforts have fo-
cused mainly on neurotransmitter sensitivity to steroid hormones.
The serotonergic pathway has received much attention, in part because of its thera-
peutic implications. Use of the serotonin agonist μ-chlorophenylpiperazine in women
with PMS acutely improves depression and anxiety. The introduction of metergoline,
a serotonin antagonist, has been shown to reproduce premenstrual symptoms in women
who had demonstrated improvement on serotonergic reuptake inhibitors. Further,
numerous placebo controlled trials of serotonin reuptake inhibitors (SRIs) have shown
superior efficacy in reduction of premenstrual symptoms.
The physical symptoms of PMS are largely unexplained. Many women with
PMS are bothered by mastalgia, fluid retention, and bloating. No consistent differ-
ences have been shown in women with PMS with respect to prolactin, cortisol, or
thyroid hormone levels. Progesterone is a substrate for deoxycorticosterone (DOC)—
a potent mineralocorticoid. Renal 21-hydroxylase converts progesterone to DOC in
the kidney. This extraglandular DOC is thought by some to mediate the bloating
and fluid retention seen in PMS. However, a recent study of desoxycorticosterone
levels showed similar menstrual cycle variation in controls and women with PMS.
In summary, the etiologies of PMS and PMDD are not understood. Current
knowledge suggests that many of the psychological symptoms occur because of an
increased central sensitivity to physiologic levels of estrogen and progesterone. This
enhanced sensitivity appears to occur through serotonergic-mediated pathways.
Physical manifestations of PMS are not understood but may ultimately prove to be
another manifestation of increased sensitivity to normal cyclic hormonal variation.
Treatment
Therapeutic strategies for management of premenstrual symptoms can be di-
vided into two phases. First, the patient records or “charts” her symptoms for two
menstrual cycles, during which lifestyle interventions may be started. If she remains
symptomatic after the charting period and initial interventions, pharmacologic
therapy should be strongly considered.
Lifestyle Interventions
Patients with mild to moderate premenstrual symptoms have reported that re-
ducing caffeine, refined sugars, or sodium intake can be helpful. Although increased
exercise has been found to reduce symptoms of major depressive disorder, there is
no definitive evidence that it results in improvement of PMDD symptoms. There
are no recent controlled studies to support the anecdotal reports of the benefits of a
healthy diet and exercise for premenstrual syndrome. Nonetheless, these interven-
tions are recommended because of their other benefits and safety.
Nutritional, Vitamin and Alternative/Complementary
Treatment Strategies
Vitamin and mineral supplementation may also be beneficial. Dietary supple-
ments with increased tryptophan have been utilized in an effort to reduce premen-
10 strual symptoms, particularly carbohydrate craving. A variety of herbal medications
have also been used for treating PMS. This has been particularly welcomed by many
patients who prefer so-called natural remedies. Other alternative strategies that have
been investigated include acupuncture, massage therapy, and homeopathic remedies.
Randomized controlled trials of Vitamin B6, calcium, and carbohydrate-rich di-
etary supplements have demonstrated efficacy in premenstrual syndrome. A recent
meta-analysis revealed that vitamin B6 in daily doses of 50-100 mg reduced premen-
strual mood and physical symptoms. Calcium supplementation has also been shown
to be efficacious in the management of moderate to severe premenstrual symptoms.
A randomized controlled trial comparing calcium carbonate to placebo revealed
that 1200 mg of calcium carbonate resulted in a significant reduction of physical
(water retention, food craving and pain) and emotional (negative affect) premen-
strual symptoms.
Magnesium supplementation has also been studied in the treatment of PMS
with inconsistent findings. An early study revealed improvement in negative affect
and reduced overall score in women treated with 360 mg of magnesium daily com-
pared to the placebo group, but this was not supported by a more recent,
placebo-controlled study. Treatment with a carbohydrate-rich beverage, PMS
EscapeTM, compared to placebo revealed improvement in premenstrual mood symp-
toms. Dosing strategies and outcomes for vitamins and other supplements are listed
in Table 10.2.
Most studies of herbal remedies have been open label, which limits the ability to
interpret positive findings. However, most open trials and several controlled trials
have shown subjective improvement in physical and some emotional symptoms in
women who have taken these agents for at least 3 menstrual cycles. Evening of
primrose oil, St. John’s Wort (hypericum perforatum), and Chaste Tree (Vitex agnus
castus) are among the herbal remedies that have been studied in the treatment of
PMS. Of the herbal remedies, chasteberry/chaste tree (vitex agnus castus) is the
most promising based on recent randomized controlled trials. Dosing strategies for
herbal remedies are noted in Table 10.2.
In summary, vitamin B6, calcium, carbohydrate-rich supplements and possibly
magnesium may prove to be beneficial for patients with PMS. However, there is not
convincing evidence to date regarding the sole use of herbal remedies or alternative
treatments for the management of PMS. Clinicians need to be aware of these op-
tions as many patients express interest in their use. Moreover, adjunctive use of these
treatment methods may be beneficial in the engagement of patients in treatment.
Table 10.2. Vitamin, nutritional, and herbal dosing strategies

for PMDD
Agent Therapeutic Dose Side Effects1
Vitamin B6 50-1002 mg Peripheral neuropathy
Calcium carbonate3 1200 mg None reported
PMS EscapeTM 4 2 drinks daily None reported
5 days prior to menses onset
Agnus vitus extract5 20 mg6 Acne, urticaria,
(chasteberry) intermenstrual bleeding
1) Studies did not consistently report common side effects. However, suggested
guidelines for dosing should be followed as risk of side effects and/or complications
may increase with dosage increases. 2) Do not exceed 100 mg daily secondary 10
to the risk of peripheral neuropathy and other adverse effects. 3) Patients may
elect to use over-the-counter agents, e.g., TUMS. It may be administered by chewing
4 tablets daily (two tablets twice daily). 4) A carbohydrate rich drink that was
available for research purposes. There may be limited general availability.
5) Patients need to be aware of the lack of safety data among all herbal medications.
Different formulations may contain different amounts of the active ingredient.
6) Most studies utilized the following formulation—Vitex agnus castus L extract Ze
440. Specific formulations including the exact extract included in the tablet need
to be examined prior to initiation of any herbal remedy. Other ingredients (fillers)
should be examined to determine presence of additional active agents, which
may cause side effects.
Psychoeducation
Clinical experience has shown that by charting symptoms daily women learn
more about when their symptoms occur and what may exacerbate or minimize them.
This close monitoring may facilitate lifestyle changes that lead to a modest but mean-
ingful degree of symptom reduction. However, the degree of symptomatic improve-
ment is rarely complete. If dietary, nutritional, herbal or psychotherapeutic
interventions have not been effective, medication is generally indicated in order to
reduce symptoms and enhance the woman’s quality of life.
Cognitive Behavioral Therapy (CBT)
Several investigators have utilized cognitive behavioral therapy to manage mod-
erate to severe PMS, but the results have been inconsistent. Recent work has com-
pared the efficacy of cognitive behavioral therapy alone and in combination with
SRIs. Both formal CBT and medications were found to reduce symptoms, but women
treated with medications had a faster onset of relief. The group who received CBT
alone experienced more sustained improvement in their symptoms compared to
those who received medication alone. Interestingly, the combination of psychotherapy
and medication therapy did not seem to offer any particular advantage over either
treatment alone.
Pharmacologic Interventions
Antidepressants
Selective serotonin reuptake inhibitors (SSRIs) are first line agents for PMDD
treatment. Recommended treatment guidelines for SSRI use in PMDD are included
in Table 10.3. Numerous double-blind, randomized controlled clinical trials have

shown that almost all SSRIs are superior to placebo for treatment of the emotional
and physical symptoms of PMDD. The majority of these trials have shown symp-
tom improvement within three cycles of active treatment. Fluoxetine and sertraline
are the most studied selective serotonin reuptake inhibitors in PMDD.
Fluoxetine has consistently proven more effective than placebo in randomized
studies. In a study including 277 patients who would meet current criteria for PMDD,
fluoxetine at doses of 20 mg or 60 mg daily was superior to placebo in reducing
premenstrual emotional and physical symptoms. This study found a statistically
significant difference in response rate during the first treatment cycle with 52 per-
cent of patients on fluoxetine demonstrating moderate improvement (defined as at
least 50 percent reduction in baseline symptoms) compared to 22 percent of pa-
tients on placebo. The 60 mg daily dose, however, produced more side effects and
10 higher dropout rates without superior efficacy compared to the 20 mg daily dose.
Other randomized controlled trials of daily and/or intermittent (luteal) dosing of
fluoxetine have found it to be more effective than placebo in the treatment of severe
premenstrual syndrome. Cohen and colleagues found that fluoxetine was more ef-
fective in the reduction of overall PMS symptoms, particularly emotional symp-
toms and social functioning at doses of 10 mg and 20 mg administered during the
premenstrual time. Twenty milligrams of fluoxetine was shown to be more effective
than both the 10 mg dose and placebo in the treatment of physical symptoms.
Fluoxetine has been found to improve physical symptoms, work functioning and
quality of life associated with PMDD as well.
Table 10.3. Continuous (daily) SSRI/SNRI dosing and treatment

strategies for PMDD
Starting Therapeutic
SSRI Dose (mg) Dose (mg) Common Side Effects1
Fluoxetine 10-20 20 Insomnia, nausea, fatigue
Sertraline 25-50 50-1502 Nausea,diarrhea, insomnia
Paroxetine 10-20 20-30 Dry mouth, constipation, nausea,
sedation
Citalopram 10-20 20-30 Headache, sweating, dry mouth,
sedation
Venlafaxine 50 50-2003 Nausea, dizziness, insomnia,
decreased libido
1) Sexual dysfunction (anorgasmia and decreased libido), sleep alterations
(insomnia, sedation, hypersomnia) and gastrointestinal distress (nausea and
diarrhea) are common side effects across all SSRIs. Specific side effects that may
be more likely to occur with the identified SSRI are listed. 2) Patients with PMDD
will typically demonstrate a response to sertraline doses of 50-100 mg daily.
However, a subset of patients may require slightly higher doses (up to 150 mg). If
a patient is taking another SSRI and tolerating it well, but has a partial response at
the dosages listed, it would be appropriate to raise the dose of the specific SSRI
prior to switching to another agent. 3) Patients with PMDD typically respond to
lower venlafaxine doses of 50-100 mg daily. However, a subset of patients may
require venlafaxine doses of 225 or 300 mg daily.
Sertraline has also been found to be more effective than placebo for PMDD in
multiple randomized controlled trials. In a study of 243 women with PMDD,
sertraline at 50 to 150 mg daily was more effective than placebo for premenstrual
emotional and physical symptoms. Overall response rate (defined by clinician ob-
server ratings of “much” or “very much” improved) in this study was significantly
different with a 62% response in the sertraline group and a 34% response in the
placebo group. Additional double-blind studies of sertraline have also shown that
doses of 50 to 150 mg administered daily or just during the luteal phase are effective
in improving overall function and reducing a range of premenstrual symptoms.
Paroxetine and citalopram have also been found to be effective for the treatment
of PMDD. Recent studies of controlled release paroxetine at doses of 12.5 mg and
25 mg daily revealed significant improvement in emotional symptoms of PMS com-
pared to placebo. Physical symptoms were noted to improve with continuous and
luteal phase administration of the 25 mg paroxetine CR dose compared to 12.5 mg 10
daily and placebo. In an early study of daily paroxetine treatment compared with
maprotoline, a noradrenergic antidepressant, and placebo, immediate release
paroxetine was found to be significantly better than maprotoline or placebo for
improvement of premenstrual mood and physical symptoms.
Although the majority of clinical trials of SSRIs have examined continuous
administration of medication throughout the menstrual cycle, SSRIs may also be
administered only when the patient is symptomatic. This method, called luteal
phase or “intermittent” dosing, involves initiating medication at the time of ovula-
tion and discontinuing it at the time of onset of menses. Several double blind,
controlled trials have documented the effective use of luteal phase dosing strategies
with SSRIs including fluoxetine, sertraline, controlled-release paroxetine, and
citalopram. Some data support intermittent dosing as the preferred strategy. One
study compared several dosing strategies for citalopram in patients with severe pre-
menstrual syndrome: continuous, “semi-intermittent” (low dose in the follicular
phase and full dose in the luteal phase) and intermittent (full dose in the luteal
phase only). As compared with placebo (given continuously), all active treatment
groups significantly reduced premenstrual symptoms, but intermittent and
“semi-intermittent” dosing strategies were more effective than continuous dosing.
The efficacy of intermittent dosing is an important finding because many patients
would prefer to take medication only during their symptomatic period. Both con-
tinuous and intermittent dosing studies with SSRIs have demonstrated symptom-
atic reduction during the initial treatment cycle with further improvement over the
course of active treatment.
To help women with PMS and regular menstrual cycles initiate intermittent or
luteal phase dosing, clinicians may instruct patients to begin the antidepressant 2
weeks prior to the time their period is expected. Patients should remain on the
medication over the two weeks and discontinue medications on the day of menses
onset. Interestingly, patients do not experience discontinuation symptoms after stop-
ping the SSRIs, nor do they develop adverse effects with start up of medication at
the time of each new cycle.
Other antidepressant agents have been studied for the treatment of PMDD.
Venlafaxine, a serotonergic and noradrenergic reuptake inhibitor, has been found to
be efficacious in treatment of PMDD. In one trial, 60% of women treated with
venlafaxine (continuous dosing) had at least a 50% reduction in total symptoms
compared to 35% of women on placebo. Many women experienced rapid relief of
symptoms within the first treatment cycle on a dose of 50 mg of venlafaxine. An

open-trial of luteal phase administration of venlafaxine at doses of 75-112.5 mg
demonstrated efficacy in the treatment of premenstrual mood and physical symp-
toms. Symptomatic improvement at these doses may be secondary to the fact that
venlafaxine has greater serotonergic activity than noradrenergic activity at lower doses
compared to the higher doses.
Fluvoxamine, another SSRI, approved for the treatment of obsessive compulsive
disorder has also been studied in the treatment of PMS, but results are inconsistent
suggesting the need for further study. Clomipramine, a tricyclic antidepressant, has
been found to be more effective than placebo for PMDD in both continuous and
luteal phase dosing studies. Open label studies have suggested that nortriptyline and
nefazodone are effective for premenstrual symptoms, but these agents have not been
tested in randomized controlled trials. Antidepressants that are not SSRIs are cur-
10 rently considered second-line therapies due to the limited data as well as reduced
tolerability and side effect profile.
Importantly, several comparative studies have found antidepressant agents with
increased serotonergic activity to be more effective than those with primary norad-
renergic activity, such as desipramine and maprotoline or dopaminergic action, such
as bupropion. These medications with minimal, if any, serotonergic activity, have
limited, or no, efficacy in the management of PMDD compared to placebo.
Anxiolytics
Alprazolam, a triazolobenzodiazepine anxiolytic agent, has also been studied in the
treatment of premenstrual syndrome. Of five randomized controlled trials, four found
alprazolam to be more effective than placebo. In positive studies, alprazolam was par-
ticularly effective for management of premenstrual anxiety. Clinicians should remain
cautious when prescribing alprazolam given its risk of tolerance and dependence.
Buspirone, a nonbenzodiazepine anxiolytic agent, has not been found to be bet-
ter than placebo for the treatment of PMS.
Hormonal Treatments
If treatment is unsuccessful with a SRI or a second-line psychotropic agent,
hormonal therapies should be considered. Spironolactone, a diuretic and ste-
roid antagonist, has been shown to reduce premenstrual bloating, weight gain
and negative emotions. Oral contraceptives are frequently used for treatment of
mild to moderate premenstrual symptoms. There are several open trials sup-
porting the efficacy of an oral contraceptive containing drospirenone, a progesto-
gen that is also an analogue of spironolactone, for moderate to severe premenstrual
symptoms.
Progesterone has also been used for the treatment of premenstrual syndrome,
but a recent meta-analysis found that progesterone and other progestogens were
no more effective than placebo. In contrast, gonadotropin releasing hormone
(GnRH) agonists, including leuprolide and buserelin, were superior to placebo in
the reduction of premenstrual emotional (irritability, depression) and physical
(bloating, breast tenderness) symptoms in four double-blind controlled studies.
Although GnRH agonists may be effective for PMDD, the parenteral route of
administration (for leuprolide), cost, and potential side effects, including hot flushes
and vaginal dryness, make them a third line treatment strategy.
Key Points
Premenstrual symptoms are common among reproductive-aged women. Mild
to moderate symptoms are reported in up to 75% of women with severe symptoms
and functional impairment (PMDD) affecting 3-8%. A comprehensive assessment
of symptoms, including prospective daily symptom ratings for at least two consecu-
tive menstrual cycles is needed to make the diagnosis of premenstrual dysphoric
disorder. While patients are recording or “charting” their symptoms across the men-
strual cycle, clinicians may encourage patients to engage in healthy lifestyle inter-
ventions (diet and exercise) as well as undergo trials of calcium supplementation
(1200 mg daily) and/or use of vitamin B6 50-100 mg daily. While patients may
express interest in herbal medications, it is important to keep in mind that the ma-
jority of positive studies have been open trials. Moreover, most alternative and comple-
mentary treatments, such as St. John’s Wort, relaxation, massage therapy and
magnesium, do not have demonstrated efficacy for treatment of PMDD. 10
If the patient does not respond to the initial interventions and a diagnosis of
severe PMS or PMDD is confirmed with the prospective ratings, a trial of an SSRI
should be initiated. The most appropriate dosing method (intermittent or luteal
phase vs. continuous administration) remains uncertain. However, recent data and
clinical experience suggest that the initial antidepressant trial should be one utilizing
a luteal phase or intermittent dosing strategy (Table 10.4). Because ovulation testing
may be too burdensome and costly, it is reasonable for patients to begin taking the
prescribed SSRI two weeks prior to the expected onset of menses, which should
approximate onset of the luteal phase. Patients should complete a course of at least
three cycles on this medication prior to considering an alternate treatment strategy.
Typically, patients will begin to notice a reduction in symptoms within three to five
Table 10.4. Intermittent (Luteal) SSRI/SNRI dosing strategies

for PMDD
Starting Therapeutic Discontinuation
SSRI/SNRI Dose (mg) Dose (mg) Effects1
Fluoxetine 10 202 Same as placebo
Sertraline3 50 50-100 Headache, nausea, dry mouth,
sexual dysfunction
Paroxetine CR 12.5 12.5-25 Nausea, asthenia, dizziness
reduced libido, diarrhea,
sweating, tremor4
Venlafaxine 75 75-112.5 Headaches, vivid dreams,
sweating, muscle cramps, insomnia
1) Luteal phase administration of SRI/SNRIs have not demonstrated significant
side effects with initiation or discontinuation with each cycle. Agents with shorter
T1/2 may be more likely to produce mild to moderate discontinuation effects. The
controlled trials of these agents did not demonstrate increased drop-out rates for
active medication compared to placebo. 2) Fluoxetine 20 mg was more effective
than 10 mg for the management of premenstrual physical symptoms. 3) Intermittent
sertraline did not demonstrate significant improvement compared to placebo for
physical symptoms. 4) Side effects were seen more often in patients on paroxetine
CR 25 mg compared to 12.5 mg.
days of medication therapy with luteal phase dosing. However, some patients may
require several cycles before noticing any significant change. There are no current
data to support switching to a different SSRI if the initial one fails or moving from
luteal phase to continuous dosing strategies. Nevertheless, clinical experience sug-
gests that these two strategies may be utilized in the event of an initial treatment
failure. Therefore, if the patient does not demonstrate any improvement in her symp-
toms after several luteal phase treatment cycles, it is reasonable to begin a trial of an
alternate SSRI for three cycles with luteal phase dosing if the patient has been com-
pliant with this regimen. Alternatively, the patient may be tried on the same or a
different SSRI with continuous dosing.
The most appropriate duration of pharmacological treatment for PMDD has
not been determined. Studies have demonstrated a return of symptoms after discon-
tinuation of treatment with a faster return of symptoms in patients with brief treat-
10 ment duration. Therefore, following the demonstration of a positive response to
treatment, it is currently recommended for the patient to remain on the effective
dose for at least 12 months.
With better identification of patients with PMDD and appropriate diagnostic
verification, clinicians will improve the quality of life for women with severe pre-
menstrual symptoms. Enhanced physician, patient and public education about
PMDD may foster more research in the area, which should lead to improved under-
standing of PMDD and to the development of more specific therapies.
Suggested Reading
1. Wittchen HU, Becker E, Lieb R et al. Prevalence, incidence and stability of premen-
strual dysphoric disorder in the community. Psychol Med 2002; 32:119-132.
2. Perkonigg A, Yonkers KA, Pfister H et al. Risk factors for premenstrual dysphoric
disorder in a community sample of young women: The role of traumatic events and
posttraumatic stress disorder. J Clin Psych 2004; 65:1314-1322.
3. Hylan TR, Sundell K, Judge R. The impact of premenstrual symptomatology on func-
tioning and treatment seeking behavior: Experience from the United States, United
Kingdom, and France. J Womens Health Gend Based Med 1999; 8:1043-1052.
4. Steiner M, Streiner DL. Validation of a revised visual analog scale for premenstrual
mood symptoms: Results from prospective and retrospective trials. Can J Psychiatry
2005; 50(6) :327-332.
5. Roca CA, Schmidt PJ, Smith MJ et al. Effects of metergoline on symptoms in women
with premenstrual dysphoric disorder. Am J Psychiatry 2002; 159:1876-1881.
6. Stevinson C, Ernst E. Complementary/alternative therapies for premenstrual syndrome:
A systematic review of randomized controlled trials. Am J Obstet Gynecol 2001;
185:227-235.
7. Hunter MS, Ussher JM, Cariss M et al. Medical (fluoxetine) and psychological
(cognitive-behavioural therapy) treatment for premenstrual dysphoric disorder. A study
of treatment processes. J Psychosom Res 2002; 53:811-817.
8. Grady-Weliky TA. Premenstrual dysphoric disorder. N Engl J Med 2003; 348:433-438.
9. Halbreich U, Bergeron R, Yonkers KA et al. Efficacy of intermittent, luteal phase
sertraline treatment of premenstrual dysphoric disorder. Obstet Gynecol 2002;
100:1219-29.
10. Borenstein J, Yu HT, Wade S et al. Effect of an oral contraceptive containing ethinyl
estradiol and drospirenone on premenstrual symptomatology and health-related qual-
ity of life. J Reprod Med 2003; 48:79-85.
11. Wyatt K, Dimmock P, Jones P et al. Efficacy of progesterone and progestogens in
management of premenstrual syndrome: A systematic review. BMJ 2001; 323:1-8.
12. Wyatt KM, Dimmock PW, Ismail KMK et al. The effectiveness of GnRHa with and
without ‘add-back’ therapy in treating premenstrual syndrome: A meta analysis. BJOG
2004; 111:585-593.
Chapter 11
Treatment of the Menopausal Woman

Ghassan Haddad and Daniel B. Williams
The Menopause
The menopause is defined by the World Health Organization as the point in
time of permanent cessation of menstruation due to loss of ovarian function. Clini-
cally, the menopause is characterized by persistent amenorrhea for a period of twelve
months. Laboratory findings in the menopause generally reveal low serum estradiol
levels with elevated follicle stimulating hormone (FSH) levels. The specific levels
may vary depending on the assay used. The perimenopause, or climacteric, is de-
fined as the period of diminishing ovarian function preceding the menopause to one
year following the final menses, generally lasting between 2 and 8 years. Currently,
the average age of menopause in the United States is approximately 51 years and the
average life expectancy is approximately 80 years. Consistent with this, almost one
half of the average woman’s life is spent in the post-menopausal period.
The Transition
The reproductive life span can be divided into three phases: the reproductive
years, the perimenopause, and the postmenopause. The perimenopause can be fur-
ther subdivided into early and late stages. The greatest stability and efficiency of
ovarian function is between the ages of 25 and 34. Ovulatory variability is greatest
before the age of 20 and after the age of 40 years, resulting in an increased frequency
of anovulatory cycles, erratic cycle length, and abnormal uterine bleeding.
The early perimenopause is characterized by slowly declining ovarian function,
increasing frequency of anovulatory cycles, irregular cycle lengths, fluctuating gona-
dotropin levels, and an overall increase in FSH and luteinizing hormone (LH) lev-
els. FSH levels, in particular, may fluctuate widely, changing with each cycle, largely
due to a decrease in the number of ovarian follicles. With loss of ovarian follicles as
well as granulosa cells, inhibin levels, which normally provide negative feedback on
the pituitary FSH secretion, decrease. This results in the loss of the negative feed-
back loop between inhibin and FSH, leading to an elevation of FSH levels. FSH
levels trend upward starting in the late reproductive years, even before changes in
the menstrual cycle, once inhibin levels fall low enough to allow a rise in FSH levels.
Thus, the routine measurement of serum FSH to determine if a woman is
perimenopausal can be misleading. Therefore, clinical evaluation becomes impor-
tant in making the diagnosis of perimenopause. Symptoms of early perimenopause
are variable but include: hot flashes, premenstrual dysphoria, breast tenderness, in-
somnia and the menstrual cycle changes described above.
As the transition proceeds to the late perimenopause phase, continued alter-
ations in the production and subsequent levels of sex steroid hormones occur. Ovu-
lation eventually ceases and the supply of ovarian follicles is eventually exhausted,
resulting in permanent loss of fertility. However, the ovarian stroma continues to

produce androstenedione and testosterone in significant amounts. As estrogen lev-
els decline into the postmenopausal range, estradiol is no longer made by the fol-
licle, but by peripheral conversion of estrone, testosterone, and, most importantly,
androstenedione. The major estrogen sources throughout this period are the adrenal
glands via the conversion of androstenedione to estrone in adipose tissue. In addi-
tion, the adrenals continue to secrete testosterone and small amounts of estrogen, as
well as dihydroepiandrostenedione (DHEA) and dihydroepiandrostenedione-sulfate
(DHEAS). However, with increasing age, the adrenals produce smaller amounts of
androgen, which also results in diminished peripheral estrogen production over time.
With the menopause, significant reductions in estrogen levels are noted with a
less significant decrease in androgen levels. FSH and LH levels increase markedly
without change in other pituitary hormones. Finally, at the completion of the late
perimenopause, now 12 months after the last menses and beginning the meno-
11 pausal phase, gonadotropin levels have reached their final menopausal levels (usu-
ally >40 mIU/ml).
Symptoms of Menopause
Common early symptoms of menopause include hot flashes, insomnia, irritabil-
ity, and mood disorders, which can occur secondary to vasomotor instability. Physi-
cal changes include vaginal atrophy, urinary stress incontinence and skin atrophy.
Long term health risks that have been attributed to the hormonal changes from
menopause, include: osteoporosis, cardiovascular disease, and in some studies
Alzheimer’s disease, macular degeneration, and stroke.
Vasomotor Symptoms
Vasomotor instability or the “hot flash” is a common complaint of the
perimenopausal and menopausal woman, affecting 60 to 85% of all women. Hot
flashes usually occur suddenly, though some women may experience an aura or
premonition of the impending hot flash, and generally begin with an intense feeling
of heat in the face and thorax. Visible flushing or reddening of the face and neck
often follows, with a rise in heart rate and skin blood flow. Skin resistance drops
rapidly, resulting in increased skin conductance of heat and a sensation of skin warmth.
An increase in peripheral blood flow, heart rate, and finger temperature can result in
palpitations and profuse sweating.
Although hot flashes occur for 0.5 to 5.0 years on average after last menses, they
may persist beyond five years, and up to 10% of women experience hot flashes for
greater than 15 years. Their frequency ranges from 5 to 50 per day, with an average
duration of 4 minutes. Women who have undergone surgical menopause are more
likely to experience hot flashes than naturally menopausal women, often reaching
an incidence of 100% in the first year postoperatively and most commonly de-
scribed as severe. Although hot flashes often occur spontaneously, they may also be
provoked by stress, emotional situations, external heat or warm weather, confining
spaces, alcohol use, or caffeine use. Therefore, avoidance/modification of these fac-
tors can improve symptoms in some patients.
The cause of hot flashes remains unclear, but they are thought to occur second-
ary to sudden changes in hypothalamic control of temperature regulation. Estrogen
is believed to reduce hot flashes by modulating the firing rate of thermosensitive
neurons in the preoptic area of the hypothalamus. Hot flashes are worse at night for
Treatment of the Menopausal Woman 109
Table 11.1. Currently available and combined oral HRT prepar-

ations in the US
Medication Brand Name Available Doses
Single Agent
Conjugated equine Cenestin 0.3, 0.625, 0.9, 1.25 (mg)
estrogens Menest 0.3, 0.625, 1.25, 2.5 (mg)
Premarin 0.3, 0.45, 0.625, 0.9, 1.25 (mg)
Estradiol Estrace 0.5, 1, 2 (mg)
Estropipate (piperazine Ogen 0.75, 1.5, 3, 6 (mg)
estrone sulfate) Ortho-Est 0.75, 1.5 (mg)
Combined Agents
Conjugated equine Prempro 0.3/1.5; 0.45/1.5; 0.625/2.5; 11
estrogens/medroxy- 0.625/5 (mg/mg)
progesterone acetate Premphase 0.625/0 x 21days, then
0.625/5 x 7 days (mg/mg)
Conjugated equine Estratest 1.25/2.5 (mg/mg)
estrogens/methyl-
testosterone
Estradiol/norgestimate Prefest 1/0 x 21 days, then
1/0.09 x 7 days (mg/mg)
Estradiol/norethindrone Activella 1/0.5 (mg/mg)
Ethinyl estradiol/ FemHRT 5/1 (μg/mg)
norethindrone
Reprinted with permission from: Moghadam KK, Williams DB. Advances in

menopausal hormonal delivery systems: A comparative review. Am J Drug Deliv
2005; 3:7-16.
many women, resulting in night sweats, multiple episodes of awakening, and overall
nonrestful sleep. The resulting decreased sleep efficiency caused by hot flashes may
explain the associated chronic fatigue and irritability from which many menopausal
women suffer. The most effective treatment for hot flushes is estrogen, which can be
given through a variety of regimens, that are described below and listed in Tables
11.1-11.3.
Regimens for Hormone Replacement
Estrogen can be administered by oral, parenteral, topical or transdermal routes
with similar effects and there are several different formulation choices available.
Continuous estrogen therapy is recommended, though doses and route of adminis-
tration can be changed relative to patient preference. Oral estrogen is the most popular
in the United States. Transdermal estrogen patches avoid the first pass effect on the
liver and offer the convenience of less frequent administration (usually weekly).
Topical estradiol gel also avoids the first pass effect; it is rubbed on the arm once
daily. Finally, a slow release vaginal ring can provide sustained symptomatic relief for
3 months at a time. There are lower doses available for the patches and pills that
prevent bone loss as well as hot flashes. It is important to remember that a woman
Table 11.2. Currently available transdermal/topical ERT prepar-

ation in the US
Single Agent
Estradiol Alora 0.05, 0.075, 0.1 (mg) 2 x per wk
Climara 0.025, 0.0375, 0.05, 0.06,
0.075, 0.1 (mg) 1 x per wk
Estraderm 0.05, 0.01 (mg) 2 x per wk
Vivelle 0.025, 0.0375, 0.05, 0.06,
0.075, 0.1 (mg) 1 x per wk
EstroGel 1.25g 1 x per day
Combined Agents
11 Estradiol/norethindrone Combipatch 0.05/0.14; 0.05/0.25 (mg/mg)
2 x per wk
Estradiol/levonorgestrel ClimaraPro 0.045/0.015 (mg/mg) 1 x per wk

2005; 3:7-16.
with an intact uterus should receive a progestin in addition to her estrogen for en-
dometrial protection.
There are a number of different progestins that can be used for HRT including
the medroxyprogesterone (MPA) and micronized progesterone, as well as 19-nor
testosterone derivatives such as norethindrone. Progestins are usually given cycli-
cally or continuously. Tables 11.1 and 11.2 list some of the combination products.
Estrogens, if given orally, are usually administered daily with differences in regi-
mens dependent on how the progestin is given. A variety of topical and transdermal
agents with weekly administration are also available (Table 11.2). Cyclic therapy
usually involves the administration of the progestin agent for 10-14 days each month.
Since the estrogen is given daily, it is easiest to administer the progestin agent from
the 1st to the 12th of each month. This usually results in a predictable, monthly,
withdrawal bleed. Quarterly therapy consists of daily administration of estrogen,
with a progestin administered for 14 days every 3 months. This typically will result
in a withdrawal bleed every 3 months, which is preferable to some patients. Con-
tinuous combined therapy involves the daily administration of both an estrogen and
a progestin. The goal of continuous therapy is to produce amenorrhea by inhibition
of endometrial growth. Tables 11.2-11.4 list the various types and doses of estrogen
and progestins that are currently available.
Alternative Treatments for Hot Flashes
There are a number of alternative therapies for women who are symptomatic
from menopausal hot flashes but cannot take estrogen therapy. Venlafaxine hydro-
chloride and paroxetine are serotonin reuptake inhibitors that effectively reduce hot
flash frequency and severity. Other drugs in this class, including fluoxetine, may also
be effective, but there are few published data. Recent studies suggest that women
Table 11.3. Currently available single intravaginal ERT prepar-

ations in the US
Conjugated equine Premarin cream 0.625 mg/g; 1-2 g daily x 2 wk,
Estrogen cream then 1 g daily 1-3 x wk
Estradiol cream Estrace cream 0.1 mg/g; 2-4 g daily x 2 wk,
then 1 g daily 1-3 x wk
Dienestrol cream Orthodienestrol 0.01 mg/g; 1-2 app qd x 2 wk,
then taper to 1-2 x wk
Estradiol tablets Vagifem tablets 0.025 mg daily x 2 weeks, attempt
to discontinue over 3 to 6 mos
Estradiol ring Estring 0.075 mg/d ring; insert ring
vaginally every 90 days
11
Femring 0.05 mg, 0.1 mg/d ring;
insert vaginally every 90 days

2005; 3:7-16.
given neurontin have fewer hot flashes than those given placebo. Low dose progestins
are effective in the treatment of menopausal symptoms to a moderate degree, but
still a form of hormonal therapy and may be a source of concern in patients with a
history of breast cancer. Two antihypertensives, clonidine and methyldopa, have
been used to treat vasomotor symptoms, suggesting a role for adrenoreceptors in the
physiology of these symptoms. Low dose clonidine, is partially effective in the relief
of hot flashes, but for many women, adequate therapy requires substantial doses and
severe side effects. Methyldopa, at doses of 500 to 1000 mg/d, has been shown to be
twice as effective as placebo for the treatment of hot flashes. Veralipride is a dopam-
ine antagonist that has been shown to be active in the hypothalamus, effectively
inhibiting flushing at a dose of 100 mg/day. However, it is associated with major
side effects such as galactorrhea and mastodynia. Bellergal is a combination of bella-
donna alkaloids, ergotamine tartrate, and phenobarbital that has been proven to be
slightly better than placebo in the treatment of hot flashes, but with significant
sedating effects.
Alternative Medicine
This approach includes dietary supplements, which are not considered to be
drugs by the Food and Drug Administration (FDA) and therefore are not subject to
the strict regulation and safety guidelines imposed on conventional medications. As
a result, significant variation can occur in the content and potency of each batch of
supplement. Phytoestrogens are plant-derived compounds with estrogen effects soy-
beans are a particularly rich source of phytoestrogens with approximately 1 to 3 mg
of phytoestrogen per gram of soy protein. Since it would be very difficult to con-
sume sufficient soy to alleviate menopausal symptoms in a typical Western diet,
some patients opt to take soy supplements. Some (but not all) studies have sug-
gested that isoflavones in soy products reduce the frequency and severity of hot
Table 11.4. WHI absolute risks/benefits*

HRT ERT
Heart disease +7 -5
Invasive breast CA +8 -7
CVA +8 +12
VTE +18 +7
Osteoporotic fracture -47 -56
Colon CA -6 +1
*Number of events per 10,000 women/yr compared to placebo.
flashes, favorably effect lipid profiles and increase bone mineral density (BMD).
11 Black cohosh or remifemin is another popular herbal medication that has been used
to treat menopausal symptoms. Clinical trials show that it is superior to placebo for
relief of hot flashes and short term safety data are reassuring. However, many of the
efficacy studies are open label and there are no long term safety studies, particularly
with respect to effects on breast and endometrium. Finally, vitamin E at a dose of
800 IU daily has been shown to be only slightly more effective than placebo in the
treatment of menopausal symptoms. Further study is needed in this area to deter-
mine whether there is a definitive benefit from these forms of therapy.
Genitourinary
With declining estrogen levels, vaginal pH rises from acidic to basic levels,
resulting in the decline of the previously predominant lactobacilli and a newly
hospitable environment to previously atypical bacteria colonizing the vagina, most
significantly enterobacteria. This is thought to result in an increased risk of uri-
nary tract infections. There are also marked atrophic changes of the urethra, re-
sulting in dysuria and frequency. Atrophy of the vulva and vagina can also be seen
in the menopause. Genital symptoms include: decreased lubrication, burning, itch-
ing, discharge, dyspareunia, and sexual dysfunction. Urinary symptoms include
frequency, dysuria, hematuria, and incontinence. Numerous studies have demon-
strated the effectiveness of local, oral, or transdermal estrogen for treating symp-
toms of vulvar and vaginal atrophy. A review of the literature shows conflicting
results regarding the role of estrogen therapy in treating urinary incontinence,
including a meta-analysis that concluded that estrogen has only a small effect, if
any, on urinary incontinence.
Local Therapy (Vaginal or Topical Administration)
Estrogen creams, estrogen tablets and the estrogen ring are options for localized
hormonal therapy, which can allow administration of a lower dose of estrogen, avoid-
ing systemic effects. The low dose estradiol vaginal ring (Estring) is placed in the
vagina delivering estrogen associated with no detectable changes in blood estradiol
or estrone levels. These alternative methods of localized estrogen therapy offer im-
portant alternatives for those women who cannot or choose not to receive oral or
transdermal therapy. Localized estrogen therapy primarily addresses symptoms re-
lated to vaginal atrophy.
Osteoporosis
Osteoporosis is defined pathologically as an absolute decrease in the amount
of bone, resulting in an increased risk of fracture with minimal trauma. It is a
major long-term health risk associated with the loss of estrogen from the meno-
pause. Hip fracture incidence appears to be race dependent, with a lifetime risk of
hip fracture of 17.5% in white women, but only of 5.6% in African American
women. However, although hip fractures are much less common in nonwhites,
they remain a significant problem for all elderly women and men, regardless of
race. By extreme old age, one of every three women and one of every six men will
have a hip fracture. Of all hip fractures 12 to 20% will be fatal and 50% of survi-
vors will require long-term nursing care, resulting in total annual costs of 6.1
billion dollars in the United States.
Pathophysiology
The pathophysiology of osteoporosis is based on a disruption of the bone re- 11
modeling unit coupling process, which involves osteoclasts, the bone resorbing cells,
and osteoblasts, the bone forming cells. In adults 25% of trabecular bone (i.e., verte-
brae, forearm) and 3% of cortical bone (i.e., hip) is absorbed and replaced each year.
Osteoporosis occurs when bone resorption by osteoclasts is greater than bone for-
mation by osteoblasts. Loss of estrogen in the early menopause can be associated
with a significant reduction in bone during the first 5-8 years of the menopause
(trabecular, 5%/yr; cortical, 1-2%/yr),
Bone loss in the early postmenopausal period is associated with increased osteo-
clast activity with normal osteoblast activity, which primarily affects trabecular bone.
In contrast, the later menopausal period is associated with normal osteoclast activity
in the face of decreased osteoblast activity, primarily affecting cortical bone. Consis-
tent with these differences, bone loss associated with early menopause occurs prima-
rily in trabecular bone (i.e., vertebral and distal forearm), while the slow progressive
bone loss consistent with aging occurs primarily in cortical bone (i.e., hip).
Risk Factors and Diagnosis
Some of the risk factors for osteoporosis include low estrogen, low bone density,
trauma, inadequate peak bone mass, family history, low body weight, inactivity,
excessive glucocorticoid use or Cushing’s syndrome, osteomalacia, long term hep-
arin therapy, multiple myeloma, long-term anticonvulsant use, hyperthyroidism,
hepatobiliary disease, excessive caffeine intake, smoking, heavy alcohol use and type
I diabetes mellitus.
Osteoporosis is generally diagnosed on the basis of low bone mineral density or
clinical evidence of bone fragility in a patient who has no other reason for low bone
mass (e.g., osteomalacia, myeloma, etc.). Bone mineral density (BMD) is usually
measured by dual-energy X-ray absorptiometry (DEXA) which utilizes transmis-
sion of two energy beams passed through bone and then compared to a standardized
control. Using DEXA, osteoporosis is defined as a BMD greater than 2.5 SD below
the mean value of peak bone mass in young normal women (T score of <-2.5).
Osteopenia, or low bone mass, is defined as T score between -1 and -2.5. A normal
bone mass is defined as T score -1 or higher. DEXA should be performed in all
postmenopausal women ≥60-65 y/o, those 50-60 y/o with one or more risk factors
for osteoporosis, and all postmenopausal women with fractures.
Biochemical markers of bone metabolism that reflect bone formation or break-

down may occasionally be useful in the clinical treatment of patients with osteoporosis.
The three principle markers of bone formation are alkaline phosphatase, osteocalcin
and procollagen I carboxy peptide, while the markers of bone resorption include:
hydroxyproline, hydroxylysine glycosides, collagen crosslink molecules and
N-telopeptide.
Prevention/Treatment of Osteoporosis
Estrogen
Estrogen is useful prevention (i.e., maintaining BMD) or treatment of osteoporo-
sis (reducing the fracture risk). Estrogens typically exert their positive effects on BMD
by inhibiting osteoclast activity. Numerous observational and prospective studies have
demonstrated the effectiveness of estrogen treatment in increasing BMD. The Women’s
Health Initiative (WHI) study also demonstrated efficacy for fracture reduction.
11 Recent data indicates that CEE doses of 0.45 mg/day are equally effective in
maintenance of BMD, and that 0.3 mg of CEE has positive effects upon hip and
spine BMD compared to placebo. This is also true of lower doses (45-50 μg) of
transdermal estradiol. The lower doses are also effective for treatment of hot flushes
or vaginal maturation indices. However, it is important to note that fracture preven-
tion data do not exist for these lower doses.
Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs) are an attractive alternative to
estrogen for the treatment of postmenopausal osteoporosis. Like estrogens, SERMs
act by inhibiting osteoclast activity. Unlike estrogen, SERMs exert mixed effects in
different tissues. SERMs have potent estrogen agonist effects in some tissues while
exerting estrogen antagonist effects in others. Raloxifene and tamoxifen are two of
the best known and most studied SERMs. Tamoxifen (an adjuvant for breast cancer
treatment) has been shown to have estrogen agonistic effects on bone, lipid profiles,
and endometrial tissue. Therefore, while tamoxifen use is associated with improved
bone mass and cholesterol profiles, stimulation of the endometrium results in an
increased risk of endometrial hyperplasia and cancer in postmenopausal women.
In contrast, raloxifene has a mixed agonist-antagonist profile that makes it par-
ticularly useful for the treatment of osteoporosis. Raloxifene has been shown to have
solely estrogen antagonist effects in the breast and endometrium, but with estrogen
agonist effects in bone and on lipid profiles, thus mitigating the risk for endometrial
hyperplasia and breast cancer. In a prospective randomized, placebo controlled trial,
raloxifene treatment significantly reduced the risk of vertebral fracture in patients
with existing osteoporosis (RR = 0.5 and 0.7 with 60 mg/day and 120 mg/day,
respectively). Interestingly, women treated with Raloxifene had a lower incidence of
breast cancer during this study, but an increased risk of venous thromboembolism
(VTE) was noted, which is similar to that seen with estrogen use. In women treated
with 60 mg/day of Raloxifene, a marked decrease in total cholesterol levels and LDL
was noted with a minimal reduction in HDL levels. Multiple studies have illus-
trated the antiestrogenic effects of raloxifene on endometrial tissue and its safety for
use in postmenopausal women. Thus, SERMs appear useful for the treatment of
osteoporosis without the increased risk of breast cancer or endometrial hyperplasia
and cancer associated with estrogen replacement use.
Bisphosphonates
Bisphosphonates are potent inhibitors of bone resorption that act by exerting a
direct inhibitory effect on mature osteoclasts. Bisphosphonates such as alendronate,
risedronate, and ibandronate, have a low bioavailability ranging from 1.5% to 3.5%.
It is important to take these medications on an empty stomach with no other liquids
than water and separate from calcium supplements, and remain upright for 30-60
minutes following administration.
Multiple clinical trials have demonstrated the utility of bisphosphonates in the
prevention and treatment of osteoporosis utilizing a variety of treatment regimens.
These data include fracture reduction risk at the hip and spine. Such regimens in-
clude daily, weekly, or more recently, monthly administration.
Further studies have explored dosing frequency by examining the benefits of
once weekly bisphosphonate dosing, to examine potential improved tolerance with-
out compromising efficacy. Overall, both the daily and weekly treatment regimens
demonstrated significant increases in BMD, but with fewer serious upper GI ad- 11
verse experiences among those patients receiving the weekly dosing regimen. Thus,
bisphosphonates are an effective alternative treatment for osteoporosis for patients
who do not require estrogen therapy.
Other Treatments
Calcitonin is another agent that can be used to prevent osteoporosis and also acts
by inhibition of the resorptive activity of osteoclasts. Calcitonin can be given as an
intranasal spray at a dose of 200 IU/day. However, there are no data regarding hip
fracture prevention with this agent.
Sodium Fluoride has also been shown to increase bone density; however, in-
creased fracture rate associated with increased skeletal fragility suggest that high
dose fluoride would be a poor choice for the treatment of osteoporosis. In con-
trast, lower doses combined with calcium may be beneficial, as suggested in some
studies.
Calcium is generally recommended in postmenopausal women with a dietary
calcium intake of 1200-1500 mg/d in addition to more specific therapy. It is clear
that calcium alone will not adequately prevent bone loss.
Cardiovascular Disease
Cardiovascular disease is the leading cause of death in women over the age of 50
in the United States. Before the age of menopause, cardiovascular disease occurs
predominantly in males. However, after menopause, the rate of cardiovascular dis-
ease in women increases until it eventually equals that of men by age 70. Numer-
ous observational studies have demonstrated an association between estrogen
replacement therapy and low risk of cardiovascular disease. Estrogen replacement
therapy has been shown to decrease total cholesterol, low-density lipoprotein, lipo-
protein A, and increase high-density lipoprotein levels; which was assumed to be
the explanation for this association. Recently, prospective randomized blinded studies
like the Heart and Estrogen/progestin Replacement Study (HERS) and Women’s
Health Initiative (WHI) failed to show any efficacy for either secondary preven-
tion (HERS) or primary prevention (WHI) of coronary artery disease. Because of
the prospective, blinded, randomized design of those two studies, they merit a
separate discussion.
HERS Study and Secondary Prevention of Cardiovascular Disease

In contrast to the findings of multiple other cohort studies regarding secondary
prevention, the findings of the HERS study challenged the concept of estrogen’s
efficacy for the secondary prevention of cardiovascular disease. In this prospective,
randomized clinical trial, estrogen therapy did not change the rate of cardiovascular
events among women with established coronary artery disease, despite favorable
changes in the lipid profile. The daily use of combination hormone replacement
therapy did not reduce the overall risk of nonfatal myocardial infarction or cardio-
vascular disease related-death. An increased incidence of deep venous thrombosis,
pulmonary emboli, and gallbladder disease was noted among women treated with
estrogen, consistent with prior observational studies. These results led the investiga-
tors to caution against starting women on estrogen therapy for secondary preven-
tion of cardiovascular disease but to suggest its continuation only among women
already receiving estrogen therapy.
11
WHI Study and Primary Prevention of Cardiovascular Disease
The Women’s Health Initiative (WHI) trial was a large, placebo controlled ran-
domized multicenter trial looking at the effects of hormone replacement therapy
(HRT) or estrogen replacement therapy (ERT) versus placebo in menopausal women.
In this study, HRT consisted of conjugated equine estrogens (CEE) 0.625 mg/d
combined with medroxyprogesterone acetate (MPA) at a dose of 2.5 mg/d. One
arm of the study looked at hysterectomized women on ERT vs. placebo (n = 10,739).
Another part of the study compared nonhysterectomized women on HRT vs. pla-
cebo (n = 16,608). Study endpoints included MI (fatal and nonfatal, breast cancer,
stroke, venous thromboembolic events (VTE), colorectal cancer and hip fracture.
Patients in the HRT arm were followed for an average of 5.2 years while patients in
the ERT arm were followed for an average of 6.8 years.
Although the goal of the WHI was to address the issue of primary prevention of
coronary artery disease, it came to similar conclusions as the HERS study, which
addressed secondary prevention. During the first year of use, the relative risk (RR)
of cardiac events in users of combined estrogen/progesterone replacement was 1.52
(1.01-2.29). In the estrogen only arm (for women who have had a hysterectomy),
there was no increased risk of cardiac events. The main criticism of WHI is that the
population studied was an older population with a mean age of 63 years. Such an
older population is very likely to have a high prevalence of preexisting subclinical
cardiac disease. Table 11.4 lists absolute risk/benefits of both study arms (number of
events per 10,000 women/yr compared to placebo). Based upon HERS and the
WHI, hormone replacement therapy is no longer an accepted treatment for preven-
tion of cardiovascular disease.
Alzheimer’s Disease
Alzheimer’s disease (AD) is a significant health problem for aging men and women
in the United States. After age 65 the prevalence of Alzheimer’s disease exponen-
tially increases with age, with the number of affected persons doubling every five
years and commonly affects women far more often than men. Multiple epidemio-
logical studies have suggested a beneficial effect of estrogen on AD, while others
have shown no benefit. In the WHI memory study (WHIMS), investigators found
an increase in all-cause dementia in the HRT arm although this was not seen in the
ERT arm. AD was not addressed separately in this study, and the results are further
limited by small numbers of cases. The women in this study were 65 years or older.
Based on the current literature, estrogen probably does not slow or improve AD
progression, and when HRT is given to older women it may increase the risk of
dementia.
Risks of Homone Replacement
Estrogen Replacement Therapy and Breast Cancer
Breast cancer is a leading cause of death in American women 40 to 55 years old
and currently, one in nine women will be diagnosed with breast cancer. Of all Ameri-
can women, 12.6% will be diagnosed with breast cancer in their lifetime and 3.5%
of all women will die of this disease. Unfortunately, the peak incidence of breast
cancer occurs among post-menopausal women, the same women for whom the choice
of whether to take HRT becomes an issue, along with its apparent risks and ben-
efits. 11
Until the results of the Women’s Health Initiative trial were published in July of
2002, there was no clear consensus on the relationship of HRT to breast cancer
incidence, although some studies showed a small increase with long-term use. The
WHI trial showed that there was a statistically significant increase in breast cancer
HRT arm (intact uterus) during the fifth year of use only (RR = 1.99, 1.18-3.35),
bringing the relative risk among users of the combined estrogen/progesterone to
1.26 (1.00-1.63) over at least 6 years. Interestingly, patients in the estrogen-only
arm did not show an increase in invasive breast cancer (RR 0.77{0.59-1.01}) but
rather showed a trend toward a decrease in the incidence of invasive breast cancer
although this did not achieve statistical significance.
Estrogen Replacement Therapy and Endometrial Cancer
Endometrial cancer is the most common gynecologic malignancy and the fourth
most common cancer in women. Risk factors for the development of endometrial
cancer have traditionally included obesity, nulliparity, and late menopause. Mul-
tiple studies have demonstrated a strong correlation between the use of unopposed
estrogen and an increased incidence of endometrial cancer. The addition of a progestin
induces endometrial regression and stabilization thereby preventing the develop-
ment of endometrial hyperplasia and cancer. Therefore, the importance of prescrib-
ing a combination estrogen and progestin therapy in women with an intact uterus
receiving hormone replacement therapy is clear.
Venous Thromboembolic Events
Venous thromboembolic events (VTEs) represent a broad category (including
pulmonary embolus and deep venous thrombosis) of potentially life-threatening
risks that are associated with ERT/HRT use. Based on prior observational studies,
and the results of prospective trials such as HERS I, HERS II, and WHI, it appears
that there is a 2-fold increase in the risk of VTE in users of ERT/HRT. Estrogens,
particularly those given orally, stimulate hepatic production of clotting factors. Ac-
cordingly, some studies suggest that women taking transdermal estrogens are not at
greater risk of VTEs. Nonetheless, the use of ERT/HRT would be contraindicated
in patients with a prior history of VTEs.
Other Risks of HRT

Observational studies of the risk of stroke among users of HRT have yielded
inconsistent results. The WHI study demonstrated an increased risk among combi-
nation HRT users as well as users of estrogen alone compared to placebo. A meta-
analysis of randomized clinical trial found that oral estrogen use was primarily
associated with increased risk of ischemic stroke rather than hemorrhagic stroke or
transient ischemic attacks.
HRT appears to increase the risk of gallbladder disease in observational studies
as well as randomized clinical trials. Estimates from the WHI suggests that the mag-
nitude of the absolute risk translates into about 3 additional cases per 1000 women.
Previous cholecystectomy is not a contraindication to HRT.
Benefits
Colon Cancer
11 Colon cancer is the third leading cancer and cause of cancer death in women.
Multiple studies (retrospective as well as observational cohort studies like the Nurses
Health Study) have suggested an association between HRT and a decreased inci-
dence of colon cancer and were confirmed by recent findings from the WHI. In the
WHI trial, patients receiving HRT had a significantly lower incidence of colon
cancer compared to placebo. However, there was no such reduction in the ERT
arm.
Macular Degeneration
Macular degeneration (MD) is the leading cause of legal blindness in the United
States, accounting for 25 to 60% of all new cases. The pathogenesis of MD is un-
known and currently there is no effective medical therapy, with surgical photoco-
agulation being useful in only a limited number of patients. Multiple retrospective
studies as well as data from the WHI has suggested that HRT may decrease the
incidence of MD.
Skin
As postmenopausal women age, there is a linear decrease in skin collagen con-
tent of 2.1% and skin thickness of 1.13% per year from premenopausal levels dur-
ing the initial 15 to 18 postmenopausal years. HRT prevents some of this collagen
loss but is not currently an indication for long term estrogen use.
Benefits of Hormone Replacement
There is an increased prevalence of sexual dysfunction following the menopause.
Causes include psychogenic, endocrinologic, vascular, neurogenic, muscular,
medication-related and infection. Endocrinologic changes associated with loss of
estrogen at the menopause include vulvo-vaginal atrophy and possibly decreased
desire or arousal. The use of ERT or HRT can improve symptoms of sexual dysfunc-
tion by improving genital sensation, as well as decreasing pain and burning during
intercourse. Some studies suggest that a combination of estrogen and testosterone
may improve libido.
Key Points on HRT Use

In the past, HRT was prescribed for women for a multitude of potential health
benefits. It was previously thought that HRT, in addition to its beneficial role in
osteoporosis, could protect against cardiac disease, stroke, and Alzheimer’s disease.
The recent prospective, randomized, and blinded studies have challenged the valid-
ity of this. Based on current literature, HRT is indicated today only for the treat-
ment of vasomotor symptoms and vaginal atrophy, and prevention/treatment of
osteoporosis. HRT should be prescribed in the lowest effective dose for the shortest
period of time. Therefore, bone-specific agents would likely be more appropriate in
patients requiring long-term osteoporosis prevention/treatment. Ultimately, the
decision regarding whether or not to take hormone replacement therapy is a per-
sonal one, to be decided by the patient herself with guidance from her physician.
Suggested Reading
1. Writing group for the women’s health initiative investigators. Risks and benefits of
estrogen plus progestin in healthy postmenopausal women: Principal results from the
11
Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321-333.
2. Shumaker SA, Legault C, Kuller L et al. Conjugated equine estrogens and incidence of
probable dementia and mild cognitive impairment in postmenopausal women: Women’s
Health Initiative Memory Study. JAMA 2004; 291:2947-2958.
3. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for
secondary prevention of coronary heart disease in postmenopausal women. Heart and
Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;
280:605-613.
4. Anderson GL, Limacher M, Assaf AR et al.Effects of conjugated equine estrogen in
postmenopausal women with hysterectomy: The Women’s Health Initiative random-
ized controlled trial. JAMA 2004; 291:1701-1712.
5. Draper MW. The role of selective estrogen receptor modulators (SERMs) in post-
menopausal health. Ann N Y Acad Sci 2003; 997:373-377.
6. Moghadam KK, Williams DB. Advances in menopausal hormonal delivery systems: A
comparative review. Am J Drug Deliv 2005; 3:7-16.
7. LeBlanc ES, Janowsky J, Chan BK et al. Hormone replacement therapy and cognition:
Systematic review and met-analysis. JAMA 2001; 285:1489-1499.
8. Shumaker SA, Legault C, Kuller L et al. Conjugated equine estrogens and incidence of
probable dementia and mild cognitive impairment in postmenopausal women: Women’s
Health Initiative Memory Study. JAMA 2004; 291:2947-2958.
9. Shumaker SA, Legault C, Rapp SR et al. Estrogen plus progestin and the incidence of
dementia and mild cognitive impairment in postmenopausal women: Women’s Health
Initiative Memory Study: A randomized controlled trial. JAMA 2003; 289:2651-22662.
10. Lindsay R, Gallagher JC, Kleerekoper M. Effect of lower doses of conjugated equine
estrogens with and without medroxyprogesterone acetate on bone in early postmeno-
pausal women. JAMA 2002; 287:2668-2676.
11. Utian WH, Shoupe D, Bachmann G et al. Relief of vasomotor symptoms and vaginal
atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone
acetate. Fertil Steril 2001; 75:1065-1075.
Chapter 12
Reproductive Endocrinology Diagnostic Imaging

Peter Klatsky and Victor Y. Fujimoto
Introduction
The last few decades have witnessed rapid advances in diagnostic and therapeutic
options in modern medicine. While the field of reproductive endocrinology has stayed
away from many diagnostic modalities using ionizing radiation, the field has ben-
efited from advances in imaging modalities such as ultrasound and magnetic reso-
nance. In this chapter, we will review the general principles of these techniques and
offer examples from reproductive endocrinology where imaging has proved helpful.
Principles of Ultrasound and Magnetic Resonance Imaging (MRI)
Sonographic imaging relies on the different transmitting and reflecting proper-
ties of ultrasound waves through various types of tissues. Ultrasound waves are trans-
mitted and reflected waveforms received through the transducer, ultimately leading
to the creation of images.
An important setting on an ultrasound transducer is the frequency of the ultra-
sound waves transmitted. Lower frequency sound waves are better able to transmit
through deeper tissue but have less clarity. These frequencies are often employed in
transabdominal imaging and are particularly helpful in larger patients with deep
adipose tissue. Abdominal ultrasound usually utilizes 3-5 MHz in transmitting im-
ages. Scans that require less penetration but greater detail, such as transvaginal ultra-
sound, are best obtained by using higher frequency sound waves, usually 7 MHz.
Abdominal ultrasound is best performed in patients with a full bladder, where
the bladder functions as a window through which ultrasound waves can travel un-
impeded to penetrate underlying pelvic structures. Transvaginal ultrasound func-
tions best in patients with empty bladders so that the uterus lies in its naturally-flexed
position and is not artificially displaced away from the vagina. An anteverted uterus
is more likely to place the ovaries closer to the transvaginal transducer.
Magnetic resonance takes advantage of the physical principle that the nuclear
spin of hydrogen ions varies depending on its chemical environment. MRI utilizes
radiofrequency to measure this spin and its variances throughout the body to create
excellent images of soft tissue structures and planes between tissues.
Ambiguous Genitalia
Diagnostic imaging assists providers in making a rapid diagnosis and planning
appropriate gender assignment and treatment strategies. The finding of ambiguous
genitalia is considered by the American Academy of Pediatrics to be a pediatric
emergency. Electrolyte abnormalities from severe congenital adrenal hyperplasia can
be life-threatening. Similarly urgent is the social crisis that results in long-term stig-
Reproductive Endocrinology Diagnostic Imaging 121
mata that develop when parents are unable to tell friends and family whether they
have just had a baby boy or girl.
The initial workup to determine the infant’s gender includes blood tests to assess
hormone levels, electrolyte concentrations, as well as karyotyping. Unfortunately,
the results of some these tests, (e.g., karyotyping) can take 48 hours or more to
obtain results.
An abdominal ultrasound can provide immediate data to assist a family in un-
derstanding their newborn’s phenotype, likely gender assignment and reproductive
potential. An abdominal ultrasound should be immediately performed to assess the
presence of a cervix, uterus, fallopian tubes, and ovaries or gonads. Evidence of a
uterus on ultrasound is the most important finding and will most likely reassure
parents that their newborn will develop into a phenotypic female. The most com-
mon cause of virilization of a female infant at birth is congenital adrenal hyperpla-
sia, which can be managed medically by replacing cortisol.
Other causes of ambiguous genitalia include gestational hyperandrogenism of-
ten related to maternal hyperandrogenism during pregnancy. A genotypic male in-
fant with 5-alpha reductase deficiency can also present initially as a minimally-virilized 12
female infant.
While ultrasound is the first step, nondiagnostic exams are not uncommon, and
MRI can also provide useful information. A diverse array of mullerian anomalies
can be identified by MRI with its improved ability to identify the cervix, uterus, and
gonads. Many of these structures cannot be seen consistently on ultrasound. One
study demonstrated that MR could identify the uterus in 93% of patients, the va-
gina in 95%, the penis in 100%, the testis in 88%, and the ovary in 74% of patients.
The advantage of MRI is that it can better elucidate soft tissue structures through
use of T1- and T2-weighted sequences and its ability to look with equal clarity through
multiple depths of tissue. MR also offers larger visual fields than ultrasound, with
multiple planes of images that can be viewed simultaneously to identify and correlate
related structures. In addition to assisting with rapid determination of accurate gen-
der assignment, MR is also useful in planning surgical reconstruction, such as with a
transverse vaginal septum or aplastic vagina in Mayer-Rokitansky-Kuster-Hauser
(MRKH) syndrome.
Amenorrhea
Many cases of mullerian anomalies present for the first time during adolescence
with primary amenorrhea (Figs. 12.1-12.5). Fifteen percent of these women will
have abnormal pelvic exams. Breast development, normal growth and pubarche in
the presence of a blind-ending or absent vagina suggests either mullerian agenesis,
transverse vaginal septum, or imperforate hymen. Lagging thelarche or pubarche in
a young woman with tall stature and a blind-ending vagina may suggest androgen
insensitivity syndrome.
After a physical exam, ultrasound and karyotyping are the first steps to assess for
a uterus, vagina, or gonads. Any patient with a female phenotype and 46 XY geno-
type must have her gonads removed after completion of puberty or sooner depend-
ing on the condition as they are at risk for malignancy.
Distinguishing a transverse vaginal septum from an imperforate hymen is im-
portant in determining an appropriate and safe therapeutic approach. While ultra-
sound is helpful, MRI is the gold standard for identifying corresponding structures
and planning surgical treatment (Fig. 12.3).
12
Figure 12.1. MRI showing sagittal view of a patient with Mullerian agenesis or
Mayer-Rokitansky-Kuster-Hauser syndrome. Note the absence of a uterus posterior
to bladder.
Mullerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome) results from

the abnormal or absent development of the mullerian duct structures (Fig. 12.1).
Patients with this condition display a variety of anomalies, most commonly com-
plete or partial agenesis of the uterus, vagina, or cervix. About 10% of patients have
a uterus but an incomplete outflow track and therefore present with cyclic pain but
absent vaginal bleeding (Figs. 12.2-12.4). Ovarian function is preserved in all of
these patients and can be evidenced by normal pubertal growth and development,
as well as by measuring basal body temperatures and serum progesterone levels to
assess ovulation.
Any patient with mullerian anomalies needs an abdominal ultrasound, MRI, or
intravenous pyelogram to examine the kidneys and ureteral development (Fig. 12.5).
Unilateral renal agenesis has been documented in 30% of cases, most commonly in
association with a unicornuate uterus with a mullerian ductal remnant. The affected
or absent kidney is generally ipsilateral to the aplastic mullerian horn.
When physical exam and ultrasound are inadequate or incompletely diagnos-
tic, MR imaging is usually successful in characterizing mullerian anomalies and
planning potential surgical treatments. In a review of 29 patients at University of
12
Figure 12.2. Abdominal ultrasound demonstrating hematometria associated with

vaginal agenesis.
Figure 12.3. MRI showing sagittal view of hematocolpometria in patient with trans-
verse vaginal septum.
12
Figure 12.4. Coronal MRI of pelvis in a patient with an obstructed Mullerian

duct remnant associated with uterine didelphis.
California - San Francisco, MRI correctly identified anatomic anomalies in all of

the patients as confirmed by surgical or further invasive findings. The MRI results
influenced or changed clinical treatment decisions in a quarter of patients who
had previously undergone ultrasound imaging. Of particular value was the im-
proved ability to identify gonads and establish that suspected adnexal lesions were
actually components of obstructed mullerian duct anomalies.
MRI can also identify vaginal tissue and determine partial or complete agenesis,
as well as duplication of vaginal and cervical development. Thin sections using trans-
verse images are most helpful in delineation of these structures, and pretreatment
with mild estrogen stimulation will assist in creating contrast along the vaginal wall.
Many mullerian anomalies present later in life, not with primary amenorrhea,
but in the workup of primary infertility or recurrent pregnancy loss. MRI may also
be useful in the evaluation of these women, for its ability to identify and distinguish
the fibrous tissue of a septate uterus from the myometrium of bicornuate uterus.
The former patients can benefit from hysteroscopic resection of their septum; the
latter patients cannot. It is important to distinguish an arcuate or didelphic uterus
from a septate uterus before recommending treatment. A uterine septum can be
safely resected, decreasing the risk of recurrent miscarriage. An arcuate uterus is a
normal variant, without negative impact on reproductive outcome and does not
require additional abdominal imaging. Conversely, patients with a didelphic uterus
12
Figure 12.5. Intravenous pyelogram showing an absent right renal collecting sys-
tem as might be seen associated with mullerian anomalies.
require imaging to rule out renal anomalies. Distinguishing a fibrous septa from a
patient with a didelphic uterus is important as attempting hysteroscopic resection in
a patient with a didelphic or bicornuate uterus can lead to unintentional surgical
perforation.
Secondary Amenorrhea
The most common cause of secondary amenorrhea in a young woman is preg-
nancy. If a patient has a positive pregnancy test, ultrasound can be performed to
date the pregnancy and to rule out an ectopic pregnancy (the latter would be of
particular concern in any patient with pain, vaginal spotting, or risk factors such as
prior tubal surgery, sexually transmitted infections or pelvic inflammatory disease).
A gestational sac should be visible by transvaginal ultrasound (TVUS) in most preg-
nancies when the serum level of human chorionic gonadotropin (βhCG) is above
1500 IU/L. An empty endometrial cavity in a patient with a βhCG level above 1500
IU/L might indicate an ectopic pregnancy, although a multiple gestation could not
be ruled out.
In patients with secondary amenorrhea or oligomenorrhea, anovulatory condi-

tions must be considered. These will be discussed along with appropriate diagnostic
procedures in the following pages.
Infertility
The workup of female infertility usually begins with an assessment of sexual and
menstrual history, followed by a diagnostic workup to identify and treat a particular
cause of infertility. Imaging techniques play a crucial role in the diagnosis of ana-
tomic infertility, especially as these techniques determine the need for surgery. In
recent years, imaging techniques have emerged as important in diagnosing ovula-
tory defects, as well.
Anatomic and Tubal Factor Infertility
Two causative tubal factors that lead to infertility are bilateral tubal occlusion
and the presence of a hydrosalpinx. Clinical risk factors for tubal factor infertility
include a history of sexually-transmitted infection, pelvic inflammatory disease,
12 tubal surgery, or severe abdominal-pelvic adhesions. The resulting adhesions block
sperm or embryo transport to prevent fertilization and implantation.
Hysterosalpingogram or sonohysterogram have become the first line tools for evalu-
ation and diagnosis of tubal and anatomic causes of infertility.
Hysterosalpingogram
One of the oldest and most widely used diagnostic imaging modalities in infer-
tility is the hysterosalpingogram (HSG); see Figures 12.6-12.8. A hysterosalpingogram
consists of a series of plain films utilizing a liquid contrast that is injected into the
cervical canal. Images are taken revealing the contour of the endometrial cavity and
fallopian tubes with spillage of contrast into the abdominal cavity (Table 12.1).
Figure 12.6. Normal appearing HSG.

12
Figure 12.7. HSG with unilateral tubal occlusion.
Figure 12.8. HSG with bilateral hydrosalpinges.

Table 12.1. Performing an HSG

1. Study should be performed on day 5-9 of menstrual cycle.
2. Premedicate with 600 mg ibuprofen (antibiotics for high risk patients).
3. Cleanse the cervix with antiseptic solution.
4. Insert HUMI or acorn tip catheter; remove open angle speculum.
5. Under fluoroscopic observation, SLOWLY instill 10 ml warm oil based contrast.
6. Take images as contrast fills uterine cavity and as soon as bilateral spill
is identified.
7. May consider oblique planes for selected images.
8. Instilling contrast and taking images should take less than one minute.
9. After uterine and tubal assessment is completed, have patient roll 360˚ and
take final image to look for fluid collections representing peritubal adhesions.
12 A normal HSG will demonstrate a smoothly-contoured endometrial cavity with-

out filling defects. It will also demonstrate thin, nearly imperceptible tubes with
contrast fluid spilling bilaterally. Tubal disease is suggested by absent spillage or
evidence of a hydrosalpinx. With time, distal tubal occlusions can lead to the devel-
opment of a hydrosalpinx which is characterized by severely damaged tubal epithe-
lium. Both tubal occlusion and dilation can cause infertility.
Even when one tube is patent, the presence of a contralateral hydrosalpinx will
decrease pregnancy rates. Presumably, the hydrosalpinx fluid has an embryotoxic
effect. Infertile patients with a hydrosalpinx should be treated with salpingostomy,
salpingectomy or proximal tubal occlusion. The latter two methods have been shown
to improve pregnancy rates and the preferred approach has yet to be determined by
a prospective, randomized trial.
Hysterosalpingography has a sensitivity of 65% and a specificity of 83% for
detecting tubal disease. A significant false positive rate with the technique is partly
attributed to tubal spasm during injection of contrast. Measurement of Chlamydia
trachomatis antibodies has been useful in identifying additional patients at risk for
tubal disease despite normal HSGs. Some providers now recommend laparoscopy
with chromopertubation despite a normal HSG, for any patient with high antibody
titers to Chlamydia trachomatis because of the relatively low sensitivity of HSG.
Peritubal adhesions secondary to prior infection or endometriosis are often missed
on HSG but can be appreciated during laparoscopy. Other authors have suggested
eliminating the HSG and using only Chlamydia antibody titers to screen for tubal
disease, but the low specificity and positive predictive value of titers alone continues
to make HSG a clinically important study.
Although water soluble contrast agents offer somewhat clearer images, the dif-
ference in diagnostic quality is not significant. Oil-based contrasts, such as ethiodized
poppy-seed oil or ethiodiol, have been associated with less pain and bleeding, and
have shown a trend toward decreased infection rates.
An additional advantage to performing an HSG with oil based contrasts is the
potential therapeutic benefit. Increased pregnancy rates have been documented within
the first several months following the procedure. These results have not been appre-
ciated using water soluble contrasts and for that additional reason we prefer oil-soluble
media, particularly in patient populations that will not be able to afford future cycles
of in vitro fertilization. The mechanism for improved pregnancy rates after HSG
with oil-based contrast is unknown, but one proposed mechanism is impairment of
phagocytosis by macrophages that are present in the peritoneum and fallopian tubes
and presumably interfere with fertilization. In vitro studies have repeatedly demon-
strated that exposure to oil-based media impairs macrophage ability to phagocytose
sperm, which may increase the chance of fertilization. Anecdotally, we have found
that patients tolerate the procedure much better when warmed contrast is used and
it is injected slowly. Patients should receive 600 mg of ibuprofen one hour prior to
the procedure to reduce cramping and discomfort. We also avoid placing a Foley or
other balloon type catheter through the internal cervical os as this can obscure intra-
cavitary distortions in the lower uterine segment and increase the risk of ascending
infection. An acorn tip or HUMI cannula does not share these properties. Antibi-
otic prophylaxis is unnecessary, although patients at high risk for infection could be
given 24 hours of doxycycline after the procedure.
Abnormalities of the uterine cavity, specifically the presence of polyps, submu-
cosal myomas, and fibrous uterine septa, have also been found to decrease live birth
rates. Therapeutic options for intracavitary lesions include D&C, polypectomy, and 12
hysteroscopic resection. Prior to the development of new sonographic techniques,
these lesions were diagnosed by either HSG or hysteroscopy. Abnormalities on HSG
appear as space occupying lesions distorting the endometrial cavity.
Sonohysterogram
In many practices, sonohysterograms (SoHGs) have replaced hysterosalpingograms
for screening to assess for lesions in the endometrial canal and rule out hydrosalp-
inges for infertile patients considering intrauterine inseminations (IUI, Table 12.2)
or in vitro fertilization (IVF, Table 12.3). SoHGs are office procedures that involve
canulating the cervix with a small catheter and instilling approximately 10 ml of
saline (Table 12.4). This procedure allows real time imaging and is quicker and less
painful than an HSG. Figures 12.9-12.17 demonstrate the types of clinical informa-
tion that can be obtained by SoHG compared to other imaging techniques.
Table 12.2. Pretreatment imaging for IUI

1. HSG and Chlamydia trachomatis titers.
2. Laparoscopy with chromotubation if elevated Chlamydia titers or endometriosis
(especially with “kissing ovaries” sign).
3. If endometrial abdominally, consider SoHG.
4. If large, obscuring fibroids, consider MRI.
Table 12.3. Pretreatment imaging for IVF

1. No need for HSG.
2. SoHG: rule out intracavitary myomas, polyps, and hydrosalpinx.
3. Antral follicle count.
4. Assessment of endometrial thickness and morphology for embryo transfer.
Table 12.4. Performing a SoHG

1. Perform study within 10 days of LMP.
2. Patient should void prior to study.
3. Consider antibiotic prophylaxis in high risk patients.
4. Clean cervix with antiseptic solution.
5. Identify 5 Fr catheter with a 2 ml balloon.
6. Balloon catheter is prepared, tested, and primed with saline.
7. Eliminate bubbles in tubing which can create artifact on ultrasound.
8. Insert catheter; slowly inflate balloon with water.
9. Remove speculum, insert vaginal ultrasound probe.
10. Slowly instill 5-10 ml of warm saline from 20-30 ml syringe.
11. Multiple images of endometrial cavity are taken in sagittal and coronal planes.
12 12. Rule out hydrosalpinx.
13. Look for spill/free fluid in bilateral adnexae.
*Note: Taking care to instill fluid slowly into both the catheter balloon and the
endometrial cavity will minimize patient discomfort.
A SoHG is ideally performed during the proliferative phase of the menstrual

cycle when the endometrial lining is thinner in order to decrease false positive find-
ings. Use of prophylactic antibiotics is not routinely recommended but could be
considered in patients at high risk for cervicitis or subsequent PID.
Figure 12.9. Septate uterus on SoHG transverse view.

12
Figure 12.10. Axial MRI image of a septate uterus.
Figure 12.11. SoHG image of endometrial polyps.

12
Figure 12.12. TVUS of endometrial polyps.
Figure 12.13. SoHG of a submucosal fibroid.

12
Figure 12.14. Axial MRI of bicornuate uterus. This may appear similar to both a
septum or arcuate uterus on HSG.
Figure 12.15. HSG of a patient with an arcuate uterus.

12
Figure 12.16. Normal SoHG, sagittal view. Note bright echogenicity of SoHG
catheter.
Figure 12.17. Normal SoHG, transverse view.

While ultrasound is not effective at identifying tubal patency, it can accurately

and comfortably assess intracavitary pathology as well as identify the presence of a
hydrosalpinx. Some authors have attempted to use sonohysterograms to identify
patients at risk for nondilated tubal occlusion as well.
By instilling more than 10 ml of saline and watching for accumulation of free
fluid surrounding the ovary, this approach attempts to demonstrate tubal patency.
Sensitivity for this test was improved by using lactose particles to increase visualiza-
tion and echogenicity in spilled fluid. Unfortunately, results are unreliable and have
a positive predictive value of only 40%.
MR-Hysterosalpingography
Although some have attempted to use 3-D dynamic MR-hysterosalpingography
to visualize both the endometrial cavity and tubes with decreased exposure to ioniz-
ing radiation from HSG imaging, we do not feel that the high costs and technical
difficulties are not outweighed by any potential benefits of this modality. This is an
expensive study that does not improve on sensitivity, specificity or patient comfort.
12
Recurrent Pregnancy Loss
Some women have no difficulties conceiving pregnancy but are plagued by re-
current early miscarriages. Common causes include chromosomal anomalies, infec-
tious and connective tissue diseases, but the most readily treatable explanation is a
problem with the uterine cavity. Anomalies of the mullerian system have been found
in approximately 15% of women with three or more early pregnancy losses. The
most common uterine anomaly in this group is a septate uterus. Endometrial pol-
yps, adhesions, and submucosal myomata are also implicated in infertility. See Fig-
ures 12.9-12.14, and Figure 12.18.
It is especially important to rule out and correct any anatomic anomalies that
could cause a spontaneous abortion, before undergoing in vitro fertilization. While
HSG and hysteroscopy used to be the gold standard for endometrial evaluation,
sonohysterography has proved more than adequate in evaluation of the uterine cav-
ity. SoHG has a greater than 90% sensitivity and a positive predictive value of
65-100% for detecting intracavitary lesions when compared to hysteroscopy. SoHG
can also be useful in detecting adhesions, or uterine synechia, that may have formed
after an intrauterine procedure such as dilation and curettage (Fig. 12.18).
Unlike hysteroscopy, SoHG can reliably distinguish between an arcuate, a bicor-
nuate, and a septate uterus. Sonohysterograms can also identify hydrosalpinges and
evidence of adnexal masses, all of which should be excised prior to proceeding with
any form of assisted reproductive technology or intrauterine insemination.
Transvaginal ultrasound without saline contrast can also be used to assess uterine
morphology, but with decreased sensitivity and specificity. Endometrial polyps ap-
pear as focal areas of increased echogenicity within a wider endometrial stripe (Fig.
12.12). Unfortunately, sensitivity for detecting polyps decreases from 93.1% to 64.5%
and the specificity decreases from 93.9% to 75.5% on transvaginal ultrasound with-
out saline contrast. A divergent endometrial stripe can be evidence of a uterine sep-
tum or arcuate uterus.
Benefits of SoHG over transvaginal ultrasound include the ability to reliably
assess the endometrial cavity in a patient with a myomatous uterus, in which
heavy “shadowing” artifact can obscure visualization of a contiguous endometrial
stripe. SoHG also better distinguishes between a hyperplastic endometrium and
12
Figure 12.18. Uterine cavity synechiae (adhesions) and polyps on SoHG.
an endometrial polyp, as well as identify the difference between an arcuate and a

septate uterus. Similarly, HSG is unreliable at distinguishing between any of these
conditions and has proven particularly unreliable at distinguishing between
mullerian anomalies, such as a septum and an arcuate uterus. SoHG is twice as
accurate as transvaginal ultrasound or HSG in identifying uterine cavity defects.
Ovulatory Disorders
The lack of regular ovulatory cycles, called anovulation, is another cause of infer-
tility. The workup for anovulation is largely hormonal, but several imaging modali-
ties can be useful as well.
Hyperprolactinemia is a treatable cause of infertility that is usually caused by a
prolactin secreting pituitary adenoma or microadenoma. Since prolactin levels cor-
relate poorly with size of an adenoma, MRI of the pituitary is indicated in any
patient with an elevated prolactin. Other authors have suggested that MRI is unnec-
essary as the natural history of a microadenoma is unpredictable and the majority
resolve or remain stable without surgery. If resources for a pituitary MRI are scarce,
it is reasonable to treat empirically with bromocriptine unless the patient has signs
of a macroadenoma, such as decreased visual fields (bitemporal hemianopsia) or
severe headache. In that case an MRI should be sought, but a lateral film of the skull
is usually sufficient to diagnose empty sella syndrome.
Polycystic ovary syndrome (PCOS) is another anovulatory condition that con-
tributes to infertility. An international consensus conference in 2003 created a working
definition for PCOS, the “Rotterdam criteria.” These criteria defined PCOS as the
presence of any two of three findings:
1. A history of oligo- or anovulation
2. Clinical or biochemical evidence of hyperandrogenism
12
Figure 12.19. Polycystic ovary with classic “ring of pearls” appearance on trans-
vaginal ultrasound.
3. Polycystic ovaries on ultrasound: Defined as 12 or more follicles measuring

2-9 mm in each ovary or ovarian volumes of greater than 10 ml.
Ovaries from a woman with polycystic ovarian syndrome classically demonstrate
an abundance of peripherally situated follicles that create the “ring of pearls” appear-
ance that typifies this syndrome (Fig. 12.19). However, authors have debated the
importance of finding multiple follicular cysts on ultrasound as many fertile women
with regular menstrual cycles have a similar ovarian appearance on ultrasound.
Diminished Ovarian Reserve
Diminished ovarian reserve is a term used to identify women who are nearing
the end of their naturally reproductive years. In older women, this may be the result
of approaching climacteric and a natural decline in follicular development. Younger
women may experience a similar phenomenon called premature ovarian failure (POF)
when it occurs before age 41. POF is often the result of an autoimmune attack on
ovarian tissue and is associated with other autoimmune diseases such as autoim-
mune hypothyroidism. Other causes include exposure to ionizing radiation or alky-
lating chemotherapeutic agents during treatment for cancer earlier in a woman’s
reproductive lives. These exposures damage developing ovarian follicles and sup-
portive stroma, leading to POF and infertility. Women with no prior history of
environmental exposures should be screened for subclinical hypothyroidism as this
is the most common associated autoimmune disease.
Diagnosis of diminished ovarian reserve has traditionally been made using bio-
chemical testing including a day 3 FSH and estradiol level, or a day 10 FSH after a
clomiphene citrate challenge of 100 mg from days 5-9 of the cycle. Both of these
12
Figure 12.20. Transvaginal ultrasound of a normal follicular ovary with 9 follicles.
markers were used to predict success rates for women undergoing various infertility
treatments. A problem with all attempts to assess ovarian reserve is that they are
nonspecific and can change with each cycle. Age alone is a good predictor and has
been associated with sonographically observed decreases in mean ovarian volume
and number of follicles. Most markers for ovarian reserve are used to plan expecta-
tions and outline treatment options for women with clinical infertility.
Ultrasound measurement of the ovarian antral follicle count (AFC) is a repro-
ducible test with low inter-observer variability at clinically important levels (low
AFC) and can predict response to gonadotropin stimulation. When compared with
age and other biochemical markers, the AFC appears to be the single best predictor
of response to IVF treatment. Patients with a basal AFC of 4 or fewer follicles have
significantly higher rates of cycle cancellation (41% vs 6.4%) and lower pregnancy
rates (24% vs 58%) in IVF cycles. These low pregnancy rates are primarily the result
of increased cancellation rates and decreased numbers of eggs retrieved,. Further-
more, an AFC of less than or equal to two follicles and ovarian volume of less than
4 cm3 are predictive of menopausal status.
AFC is reliable in women over 35 (Fig. 12.20). Younger women have greater
intercycle variation in AFC and less reliable correlation between the AFC and re-
sponse to IVF. In women over 35, accurate measurement of antral follicle count can
help predict responsiveness before proceeding with expensive assisted reproductive
technologies. Patients with discouraging results should be counseled sympatheti-
cally about alternative methods of family development such as ovum donor cycles
and adoption.
12
Figure 12.21. Transvaginal ultrasound of endometrioma with homogenous low

level echoes.
Endometriosis
Endometriosis is characterized by ectopic endometrial tissue outside the uterine
cavity which can cause pain, adhesions and infertility. Endometriosis often presents
clinically with a long history of cyclic pelvic pain that may be exacerbated by vaginal
penetration.
The evidence that endometriosis is implicated in infertility derived from obser-
vations that endometriosis is present at laparoscopy in 21% of women being evalu-
ated for infertility and only 6% of fertile women undergoing laparoscopic tubal
ligation. It is estimated that 30% to 50% of women with endometriosis are infertile.
Laparoscopy remains the gold standard for diagnosis and treatment for this dis-
order; however as less invasive diagnostic modalities have also gained favor,
noninvasive diagnostic imaging techniques have proved worthwhile as well.
The most commonly used imaging technique in endometriosis is ultrasound.
Transvaginal ultrasound is useful in identifying endometrial cysts or endometrio-
mas. These lesions are often found during a pelvic pain or infertility evaluation, but
they can be found incidentally during imaging of the abdomen and pelvis for other
indications.
Endometriomas typically appear as homogenous, hypoechoic ovarian cysts with
low level echoes (Fig. 12.21). They often have septations and can occur in multiples
or as a single cystic mass. While mural nodularity suggests neoplasm, these nodules
must be distinguished from hyperechoic wall foci, a finding which correlates strongly
12
Figure 12.22. “Kissing ovaries” sign. Note how dense adhesions bring the ova-
ries together in the posterior cul de sac.
with endometriomas. These densities are usually smaller and more echogenic than
those associated with neoplasia. In the presence of septations, low level internal
echoes, and hyperechoic wall foci, a multiloculated mass is 64 times more likely to
be an endometrioma than any other adnexal mass.
With in vitro fertilization, simple endometriomas need not be removed prior to
proceeding with a cycle. Care should be taken to avoid entering the endometrioma
during egg retrieval as its contents are potentially toxic to the ovaries.
The “kissing ovaries” sign is an interesting sonographic feature seen in patients
with severe endometriosis and pelvic adhesions (Fig. 12.22). Identifying adjacent and
“kissing” ovaries at ultrasound is a strong marker for the presence of severe endometriosis.
This is one of the few times that ultrasound can be reliably used to diagnose pelvic
adhesions. One study demonstrated a positive predictive value of greater than 90% for
endometrial implants involving the bowel and fallopian tubes in these patients. Other
signs of adhesions include posteriorly-displaced uterus and ovaries which may be ap-
preciated by ultrasound as a fixed, retroverted uterus. Thus, these findings can elimi-
nate the need for further invasive diagnostic procedures, and laparoscopy can be avoided
in a patient wishing to attempt hormonal control of her disease.
A concerning characteristic of endometriomas is the presence of hyperechoic
deposits in the cyst wall. Nevertheless it can be difficult to distinguish between true
endometriomas and neoplasms. In order to better characterize an adnexal mass that
may be a neoplasm or an endometrioma, both CT and MRI can be used. When
available, MR imaging avoids exposure to ionizing radiation and can improve the
diagnostic accuracy and specificity of ultrasound. MR images are not as badly af-
fected by adhesive disease and allow for a larger field of view than ultrasound.
Magnetic resonance imaging may reduce the need for invasive surgical diagnos-
tic procedures. Endometriosis appears as a region of a low signal intensity on T1
within an area of high signal intensity on T2. High intensity nodules on the bowel
or bladder suggest involvement of these tissues. An additional advantage of MR over
laparoscopy is its ability to show extraperitoneal sites of involvement and lesions
that would be obscured by dense adhesions on laparoscopy. Unfortunately, MR
performs poorly at diagnosing peritoneal adhesions that do not involve the ovaries.
MRI and laparoscopy can therefore be complementary in severe cases.
Fibroids
Leiomyomata are benign smooth muscle neoplasms. The predominant symp-
toms in patients with large fibroids are menorrhagia and pelvic pressure. They are
usually diagnosed by ultrasound or physical exam, but ultrasound can be limited in
a very enlarged uterus with multiple myomas. In an enlarged uterus, MR can help
identify clinically important submucosal myomas and plan surgical treatment. 12
SoHGs are helpful in identifying location of fibroids and whether they can be
removed hysteroscopically. Hysteroscopic removal is attempted in all patients with
submucosal fibroids with at least half of their volume in the endometrial canal.
The clinical significance of intramural and subserosal fibroids is controversial.
Some authors suggest myomectomy for patients with repetitive failed IVF cycles
and no explanatory factors except intramural fibroids. Large fibroids that distort the
endometrial canal are particularly worrisome. Ultrasound and SoHG have been rec-
ommended to evaluate the endometrial cavity and location of women with small to
moderate-sized fibroids. Women with large fibroids can benefit from MRI studies
in order to assist in preoperative visualization and surgical planning. MR is also
useful in identifying the endometrial stripe and ovaries in patients whose large myo-
mas cause too much shadowing and artifact to accurately assess the endometrium or
adnexae (Fig. 12.23).
Although extremely rare, malignant leiomyomata have a characteristic appear-
ance on MR. Malignant leiomyomata appear as ill-defined lesions which can be
hyperintense on T1 images secondary to hemorrhagic changes. Well-defined lesions
are nearly always benign.
MRI can also appreciate different signal intensities to differentiate adenomyosis
from an enlarged, myomatous uterus. Different signal intensities within myomas
can also be helpful in predicting response to treatment in patients considering treat-
ment with GnRH or uterine artery embolization. Embolization occludes vessels
leading to myomas and causes them to regress by cutting off their blood supply.
Although submucosal fibroids respond well to embolization, this procedure is still
not recommended in women desiring future fertility as there are only limited data
available on pregnancy outcomes.
Key Points
After reading this chapter you should be able to understand and identify:
1. The strengths and weaknesses of different diagnostic imaging modalities
used in reproductive endocrinology
2. Appropriate clinical situations to utilize different imaging modalities
3. How to perform and interpret hysterosalpingograms and sonohysterograms
4. The appropriate imaging modalities used in the clinical workup for infertility
12
Figure 12.23. Axial MRI of myomatous uterus.
Special thanks to Dr. Fergus Coakley and the Department of Radiology at UCSF
for assistance in providing radiographic images.
Suggested Reading
1. Practice committee of the American Society of Reproductive Medicine. Current Evalu-
ation of amenorrhea. Fertil Steril 2004; 82:S33-39, [Excellent text: Highly recom-
mended for a basic understanding of the causes and appropriate diagnostic evaluation
of patients with amenorrhea and primary or secondary infertility].
2. Hricak H, Chang YC, Thurnher S. Vagina: Evaluation with MR imaging. Part I. Nor-
mal anatomy and congenital anomalies. Radiology 1988; 169(1):169-74.
3. Lindheim SR, Adsuar N, Kushner DM et al. Sonohysterography: A valuable tool in
evaluating the female pelvis. Obstet Gyn Survey 2003; 58:770-84.
4. Ayida G, Chamberlain P, Barlow D et al. Uterine Cavity assessment prior to in vitro
fertilization: Comparison of transvaginal scanning, saline contrast hysterosonography
and hysteroscopy. Ultrasound Obstet Gynecol 1997; 10:59-62, [Excellent article high-
lighting the importance of using sonohysterograms to evaluate the endometrial cavity].
5. Soares SR, Barbosa dos Reis MM, Carnagos AF. Diagnostic accuracy of
sonohysterography, transvaginal sonography, and hysterosalpingography in patients
with uterine cavity diseases. Fertil Steril 2000; 73:406-11.
6. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised
2003 consensus on diagnostic criteria and long-term health risks related to polycystic
ovary syndrome. Fertil Steril 81(1):19-25, [Important paper addressing a major condi-
tion in reproductive endocrinology].
7. Bansci LF, Broekmans FJ, Eijkemans MJ et al. Predictors of poor ovarian response in
in vitro fertilization: A prospective study comparing basal markers of ovarian reserve.
Fertil Steril 2002; 77(2):328-36.
8. Bis KG, Vrachliotis TG, Agrawal R et al. Pelvic endometriosis: MR imaging spectrum
with laparoscopic correlation and diagnostic pitfalls. Radiographics 1997; 17(3):639-55.
Part II
Infertility
Chapter 13
An Overview of Female Infertility

Sandra L. Torrente and Valerie Montgomery Rice
Overview
According to the 1995 National Survey of Family Growth, the percentage of
women reporting some form of fecundity impairment rose from 8% in 1988 to
10% in 1995 which some believe is related in part to a trend toward delayed child-
bearing. Numerous observational studies have demonstrated that 80-90% of couples
that have unprotected intercourse for 12 months will conceive. Thus, the accepted
definition of an infertile couple is the failure to conceive after 12 months of inter-
course without any form of birth control. Evaluation for infertility is indicated for
couples who fit this definition as well as those who have significant risk factors for
infertility who may have less than 12 months of exposure to the possibility of preg-
nancy (e.g., history of oligomenorrhea or sexually transmissible infections). The
general causes of infertility and the frequencies are listed in Table 13.1. In this chap-
ter we will focus on the female factors affecting infertility (Table 13.2).
An increasing number of women are waiting to start their families until comple-
tion of education and/or training, one factor that has led to women seeking preg-
nancy later in life. In the 1970s women over 35 years of age accounted for 5% of
pregnancies and today they account for up to 14% of the pregnancies. Women in
general will experience a decreased fecundity rate at 37.5 years of age. This is attrib-
uted in great part to a decline in the number of healthy oocytes, directly influencing
the rate of conception.
When evaluating a patient for infertility, ideally the medical history and physi-
cal exam are obtained from the couple. One must obtain a complete obstetrical
and gynecological history from the female. The menstrual history is an excellent
indictor of ovulatory status. A complicated obstetrical history may suggest the need
for maternal fetal medicine consultation prior to initiating therapy, especially if the
planned infertility treatment predisposes to multiple births. The gynecologic his-
tory can give clues about risk factors for tubal scarring (Chlamydia infection, sur-
gery for endometriosis) or cervical factor infertility (ablation for abnormal Pap smear).
The sexual history is obviously relevant. The sexual history should include fre-
quency of coitus especially in the periovulatory period. Complaints of sexual dissat-
isfaction are common among infertile couples who often feel that spontaneity is lost
in striving to achieve pregnancy. Dyspareunia may suggest that endometriosis is the
problem. Use of a lubricant may affect sperm motility. Finally, the history of contra-
ception use is important to establish if the patient has experienced any complica-
tions with hormonal therapy, particularly a deep venous thrombosis. It is not
uncommon for couples to seek help from different medical providers; therefore, try
to obtain any previous infertility work up the couple has been through.
Table 13.1. General causes of infertility

Female factor 40%
Male factor 40%
Unexplained factors 20%
Table 13.2. Causes of female infertility

Tubal factor 35%
Ovulatory dysfunction 35%
Endometriosis 20%
Unexplained 10%
Cervical factor 3%
Uterine factor Rare
13
A general medical history is imperative in determining other major medical prob-
lems affecting a patient’s fertility. A patient should be in optimal health prior to
initiating fertility therapy. Many common chronic medical conditions such as diabe-
tes mellitus, hypertension and obesity will increase a patient’s risk for miscarriage and
pregnancy complications. Lastly, taking a social history will identify any habits which
may influence a patient’s fertility. Tobacco, marijuana, and cocaine use will affect
fecundity rates in women as well as men. There is a known dose-response relation-
ship between the number of cigarettes smoked and length of time it takes to achieve
pregnancy. Marijuana affects the fertility directly by inhibiting secretion of GnRH in
both men and women. Cocaine is also known to decrease spermatogenesis.
An example of a history form for an infertile woman is provided in Table 13.3.
Steps in the evaluation of infertility are summarized in Table 13.4 and Figure 13.1.
Ovulatory Disorder
Patients with an ovulatory disorder that is not due to ovarian failure have several
medical options available. There are three types of ovulatory dysfunction that are
classified by the World Health Organization (WHO):
Hypothalamic-Pituitary Failure (Hypogonadotropic Hypogonadal
Anovulation)
Patients with this form of anovulation suffer from hypothalamic amenorrhea.
Patients will have low estrogen levels, low gonadotropin levels (FSH and LH), nor-
mal prolactin levels and will not bleed after a progesterone challenge. The classic
patients seen with this disorder are those that suffer from anorexia nervosa, or ath-
letes with a low BMI (<17), and women under high stress.
Treatment
• Lifestyle modification including reducing exercise, improving nutritional
intake, and addressing any underlying psychological issue will help return
ovulatory function. If lifestyle modification does not improve anovulation
use of gonadotropins can be considered. Because of low estrogen levels, these
patients do not usually respond to clomiphene.
An Overview of Female Infertility 147
Table 13.3. Infertility History (female)

Marital History
Married___ # of years_____# Prior marriages_____
Single___ Separated___ Divorced___ Widowed___
Menstrual History
Last menstrual period________ Regular ___yes ___no
Menarche_____ Intermenstrual bleeding ___yes ___no
Interval_____ Dysmenorrhea ___yes ___no
Duration_____
Amenorrhea___ primary___ secondary___
Virilization: ___hirsutism ___balding ___acne ___voice changes
Obstetric History
Gravida: __term __premature __stillborn __spontaneous abortion __induced abortion
Ectopic pregnancies: ___right ___left
Complications: ___pregnancy ___postpartum
Gynecologic History
Last Pap smear________
13
Previous abdominal
or pelvic surgery ___yes ___no DES exposure ___yes ___no
Endometriosis ___yes ___no PID ___yes ___no
Abnormal pap ___yes ___no STD ___yes ___no
Previous Infertility or Endocrinology Studies
PCT ___yes ___no Hormonal studies ___yes ___no
HSG ___yes ___no Semen analysis ___yes ___no
BBT ___yes ___no Medication ___yes ___no
Endometrial BX ___yes ___no
Laparoscopy ___yes ___no Other studies ___yes ___no
Sexual History
Frequency _____ time per _____ Contraception:
None___
Satisfied ___yes ___no Oral contraceptive ___yes ___no
Dyspareunia ___yes ___no IUD ___yes ___no
Diaphragm ___yes ___no
Lubricant use ___yes ___no Female sterilization ___yes ___no
Male sterilization ___yes ___no
Habits
Cigarettes ___yes ___no ___# per day
Alcohol ___yes ___no ___# drinks per _____
Marijuana ___yes ___no ___# times used per _____
Other drugs ___yes ___no ___# times used per _____
Past Medical History
Patient Family
Operations:
Hospitalizations:
Current medications:
Birth defects:
Inherited disease (i.e., cystic fibrosis, sickle cell):
Table 13.4. Evaluation of infertility

Test Purpose Time of Cycle
Serum FSH Evaluate ovarian reserve Day 2 or 3
Hysterosalpingogram Tubal patency and Day 7-11
uterine configuration
Serum progesterone Establish ovulation About 7 days after LH surge
Serum TSH Confirm euthyroid state N/A
Serum prolactin Rule out adenoma Luteal phase
Semen analysis Evaluate male N/A
on partner
13
Figure 13.1. Infertility algorithm.
Hypothalamic-Pituitary Dysfunction (Normogonadotropic

Normoestrogenic Anovulation)
Patients with this form are usually oligomenorrheic women. Many women in
this category have polycystic ovarian syndrome (PCOS) and will have an elevated
LH/FSH ratio, elevated androgens, and enlarged ovaries with multiple follicles. Of
the three types of ovulatory dysfunction, this is the most common.
Treatment
• Lifestyle style modification for women with anovulatory infertility often
consists of weight loss. Women with a BMI>27 and oligomenorrhea should
be counseled on weight loss as first line therapy for infertility. A loss of
5-10% of body weight may be enough to restore ovulation.
• Ovulation induction is the initial step taken if weight is not an issue or if the
patient remains anovulatory after weight loss. The first line of therapy is
clomiphene citrate, a SERM with estrogen antagonist and agonist effects
that increases gonadotropin release. Clomiphene is given on cycle days 5
through 9 at a dose of 50 mg/day (if ovulation does not occur in the first
cycle the dose is increased in subsequent cycles). The LH surge will occur
3-12 days after the last dose of clomiphene. The LH surge can be deter-
mined using urinary ovulation predictor kits. Ovulation can be expected to
occur 24-48 hours after detection of a positive result.
• Insulin sensitizing agents (Metformin) used concurrently can improve the
response to clomiphene in PCOS patients. Metformin works to decrease
gluconeogenesis, and intestinal uptake of glucose.
• Once ovulation is established, if the patient does not become pregnant in six 13
cycles, intrauterine insemination (IUI) should be considered.
• If ovulation induction with IUI does not achieve pregnancy after three to six
cycles of positive ovulation IVF should be considered.
Ovarian Failure (Hypergonadotropic Hypoestrogenic Anovulation)
Patients with this form of anovulation present with premature ovarian failure
Gonadotropin levels are elevated and estrogen levels are low.
Treatment
• Oocyte donation and IVF is highly successful for this group of patients.
• Hormone replacement therapy is generally recommended for symptomatic
relief and to prevent osteoporosis.
Hyperprolactinemic Anovulation
Patients will present with oligomenorrhea or amenorrhea and sometimes galac-
torrhea. Fasting prolactin levels are elevated and estradiol levels are often decreased.
First one must rule out a pituitary adenoma with an MRI.
Treatment
• A dopamine agonist is generally the first line treatment.
Tubal Disorders
Infertility occurs when the fallopian tubes or fimbria are scarred or blocked and
cannot transport the ovum or sperm, or serve as the site of fertilization. Previous
history of salpingitis (tubal infection), pelvic inflammatory disease, endometriosis,
or abdominal surgery can all lead to tubal scarring. Seventy-five percent of tubal
disease can be attributed to a previous Chlamydia infection, often asymptomatic.
The United States Preventative Task Force (USPSTF) recommends that clinicians
routinely screen women under the age of 25 and sexually active and other asymp-
tomatic women at increased risk for Chlamydia infection. Hysterosalpingography
(HSG) is used to evaluate tubal patency.
Treatment
• Surgical options for tubal repair depend on the site of obstruction and
severity of tubal damage.
• Proximal tubal obstruction can be treated with hysteroscopic or
fluoroscopically-guided catheterization of the fallopian tube.
• IVF is the treatment of choice for tubal disease that cannot be surgically
corrected. If there is a hydrosalpinx present, salpingectomy prior to IVF
improves the outcome with IVF.
Endometriosis
Patients with known endometriosis may suffer from infertility, sometimes due to
adhesions causing tubal blockage or decreased tubal motility. However, the mecha-
nism of infertility is not understood for patients with mild disease and no apparent
anatomic distortion. Some studies suggest that patients with minimal to mild en-
dometriosis that do not apparently have tubal blockage still should undergo ablative
treatment to reduce endometriosis, as a means of improving fertility.
13 Treatment
• Laparoscopic resection or ablation of endometriosis and adhesiolysis is pref-
erable to medical treatment for infertile patients.
• Ovulation induction (clomiphene or gonadotropins) and IUI can be of-
fered if there is at least one normal, patent fallopian tube.
• IVF should be offered if surgery and ovulation induction/IUI fail or if the
endometriosis is extensive.
Uterine Disorders
Patients with uterine abnormalities will present more likely with recurrent preg-
nancy loss and not primary infertility. The uterine abnormalities most commonly
seen are submucosal leiomyomas, endometrial polyp, septate uterus, and uterine
synechiae which all can interfere with implantation.
Treatment
• Leiomyomas—The need for surgery in an otherwise asymptomatic infertile
woman depends upon the size and location of the fibroids. Abdominal myo-
mectomy is the treatment of choice for large intramural or subserosal
leiomyomas, especially if they distort the endometrial cavity. Small fibroids
in these locations do not require treatment. Hysteroscopic myomectomy is
preferred for submucosal leiomyomas which are associated with increased
miscarriage rate unless resected.
• Endometrial polyps—should be removed by operative hysteroscopy.
• Septa and synechiae—should be treated with hysteroscopic resection.
Cervical Disorders
Unfavorable cervical mucus at midcycle may act as a physical barrier for sperm
penetration. Similarly, the cervix may cause infertility in women with stenotic cervi-
cal os, cervical surgery or ablation for dysplasia or chronic cervicitis.
Treatment
• Bypass the cervix with IUI and IVF if necessary.
• Treat cervicitis, if present.
Unexplained Infertility
Ten to fifteen percent of couples present with a completely normal workup.
Patients in this group may have problems that cannot be detected by available test-
ing: ovum pick up, sperm transport, fertilization or implantation. However, older
female age with decreased ovarian reserve or borderline semen parameters are com-
mon in couples with this diagnosis. Randomized, controlled clinical trials support
the use of superovulation and IUI as first line treatment, resulting in 2-3 fold in-
crease in cycle fecundity depending upon patient selection and the regimen used.
Superovulation increases the number of eggs available to the sperm and corrects any
subtle ovulation problems. The insemination delivers greater numbers of motile
sperm closer to the egg for fertilization.
Treatment
• Clomiphene alone or with IUI is the usually the first line of therapy.
• Gonadotropin therapy with IUI has a higher multiple birth rate and is usu-
ally reserved for patients who fail to conceive with clomiphene.
• If three cycles of gonadotropins and IUI fail, ART can be offered.
13
Definitions
1. Assisted reproductive technologies (ART)—all methods that involve direct
retrieval of oocytes from the ovary (see chapter on ART).
2. Basal body temperature (BBT)—a test used to confirm ovulation. Patient is
asked to record their oral temperature every morning before arising, starting
with the onset of menstrual flow. The rise should be greater than 0.4 degrees
Fahrenheit for the ten days or more preceding menses to indicate ovulation.
3. Clomiphene citrate—A selective estrogen receptor modulator (SERM) that
acts as an estrogen antagonist and agonist. The agonist effect increases gona-
dotropin release. The starting dosage is generally 50 mg/day for 5 days start-
ing on cycle day 5 (see Chapter 15).
4. Fecundability—The probability of achieving a pregnancy within one men-
strual cycle.
5. Fecundity—The ability to achieve a live birth within one menstrual cycle.
6. Follicle-stimulating hormone (FSH)—A hormone produced by the pitu-
itary gland. Pharmacologic preparations can be given as to cause follicle
recruitment and growth within the ovary.
7. Hysterosalpingogram (HSG)—a radiological test that is performed to iden-
tify any uterine cavity or tubal defects.
8. Infertility—One year of unprotected coitus without conception.
9. In vitro fertilization (IVF)—A type of ART that includes ovarian stimula-
tion, egg retrieval and sperm collection, the eggs are fertilized and incubated
in the laboratory. Resulting embryos are later transferred to the uterus.
10. Intrauterine insemination (IUI)—Introduction of “washed” sperm into the
uterus.
11. Intracytoplasmic sperm injection (ICSI)—Direct injection of a single sperm
into an oocyte.
12. Luteinizing hormone (LH)—A hormone produced by the pituitary gland,
which causes follicle development, egg maturity, and ovulation. LH can also
be given as a medication.
13. Ovarian hyperstimulation syndrome—A complication of ovulation induc-

tion therapy. There three grades: mild which consists of mild abdominal
pain and the ovaries are <5 cm in diameter on ultrasound exam; moderate
which the ovaries measure 5-10 cm in diameter; and severe in which the
patient presents with intraperitoneal fluid and may also have oliguria, hy-
potension, and pleural effusions (see Chapter 15).
14. Post coital test (PCT)—A test to establish if the sperm and cervical mucus
are compatible. The test is performed 2-8 hours after intercourse around the
time of ovulation and requires a microscopic evaluation of the cervical mu-
cous for the presence of motile sperm. Because of poor reproducibility and
lack of predictive power, this test is not routinely recommended in the evalu-
ation of the infertile couple.
Key Points
1. Establish if the cause of infertility is reversible or irreversible. If it is revers-
ible (i.e., PCOS) correct the issue with appropriate medical or surgical therapy.
If it is irreversible (i.e., ovarian failure) counsel in regards to ART with pos-
13 sible oocyte donation.
2. The most common cause of female infertility is ovulatory dysfunction. For-
tunately with minimally invasive infertility therapy patients can reach a fe-
cundity rate similar to that of couples without fertility problems.
3. Ensure appropriate counseling of the risk involved when using ovulation
induction medication and IVF.
4. Women with known endometriosis should have optimal ablation or resec-
tion of endometriosis prior to infertility therapy. One must also ensure tubal
patency.
Suggested Reading
1. Speroff ’s, Clinical Gynecologic Endocrinology and Infertility. 7th ed. Lippincott Wil-
liams and Wilkins, 2005, [For a thorough review of female infertility, Speroff ’s 7th ed,
is the book all residents should have. It is what one should read during their RE/I
rotation. Specifically Chapters 27 and 31 were referenced for this review].
2. ACOG Practice Bulletin #34, February 2002. Management of Infertility Caused by
Ovulatory Dysfunction, ACOG Compendium. 2005, [For a much more abbreviated
review, but helpful for both interns and residents the ACOG Compendium is what
one should read for a quick reference].
3a. Smith S, Pfeifer S, Collins J. Diagnosis and management of female infertility. JAMA
2003; 290:1767-1770.
3b. Lobo R, Potential options for preservation of fertility in women. New England Journal
of Medicine 2005; 353:64-73.
Chapter 14
Surgical Treatment of Female Infertility

Mohammed Al-Sunaidi and Togas Tulandi
Introduction
Due to widespread availability of assisted reproductive technologies, the need
for reproductive surgery in infertile women has declined in recent decades. How-
ever, surgery still has a place in the management of infertile women. For example,
young women with pelvic adhesions or blocked fallopian tubes that impair their
fertility may benefit from early surgical intervention. On the other hand, women
over the age of 35 with a long history of infertility or those who require a laparo-
tomy for correction of their disorders are better treated with in vitro fertilization.
Compared to laparotomy, reconstructive surgery by laparoscopy is preferable. In
fact, most procedures that previously required a laparotomy can be performed by
laparoscopy with equal or better results. In addition, laparotomy causes more adhe-
sion formation. The incidence of adhesion formation after a single laparotomy is 47%
after appendectomy and up to 91% after pelvic surgery. Almost all patients will de-
velop adhesions after myomectomy by laparotomy, whereas the adhesion rate is about
70% after laparoscopic myomectomy. Laparoscopic surgery lessens adhesion forma-
tion due to minimal handling of the internal organs and elimination of operative site
contamination with glove powders or lint. In addition there is a lower incidence of
infection, and the relatively closed environment of laparoscopy helps to maintain tis-
sue moistness. Moreover, patients prefer the faster recovery time with laparoscopy.
Over the years, many laparoscopic modalities have been advocated including
laser and ultrasound-scalpel; however the results are comparable to the use of con-
ventional instruments such as scissors. One of the newest techniques is the use of
robotic surgery during laparoscopy. Compared to human wrist movement, the ro-
botic arm allows rotation of 360 degrees. The major disadvantage of robot-assisted
endoscopy is the lack of tactile feedback or haptics. The large size of some of the
robotic systems may also be a limitation. More importantly, to date there are no
published data demonstrating that robotic surgery results in a better pregnancy rate
than conventional laparoscopic surgery.
Diagnostic Laparoscopy
Laparoscopy should only be performed after complete investigation of infertility
such as semen analysis, hysterosalpingogram and assessment of ovulation. In the era
of assisted reproductive technology, laparoscopy is not a routine test. However, it is
indicated in young women with an abnormal hysterosalpingogram or a history of
salpingitis, sexually transmitted disease, previous pelvic surgery, or endometriosis.
The incidence of abnormal laparoscopic findings in infertile females with a normal
hysterosalpingogram ranges from 21-68%. Abnormal findings can usually be cor-
rected at the same laparoscopic setting.
14
Figure 14.1. Adhesions on the posterior wall of the uterus..
During the course of a diagnostic laparoscopy for infertility, the pelvis is care-
fully surveyed for the presence of endometriosis, adhesions and uterine abnormities.
Tubal patency is checked by injecting dilute solution of methylene blue into the
uterine cavity through the cervix. Tubal patency is indicated by the passage of the
blue dye from the fimbriated end of the tube.
Laparoscopy Promoting Fertility
Adhesiolysis
Pelvic adhesions can result from pelvic inflammatory disease, previous pelvic
surgery, endometriosis or previous appendicitis. Periadnexal adhesions impair tu-
bal mobility and ovum pick-up mechanism (Figs. 14.1 and 14.2). Although preg-
nancy is possible in women with periadnexal adhesions, liberation of the adhesions
can increase the pregnancy rate. When adhesions are extensive or involve vital
organs (e.g., ureter or bowel), the patient may be better served by attempting
pregnancy through in vitro fertilization.
Treatment of Endometriosis
In infertile women with no other cause of infertility, endometriosis can be
found in 40-50% of cases (Figs. 14.2-14.4). Endometriosis can be classified into
minimal, mild, moderate and severe or stage I to IV. Its presence regardless of
the stage decreases fertility. Compared to women whose endometriosis was not
treated, treatment of stage I or II endometriosis is associated with a higher preg-
nancy rate.
Surgical Treatment of Female Infertility 155
14
Figure 14.2. Close-up appearance of endometriosis in the cul-de-sac (“gun-powder”

spots and white lesions).
Figure 14.3. Endometriosis vesicles on the ovary.
Treatment can be achieved with excision, ablation with electrocautery, laser,

or harmonic scalpel. Pregnancy rates are similar with all of these modalities.
Medical treatment by ovarian suppression with gonadotropin releasing hormone
agonist (GnRHa) will improve the symptoms of endometriosis, but it delays
14
Figure 14.4. Obliteration of the posterior cul-de-sac due to endometriosis.
conception for several months, and there is no evidence that pregnancy rates
improve.
Ovarian cysts due to endometriosis are called endometriomas (Fig. 14.5). An
endometrioma that is ≥ 3 cm in diameter automatically qualifies for a classification
of stage III or IV in severity. GnRHa treatment is ineffective in reducing the size of
endometriomas of >1 cm. Treatment is surgical. It can be achieved either by fenes-
tration and ablation (removal part of the cyst wall followed with coagulation of the
inner side of the wall) or excision of the endometrioma cyst wall (Fig. 14.5). Exci-
sion of the endometrioma is associated with a higher pregnancy rate than fenestra-
tion and ablation. Furthermore, recurrence after fenestration and ablation is more
likely than after excision.
In advanced stage IV endometriosis, severe pelvic adhesions enveloping the
whole pelvis can be encountered (frozen pelvis). Instead of subjecting the patients
to a laparotomy with a low pregnancy rate, the patients are better treated with in
vitro fertilization.
Treatment of Distal Tubal Occlusion
The fallopian tube can be occluded proximally at the uterotubal junction, at
the mid-portion, or distally. The most commonly encountered tubal obstruction
is distal tubal occlusion, usually due to PID. Mid-tubal blockage is usually iatro-
genic due to tubal sterilization. Hysterosalpingographic findings of proximal tu-
bal occlusion should be interpreted with caution. It could be true tubal occlusion
or tubal spasm.
14
Figure 14.5. Excision of ovarian endometrioma.
Figure 14.6. Tubal anastomosis has been completed.

Fimbrioplasty
Fimbrioplasty is performed for the treatment of fimbrial phimosis, which is a
partial obstruction of the distal end of the fallopian tube. The tube is patent, but
there are adhesive bands surrounding its terminal end. The procedure involves di-
viding the peritoneal adhesive bands that surround the fimbria releasing fimbrial
agglutination. In one series, treatment of severe fimbrial phimosis with laparoscopic
fimbrioplasty resulted in 51% intrauterine pregnancy rate, 37% live birth rate and
23% ectopic pregnancy rate at two years of follow-up.
Terminal Salpingostomy
Hydrosalpinx is complete distal tubal occlusion. Tubal reconstruction of hydro-
salpinx is called terminal salpingostomy. The results depend on the degree of tubal
damage. In general, the results are poor. The average pregnancy rate following salp-
ingostomy is 30%, with an ectopic pregnancy rate of 5%. However, the rate of
pregnancy can be as low as zero if the tube is rigid and thick without mucosal folds,
and as high as 80% when tubal damage is minimal.
In general, salpingostomy is recommended only for young women with mild
distal tubal disease. Tubal surgery has the advantages of allowing for several preg-
14 nancies from a single procedure with no increase in multiple birth rate. In vitro
fertilization is a better alternative for older patients, patients with severely damaged
tubes and those with infertility due to multiple etiologies.
Surgical Management of Hydrosalpinx Prior to IVF
The presence of hydrosalpinx reduces the probability of achieving a pregnancy
in IVF. A meta-analysis showed that hydrosalpinx reduces the pregnancy rate in IVF
cycles by 50%. This has been attributed to the leakage of hydrosalpinx fluid into the
uterine cavity that could be toxic to the embryo. The fluid might also flush the
embryo out of the uterine cavity or impair implantation. Removal of the hydrosal-
pinx (salpingectomy) significantly improved the pregnancy and live birth rates (36.6%
versus 23.9% without salpingectomy and 28.6% versus 16.3%, respectively).
Patients who benefit most from salpingectomy are those with hydrosalpinges
visible on ultrasound (live birth rate 40% versus 17% without salpingectomy).
Moreover, salpingectomy of bilaterally visible hydrosalpinges increased the delivery
rate 3.5-fold (live birth 55% versus 15.8%), in one study.
An alternative to salpingectomy is occlusion of the isthmic portion of the tube
in the same manner as tubal sterilization. Ultrasound-guided aspiration of the
hydrosalpinges fluid has also been advocated, but rapid built up of the fluid can
occur. A simpler and yet effective approach is administration of antibiotics to
women with hydrosalpinx undergoing IVF. Finally, young women with hydrosal-
pinx can be offered salpingostomy if the tubal damage is not extensive.
Treatment of Proximal Tubal Occlusion
Proximal tubal occlusion, suggested by failure of contrast medium to enter the
intramural or isthmic portion of either tube, is diagnosed in 10%-20% of hystero-
salpingography. This could be due to tubal spasm, mucus plugs, debris, or true
cornual blockage. In order to distinguish between true cornual obstruction and
other pathologies, several methods including laparoscopy have been advocated.
During laparoscopy, tubal patency can be assessed and some surgeons can also
perform tubal reconstruction.
Selective Tubal Catheterization

A less invasive technique than tubal surgery is selective tubal catheterization (STC)
or transcervical tubal cannulation. It consists of passing a catheter through the cer-
vix into the proximal tubal ostium, and injecting contrast medium. Increased pres-
sure generated by direct injection may overcome obstructions associated with
plugging. It could be performed using balloon angiographic catheters or guide wires
under fluoroscopic, hysteroscopic or ultrasound guidance.
Due to the high incidence of false positive on hysterosalpingography, STC is the
first line of treatment for bilateral proximal “tubal blockage”. Approximately, a quarter
of patients diagnosed with bilateral proximal occlusion on hysterosalpingography
do not have tubal obstruction. Among those with true occlusion, STC leads to an
overall pregnancy rate of 34%. True cornual occlusion is usually due to salpingitis
isthmica nodosa, where the cornual part of the tube is occluded and replaced by a
firm nodule. The cumulative probability of conception after STC was 28%, 59%,
and 73% at 12, 18, and 24 months of follow-up, respectively.
In approximately 20% of patients, the tubes cannot be catheterized and the
patients are best treated by IVF. Surgical treatment of such a blockage is not highly
successful due to the severity of tubal damage or the presence of concomitant distal
tube abnormalities. There are two operative procedures to correct proximal tubal 14
blockage, cornual reimplantation and microsurgical tubocornual anastomosis. Tra-
ditionally tubal reimplantation is performed by laparotomy and the success rate is
poor. Tubocornual anastomosis can also be performed by laparoscopy; however the
number of reported cases is small.
Treatment of Mid-Tubal Occlusion
Treatment of mid-tubal occlusion is tubal anastomosis where the occluded por-
tion of the tube is removed followed by anastomosis of the healthy segments (Figs.
14.6 and 14.7). Mid-tubal occlusion is usually due to previous tubal sterilization or
previous ectopic pregnancy.
Sterilization reversal is the most successful surgical reconstructive procedure for
improving fertility. Factors influencing the success are patient’s age, sterilization tech-
nique, and tubal length. High pregnancy rates of up to 70% could be achieved in
patients with tubal length of >4 cm compared to only 19% in those with shorter
tubes.
We consider laparoscopic sterilization-reversal in women younger than 39 years
who have ≥4 cm of residual tube. For others, IVF is a better option.
Laparoscopic Treatment of Polycystic Ovary Syndrome (PCOS)
The first line of treatment for anovulatory women with polycystic ovary syn-
drome is ovulation induction with ovulation-inducing drugs . This has replaced the
outdated surgical treatment with ovarian wedge-resection. A modification of ova-
rian wedge resection is laparoscopic ovarian drilling (Fig. 14.9). This is performed
by creating multiple holes on the surface of the ovary using either electrocautery or
laser. As a result, the circulating level of androgen is reduced followed by restoration
of pituitary-ovarian axis restoring ovulation. Ovarian drilling is associated with an
ovulation rate of 80% and cumulative pregnancy rates at 12, 18, and 24 months of
54-68, 62-73, and 68-82 % respectively.
There are two potential complications associated with ovarian drilling, periadnexal
adhesion formation and premature ovarian failure. The incidence of postoperative
14
Figure 14.7. Tubal insufflation following tubal anastomosis showing methylene

blue dye solution.
Figure 14.8. Polycystic ovary.

14
Figure 14.9. Laparoscopic ovarian drilling.
adhesion formation is estimated to be 19-43% and may be as high as 82%. This

complication is more frequent with laser treatment than with electrocoagulation.
Outcomes with medical treatments have rarely been directly compared with
surgical outcomes. In a randomized trial, Palomba et al compared ovarian drilling
with metformin treatment. The pregnancy rate at 6 months follow-up in the
metformin group was 18.6% and in the ovarian drilling group was 13.4%. The
live birth rate was higher in the metformin group (82.1%) than in the surgical
group (29%).
The management strategy favored by most reproductive endocrinologists is to
advocate weight loss and or medication, including metformin. Laparoscopic ova-
rian drilling, though often successful, is used sparingly.
Hysteroscopy in Infertility
Hysteroscopy is an operation to examine the uterine cavity using a thin caliber
telescope (hysteroscope) introduced through the cervix. It gives information whether
the uterine cavity is normal or contains a septum, fibroid, polyp, or adhesions. Hys-
teroscopy should be done in early follicular phase of the cycle or approximately 4
weeks after an injection of gonadotropin releasing hormone analog (GnRHa). GnRHa
suppresses FSH and estrogen production and subsequently makes the endometrium
thin. This allows optimal visualization of the uterine cavity.
Diagnostic Hysteroscopy
Diagnostic hysteroscopy is usually performed under local anesthesia or
paracervical block. It is done in the clinic or doctor’s office as an extension of a
gynecological examination. In some cases the cervical opening needs to be dilated

to allow passage of the hysteroscope. Office hysteroscopy involves the use of a
small caliber rigid hysteroscope usually 3.5 mm or a fiberoptic 2.4 mm flexible
hysteroscope. The most commonly used distending media are normal saline,
Ringer’s lactate, or carbon dioxide gas. Compared to the use of CO2 gas, liquid
distending medium is less irritating and associated with less pain. Furthermore,
blood and gas produce bubbles that impair visualization. Endometrial polyps can
sometimes be removed in the same setting using a polyp snare or hysteroscopic
scissors.
Hysteroscopy is a good diagnostic tool to verify findings that cannot be accu-
rately diagnosed by other imaging techniques including hysterosalpingogram, ultra-
sound, or magnetic resonance imaging (MRI). Its use is invaluable in infertility. It
has been shown that up to 50% of women in whom IVF-ET repeatedly failed were
found to have intrauterine abnormalities.
Correction of uterine abnormalities improved the pregnancy rate. In a review of
1000 office-based hysteroscopies prior to IVF, it was found that routine hystero-
scopy examination detected uterine abnormalities in 30% of women starting IVF
treatment.
14 Operative Hysteroscopy
For treatment purposes, the operation is done under general or spinal anesthe-
sia in the operating room. A solution of glycine 1.5% or sorbitol 3% is used to
distend the uterine cavity. The possible complications of hysteroscopy include
uterine perforation, bleeding, infection, and fluid overload in the lung or brain.
These complications are rarely encountered; however severe electrolytes imbal-
ance can be fatal.
Lysis of Intrauterine Adhesions
Intrauterine adhesions (Asherman’s syndrome) usually occur after repeated
curettages particularly those performed in the pregnant state (postpartum or abor-
tion). Asherman’s syndrome can present with amenorrhea, hypomenorrhea, infertil-
ity or repeated miscarriage. Hysteroscopy is the best tool to diagnose and treat this
condition. Adhesions are removed using hysteroscopic scissors or unipolar loop elec-
trode. In order to allow rapid regeneration of the endometrium, a course of estrogen
treatment is usually administered after the procedure. In general, 90 percent of pa-
tients will resume normal menses and 80 percent will achieve a term pregnancy,
depending on the extent and severity of the adhesions.
Excision of Submucous Fibroid or Polyp
Submucous myomas or endometrial polyps can cause excessive uterine bleed-
ing. Furthermore, submucous myomas are associated with infertility or repeated
miscarriages (Fig. 14.10). Treatment is by hysteroscopic excision. Varasteh et al.
found that hysteroscopic removal of myoma of >2 cm led to a significantly higher
pregnancy rate (62.5%) than that of <2 cm (33%). Cumulative live birth rates
after removal of myoma of <2 cm were 25.0%, >2 cm were 41.7%, and >3 cm
were 75.0%.
Perez-Medina conducted a randomized study comparing the pregnancy rate af-
ter intrauterine insemination among women whose endometrial polyp was removed
14
Figure 14.10. Hysteroscopic view of a submucous myoma.
or left in situ (control group). They found that after 4 cycles of insemination, the
pregnancy rate in the polypectomy group was significantly higher (51.4%) than the
control group (25.4%). Furthermore, 65% of women in the polypectomy group
conceived prior to the first insemination. The authors postulated that endometrial
polyp produces excessive amount of glycodelin impairing implantation. Glycodelin
is a protein that facilitates implantation by decreasing natural killer cell activity.
Treatment of Uterine Septum
The presence of uterine septum is associated with recurrent pregnancy loss
rather than infertility. Uterine septum is relatively avascular. Hysteroscopic re-
moval of uterine septum in women with recurrent miscarriages is associated with
a live birth rate of 70%.
Key Points
In this modern era of assisted reproductive technologies, reproductive surgery
still has a place in the management of infertile women. Early surgical intervention
can be offered to young women with a history of pelvic inflammatory disease, pelvic
adhesions, blocked Fallopian tubes, and endometriosis. Most if not all
reconstructive-operations can be performed by laparoscopy. On the other hand,
women over the age of 35 with a long history of infertility or those who require a
laparotomy are better treated with in vitro fertilization.
Intrauterine abnormalities such as uterine septum, submucous myoma or en-
dometrial polyp can impair live-birth rate. This can be improved by hysteroscopic
treatment of these abnormalities.
Suggested Reading
1. Al-Fadhli R, Tulandi T. Tubal disease in relation to infertility. In: Falcone T, Hurd
WW, eds. Clinical Reproductive Medicine and Surgery. PA: Elsevier, (In Press).
2. Al-Jaroudi D, Herba MJ, Tulandi T. Reproductive performance after selective tubal
catheterization. J Min Inv Gynecol 2005; 12:150-2
3. Beretta P, Franchi M, Ghezzi F et al. Randomized clinical trial of two laparoscopic
treatments of endometriomas: Cystectomy versus drainage and coagulation. Fertil Steril
1998; 70:1176-80.
4. Hurst BS, Tucker KE, Schlaff WD. Hydrosalpinx treated with extended doxycycline
does not compromise the success of in vitro fertilization. Fertil Steril 2001; 75:1017-9.
5. Johnson NP, Mak W, Sowter MC. Surgical treatment for tubal disease. Surgical treat-
ment for tubal disease in women due to undergoing in vitro fertilisation. The Cochrane
Database of Systematic Reviews. 2004, (Issue 3. Art. No.: CD002125.pub2).
6. Marcoux S, Maheux R, Berube S et al. Laparoscopic surgery in infertile women with
minimal or mild endometriosis. N Engl J Med 1997; 337:217-22.
7. Palomba S, Orio Jr F, Falbo A et al. Prospective parallel randomized, double-blind,
double-dummy controlled clinical trial comparing clomiphene citrate and metformin
as the first-line treatment for ovulation induction in nonobese anovulatory women
with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90:4068-74.
8. Perez-Medina T, Bajo-Arenas J, Salazar F et al. Endometrial polyps and their implica-
tion in the pregnancy rates of patients undergoing intrauterine insemination: A pro-
14 spective, randomized study. Human Reprod 2005; 20:1632-5.
9. Pirwany I, Tulandi T. Laparoscopic treatment of polycystic ovaries: Is it time to relin-
quish the procedure? Fertil Steril 2003; 80:241-51.
10. Sacks G, Trew G. Reconstruction, destruction and IVF: Dilemmas in the art of tubal
surgery. BJOG 2004; 111:1174-81.
11. Varasteh NN, Neuwirth RS, Levin B et al. Pregnancy rates after hysteroscopic polypec-
tomy and myomectomy in infertile women. Obstet Gynecol 1999; 94:168-71.
12. Zeyneloglu HB, Arici A, Olive DL. Adverse effects of hydrosalpinx on pregnancy rates
after in vitro fertilization-embryo transfer. Fertil Steril 1998; 70:492-9.
Chapter 15
Ovulation Induction
Jon C. Havelock and Karen D. Bradshaw
Introduction
Approximately 25% of infertility can be attributed to ovulatory disorders. The
goal of ovulation induction is to restore fecundity by restoring regular, ovulatory
cycles. Ovulation induction may also be used for controlled ovarian hyperstimula-
tion (COH) for treatment of other causes of infertility such as mild/moderate en-
dometriosis, unexplained infertility, and for assisted reproductive techniques such as
in vitro fertilization (IVF). When used in ovulatory patients, the goal of ovulation
induction is not to restore ovulatory cycles but to increase fecundity through ova-
rian stimulation (Table 15.1).
The World Health Organization (WHO) has provided a simplified classifica-
tion system for disorders of ovulation. This grouping system describes the etiology
of anovulation, and the most appropriate treatment for patients with ovulatory dys-
function is determined by their classification. WHO Group I patients have low
follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels and low
estradiol levels. These patients have hypothalamic-pituitary hypofunction, either
congenital or acquired and have a negative progestin challenge test due to low en-
dogenous estradiol levels. WHO group II patients have normal FSH and LH levels,
and normal estradiol levels. Most anovulatory patients fall within this category, and
>90% of these patients have polycystic ovarian syndrome (PCOS). These patients
will have a positive progestin challenge test due to normal endogenous estradiol
levels. WHO group III patients have elevated FSH and LH levels. Gonadotropins
are elevated (often in the menopausal range) secondary to ovarian follicle depletion.
These patients respond poorly to ovulation induction and are candidates for
IVF-oocyte donation. Finally, hyperprolactinemic patients (WHO group V/VI),
with or without a pituitary adenoma, may have ovulatory dysfunction. Elevated
prolactin levels interfere with gonadotropin releasing hormone (GnRH) pulsatility
and, as a result, impair ovulation.
Testing Prior to Ovulation Induction
Since ovulation induction is pursued in the course of fertility treatment, a com-
prehensive fertility investigation should be performed prior to instituting therapy. A
thorough history and complete physical examination of the female and male part-
ner should be undertaken. Basic investigations for anovulation should include a day
3 FSH level (or random FSH if amenorrhea), thyroid stimulating hormone (TSH)
level, and prolactin level. A progestin challenge test may be performed to determine
the estrogen status and serves to help distinguish WHO group I from group II. A
semen analysis should be performed as 25-40% of infertility has a male-factor com-
ponent. A hysterosalpingogram may be ordered initially to evaluate uterine and
15
166
Table 15.1. Ovulation induction treatment and indications

Ovulatory
WHO Group I WHO Group II WHO Group III WHO Group V/VI Infertility
Etiology Hypogonadotropic Eugonadotropic Hypergonadotropic Hyperprolactinemia Unexplained infertility
hypogonadism hypogonadism hypogonadism Endometriosis
Male-Factor infertility
IVF
Primary Gonadotropins Weight Loss Oocyte donation Dopamine agonists Clomiphene citrate or
treatment Clomiphene citrate gonadotropins
Secondary Pulsatile gonadotropin Metformin Gonadotropins Clomiphene citrate or
treatment releasing hormone Aromatase inhibitors gonadotropins
Gonadotropins
Adjuvant Intrauterine Laparoscopic Intrauterine Intrauterine Intrauterine
treatment insemination ovarian diathermy insemination insemination insemination
Glucocorticoids
Intrauterine insemination
Ovulation Induction 167
tubal anatomy, but this may be delayed in an anovulatory patient if there is no

evidence of uterine/tubal disease on history and or physical examination. In
hyperandrogenic PCOS patients, serum testosterone, dehydroepiandrosterone sul-
fate (DHEAS), and 17-hydroxyprogesterone levels may be obtained to determine
the origin of the elevated androgens. A pelvic ultrasound may be performed as part
of the 2003 criteria for PCOS diagnosis. These basic investigations ensure that the
cause of anovulation is obtained and determine whether other causes of infertility
are present. If other infertility factors are present, these may require additional treat-
ments that are not addressed with ovulation induction, alone.
Ovulation Induction Monitoring
The goal of ovulation induction is to maximize the chance of pregnancy while
minimizing the complications, namely multiple pregnancy and ovarian hyperstimu-
lation syndrome (OHSS). This is facilitated through ovulation induction monitor-
ing. Ovulation induction monitoring may take the form of a menstrual diary, urine
or serum LH measurements, or serial ultrasound with or without serial estradiol
measurements. Since ovulation induction is used in conjunction with timed inter-
course or intrauterine insemination (IUI), efforts are made to time ovulation with
the presence of fresh sperm in the female reproductive tract. Since the oocyte has a
lifespan of approximately 24 hours in the female genital tract, and sperm can survive
up to 72 hours, the best chance for conception occurs if the sperm are present at the 15
time of, or just prior to ovulation. Ovulation occurs 34-36 hours after the start of
the LH surge, 17-26 hours after urine LH detection, and at a follicular diameter of
20-27 mm. Furthermore, when ultrasound is used to monitor follicle development
and human chorionic gonadotropin (hCG) is administered for final oocyte matura-
tion (a pharmacological mimic of the LH surge), it appears that 15 mm is the small-
est follicular size sufficient for ovulation. These surrogate markers for ovulation serve
as a guideline for timing of intercourse or IUI.
Estradiol levels are often used in conjunction with ultrasound for monitoring
ovulation induction cycles. In unstimulated, monofollicular cycles, estradiol and
follicle size show a highly correlated linear increase in the five days preceding ovula-
tion, with a daily increase in follicular diameter of 1.2-2 mm/day (Randall and
Templeton, 1991) and a corresponding increase in estradiol to an average preovula-
tory estradiol of 250 pg/ml. In COH cycles, greater preovulatory follicle numbers
and estradiol levels are seen. Compared to natural cycles, there is a weaker correla-
tion between follicle numbers and estradiol levels in multifollicular development.
Nonetheless, estradiol levels typically reach 250 pg/ml per preovulatory follicle.
Ultrasound monitoring of ovulation induction serves an additional purpose in
monitoring endometrial development. A periovulatory endometrial thickness of ≥
10 mm is a good prognostic factor for conception in COH cycles, and endometrial
thickness of <7 mm is associated with a very poor likelihood of pregnancy. The
finding of a thin endometrium by ultrasound gives prognostic information that
may allow for changes in treatment to promote endometrial development.
Complications of Ovulation Induction
Multiple Pregnancy
One of the greatest concerns in ovulation induction is multiple pregnancy,
especially higher order multiple pregnancy (triplets or greater). Multiple preg-
nancy is associated with significantly higher perinatal morbidity and mortality,
primarily related to premature birth. Risk factors for higher order multiple preg-
nancy in ovulation induction include: age <32 years, PCOS diagnosis, estradiol
>2000 pg/ml, ovulation induction with gonadotropins, and when more than three
follicles are ≥14 mm. With careful monitoring of cycles, the risk of multiple preg-
nancy can be decreased.
Ovarian Hyperstimulation Syndrome (OHSS)
Ovarian hyperstimulation syndrome is a clinical syndrome encompassing a con-
stellation of signs and symptoms, including abdominal pain and distension, ovarian
enlargement, nausea and vomiting, and ascites. Severe cases may include hydrotho-
rax, oliguria, increased hematocrit, decreased renal function, and thromboembolic
complications. Numerous severity classification systems have been described, and
hospitalization is required in severe instances. The risk factors for OHSS are similar
to the risk factors for multiple pregnancy: estradiol level >3000 pg/ml, large num-
bers of follicles and in younger age. For OHSS the best cure is prevention. Ovarian
hyperstimulation syndrome does not occur in the absence of ovulation. In ovulation
induction cycles deemed to be at risk for OHSS, cycle cancellation and withholding
the injection for final follicular maturation (discussed later) will usually prevent
OHSS. Another commonly used method of prevention of OHSS involves “coast-
ing.” This involves terminating the ovulation induction medication (gonadotro-
15 pins) once the largest follicle is ≥14 mm, for 1-4 days, and the estradiol level is
<3000 pg/ml. Other methods of prevention and treatment of OHSS are beyond the
scope of this chapter.
Methods of Ovulation Induction
The majority of patients seeking ovulation induction are women with PCOS.
An ovulation induction treatment algorithm for women with PCOS can be seen in
Figure 15.1.
Weight Loss
Weight loss can restore ovulatory cycles for many women with PCOS. Approxi-
mately 80% of women with PCOS are obese, which is associated with
hyperinsulinemia. The increased insulin has a direct effect on the ovary, resulting in
increased androgen production. Weight loss of >5% has been shown to restore ovula-
tion in some PCOS women. In addition, PCOS women who did not conceive with
previous treatment and had a mean weight loss of 10.2 kg went on to have a 77%
pregnancy rate with treatment. While this is an often overlooked mode of treatment,
it should be considered first line treatment for overweight women with PCOS.
Clomiphene Citrate
Clomiphene citrate (CC) is an estrogen analog that was first shown to induce
ovulation in 1961 and was approved for clinical use in the United States in 1967.
Clomiphene belongs to a family of compounds known as selective estrogen receptor
modulators (SERMs). Other well-known SERMs include tamoxifen (breast cancer
treatment) and raloxifene (osteoporosis treatment). Clomiphene is used for ovula-
tion induction or controlled ovarian hyperstimulation in patients with normal en-
dogenous estrogen levels.
Clomiphene exerts both estrogen agonist and antagonist effects. Clomiphene
blocks the negative feedback of endogenous estrogen at the hypothalamic and
15
Figure 15.1. Ovulation induction treatment algorithm for polycystic ovarian syn-
drome (PCOS). DHEAS, dehydroepiandrosterone sulfate; IVF, in vitro fertilization.
pituitary levels. This results in a >50% increase in endogenous FSH which subse-
quently stimulates follicular growth. Ovulation rates approach 80%, with cumu-
lative pregnancy rates of 30-40% over the course of a few cycles. This discrepancy
between ovulation and pregnancy rates is thought to be due to the estrogen an-
tagonist effects on the endometrium and cervical mucus. This may be detected by
an endometrial thickness of <7 mm on ultrasound, which would suggest other
forms of ovulation induction would be more effective.
Clomiphene citrate (CC) is administered in a dose of 50-150 mg/day for 5 days,
starting on day 2, 3, 4, or 5 of the menstrual cycle. The lowest starting dose is used
initially and is only increased in subsequent cycles if the patient remains anovula-
tory at a given dose. While some physicians have used longer treatment regimens
and higher doses, there is little evidence for effectiveness at doses greater than 150
mg. Once a patient is ovulatory with CC treatment, it is usually continued for up to
3-6 ovulatory cycles. Approximately 75% of conceptions occur in the first three
treatment cycles. Ovulation can be confirmed with a single mid-luteal (7 days after
ovulation) serum progesterone level of >5 ng/ml.
Monitoring of clomiphene citrate cycles may be managed using ovulation pre-
diction kits, basal body temperature monitoring, or ultrasound monitoring. If the
woman is attempting conception in conjunction with timed intercourse, the fertile
period is a 6-day period which is generally the day of ovulation and the 5 days
preceding ovulation (Dunson et al, 1999), and intercourse every second day is rec-
ommended. If ovulation induction is used in conjunction with IUI, then the IUI
should be performed the day of, or the day following a positive ovulation predictor
test. Ultrasound monitoring of CC stimulated cycles has demonstrated that on the

day of spontaneous LH surge, the preovulatory follicles are usually slightly larger
than in natural, unstimulated cycles. If ultrasound monitoring is used in conjunc-
tion with IUI, hCG (5,000-10,000 IU) is typically administered when the lead
follicle is ≥18 mm, and IUI is performed 36 hours later. While high-technology
monitoring has not been shown to increase pregnancy rates over low-technology
monitoring, ultrasound monitoring adds additional information on the endome-
trial effects of CC.
Complications of CC include OHSS and multiple pregnancies. Original reports
demonstrated twin pregnancy rates of 10% and higher order multiple rate (triplets
or greater) of 1%. Clinically significant OHSS is uncommon in CC stimulated
cycles. Side effects of CC include breast tenderness, bloating, hot flashes, abdominal
discomfort, and mood changes. A rare side effect is changes in vision or sensitivity
to light, which requires immediate discontinuation of the medication, as continua-
tion may cause permanent visual changes.
Metformin
There has been a plethora of evidence that PCOS is associated with
hyperinsulinemia, which leads to the widespread use of insulin sensitizing agents
for treatment. The most studied agent is the oral biguanide, metformin. The exact
15 mechanism of action of metformin in PCOS is unclear, but may be related to
weight loss or direct suppression of androgen production by the ovary. Metformin
is typically used at doses between 1500-2000 mg/day, and the main side effect is
GI upset.
Metformin may be used alone or in conjunction with CC. When metformin is
used alone as an ovulation induction agent, ovulation rates are typically between
30-40%, but evidence for a significant increase in pregnancy rates is lacking. When
metformin and CC are used together, ovulation rates approach 90%. In patients
who did not previously ovulate with CC therapy, ovulation rates are approxi-
mately 75% when treated with CC plus metformin. A recent meta-analysis sug-
gests that CC plus metformin has an approximately 3-fold greater pregnancy rate
in PCOS women than CC alone. In clinical practice, metformin is usually used in
conjunction with CC in obese PCOS patients or in patients who do not respond
to CC. Currently, a large, randomized, double-blind, clinical trial comparing preg-
nancy rates in patients treated with CC, metformin, or CC plus metformin, is
ongoing. This trial should determine the best treatment regimen for achieving
pregnancy.
Aromatase Inhibitors
Aromatase inhibitors are orally active agents that inhibit estrogen biosynthesis
by inhibiting the aromatase enzyme, resulting in decreased circulating levels of es-
tradiol. Under low estrogen conditions, there is decreased negative feedback and
greater pituitary FSH release. While this medication is not approved for ovulation
induction, it is increasingly being used for this purpose. The most commonly used
aromatase inhibitor given for ovulation induction is letrozole. It is typically admin-
istered at a dose of 2.5-7.5 mg/day for a 5-day regimen, starting on day 3 of the
menstrual cycle or occasionally as a single 20 mg dose given on day 3. While aromatase
inhibitors have not been shown to be superior to CC, there are some studies that
suggest they may be useful in patients who do not respond to CC.
Laparoscopic Ovarian Diathermy

Laparoscopic ovarian diathermy (LOD) is an endoscopic surgical procedure that
has been found to be an effective mode of ovulation induction. This procedure
involves creating 3-10 holes per ovary with an electric current or laser (see Chapter
14). Its use has primarily been in the CC resistant population, and a randomized,
controlled study in this population has shown similar pregnancy rates in patients
undergoing LOD compared to gonadotropin therapy. Furthermore, LOD has been
shown to have equivalent pregnancy rates after 6-12 months when compared to 3-6
cycles of gonadotropin therapy with significantly lower multiple pregnancy rates in
the LOD group. A recent study comparing metformin treatment versus LOD in a
CC resistant population demonstrated similar ovulation rates, but higher pregnancy
rates in the metformin group. With an expanding number of ovulation induction
agents, the role of LOD in contemporary ovulation induction appears to be limited.
Glucocorticoids
While not an ovulation induction agent on its own, glucocorticoids (namely
dexamethasone) have occasionally been used in conjunction with CC in women
who are unresponsive to CC. A subset of patients with PCOS have increased adre-
nal androgen production, reflected by elevated DHEAS levels. Administration of
dexamethasone suppresses adrenal androgen production and can increase the ovula-
tion rate among women with DHEAS levels >200 μg/dl. The most widely used 15
protocol includes dexamethasone administered at nighttime in a dose of 0.5 mg
orally in conjunction with CC treatment.
Pulsatile Gonadotropin Releasing Hormone
Gonadotropin releasing hormone (GnRH) was first identified in 1971 and is
the hypothalamic releasing hormone responsible for FSH and LH synthesis and
release from the pituitary. While it is rarely used in clinical practice, it is the most
physiological method of ovulation induction for WHO group I ovulatory disorders,
namely women who have hypogonadotropic hypogonadism. These women typi-
cally do not have the pulsatile GnRH secretion required for the synthesis and release
of gonadotropins from the pituitary that are responsible for ovarian folliculogenesis
and regular, cyclic menses. GnRH is typically administered in doses from 2.5-20 μg
every 60-120 minutes. GnRH pulsatile therapy may be administered intravenously
(IV) or subcutaneously (SC) but appears to be more effective by IV route. The LH
surge and subsequent ovulation occur spontaneously, therefore not requiring an
injection of hCG to induce follicular maturation, and pulsatile GnRH can be con-
tinued in the luteal phase to provide support for the corpus luteum. Ovulation rates
are typically 75%/cycle, with pregnancy rates of 23%/ovulatory cycle and multiple
pregnancy rate of 3.8%/cycle. The low multiple pregnancy rate is due to
monofollicular development using this method of ovulation induction. In spite of
high pregnancy rates and low multiple pregnancy rates, due to the need for a pump
and indwelling catheter, this method of ovulation induction is not frequently used.
Dopamine Agonists
Dopamine agonists are the first-line therapy for patients with anovulation related
to hyperprolactinemia. Hyperprolactinemia is often due to prolactin-secreting pitu-
itary adenomas. Hyperprolactinemia interferes with GnRH pulsatile secretion, thereby
causing anovulation. Dopamine inhibits prolactin secretion, and administration of
dopamine agonists results in both a decrease in tumor volume and restoration of

ovulatory cycles. The most commonly used dopamine agonist for ovulation induc-
tion is bromocriptine, which is administered in a dose of 2.5-10 mg, daily in divided
doses. Cabergoline is another dopamine agonist with a better side-effect profile and
patient tolerability and is administered in a dose of 0.25-1 mg, given twice weekly.
Cumulative pregnancy rates of 80% can be expected with bromocriptine treatment
for anovulation due to hyperprolactinemia. Dopamine agonists are typically stopped
once conception has occurred.
Gonadotropins for Ovulation Induction
Background
The anterior pituitary gonadotropins, LH and FSH, and the placental gona-
dotropin, hCG, are the three identified gonadotropins and all are used in ovula-
tion induction. LH serves two distinct and essential functions. First, it is responsible
for stimulating the synthesis of ovarian androgens in ovarian theca cells. These
androgens serve as precursors for ovarian estrogen synthesis. Second, the LH surge,
which occurs in response to a positive feedback effect of estradiol produced from
a preovulatory follicle, causes oocyte maturation with resumption of meiosis, oo-
cyte release, and a shift in production of ovarian steroids from a predominantly
15 estrogen-producing follicle to a progesterone-producing corpus luteum. The pla-
cental gonadotropin, hCG, is produced by the early pregnancy and functions
through the same receptor as LH. As a result, it has the same activity as LH, and
its primary biological purpose is to continue to support progesterone production
by the corpus luteum throughout the first trimester and until the placenta devel-
ops. Finally, FSH stimulates ovarian follicle growth and stimulates aromatase ac-
tivity in granulosa cells. The aromatase activity is responsible for conversion of the
LH stimulated androgens from the theca cells into estrogens. While the physi-
ological function of these hormones is to ensure regular, monofollicular ovulation
and hormonal support in early pregnancy, these hormones can be used pharmaco-
logically to induce ovulation in women with ovulatory defects or to induce su-
perovulation (e.g., multifollicular development) in ovulatory patients to increase
the chance of pregnancy.
The first live birth from gonadotropin therapy occurred in 1962. The gona-
dotropins were obtained from the purified urine of postmenopausal women. These
preparations were termed human menopausal gonadotropins (hMG) and initially
contained 5% gonadotropins and numerous urinary protein contaminants. Due
to the impurity and batch-to-batch variability of these preparations, mass was not
an appropriate indicator of gonadotropin content. As a result, gonadotropin prepa-
rations have traditionally been expressed in international units (IU) of activity, as
measured by a standard bioassay. Initial hMG preparations contained equivalent
amounts of FSH and LH per unit. These preparations were typically administered
by intramuscular injection (IM). Years later, a urinary FSH (uFSH) product was
developed that had most of the LH activity removed although it still contained
significant impurities. The rationale for this was that endogenous LH levels were
adequate and that excessive LH activity could be harmful to folliculogenesis. Sub-
sequently, a highly purified urinary FSH (uFSH-HP) was developed. This was
>95% pure and offered the advantage of subcutaneous administration with little
local irritation. Finally, the end of the last millennium brought the development
of recombinant DNA technology and with it the development of recombinant

FSH (rFSH). These products contain exclusively recombinant FSH, >99% pure,
without significant batch-to-batch variation. Similarly rLH and rhCG have been
developed and are available for clinical use.
While there has been much progress in the development and use of gonadotro-
pins, there is a paucity of evidence that any one preparation is clinically superior to
another. Two different meta-analyses of several randomized, controlled trials gave
different results with respect to pregnancy rates when comparing ovulation induc-
tion using FSH to hMG. The initial meta-analysis demonstrated a higher preg-
nancy rate in when FSH was used for ovarian stimulation for in vitro fertilization.
In contrast, a reanalysis of this data with a larger number of studies showed little
difference between these two preparations. Most recently, a meta-analysis compar-
ing rFSH to hMG demonstrated no difference in clinical pregnancy rates. While
the recombinant preparations are more expensive and at this point, they do not
appear to offer any clinical advantage over hMG or uFSH, they have less batch
variability, virtually no infectious risk that theoretically exists with urinary prepara-
tions, an essentially limitless supply that is not constrained by access to urine from
postmenopausal women, and the ability to develop novel ovulation induction regi-
mens with varying doses of rFSH, rLH, and rhCG. For most clinical purposes, any
of the FSH or hMG preparations may be used interchangeably.
Multiple pregnancy and OHSS occur with higher frequency in patients treated
15
with gonadotropins. A recent study of over 4000 gonadotropin plus IUI cycles re-
vealed a 14.4% pregnancy rate/cycle, with an overall 25% multiple pregnancy rate,
with a higher order multiple pregnancy rate of 6%. OHSS rates can be up to 11% in
PCOS patients undergoing gonadotropin ovulation induction.
Follicular Maturation with hCG—The Terminal Act
in Ovulation Induction
The purpose of the LH surge is to initiate ovulation, maturation of the oocyte,
and development of the corpus luteum. This can occur spontaneously with most
types of ovulation induction but is usually brought on pharmacologically in large
part for practical reasons. By administering an agent that mimics the LH surge, we
are virtually ensure that the events that occur as a result of the LH surge take place,
and we can also control the timing of these events. Since the LH surge precedes
ovulation by approximately 36 hours, timing of IUI or intercourse may be coordi-
nated with the pharmacologically induced surge.
The most common agent used for follicular maturation is hCG. The structure of
hCG is similar to LH, and it acts through the LH receptor to mimic the LH surge.
There are both uhCG and rhCG products available. It is typically administered in
doses of 5000-10000 IU for uhCG administered IM or SC, or 250 μg of rhCG
administered SC. Both agents are equally effective in ovulation induction. The lower
dose of uhCG may lower the risk of OHSS in patients at greatest risk.
While hCG is the most common agent for inducing final follicular maturation,
both LH and GnRH agonists may be used. The clinical use of LH for follicular
maturation has been limited due to the large dose required for this purpose and its
shorter half-life than hCG. GnRH agonists have been also been used, and they hold
the advantage of stimulating an endogenous LH surge from the pituitary that is
more physiological, potentially lowering the risk of OHSS.
Gonadotropin Ovulation Induction in PCOS

There are numerous protocols for ovulation induction with gonadotropins in
PCOS women. The two most common protocols are the low dose step-up protocol
and the step-down protocol, both of which are adequate. It has been suggested that
the low dose step-up protocol has a lower rate of OHSS and multiple pregnancies,
and possibly a higher pregnancy rate. Whatever protocol is used, close ultrasound
and estradiol monitoring is essential for avoiding complications.
The step-up protocol is typically started on cycle day 2 or 3 of the menstrual
cycle, often after a progestin-induced withdrawal bleed (Fig. 15.2). The initial FSH
starting dose is typically 75 IU/day, but has been effective at lower doses. The initial
dose is given for 7 days, and ultrasound and estradiol levels are obtained. If follicles
>10 mm are seen, the same dose is continued and patients return for ultrasound and
estradiol testing every 1-2 days until the lead follicle is ≥17 mm in diameter. Follicu-
lar maturation is then initiated with hCG, but this may be withheld if there are
greater than four follicles with ≥14 mm diameter or estradiol >2000 pg/ml, due to
the risk of OHSS and multiple pregnancy. If after 7 days of initial stimulation the
follicles are ≤10 mm, the same dose is continued for another 7 days and ultrasound
examination is performed again. If the follicles are >10 mm, then the protocol is
continued at the same dose (threshold dose) until a follicle ≥17 mm is seen. If the
15 follicles remain ≤10 mm, FSH dose is increased 37.5 IU daily for 7 days, and is
increased 37.5 IU every 7 days until a threshold dose is reached.
Figure 15.2. Low dose step-up protocol for gonadotropin ovulation induction. FSH,
follicle stimulating hormone; hCG, human chorionic gonadotropin; IUI, intrauter-
ine insemination; IU, international units.
The step-down protocol is started on cycle day 2 or 3 of the menstrual cycle at an

FSH starting dose of 150-225 IU/day for 5 days (Fig. 15.3). Ultrasound and estra-
diol levels are then performed. If follicles ≥10 mm are seen, the dose is decreased by
37.5 IU every 3 days and the cycle monitored with ultrasound and estradiol every
1-2 days until the lead follicle ≥17 mm. Follicular maturation is then initiated with
hCG unless the risk of OHSS or multiple pregnancy is too great. If after 5 days of
initial stimulation, all follicles are <10 mm, the dose is increased by 37.5 IU every
2-3 days and monitored every 2-3 days, for up to 10 days, until follicles ≥10 mm are
seen. At this point, the dose is decreased by 37.5 IU every 3 days until a mature
follicle is seen. If there is still no growth after 10 days at the higher dose, the cycle is
cancelled and a low dose step-up protocol may be considered.
Ovulation in Hypogonadotropic Hypogonadism
Anovulation of this type, also termed WHO group I anovulation or hypotha-
lamic anovulation, is due to low FSH and LH. As a result, these patients generally
require a gonadotropin preparation that contains LH activity. This could be in the
form of hMG, rFSH plus rLH, or rFSH plus low-dose rhCG. In hypogonadotropic
hypogonadism, estradiol levels remain low in women stimulated with FSH only,
due to the absence of LH activity driving ovarian androgen precursor production.
In the absence of LH activity, ovulation is significantly diminished. As a result,
stimulation protocols must contain LH activity. Ovulation induction for these 15
Figure 15.3. Step-down protocol for gonadotropin ovulation induction. FSH, Fol-
licle stimulating hormone; hCG, Human chorionic gonadotropin; IUI, Intrauterine
insemination; IU, International units.
patients may be performed using either hMG or rFSH plus 75 IU rLH daily. Risk of
OHSS and multifollicular development is lower than in WHO group II anovula-
tion. As a result, increased doses of gonadotropins may be used.
Ovulation induction is usually started with a dose of 75-225 IU/day of hMG or
75-225 IU/day rFSH plus 75 IU/day of rLH, for 5 days. Ultrasound and estradiol
monitoring are performed after 5 days, and dose adjustments of hMG or rFSH may
be increased or decreased by 75 IU/day, depending on the adequacy of response.
This is continued until the lead follicle reaches at least 17 mm. Follicular matura-
tion is then initiated with hCG unless the risk of OHSS or multiple pregnancy is
excessive.
Gonadotropins in Controlled Ovarian Hyperstimulation (COH)
Gonadotropins may be used in regularly ovulating women in order to increase
their fecundability. Gonadotropin therapy is often used in conjunction with IUI
in patients with unexplained infertility, mild male-factor infertility, and mild/
moderate endometriosis, with improved pregnancy rates. In women with en-
dometriosis, gonadotropin treatment with IUI resulted in a 5-fold increase in
pregnancy rates when compared to no treatment. In unexplained or male-factor
infertility, gonadotropin treatment with IUI resulted in a 1.7-fold increase in preg-
nancy rates when compared to IUI alone. Controlled ovarian hyperstimulation is
15 often performed with a fixed-dose protocol, starting stimulation on cycle day 3 at
an FSH or hMG dose of 150-225 IU/day for 5 days. Ultrasound and estradiol
monitoring is then performed every 1-2 days once a follicle >10 mm is identified.
Criteria for follicular maturation with hCG are identical to other ovulation in-
duction protocols, and the same caution for OHSS and multiple pregnancy risks
must be observed.
COH with Gonadotropins in in Vitro Fertilization (IVF)
Gonadotropin stimulation is the mainstay of COH in IVF. The purpose of COH
in IVF stimulation is to produce multiple follicles for transvaginal oocyte retrieval,
in vitro fertilization of oocytes, and subsequent transfer of 1-3 embryos into the
uterus after 3-5 days of in vitro embryo culture. The details of these protocols ex-
tend beyond the scope of this chapter.
Key Points
1. Ovulation induction remains a mainstay of infertility treatment of women
with ovulatory disorders.
2. Weight loss and clomiphene citrate ± metformin are the first-line ovulation
induction methods in PCOS women.
3. Gonadotropins are first-line for anovulation due to hypogonadotropic hy-
pogonadism and are second-line therapy for PCOS.
4. The major risks of ovulation induction are OHSS and multiple pregnancy.
These risks can be reduced with appropriate monitoring.
5. Future directions in ovulation induction will be directed at greater individu-
alization of protocols to increase pregnancy rates and decrease multiple births
through monofollicular ovulation.
Suggested Reading
1. Dickey RP, Taylor SN, Lu PY et al. Risk factors for high-order multiple pregnancy and
multiple birth after controlled ovarian hyperstimulation: results of 4,062 intrauterine
insemination cycles. Fertil Steril 2005;83:671-83, [A large review of the risk factors for
higher order multiple pregnancy in gonadotropin ovulation induction].
2. Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for
patients with polycystic ovarian syndrome. Hum Reprod 2004;19:2474-83, [A review
of the role of pregnancy and ovulatory rates in ovulation induction protocols using
metformin].
3. Guzick DS, Carson SA, Coutifaris C et al. Efficacy of superovulation and intrauterine
insemination in the treatment of infertility. National Cooperative Reproductive Medi-
cine Network. N Engl J Med 1999;340:177-83, [A randomized controlled trial exam-
ining the pregnancy rates in COH ± IUI in patients with unexplained and mild
male-factor infertility].
4. Dunson DB, Baird DD, Wilcox AJ et al. Day-specific probabilities of clinical preg-
nancy based on two studies with imperfect measures of ovulation. Hum Reprod 1999;
14:1835-1839.
5. Farquhar C, Vandekerckhove P, Lilford R. Laparoscopic “drilling” by diathermy or
laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane
Database Syst Rev 2001; CD001122.
6. Filicori M, Flamigni C, Dellai P et al. Treatment of anovulation with pulsatile
gonadotropin-releasing hormone: Prognostic factors and clinical results in 600 cycles.
J Clin Endocrinol Metab 1994; 79:1215-1220.
7. Haas DA, Carr BR, Attia GR. Effects of metformin on body mass index, menstrual 15
cyclicity, and ovulation induction in women with polycystic ovary syndrome. Fertil
Steril 2003; 79:469-481.
8. Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associ-
ated with polycystic ovary syndrome: Rationale, results, reflections and refinements.
Hum Reprod Update1999; 5:493-499.
9. Mitwally MF, Casper RF. Aromatase inhibitors in ovulation induction. Semin Reprod
Med 2004; 22:61-78.
10. Randall JM, Templeton A. Transvaginal sonographic assessment of follicular and en-
dometrial growth in spontaneous and clomiphene citrate cycles. Fertil Steril 1991;
56:208-212.
11. van Santbrink EJ, Hop WC, van Dessel TJ et al. Decremental follicle-stimulating
hormone and dominant follicle development during the normal menstrual cycle. Fertil
Steril 1995; 64:37-43.
12. van Wely M, Westergaard LG, Bossuyt PM et al. Human menopausal gonadotropin
versus recombinant follicle stimulation hormone for ovarian stimulation in assisted
reproductive cycles. Cochrane Database Syst Rev 2003; CD003973.
Chapter 16
Assisted Reproductive Technology

Tiffany Von Wald and Kim Thornton
Introduction
Assisted reproductive technology (ART) is by definition any treatment or proce-
dure that includes the handling of oocytes and sperm or embryos outside the body
for the purpose of establishing a pregnancy. In vitro fertilization (IVF) is the most
common ART procedure. The first IVF baby was conceived in 1978 (Louise Brown)
in Lancashire, England. IVF has been used in the United States since 1981.
Definitions
In vitro fertilization (IVF): A process including controlled ovarian hyperstimu-
lation, surgical removal (retrieval) of oocytes, fertilization in the laboratory, and
transcervical transfer of embryos into the uterus.
Gamete intrafallopian transfer (GIFT): A procedure that involves removing
oocytes from a woman’s ovary, combining them with sperm, and using laparoscopy
to assist in placing the unfertilized oocytes and sperm into the fallopian tubes.
Zygote intrafallopian transfer (ZIFT): A procedure that involves removing
oocytes from a woman’s ovary, fertilizing them in the laboratory with sperm, then
placing the single-cell embryo (zygote) directly into the fallopian tube utilizing
laparoscopy.
Tubal embryo transfer (TET): A procedure that involves removing oocytes from a
woman’s ovary and fertilizing them in the laboratory with sperm. The resultant embryo(s)
are placed directly into the fallopian tube utilizing laparoscopy 2-3 days later.
Donor oocytes: Eggs that are removed from one woman’s ovaries to be used by
another for IVF. Indications often include premature ovarian failure, gonadal dys-
genesis, recurrent IVF failure, natural menopause, and inheritable disorders.
Gestational surrogacy: Treatment by which the gametes of the intended par-
ents (genetic parents) are used to produce embryos, which are subsequently trans-
ferred to a woman who agrees to act as a host or surrogate carrier of the pregnancy.
Microsurgical epididymal sperm aspiration (MESA): A technique whereby a
small needle is used to extract fluid and relatively mature sperm directly from an
epididymal tubule.
Testicular sperm extraction (TESE): A procedure for extracting sperm by re-
moving a small sample of testicular tissue through an incision in the testes under
local anesthesia.
Intracytoplasmic sperm injection (ICSI): A micromanipulation technique that
involves injecting a sperm directly into an egg in order to facilitate fertilization.
Assisted hatching (AH): A technique in which the zona pellucida (outer shell of
the egg) is chemically or mechanically thinned prior to embryo transfer in order to
improve the likelihood of subsequent hatching and implantation of the embryo.
Assisted Reproductive Technology 179
Preimplantation genetic diagnosis (PGD): A technique used during IVF to

test embryos for genetic disorders (aneuploidy or structural chromosomal abnor-
malities), inheritable single gene disorders, or gender, prior to embryo transfer. The
procedure can involve evaluating the chromosomal composition of the oocyte via
the extruded polar body, removing one or two blastomeres from the cleavage stage
embryo, or by biopsy of the trophoectoderm of the blastocyst stage.
Infertility History and Evaluation
An initial infertility evaluation is traditionally begun after one year of unpro-
tected intercourse; however, an earlier evaluation may be indicated for increased
maternal age, irregular menstrual cycles, previous pelvic inflammatory disease (PID)
or pelvic surgery.
One of the most important aspects of evaluating infertility is obtaining a thor-
ough history from both partners. When evaluating the female partner, it is impor-
tant to include the items listed in Table 16.1. When evaluating the male partner, it
is important to include the items listed in Table 16.2.
Every infertility evaluation should begin with a complete physical exam. When
examining the female partner, it is important to document height and weight, as
well as body mass index (BMI = weight in kilograms/height in meters squared).
There is a clear association between weight and infertility as well as a correlation
between the woman’s weight and the amount of gonadotropins needed to stimu-
late the ovaries. It is important to check for thyroid enlargement, nodules, or ten- 16
derness, as well as identifying excessive acne or facial hair, which may be associated
with increased androgen levels. Evidence of acanthosis nigricans often indicates
Table 16.1. Evaluation of female partner

Female:
General Category Specific Points
Length of infertility Coital frequency, previous treatment
Gravity and parity History of spontaneous pregnancy, specific pregnancy
outcomes, complications, history of recurrent
pregnancy loss
Menstrual history Length of cycles (normal 21-35 days), duration and type
of flow (may indicate fibroids or oligovulation), menstrual
cramps and breast tenderness (molimina-signs of
ovulation), dyspareunia
Family history Recurrent pregnancy loss, endometriosis, birth defects,
premature ovarian failure
Surgical history Tubal ligation, ovarian cysts, endometriosis, pelvic
infections, appendectomy, D&C
Gynecologic history STDs, PID, abnormal pap smears and subsequent treatment
Medication
and allergy history
Social history Tobacco use, alcohol use, illicit drug use
Review of systems Symptoms of thyroid disease, pelvic or abdominal pain,
weight changes, hirsutism, galactorrhea
Table 16.2. Evaluation of male partner

Male:
General Category Specific Points
Length of infertility Coital frequency, previous fertility, previous infertility
treatment
Childhood illnesses Mumps, testicular injuries, undescended testes
and injuries
Family history Infertility history, inheritable disorders
Urologic surgery Vasectomy, herniorrhaphy
Past medical history Diabetes, multiple sclerosis, STDs, recent febrile illnesses
Environmental toxins Heat, pesticides, industrial toxins
Medication Sulfasalazine, cimetidine (gonadotoxic but reversible);
and allergy history antihypertensives, antipsychotics, antidepressants
(ejaculatory dysfunction); anabolic steroids (decreased
spermatogenesis)
Social history Tobacco use (decreased motility), alcohol use, illicit
drug use (marijuana- decreased sperm count)
Review of systems Impotence, ejaculatory dysfunction
16
insulin resistance, a common finding with polycystic ovarian syndrome (PCOS).
Other important features to note are: a “buffalo hump” (Cushing’s syndrome);
short stature, webbed neck, and shield chest (Turner’s syndrome). Finally, a com-
plete pelvic examination is crucial during the initial visit and should include
evaluation for Mullerian defects, pelvic or abdominal masses, or tenderness, cer-
vical abnormalities, and nodularity in the cul-de-sac. One should consider per-
forming a cervical culture as well due to the association of chlamydia cervicitis
and PID.
During the examination of the male partner, one should first evaluate height,
evidence of disproportionate limb length, secondary sexual characteristics, and gy-
necomastia (Klinefelter’s syndrome). The genitourinary examination should include
location of the urethral meatus (hypospadias), palpating the testes for location and
size, palpating bilateral vas deferens, and noting any varicocele.
The evaluation of the infertile couple often includes a panel of screening tests. This
includes a cervical Pap smear, maternal blood type and Rh, antibody screening, ru-
bella status, RPR (syphilis), varicella status, hepatitis B, and cystic fibrosis. Screening
for sexually transmitted diseases is also recommended for patients at high risk, and
would include hepatitis C, HIV 1 and 2, HTLV, CMV, chlamydia, and gonorrhea.
Once the initial screening tests are obtained, it is important to first document
evidence of ovulation. This may be performed using basal body temperature chart-
ing (biphasic→ovulatory), urinary LH surge detection kits, or serum progesterone
levels (>5 ng/ml→ovulatory). An endometrial biopsy (showing secretory phase) may
also be performed, but this has limited use due to the cost and invasive nature of the
test. “Luteal phase defect” is a condition in which inadequate progesterone is pro-
duced by the corpus luteum as evidenced by endometrial histological dating. This is
a controversial topic when used in the evaluation of the infertile couple, and recent
evidence suggests that an endometrial biopsy for histological dating does not differ-
entiate fertile from infertile women, and thus, should not be used in the routine
evaluation of infertility.
Routine laboratory tests for infertility include a prolactin level (normal <20 ng/
mL) and TSH (normal <5 mIU/mL but varies with individual laboratories). Occa-
sionally, one will want to obtain labs for excess androgen states (PCOS), such as free
or total testosterone, DHEA-S, and 17-OH progesterone. A fasting glucose/insulin
ratio is obtained in women with PCOS to identify insulin resistance, and a 24-hour
urinary cortisol may be needed to rule out Cushing’s syndrome.
An important feature of the infertility evaluation includes ovarian reserve test-
ing. This is often performed by obtaining a cycle day 3 (CD3) serum FSH level.
In general, a CD3 FSH <10 mIU/mL is considered normal, where 10-15 mIU/
mL is considered the “gray zone” and a CD3 FSH >15 mIU/mL is considered
abnormal with diminished ovarian reserve. A CD3 estradiol is also often obtained,
and if elevated, may indicate a shortened follicular phase with decreased ovarian
reserve. A clomiphene challenge test is another route to evaluate ovarian reserve.
It is often used in older women (>35 years) or those with shortened menstrual
cycles. To perform the test, a CD3 FSH is obtained. Then, clomiphene 100 mg is
given orally on days 5-9. On CD10, a repeat FSH level is drawn. If either the
CD3 or CD10 FSH level is elevated (>10 mIU/mL), the test is abnormal. There is
some evidence that the sensitivity of the clomiphene challenge test is higher than
a basal CD3 FSH level (26% vs. 8%), although both tests are routinely used. 16
Lastly, an antral follicle count (AFC) may be obtained using transvaginal ultra-
sonography to assess the number of primordial follicles during the early follicular
phase. In general, an AFC count of <4 follicles is associated with a poor ovarian
response.
Tubal patency and uterine cavity contour should be evaluated prior to beginning
any infertility treatment. The most widely used test is the hysterosalpingogram (HSG).
This is a radiological test performed as an outpatient procedure where dye is in-
jected into the uterus through a small catheter and is imaged as it passes through the
uterine cavity and fallopian tubes. It can display evidence of uterine fibroids, polyps,
and synechiae (adhesions), as well as tubal patency. A sonohysterogram is an office
procedure where saline is injected into the uterus under ultrasound guidance. Al-
though it can detect uterine cavity abnormalities, it cannot show tubal patency. A
hysteroscopy/laparoscopy may also be utilized to evaluate the uterine cavity and
well as tubal patency through chromotubation, but this procedure is obviously much
more invasive and requires general anesthesia.
Finally, a semen analysis is required to rule out a male infertility factor. If the first
semen analysis is abnormal, it should be repeated. Although normal reference values
can vary between laboratories, the World Health Organization recommends the
following normal reference values (Table 16.3).
Indications for ART
As mentioned previously, IVF is the most common ART procedure performed.
Although IVF was originally designed to treat tubal disease, it is now utilized as a
treatment for many causes of infertility. In addition to tubal factor infertility, other
indications include endometriosis, male factor infertility, ovulatory disorders, unex-
plained infertility, ovarian failure, and a history of inheritable disease.
Table 16.3. Semen analysis: WHO normal reference values

Volume 1.5-5.0 mL
pH >7.2
Viscosity <3 (scale 0-4)
Sperm concentration >20 million/mL
Total sperm number >40 million/ejaculate
Percent motility >50%
Forward progression >2 (scale 0-4)
Normal morphology >14% normal
Round cells <5 million/mL
Sperm agglutination <2 (scale 0-3)
Tubal Disease
Tubal disease accounts for approximately 13.6% of indications for ART proce-
dures in the US. Some patients with mild distal tubal obstruction may benefit from
reconstructive surgery prior to proceeding with IVF. However, the pregnancy rates in
general are lower than with IVF, and the risk of ectopic pregnancy is greater. IVF is the
16 recommended treatment for women who remain infertile after one year following
reconstructive surgery. For women with severe distal tubal disease, IVF is the primary
treatment. There is substantial evidence that pregnancy rates are improved in women
who have surgical removal of hydrosalpinges prior to undergoing IVF. In one
meta-analysis of three randomized controlled trials, the odds of pregnancy (OR =
1.75, CI 1.07-2.86) and of ongoing pregnancy and live birth (OR = 2.13, CI 1.24-3.65)
were increased with laparoscopic salpingectomy for hydrosalpinges prior to IVF. The
mechanism of this effect is not well understood, but fluid from the hydrosalpinges is
inflammatory and may have a toxic effect on the embryo or the endometrium.
Proximal or mid-tubal obstruction is also an indication for IVF. The most com-
mon reason for proximal obstruction is previous tubal sterilization. Microsurgical
tubal reanastomosis can be effective in select candidates, although IVF may be a
better choice for women who are poor surgical candidates and those who only desire
one additional pregnancy.
Endometriosis
Endometriosis accounts for approximately 6.7% of indications for ART in the US.
Mild, moderate, and severe endometriosis has been shown to decrease fertility rates in
women undergoing both IUI and IVF Pregnancy rates in patients with endometriosis
have been demonstrated to have an approximate 45% reduction in pregnancy rates
with IVF. Women with moderate and severe disease have a worse prognosis than those
with mild and minimal disease. The proposed mechanisms include distorted anatomy
(adhesive disease), abnormalities with oocyte development, and diminished endome-
trial receptivity. Although surgical management is an option for infertility treatment
in women, IVF is often the treatment of choice in women who are older, those with
other infertility diagnoses, or previous treatment failures.
Male Factor Infertility

Male factor infertility as a single reason accounts for approximately 18.8% of
indications for ART in the US. Male factors can contribute to infertility in up to
35% of couples. The vast majority of sperm problems can be detected by a simple
semen analysis. In men with mild semen abnormalities, intrauterine insemination
with washed and concentrated sperm may be effective. In patients who fail to con-
ceive after intrauterine inseminations with ovulation induction, the next step in treat-
ment is IVF. IVF allows an assessment of whether fertilization occurs. In cases of no
fertilization, intracytoplasmic sperm injection (ICSI) is then indicated. In men with
severe abnormalities (references vary), poor fertilization is often expected. In this
instance IVF is indicated as a first line therapy with the addition of ICSI. The indi-
cations for ICSI remain controversial but often include the following parameters:
• Total motile sperm count <1 million
• <4 % normal morphology
• Previous IVF cycle with no or poor fertilization
• Epididymal or testicular spermatozoa
Because the manipulation with ICSI overrides potential natural protection to
prevent fertilization by sperm with damaged DNA, there is the potential that chil-
dren born after ICSI might be at increased risk for congenital birth defects and/or
chromosomal abnormalities. However, most studies to date have failed to identify
any increased incidence of major malformations above baseline in children born
after ICSI. 16
Ovulatory Disorders
Chronic anovulation is a common cause of infertility and accounts for 6% of
indications for ART procedures in the US. In most women with chronic anovula-
tion, polycystic ovarian syndrome is the cause. Polycystic ovarian syndrome is a
disorder characterized by hyperandrogenism and anovulation. Many women with
polycystic ovarian syndrome are also very obese and may have insulin resistance.
The majority of these patients will respond to conventional ovulation induction
(clomiphene or gonadotropins). In women who are obese or insulin resistant,
their response to ovulation induction may be enhanced with the use of insulin
sensitizing agents such as metformin. When these treatment regimens fail, IVF is
a reasonable and useful option. Although women with PCOS often obtain a larger
number of oocytes during retrieval, there appears to be a lower fertilization rate,
presumably due to the endogenous hormonal imbalance. Despite a reduced fer-
tilization rate, IVF pregnancy rates in women with PCOS are comparable to ovu-
latory women. Women with PCOS who have high estradiol levels and a large
number of preovulatory follicles are particularly at risk for the development of a
syndrome called ovarian hyperstimulation syndrome (OHSS) because of their
exaggerated response to gonadotropins. Women with a PCOS like response to
gonadotropins are also at risk. Typical symptoms of OHSS include abdominal
distension as a result of fluid shifts from the vascular space to body cavities, dehy-
dration, nausea, and shortness of breath, weight gain, and pelvic pain. Depending
on the severity, OHSS may be treated conservatively with fluid restriction or with
paracentesis (removal of fluid from the abdominal cavity).
Unexplained Infertility
Although the exact prevalence of unexplained infertility is unknown due to dif-
fering diagnostic criteria, it ranges from 10-30%. In 2002, unexplained infertility
accounted for 11.1% of indications for ART procedures in the US. The highest
success rates for treatment are with IVF (28.5%). As one might expect, the success
rates decrease in all forms of treatment as maternal age increases.
Diminished Ovarian Reserve
Diminished ovarian reserve is a common diagnosis in ART centers and accounts
for approximately 6.7% of indications for ART in the US. Diminished ovarian re-
serve implies that the ability to produce eggs is reduced. Causes of diminished ova-
rian reserve may include surgery, congenital abnormalities and advancing maternal
age. Many women with diminished ovarian reserve will be diagnosed by ovarian
reserve testing or after a previous stimulation cycle demonstrates production of low
numbers of oocytes.
Other Indications for ART
Women who have a family history of an inheritable disease may be candidates
for IVF with preimplantation genetic diagnosis (PGD). PGD is most often utilized
in this scenario when there is a single-gene disorder, sex-linked disorder, autosomal
recessive disorder, or balanced translocation. PGD is also utilized in some women
16 with recurrent pregnancy loss, but the data are not clear regarding improved out-
comes. To perform PGD one or two cells are removed from the embryo. These cells
may then be analyzed for the presence or absence of a single gene order or for the
presence of the correct number of chromosomes. This will enable couples to
preconceptually evaluate embryos so that they can preferentially transfer those em-
bryos that are not affected with a genetic disease or that have a normal chromosomal
number. PGD is occasionally used for sex selection and family balancing, but this is
highly controversial.
Donor oocytes are indicated when a woman has premature ovarian failure, has
undergone natural menopause or if a woman has demonstrated poor oocyte recov-
ery and embryo quality with her own eggs. The latter indication is most often seen
in women of advanced maternal age.
Women who have Mullerian anomalies (congenital absence of the uterus and
vagina) are often candidates for gestational carriers (surrogates). Likewise, women
with severe uterine abnormalities (fibroids, adhesions) or a previous hysterectomy
may also be candidates for gestational surrogacy. Because the success rates for IVF
are so high, other techniques such as GIFT and ZIFT are rarely used. Occasionally,
GIFT is performed for religious preferences. MESA and TESE are clearly performed
for severe male factor infertility and oligo- or azoospermia. Assisted hatching is con-
troversial and is used to potentially improve implantation rates. It is most frequently
utilized in couples with recurrent failed cycles or prolonged in vitro culture, when a
thickened zona pellucida is suspected.
Success Rates
Success rates for IVF centers are difficult to quantify because they are site-specific
and depend on numerous factors. These include but are not limited to: patient
characteristics, degree of ovarian stimulation, embryo culture quality, number of
Table 16.4. IVF pregnancy success rates based on maternal age,

2003
Maternal Age (in years) Live Births/Cycle
<35 37%
35-37 30%
38-40 20%
41-42 11%
>42 4%
embryos transferred, and transfer technique. In general, success rates are reported
using the following terminology:
• Pregnancy rate: definition varies from a positive serum or urine βhCG to
live birth
• Clinical pregnancy rate: the percent of patients with at least one gesta-
tional sac in the uterine cavity with fetal cardiac activity
• Live birth rate: percentage of patients with a live birth from an ART cycle
• Implantation rate: the number of clinical pregnancies divided by the num-
ber of embryos transferred
The Centers of Disease Control and Prevention (CDC) reports the most recent 16
ART success rates from reporting centers in the US. In 2003, the total number of
ART cycles reported was 112,872 while the number of live babies born as a result of
ART cycles was 35,785. Of all the ART procedures performed, 74% were fresh,
nondonor egg cycles. Of all the cycles cancelled, 82.9% were due to inadequate egg
production. The rate of spontaneous abortion increases dramatically as the maternal
age increases. The overall live birth rate per retrieval for different ART procedures
using fresh, nondonor eggs was as follows:
• IVF without ICSI (intracytoplasmic sperm injection), 33.4%
• IVF with ICSI, 31.9%
• GIFT 20.8%
• ZIFT 25.9%
• Combination of IVF with or without ICSI and either GIFT or ZIFT, 28.3%
It is important to remember the success rates vary depending on the factors
listed above, in addition to patient diagnosis. For example, in 2003 the highest live
birth rate for fresh, nondonor cycles was in the ovulatory dysfunction infertility
group (33.9%), while the lowest success rate was in the group with diminished
ovarian reserve [14.3%]. The success rates also vary dramatically based on maternal
age (Table 16.4).
Complications
Multiple Gestation
By far the greatest risk of IVF today is multiple gestations. Multiple gestations
ultimately depend on the number of embryos transferred; thus the risk is primarily
iatrogenic. In women under the age of 35 years, twin pregnancy rates can be as high
as 40% when two high quality embryos are transferred. In general, ART increases the
risk of multiple pregnancies by 10-fold above baseline (35% vs. 3% in the general
population). It is true that the success rates in IVF improve with a greater number of
embryos transferred, but only to a certain point. Beyond this point, only the risk of
multiple pregnancy increases. Another risk factor for multiple pregnancy is maternal
age. Younger women tend to be at higher risk of multiple pregnancy when more than
one embryo is replaced. The problem with multiple gestations lies in the risks during
pregnancy to both the fetuses and the mother. A greater risk of preterm delivery is the
most significant consequence of multiple gestation. Multiples also have a higher risk
of congenital malformations, and monochorionic twins are at increased risk of
twin-twin transfusion syndrome. This can cause significant morbidity or even mor-
tality for one or both fetuses. There also appears to be an increased risk of cerebral
palsy in multiple pregnancies compared to singletons. Lastly, there appears to be a
slightly higher risk of monozygotic twinning following ART compared to the general
population. The mechanism of this is not well understood but is believed to be due to
trauma to the zona pellucida with herniation of the blastocyst.
Parents with multiple gestations, especially high-order multiples (three or more),
frequently must face the decision of multifetal pregnancy reduction. This can be
emotionally traumatic for couples that have struggled with the inability to become
pregnant for long periods and the psychological morbidity is well documented.
There are obstetrical risks for the mother associated with a multiple pregnancy as
well. Women carrying multiple gestations, especially higher order gestations, are at
increased risk of hypertension, preeclampsia, and preterm labor. They are more fre-
16 quently treated with prolonged bed rest and operative delivery compared to women
carrying singleton pregnancies.
Ovarian Hyperstimulation Syndrome (OHSS)
OHSS can occur when a woman over-responds to high-dose gonadotropin stimu-
lation. Risk increases with larger numbers of developing follicles and greater num-
ber of eggs retrieved. Younger women also tend to be at higher risk of OHSS compared
to older women. Pregnancy will also increase the risk of OHSS as well as the severity
and duration of it. Although the pathogenesis is not well defined, OHSS appears to
be dependent on hCG as well as angiogenic factors. Most women who present with
OHSS show signs of increasing abdominal distention, ascites, nausea, vomiting,
decreased urine output, hypercoagulability, and electrolyte imbalance. If symptoms
are severe, there is also an increased risk of deep venous thrombosis. OHSS can be
classified as mild, moderate, or severe; however it is uncommon to see severe OHSS
requiring hospitalization. Most of the time, women with OHSS can be treated symp-
tomatically with expectant management. Occasionally, women will need to undergo
a paracentesis to remove excess abdominal fluid (often done transvaginally under
ultrasound guidance). This procedure frequently results in immediate improvement
in patient discomfort and symptoms.
Ectopic Pregnancy
Pregnancies implanted outside the uterus are much more common in
ART-conceived cycles than the general population (5% vs. 1-2%). The risk is
higher in women with tubal disease or a prior history of ectopic pregnancy. The
mechanism is not well understood but is likely due to natural migration of the
embryo into the tube after transfer or inadvertent direct tubal embryo transfer.
The risk of heterotopic pregnancy in the general population is very rare (1 in
10,000), but the risk is increased substantially in women who conceive after IVF
or ovulation induction.
Other Risks
There is a small risk of internal bleeding, vascular injury, and infection from
oocyte retrievals. Bleeding from the vaginal wall is fairly common after oocyte re-
trieval and usually stops spontaneously after the procedure or with the application
of pressure. Severe pelvic infection is rare (<1%), and prophylactic antibiotics are
usually not needed unless the patient is at high risk for pelvic inflammatory disease.
Fetal Risks
There are currently a number of studies suggesting an increased risk of birth
defects in babies conceived after IVF. In cases where IVF and ICSI has been per-
formed for a severe male factor, a several-fold increase was found in spontaneous
anomalies of the sex and autosomal chromosomes and an increased risk of inherited
chromosomal defects. Another study has suggested an increased incidence, albeit
small, of Beckwith-Wiedemann and Angelman syndromes, which are complex dis-
orders of growth and development associated with aberrant imprinting at chromo-
some 11q15.5 and the UBEA3 gene locus on chromosome 15q11-13, respectively.
These disorders are the result of genetic alterations affecting the regulatory mecha-
nism of genes, rather than DNA sequence (imprinting). Finally, there is some evi-
dence to indicate that the risk of birth defects (heart, muscle or skeletal) is slightly 16
higher in babies conceived through IVF as compared to babies conceived naturally.
What remains to be determined is whether it is the IVF procedure itself or whether
the increased risk is due to the infertility population undergoing treatment. Cer-
tainly ongoing research is required to better investigate the true fetal risks associated
with ART outcome. Appropriate counseling of couples regarding the potential for
risk associated with ART is recommenced.
Key Points
1 The infertility work-up involves a thorough evaluation of both male and
female partner.
2. Indications for ART include male factor infertility, unexplained infertility,
ovulatory disorders and ovarian failure.
3. Advanced ART procedures include PGD, oocyte donation and gestational
surrogacy.
4. Interpretation of success rates must consider the IVF center, patient charac-
teristics, stimulation protocols, number and quality of embryos transferred
and transfer techniques.
5. Complications with ART are rare but include bleeding, infection, ovarian
hyperstimulation and multiple pregnancy.
Suggested Reading
1. Steptoe PC, Edwards RG. Birth after the preimplantation of a human embryo. Lancet
1978; ii:366.
2. Wickland M, Enk L, Hamberger L. Transvesical and transvaginal approaches for the
aspiration of follicles by use of ultrasound. Ann N Y Acad Sci 1985; 442:184.
3. Palermo G, Jorid H, Devroey P et al. Pregnancies after intracytoplasmic injection of
single spermatozoon into an oocyte. Lancet 1992; 340:17.
4. Van Steirteghem AC, Liu J, Joris H et al. Higher success rate by intracytoplasmic
sperm injection than by subzonal insemination Report of a second series of 300 con-
secutive treatment cycles. Hum Reprod 1993; 8:1005.
5. Handyside AH, Kontogianni EH, Hardy K et al. Pregnancies from biopsied human
preimplantation embryos sexed by Y-specific DNA amplification. Nature 1990; 3:768.
6. Green BB, Weiss NS, Daling JR. Risk of ovulatory infertility in relation to body weight.
Fertil Steril 1988; 50(5):721-6.
7. Chong AP, Rafael RW, Forte CC. Influence of weight in the induction of ovulation
with human menopausal gonadotropin and human chorionic gonadotropin. Fertil
Steril 1986; 46(4):599-603.
8. Westrom L, Wolner-Hanssen P. Pathogenesis of pelvic inflammatory disease. Genitourin
Med 1993; 69(1):9-17.
9. Gardner D et al. Textbook of assisted reproductive techniques. 2nd ed. London: Tay-
lor and Francis, 2004.
10. Speroff L, Fritz M. Clinical gynecologic endocrinology and infertility. 7th ed. Phila-
delphia: Lippincott Williams and Wilkins, 2005.
11. Coutifaris C et al. Histological dating of timed endometrial biopsy tissue is not related
to fertility status. Fertil Steril 2004; 82(5):1264-72.
12. Barnhart K, Osheroff J. Follicle stimulating hormone as a predictor of fertility. Curr
Opin Obstet Gynecol 1988; 10(3):227-32.
13. Hendricks DJ et al. Antral follicle count in the prediction of poor ovarian response and
pregnancy after in vitro fertilization: A meta-analysis and comparison with basal
follicle-stimulating hormone level. Fertil Steril 2005; 83(2):291-301.
14. World Health Organization. Laboratory manual for the examination of human semen
and sperm-cervical mucus interaction. 4th ed. Cambridge University Press, 1999.
16 15. Johnson NP, Mak W, Sowter MC. Laparoscopic salpingectomy for women with hyd-
rosalpinges enhances the success of VF: A Cochrane review. Hum Repro 2002;
17(3):543-8.
16. Adapted from the Centers for Disease Control and Prevention (CDC). 2003 ART
Success Rates (www.cdc.gov/reproductivehealth/art.htm).
17. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertili-
zation. Fertil Steril 2002; 77(6):1148-55.
18. DeBaun MR, Niemitz EL, Feinberg AP. Association of in vitro fertilization with
Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am J
Hum Genet 2003; 72:156-160, [CrossRef ] [ISI] [Medline].
19. Maher ER, Brueton LA, Bowdin SC et al. Beckwith-Wiedemann syndrome and as-
sisted reproduction technology (ART). J Med Genet 2003; 40:62-64.
20. Olson CK, Keppler-Noreuil KM, Romitti PA et al. In vitro fertilization is associated
with an increase in major birth defects. Fertil Steril 2005; 84(5):1308-45.
Chapter 17
Alternative Medicine and Female Infertility

Hey-Joo Kang, Pak Chung and Raymond Chang
Acupuncture
Acupuncture is a vital therapeutic modality in traditional Chinese Medicine and
its use can be traced back for centuries. The theory behind acupuncture is based
upon the premise that there are patterns of energy flow, or Qi, through the body,
which are essential for health. When a disease state exists, the flow of Qi is inter-
rupted and its correction will assist in the healing process. Acupuncture can correct
imbalances of flow at identifiable points close to the skin. The flow of Qi is based
upon a meridian system of vital channels. The meridians consist of 20 channels
interconnected by about 400 acupoints. These acupoints correspond to specific ar-
eas on the surface of the body, which demonstrate higher electrical conductance,
thought to be due to the increased density of gap junctions along cell borders. These
gap junctions serve as “sinks,” or converging points for electromagnetic fields. In
addition, a higher metabolic rate, temperature, and calcium ion concentration are
also observed at these points.
The role of acupuncture in reproductive endocrinology is based upon a more
modern and scientific approach that has begun to emerge in the past two decades.
A review on acupuncture and female infertility suggested possible etiologies why
acupuncture may improve female fertility. Acupuncture has been shown to induce
a rise in β-endorphin levels that persists for up to 24 hours after treatment.
Beta-endorphin is derived from its precursor protein, pro-opiomelanocortin
(POMC), which is present in abundant amounts in neuronal cells of the arcuate
nucleus of the hypothalamus, pituitary, medulla, and in peripheral tissues includ-
ing intestines and ovaries. POMC cleaves to form adrenocorticotropic hormone
and β-lipoprotein. Cleavage of β-lipoprotein results in the formation of neuropep-
tides including β-endorphin.
Endogenous opioid/neuropeptides are believed to influence the menstrual cycle
by their actions on gonadotropin releasing hormone (GnRH) secretion. The close
proximity of the hypothalamic GnRH pulse generator and β-endorphin center within
the arcuate nucleus allows neuropeptides to influence GnRH secretion and, in turn,
play a role in ovulatory function. β-endorphin acts to curtail the release of GnRH
and blunt the effects of other neuropeptides that are excitatory to the hypothala-
mus. The role of these opioid peptides has also been implicated in the initiation of
the midcycle luteinizing hormone (LH) surge in normal ovulatory women. In fact,
the levels of β-endorphin in ovarian follicular fluid of ovulatory women are higher
than levels in circulating plasma. Levels of β-endorphin are highest in the preovula-
tory follicle, compared to other times in the menstrual cycle.
Since acupuncture treatment impacts β-endorphin levels, which in turn affects
GnRH secretion and the menstrual cycle, it is logical to hypothesize that acupuncture
may influence ovulation and fertility. Animal studies have revealed that acupuncture
treatment normalized GnRH secretion and affected peripheral gonadotropin levels.
In human data, various authors have shown that in normally ovulatory or even
anovulatory women, acupuncture also influenced plasma levels of follicle stimu-
lating hormone (FSH), LH and estradiol.
The use of electroacupuncture for ovulation induction in anovulatory women with
polycystic ovarian syndrome has been reported. The percentage of ovulatory cycles in
all subjects was shown to improve from 15% to 66% up to three months after treat-
ment. Responsive patients had significantly lower body mass index, waist-to-hip cir-
cumference ratio, serum testosterone concentration, serum testosterone/sex hormone
binding globulin ratio, and serum basal insulin level. Therefore, in these selected pa-
tients with polycystic ovarian syndrome, acupuncture could be utilized as an alterna-
tive or adjunct to conventional pharmacological ovulation induction.
Besides the central modulation of the hypothalamic-pituitary-ovarian axis, the
effect of acupuncture on the autonomic nervous system has been described. Acu-
puncture induces long lasting cardiovascular effects via actions that are
sympatho-inhibitory. Sympathetic nerve activity, as measured by norepinephrine
levels, skin temperature, blood pressure and pain tolerance threshold, is noted to
decrease after acupuncture.
Endometrial thickness, morphology, and uterine artery blood flow have been
implicated as crucial parameters for implantation success of human embryos. De-
spite conflicting results in the utilization of these parameters to predict outcome of
17 in vitro fertilization cycles, it is generally assumed that adequate endometrial thick-
ness with a normal pattern is required to optimize pregnancy rates. Since endome-
trial thickness correlates with the adequacy of uterine artery blood flow via its central
sympatho-inhibitory effect, acupuncture may reduce uterine artery impedance and
therefore increase blood flow to the uterus. Pulsatility indices have been found to be
reduced, hence, blood flow increased, following eight consecutive treatments of
electroacupuncture. This effect was believed to be caused by a central inhibition of
sympathetic activity.
To date, there have been few well-designed studies on the potential impact of
acupuncture on infertility treatment outcome. One of the most frequently quoted
studies is a prospective study by Paulus et al, who evaluated the effect of acupunc-
ture on pregnancy rate in 160 women undergoing in vitro fertilization. Acupunc-
ture was performed in half of the patients 25 minutes before and after embryo transfer
while the control group did not receive any acupuncture treatment. Clinical preg-
nancies were found to be higher in the acupuncture group than the control group
(42.5% vs. 26.3%, respectively). The exact mechanism accounting for this result is
not known.
Other than its potential central role in affecting hypothalamic pituitary ovarian
function and peripheral role in improving uterine blood flow and implantation func-
tion, acupuncture has been definitively shown to reduce stress and anxiety through
its sympatho-inhibitory property. Undoubtedly, infertility is stress inducing and
anxiety provoking. The use of acupuncture to reduce stress is a very viable option
when couples undergo the stringent process of evaluation and treatment of infertil-
ity. Compared to the conventional administration of antidepressants and anxiolytic
drugs, side effects of which are largely unknown on the outcome of infertility treat-
ment, acupuncture presents a relatively benign and simple alternative.
Alternative Medicine and Female Infertility 191
Herbal Treatments
Tonic herbs are generally nontoxic—the safest of all herbs—and usually can be
taken on a long-term basis. They can be administered either individually or in com-
pound remedies in which several herbs work together synergistically to strengthen
and tone your body. Tonics can be taken as capsules, tinctures, decoctions, infusion
or tea. Tonic herbs are commonly thought to enhance female fertility. They are
often used in traditional Chinese medicine and by holistic and alternative medical
practitioners to boost or balance hormone production in women. It should be cau-
tioned that the mechanism of action and efficacy of many of these herbs have not
been substantiated by conventional Western standards.
Chaste berry (vitex agnus-castus)—This European herb is one of the more
well-established Western herbs relating to female hormone regulation. It is thought
that the sites of action of chaste berry are the hypothalamus and pituitary gland, and
that chaste berry increases LH secretion and regulates the release of FSH. Serum
progesterone level has been observed to increase with its consumption. The use of
chaste berry has been implicated in women with short luteal phase or documented
luteal phase defect. Whether this reversal of luteal phase defect is due to improved
folliculogenesis or ovulatory event is largely unknown. Chaste berry also inhibits
prolactin release and may have a role in the setting of hyperprolactinemia-related
menstrual irregularities and infertility. It is also thought to soothe premenstrual ten-
sion. To be able to derive the potential benefits of chaste berry, it may have to be
taken for three to four months.
Other commonly used herbs which have been anecdotally shown to be benefited 17
for female fertility include Black Cohosh, or Cimicifuga racemosa, Red Clover, or
Trifolium pretense, and Dong Quai, or Angelica sinensis.
The use of herbs during infertility treatment, however, has to be carefully
considered. Most of the commonly used herbs for fertility enhancement contain
a fair amount of plant estrogens or phytoestrogens. Therefore, the decision on
medication dosage adjustment during treatment, such as in vitro fertilization,
which normally hinges upon estrogen levels, may be impacted by the ingestion of
these herbs.
Vitamins and Dietary Supplements
Many vitamins have been implicated in promoting human reproduction. Ascor-
bic acid (vitamin C) has long been associated with fertility through three of its
principal functions, namely promotion of collagen synthesis, hormone produc-
tion, and protection of cells via production of free radicals. There is evidence that
both ovary and testis accumulate ascorbic acid, and both gonads show cycles of
tissue remodeling and of steroid secretion that is ascorbate-dependent. One study
on in vitro fertilization suggests that the supply of ascorbic acid to the ovary might
be a rate-determining factor in the ability of the preovulatory follicle to respond
to gonadotropin stimulation. Ascorbic acid may also prevent gametes from dam-
age by free radicals during fertilization. Further research is required to study the
exact mechanism of action of ascorbic acid in gonadal physiology and fertility.
Vitamin B12 (cobalamine) deficiency has been reported as an etiology in infer-
tility. Pernicious anemia, though rarely encountered in women of childbearing age
in developing countries, has been associated with oligo- to anovulation. Once treated,
conception was noted to quickly occur through resumption of ovulation.
Vitamin B6 (pyridoxine) and vitamin E have been shown to be vital to human

reproduction. Women deficient in these vitamins demonstrate return of normal
menstrual function and fertility upon replacement. Vitamin B6 has been used in the
treatment of premenstrual symptoms, but whether symptoms are actually due to
primary insufficiency is unclear.
There are many dietary supplements which have been associated with improving
female fertility: folic acid, magnesium, selenium, iron and zinc. In a study inves-
tigating the effects of caffeine on conception, women drinking green tea (as op-
posed to other caffeinated beverages) were found to approximately double their
odds of conception, though the design of the study did not control for several po-
tential variables.
One supplement, L-arginine, an amino acid, was used as an adjunct in poor
responders during in vitro fertilization treatment. Believed to be able to improve
circulation to the reproductive organs, including the endometrium, L-arginine may
play a role in enhancing oocyte development and implantation of the embryo.
Battaglia et al studied uterine and follicular Doppler flow in response to L-arginine
treatment during in vitro fertilization treatment in poor responders. The L-arginine
treatment group showed multiple benefits, including improved Doppler flow rates,
a lower cancellation rate and an increased number of oocytes collected and embryos
transferred. Out of 17 women supplemented with L-arginine, 3 conceived as com-
pared to 0 of 17 in the nonsupplemented group.
Many studies have attempted to show particular vitamins or dietary supplements
17 may be involved in regulation or improvement of female fertility are small and not
necessarily randomized or placebo-controlled. Given the benign nature of these
supplements (in appropriate dosages) and lack of adverse effects in general, it seems
reasonable to recommend that women interested in fertility evaluate their own nu-
tritional needs and personalize inclusion of these elements in their diet or as daily
supplements. More studies are needed to establish their exact role in reproduction.
Mind/Body Techniques
Infertile women most often turn to modern western medicine to increase their
chances of conception. However medical treatments may only represent part of the
solution. Some believe that adding mind/body techniques may help women cope
with the mental and physical stress associated with the evaluation and treatment
process. Although it is difficult to quantify the impact of stress on the outcome of
infertility treatment, mind/body programs have been positively shown to improve
handling of stress, reduce anxiety, change one’s attitude and outlook, and banish
negative thoughts. These attributes will benefit infertile women in regaining control
of their lives and improve a couple’s relationship during their struggle to conceive.
In one well-known study done in Boston on 284 infertile women, stress level was
significantly reduced, and 42% became pregnant within 6 months of completing
the mind/body program.
Key Points
Alternative medicine encompasses various approaches to female fertility. Acu-
puncture has been used for thousands of years in traditional Chinese medicine. Its
benefits have long been recognized to improve health, decrease stress, and more
recently, potentially improve reproductive capabilities. Herbal treatment has also
been an integral part of alternative medicine to treat menstrual and ovulatory
Alternative Medicine and Female Infertility 193
dysfunction, and indirectly infertility. Certain vitamins and dietary supplements

are vital in the metabolism and health of reproductive cells and organs. Last but
not least, mind/body programs and psychological counseling will serve to relieve
stress and anxiety associated with infertility. Western medicine is usually quite
targeted at the ‘diseased’ organ whereas the approach in alternative medicine is
toward the entire body. When the overall well being of the individual is cared for,
improvement in reproductive function should follow. We have only begun to cor-
relate the beneficial effects of alternative approaches in infertility treatment with
western biologic plausibility.
Suggested Reading
1. Chang R, Chung P, Rosenwaks Z. Role of acupuncture in the treatment of female
infertility. Fertil Steril 2002; 78:1149-1153.
2. Paulus W, Zhang M, Strehler E et al. Influence of acupuncture on the pregnancy rate
in patients who undergo assisted reproduction therapy. Fertil Steril 2002; 77:721-724.
3. Stener-Victorin E, Waldenstrom U, Andersson SA et al. Reduction of blood flow im-
pedance on the uterine arteries of infertile women with electro-acupuncture. Hum
Reprod 1996; 11:1314-7.
4. Hardy M. Herbs of special interest to women. J Am Pharm Assoc 2000; 40(2):234-42.
5. Luck MR, Jeyaseelan I, Scholes RA. Ascorbic acid and fertility. Biol Reprod 1995;
52:262-266.
6. Battaglia C, Salvatori M, Maxia N et al. Adjuvant L-arginine treatment for in vitro
fertilization in poor responder patients. Hum Reprod 1999; 14:1690-1697.
7. Westphal LM, Lake Polan M, Sontag Trant A et al. A nutritional supplement for im-
proving fertility in women. J Reprod Med 2004; 49:289-293.
8. Domar AS, Seibel MM, Benson H. The mind/body program for infertility: A new
17
behavioral treatment approach for women with infertility. Fertil Steril 1990; 53:246-9.
Chapter 18
Male Infertility
Stephanya Shear and Jeanne O’Brien
Epidemiology
Male infertility is the sole cause of 20% of couple infertility and contributes an
additional 30% as a cause for combined couple infertility. Most men seeking infer-
tility counseling and evaluation are referred through gynecologists or primary care
physicians caring for the female partner. Thus, specialized knowledge or training
about infertility is very important as is the ability to work closely with reproductive
endocrinologists and gynecologic physicians. With the advancement of assisted re-
productive technologies (ART) and microsurgical techniques, many men previously
labeled as sterile are now capable of fathering children.
Physiology
Physiologically, male fertility requires good erectile function; spermatogenesis;
normal endocrine function (specifically testosterone and FSH); and ejaculation. In
addition, sexual intercourse timed appropriately to ovulation is an important key to
conception.
Because of the anxiety and stress that is often associated with couple infertility,
male patients often describe difficulty with erections. Obviously, if sexual inter-
course is not occurring then conception is impossible! This information must be
addressed specifically with the patient as he may not volunteer it. Erectile dysfunc-
tion secondary to various disease states including diabetes and atherosclerosis must
also be elucidated. Any previous history of genitourinary cancers or pelvic surgeries
that may have impaired erectile function should also be addressed.
Spermatogenesis has traditionally been described as requiring a 74 day cycle (re-
cent studies have indicated it may actually be shorter than this time period). Any
insult or intervention will usually require at least one spermatogenic cycle prior to
seeing its effect.
Follicle stimulating hormone (FSH) and testosterone are imperative for normal
spermiogenesis. When FSH is elevated it can be an indication that the testes are not
producing sperm in normal amounts related to various causes including: testicular
failure; genetic abnormalities, toxic exposures (including radiation, chemotherapy,
and heat). The teaching used to be if FSH was elevated by at least twice the upper
limit of normal, the probability of finding sperm even on testicular biopsy was almost
zero. This has changed with the development of new microsurgical techniques, in-
cluding microscopic testicular sperm extraction (micro TESE). Nonetheless, FSH
levels are useful in counseling patients on potential outcomes of the infertility evalu-
ation. If FSH is elevated (greater than twice normal) in a patient with severe oli-
gospermia or azoospermia, the patient must be instructed that advanced reproductive
techniques (ART) would most likely be required in order to have a biological child. If
Male Infertility 195
the patient is unwilling, financially or psychologically, to undergo ART, other options

such as donor sperm insemination or adoption should be discussed. Testosterone,
another crucial hormone, contributes to libido, erectile function, and sperm produc-
tion. Obviously, intercourse must be timed to the periovulatory period. Sperm are
able to live in the cervical mucus for an average of approximately 48 hours. Patients
should be instructed to have sexual intercourse near the time of anticipated ovulation.
Differential Diagnosis
Differential diagnosis of the causes of male infertility may be broken down into
three categories:
Pretesticular (endocrine) causes include:
• Pituitary disease: e.g., hypogonadotropic hypogonadism: low LH, FSH and
testosterone levels; Kallman syndrome (associated anosmia); isolated FSH
deficiency
• Congenital syndromes: Prader-Willi syndrome
• Elevated exogenous or endogenous androgen levels: anabolic steroid use, meta-
bolic disorders or androgen secreting tumor
• Elevated estrogen levels: hepatic dysfunction (e.g., cirrhosis), estrogen secret-
ing tumors, morbid obesity
• Elevated prolactin: pituitary prolactin secreting tumor, idiopathic
hyperprolactinemia
• Elevated glucocorticoids
• Hyperthyroidism
Testicular causes include:
• Genetic/karyotypic abnormalities 18
• Anatomic abnormalities: cryptorchidism (bilateral/unilateral); vanishing tes-
tes syndrome (bilateral anorchia—XY males with impalpable testes)
• Gonadotoxins: chemotherapy, radiation; cigarettes, marijuana, alcohol abuse,
heavy metal exposure (lead, mercury), sulfa drugs
• Varicocele: Primary laboratory characteristic is combined finding of low mo-
tility and low sperm count. Increased abnormal morphology secondary to a
stress pattern may be seen as well. Varicoceles can be diagnosed in approxi-
mately 35% of infertile men on physical exam only. Varicoceles diagnosed
with scrotal ultrasound are defined as subclinical and there is no proven
benefit to surgical repair.
• Structural defects (structural sperm defects which prevent normal motility):
immotile cilia syndrome; immotile viable sperm
• Orchitis: Post pubertal mumps, epididymo-orchitis, syphilis, gonorrhea, and
leprosy
• Antisperm antibodies (testicular injury, previous vasectomy)
• Testicular cancer
• Idiopathic: occurs in as many as 25% of patients with abnormal semen analysis
Post-Testicular causes include:
• Ductal obstruction (CBAVD, vasectomy, scarring from sexually transmit-
ted diseases)
• Retrograde ejaculation (multiple sclerosis, diabetes, retroperitoneal lymph
node dissection)
• Anejaculation (spinal cord injury, retroperitoneal lymph node dissection,
diabetes)
Evaluation
History and Physical
The comprehensive history should include all past and current medical prob-
lems related to reproductive function. Men who have previously fathered children
or a pregnancy with the same or different partner are said to have secondary infertil-
ity. Men who have never fathered a child are considered to have primary infertility.
The length of time the couple has been attempting a pregnancy and the frequency
of intercourse should be ascertained. The ideal frequency of intercourse is every day
to every other day. Use of artificial lubricants, even water soluble or natural sources,
should be discouraged as they may impair sperm motility.
Men should be asked about exposures to pesticides, chemicals, organic solvents,
or heat (tanning booths, short order cooks, and foundry workers). Men who smoke
tobacco or marijuana are at risk for infertility as these drugs decrease sperm concen-
tration (oligospermia) and effect motility. Illicit drug and copious alcohol use can
disrupt the hypothalamic-pituitary axis and adversely affect testicular function.
Anabolic steroids can result in testicular atrophy and abnormal or absent spermio-
genesis. Many medications can affect sperm concentrations and function including:
prescription and over-the-counter medications, vitamin and protein supplements
and herbal remedies. A list of pharmacological and environmental causes of infertil-
ity is given in Table 18.1.
The surgical history should include questions regarding a history of cryptorchid-
ism (undescended testis) and patient’s age at the time of repair. Cryptorchidism can
18 cause oligospermia or even azoospermia, if bilateral. Correction of hypospadias,
chordee or hernia should also be ascertained as well as any surgery on the bladder
neck, urethra, rectum or pelvis. A history of urethral strictures and/or STDs may
result in urethral and ductal obstruction causing reduced sperm counts. Men who
have been treated for testicular cancer or Hodgkin’s lymphoma may have reduced
sperm counts related to their disease as well as treatments such as chemotherapy and
radiation. Surgery for testicular cancer may include retroperitoneal lymph node dis-
sections and this can injure the sympathetic nerves involved in ejaculation.
The review of systems should include questions regarding diabetes (partial or
retrograde ejaculation), cystic fibrosis (CF)—pertinent positives include: history of
pneumonia, recurrent sinusitis or bronchitis—(congenital absence of the vas defer-
ens), multiple sclerosis (impaired ejaculation), and spinal cord injuries (erectile dys-
function). There are several rare conditions which impact fertility that can be
Table 18.1. Pharmacological and environmental causes of infertility

Diethylstilbesterol (DES) Radiation
Testosterone Chemotherapy
Ketoconazole Heat
Nitrofurantoin Pesticides
Calcium channel blockers Lead
Cigarettes Alcohol
Cocaine Marijuana
Sulfa drugs Solvents
uncovered during the review of systems. Recurrent respiratory infections can be

associated with nonmotile sperm and may suggest primary ciliary dyskinesia
(Kartagener’s syndrome). Congenital anosmia (inability to smell) may be associated
with Kallmann’s syndrome—hypogonadotropic hypogonadism.
Emphasis is placed on a thorough genitourinary examination. The male patient
should be examined in a warm room. Normal virilization should be noted. The
presence of gynecomastia should prompt questions regarding marijuana use or an
evaluation for a prolactin producing pituitary tumor. Normal testicular size is 20
cm3 and the testicle should be firm but not hard,not unlike the feel of a hard boiled
egg. An orchidometer can be used to assess size or it can be approximated by mea-
suring. A normal testicle is at least 2.5 × 3 × 4 cm. The epididymis and vas deferens
should be palpated and any thickening should suggest the possibility of obstructive
causes of infertility.
The spermatic cords should be examined in the upright position to evaluate the
man for a varicocele-dilation of the spermatic pampiniform plexus. It is thought
that varicoceles may impact sperm quality by increasing testicular temperature or
perhaps by causing reflux of adrenal metabolites via incompetent veins. However,
15% of the general male population has a varicocele, and up to 45% of men with
infertility present with a varicocele. Grading of varicoceles is based on physical exam
alone though occasionally ultrasound may be used as a confirmatory study or if
body habitus makes examination difficult. Absence of the vas deferens is found in
1-2% of all infertile men and 10% of men with low sperm counts. It can be unilat-
eral or bilateral. It is often associated with other genitourinary abnormalities such as
absence of the ipsilateral kidney or incomplete epididymis formation. Importantly,
18
80% of men with bilateral congenital absence of the vas (CBAVD) have at least one
cystic fibrosis mutation. Men with CBAVD and their partners should undergo ge-
netic testing and counseling regarding possible CF gene carrier status.
Laboratory Studies
All men undergoing infertility evaluation and counseling should have a semen
analysis. Two samples should be given one week apart with two or three days of
abstinence prior to the sample for optimal analysis. Masturbation without use of
lubricants is preferred. Normal semen parameters, based on World Health Organi-
zation criteria, are given in Table 18.2. More than one abnormal parameter is com-
mon. If ejaculate volume is low, the man should give a urine sample within minutes
of ejaculation to look for sperm in the urine after ejaculate collection errors are ruled
out (spilled specimen, incomplete collection). If sperm are found in the urine and
his history is not indicative of obstruction, the man is considered to have retrograde
Table 18.2. Classification of semen abnormalities*

Oligospermia <20 million sperm/ml
Azoospermia Absence of sperm in the ejaculate
Teratospermia <30 % normal morphology
Asthenospermia <50% sperm motile
Leukocyto(Pyo)spermia >1 million/ml WBCs
*Based on WHO criteria.
ejaculation. Low sperm volume with no sperm in the post ejaculatory urine sample
may be secondary to ejaculatory duct obstruction or ejaculatory duct absence. Both
can be further evaluated by transrectal ultrasound.
A reduced sperm count, or oligospermia, is defined as an ejaculate with <20
million sperm per milliliter. Azoospermia is defined as the absence of sperm in
the ejaculate. Men with either should undergo hormonal analysis to determine if
the source of low sperm count is pretesticular—the hypothalamic-pituitary axis,
testicular—primary testicular failure, or post testicular—obstruction or absence
of the vasa. Treatment ultimately depends on the source: medical intervention
for hypothalamic abnormalities, sperm cryopreservation for severe oligospermia
with primary testicular failure versus surgical correction for post testicular ob-
struction.
Sperm should have tail movement regardless of motility. Asthenospermia or poor
motility is most often seen in the setting of other semen abnormalities. Movement
of the tails without progression may be secondary to presence of sperm antibodies or
agglutination (clumping) of the sperm. If antibodies are present, couples have suc-
cessfully had pregnancies after in vitro fertilization and intracytoplasmic sperm in-
jection (ICSI).
Teratozospermia is the presence of a disproportionate concentration of morpho-
logically abnormal sperm. According to the World Health Organization (WHO),
30% of the sperm should be classified as structurally normal. Others who advocate
for more stringent histologic grading use strict criteria to examine the sperm head.
Using the so-called strict criteria, only four percent of sperm are typically defined as
18 normal. Morphologically abnormal sperm are less likely to fertilize an egg.
Pyospermia-—white blood cells in the ejaculate is often treated with antibiotics
though often without a documented source of infection. Patients are instructed to
ejaculate frequently and a repeat semen analysis is completed after antibiotic treat-
ment. There are various tests to analyze sperm function (such as electron micros-
copy for 0% motility) if the semen analysis appears normal. As a practical matter,
these tests are not frequently performed as couples usually proceed to in vitro fertili-
zation (IVF) and intracytoplasmic sperm injection (ICSI) if a functional problem is
suspected.
Depending on the history, physical exam and semen analysis, a patient may
require hormone analysis. Useful serum tests include FSH, LH, testosterone, and
prolactin. Endocrine evaluation will often assist in distinguishing between pretesticular
and testicular causes of infertility though endocrine causes of male infertility are
fairly rare.
In clinical practice, the initial consult is sometimes performed without the re-
quired two semen analyses. Laboratory tests and sperm testing can be performed at
a future date with follow up scheduled to review all results and formulate a possible
treatment plan.
Radiologic Studies
If an abnormality is noted on the testicular exam, an ultrasound should be per-
formed immediately to look for testicular masses consistent with cancer. Men with
testicular cancer can have reduced sperm counts and will often present seeking con-
sultation for infertility. Men with a low ejaculate volume and a negative
post-ejaculatory urinalysis, normal testosterone and palpable vasa should undergo
transrectal ultrasound. Findings of dilated seminal vesicles (>1.5 cm in AP diam-

eter) are suggestive of partial or complete obstruction. Patients with CBAVD may
also have dilation of the seminal vesicles, but diagnosis of vasal agenesis is made by
clinical examination alone and does not require ultrasound. Scrotal ultrasound is
not indicated for nonpalpable varicocele as these are of little clinical significance.
Management
The results of the diagnostic evaluation will guide treatment. Pretesticular eti-
ologies are differentiated by endocrine analysis, and the specific findings will deter-
mine the treatment. High testosterone, low FSH and LH are indicative of anabolic
steroid use. Low FSH, LH, T and high prolactin are suggestive of a prolactin pitu-
itary tumor and warrant MRI evaluation. These etiologies are generally treated with
medications or patient counseling.
The most common cause of infertility is a varicocele. Clinically significant
varicoceles are diagnosed by physical examination alone. Semen analysis and endo-
crine profile supplement the physical examination and aid the physician and the
patient in determining whether surgical repair would be beneficial. Surgical man-
agement of varicocele includes microsurgical subinguinal varicocelectomy,
laparoscopic ligation of the varicocele and radiologic embolization. Recent studies
have indicated that varicoceles when repaired surgically may result in sperm in the
ejaculate in 55% of azoospermic men though many of these men will require ART
for successful pregnancy. Postoperative varicocele pregnancy rates can be as high as
40% for all grades of varicocele.
Intervention for obstruction of the vas deferens or the epididymis is reconstruc-
tion: either vasovasostomy or vasoepididymostomy. As noted above, transrectal ul- 18
trasound can support a diagnosis of seminal vesicle or ejaculatory duct obstruction
if dilated seminal vesicles (>1.5 mL), ejaculatory duct cysts or prostatic utricular
cysts are present. Obstruction from a prostatic utricular cyst or ejaculatory duct
obstruction is treated with transurethral resection of the cyst or transurethral resec-
tion of the ejaculatory ducts, respectively.
Treatment of male infertility depends on the classification. Final treatment relies
on diagnosis; however testicular causes, with the exception of a varicocele, are chal-
lenging to treat as they are often irreversible. Testicular biopsy is indicated when
diagnosis cannot be made by physical exam, semen analysis, and endocrine profile.
For example, azoospermic men with ductal obstruction will have normal hormone
parameters and a normal testicular exam. Testicular causes of infertility are varied
and may include cryptorchidism, viral orchitis, trauma, infections, obstruction, toxins
and idiopathic etiologies. Men can attempt ART with sperm taken from the ejacu-
late, testicular extraction /biopsy or sperm aspiration from the epididymis even if
the etiology of the infertility is idiopathic or is not amenable to surgical or medical
correction.
Post Evaluation—Follow Up Care
All patients should have a follow up semen analysis three months after any treat-
ment, whether it is a medical or surgical. If there is no change in seminal parameters
within a designated period of time (usually one year for surgery, and 1-2 spermio-
genesis cycles for medical therapy) the couple should be counseled regarding ART,
donor sperm, and adoption.
Other Surgical and Medical Treatments for Infertility

Retrograde ejaculation—sympathomimetic medications (ephedrine, pseudoephe-
drine). Urine can be alkalinized with oral sodium bicarbonate and the sperm sepa-
rated and used for ART anejaculation in the spinal cord patient—electrostimulation
to the glans penis or prostate/seminal vesicle. With the latter two, the patient must
be pretreated with nifedipine and closely monitored for autonomic hypertensive
dysreflexia. Urethral strictures—stricture ablation or reconstructive repair.
Key Points/Summary
• Male factor infertility can be caused by pretesticular, testicular and post tes-
ticular abnormalities. History, physical exam, endocrine analysis and radio-
logic studies will guide diagnosis and treatment.
• A full examination for male infertility should include a complete medical
and reproductive history, a physical exam by a urologist or male reproduc-
tive specialist and at least two semen analyses.
• An endocrine evaluation should be performed if there is an abnormal semen
analysis, combined with impaired sexual function, and/ or physical exam
findings suggestive of hormonal dysfunction.
• Men with an abnormal testicular exam should have an immediate scrotal
ultrasound to look for testicular masses consistent with cancer.
Suggested Reading
1. Goldstein M. Surgical management of male infertility and other scrotal disorders. In:
Walsh PC et al, eds. Campbell’s Urology. Philadelphia: WB Saunders, 2002.
18 2. Sigman M, Jarow J. Male Infertility. In: Walsh PC et al, eds. Campbell’s Urology.
Philadelphia: WB Saunders, 2002.
3. Lipshultz LI et al. Infertility in the Male. Baltimore: Mosby, 1997.
Chapter 19
Your Environment; Your Fertility—

Is There a Link?
Shanna H. Swan
Introduction
Fertility, the ability of people to produce offspring, was a concept formerly ap-
plied only to the female. Demographers traditionally defined the fertility rate as the
average number of live-born children per woman of reproductive age. However,
fertility is one of the few measures that reflect the joint health of two individuals,
and we have only recently begun to appreciate the extent to which fertility depends
on the health and environment of both the male and female partner, as well as the
interaction between partners. Males appear to be solely responsible for infertility in
about 20% of infertile couples and contribute to infertility in another 30-40%.
Using the demographic definition above, fertility declined 50% worldwide be-
tween 1950 and 2000. Between 1976 and 1998, the percent of women in the United
States aged 35-39 who were childless increased from 10.5% to 19.8%. Moreover,
the number of annual office visits for infertility increased from 600,000 to 2 million
between 1968 and 1990. While these data indicate that fertility, at least by the
demographers’ definition, has declined, they do not answer the critical question;
Are a woman and her partner who desire pregnancy less able to conceive today than
a comparable couple of the same age 50 years ago? They also do not address causes
of the decline and, in particular, the role of environmental factors, which is the focus
of this discussion.
These trends undoubtedly reflect, at least in part, changes in nonenvironmental
factors that affect a couple’s ability and/or desire to conceive. Women and their
partners may choose to delay childbearing, resulting in decreased fertility when their
first pregnancy attempt occurs at an older age. Several nonenvironmental factors
may also influence trends in fertility: increasing access to and acceptability of con-
traception and assisted reproduction, changes in attitudes towards voluntary preg-
nancy termination, rates of sexually transmitted diseases, and the education of women
and their role in the workforce.
These factors vary geographically, temporally, and within ethnic/racial groups.
Moreover, they are interrelated in complex ways. Several more useful measures of
“fertility potential” are available. Fecundity (or fecundability) has been defined as,
“the monthly probability of conception in the absence of contraception outside the
gestation period and the temporary sterile period following the termination of a
pregnancy”. The National Center for Health Statistics uses a measure of decreased
fecundity, “impaired fecundity”, which they define as a woman’s inability to con-
ceive or bear a child to term. The number of cycles of unprotected intercourse with-
out conception, or “time-to-pregnancy” (TTP) is another useful measure and infer-

tility is often diagnosed when TTP exceed 12 months (or cycles).
Changes in fecundity and impaired fecundity in the US have been examined by
comparing responses to the National Survey for Family Growth (NSFG) in 1982,
1988 and 1995. This analysis found increases in impaired fecundity over that time
period, and the authors suggested that this change was due to more couples volun-
tarily delaying child-bearing. We questioned that interpretation, however, since the
greatest increase in impaired fecundity was seen in women under 25, precisely the
age group in which subfecundity, because of delayed childbearing, would be least
likely. These data suggest that, at least in the US, fecundity declined between 1982
and 1995. Limited data have recently become available from the sixth cycle of the
NSFG. However, data on live birth rates between 1990 and 2000 suggest a reversal
of the decline seen in previous reports. This reversal is seen across race/ethnic groups
and for most age groups. Data on impaired fecundity, perhaps the most relevant
statistics for assessing trends in involuntary subfertility, are not yet available but are
expected later in 2006. On balance, the limited data available do not allow us to
draw any conclusions about trends in fecundity.
Reproductive health is affected by the interaction of multiple factors, among
them age, genetics, nutrition, lifestyle behaviors, reproductive tract infections, stress,
and pharmaceutical use. In recent years, scientists have increasingly reported evi-
dence that certain pollutants in the environment may also play an important role,
contributing at least in some cases to underlying causes of fertility problems. A
surprisingly wide range of compounds has been implicated, particularly in studies
of laboratory animals and wildlife, although for the most part the data on the effects
of these chemicals on human fertility is still inconclusive.
19 What is now clear is that environmental chemicals may impact fertility at multiple
developmental stages, with differing effects. Many chemical exposures have been shown
to impact human and/or animal fertility when exposure occurs during adulthood.
These are summarized in Table 19.1. Adult exposures tend to cause changes that are
transient; for example, men exposed to DBCP who were azoospermic recovered the
ability to produce sperm once exposure had ceased. On the other hand, exposures
during development, summarized in Table 19.2, cause changes that are permanent
(such as DES-caused cervical and uterine abnormalities) and often cause effects at
much lower levels than those needed to cause changes in adults. These tables are not
intended to be exhaustive but rather to give examples of such exposures.
The Environment and Reproductive Factors in the Male
One action of environmental exposures on fertility is through their effect of
semen quality. This question was first examined in the workplace, where exposures
are usually far higher than those encountered environmentally. There is a large body
of literature demonstrating strong relationships between work place exposures and
decreases in semen quality and other factors that can affect a couples’ fertility. For
example, widespread concern was generated in the late 1970s following reports of
sterility and decreased sperm counts in workers exposed to the agricultural nemato-
cide DBCP. The chlorinated hydrocarbon pesticide chlordecone (kepone) was with-
drawn because of its severe effects on semen quality. Ethylene dibromide (EDB) was
an active component of approximately 100 pesticides. Its use was severely restricted
in 1984 due to reduced sperm counts and semen quality. For a more complete
treatment, see Schettler et al, Generations at Risk (1999).
Your Environment; Your Fertility—Is There a Link? 203
More recently, adult exposure to several pollutants at low environmental levels

has been linked to reduced semen quality. If these exposures have increased over
time, these could, in principle, contribute to the reported declines in sperm concen-
tration. For example, after we saw significantly poorer semen quality in men living
in agricultural mid-Missouri compared to men living in urban centers, we examined
pesticide metabolite levels in the men’s urine. We found several (alachlor, atrazine
and diazinon, particularly) to be linked to poor semen quality. A range of other
low-level environmental exposures have been linked to impaired semen quality in-
cluding phthalates, PCBs and DDT, maternal smoking, water chlorination
by-products and air pollution.
Does it follow that men (or couples) exposed to these environmental chemicals
have impaired fecundity? Among Danish couples attempting to conceive for the
first time, men whose initial sperm concentration was less than 40 x 106/ml had
significantly reduced fecundability and took longer to conceive. In mid-Missouri,
sperm concentration of 35% of fertile men fell below 40 x 106/ml, a point below
which fecundity decreases significantly. Among men living in central Minneapolis,
only 19% fell below this cut-off. Since poor semen quality in these men was linked
to pesticide exposure, it is plausible—though far from proven—that these chemicals
can impair human fecundity.
We cannot, however, conclude that a decrease in sperm count directly implies
a decrease in fecundity on a population level. Even if semen quality is declining,
there may be no net decrease in couple fecundity. For example, if couples trying to
conceive are better educated (such as through the use of home kits to detect ovu-
lation), this will tend to increase conception success. Increased female fertility, for
example, as a result of the declining incidence of sexually transmitted disease,
which has occurred in the United States since 1980 (CDC 2000), will also in- 19
crease couple fecundity.
The Environment and Reproductive Factors in the Female
Measures of female fertility are more difficult to quantify. For example, a mea-
sure analogous to sperm count, ovarian follicular number, is more difficult to
ascertain, as it requires a vaginal ultrasound. Thus, this endpoint has been rarely
studied. However, failure to conceive may be the reflection of a hidden increase in
early pregnancy loss. Since a marker for early loss must be ascertained in urine
samples collected soon after conception, this too is logistically difficult and few
studies have related this endpoint to environmental exposures. Endometriosis is a
fertility-related endpoint that has been examined with respect to some environ-
mental exposures, notably dioxin; human data on this association are conflicting.
Alterations in menstrual function, such as short follicular phase, may contribute
to impaired fecundity. These studies are also quite difficult since they require pro-
spective collection of daily urine samples and extensive hormonal analysis. For
these reasons, there are far fewer studies of environmental causes of impaired fe-
male factors than male. However, many environmental agents that have been shown
to adversely effect male fertility have also been related to impaired female repro-
ductive function when that has been examined. Examples include; cigarette smoke,
radiation, lead, ethylene glycol ethers and water chlorination by-products (total
trihalomethane).
19
204
Table 19.1. Chemical exposures during adulthood that may alter fertility-related endpoints
Exposure Reported Effects in Females Reported Effects in Males
Sources and Uses (in animals (A) and/or humans (H)) (in animals (A) and/or humans (H))
Bisphenol A (BPA) Chromosomal abnormalities, (A) Decreased semen quality* (A)
Monomer used to make polycarbonate Recurrent miscarriage (H)
plastic, resins
Chlorinated hydrocarbons Menstrual irregularitiesΔ (H, A) Decreased semen quality* (H)
Dioxins/furans, PCBs, some pesticides Hormonal changes (H, A) Hormonal changes (H, A)
(organochlorines) and wood preservative Reduced fertility‡ (A)
(pentachlorophenol) Endometriosis (H, A)
Fetal loss^ (H, A)
Disinfection by-products Fetal loss^ (H) Decreased semen quality* (H,A)
Result of drinking water treatment Menstrual irregularitiesΔ (H)
Ethylene oxide Fetal loss^ (H, A) Decreased semen quality* (H)
Chemical sterilizer used in dental Fetal loss in female partner (H)
and medical practices
Heavy metals Fetal loss^ (H, A) Decreased semen quality* (H)
Lead, mercury, manganese, cadmium Reduced fertility‡ (H) Reduced fertility‡ (H, A)
Hormonal changes (A) Hormonal changes (H)
Menstrual irregularitiesΔ (H)
Pesticides Menstrual irregularitiesΔ (H) Decreased semen quality* (H, A)
Includes insecticides, fungicides, herbicides, Reduced fertility‡ (H, A) Reduced fertility‡ (H, A)
rodenticides, and fumigants Fetal loss^ (H, A) Fetal loss in female partner (H)
Sperm chromosome abnormalities (H)
Hormonal changes (H)
Phthalates Fetal loss^ (A) Decreased semen quality* (H)
Plasticizers added to soften plastics like PVC; Menstrual irregularitiesΔ (A)
also in cosmetics, toys, pharmaceuticals, Reduced fertility‡ (A)
and medical devices
Glycol ethers Fetal loss^ (H) Decreased semen quality* (H)
Paints, varnishes, thinners, printing inks, Reduced fertility‡ (H)
semiconductor industry
Other solvents Reduced fertility‡ (H) Decreased semen quality* (H)
Benzene, toluene, xylene, styrene, Fetal loss^ (H, A) Reduced fertility‡ (H)
1-bromopropane, 2-bromopropane, Hormonal changes (H, A) Fetal loss in female partner (H)
perchloroethylene, trichloroethylene, Menstrual irregularitiesΔ (H)] Hormonal changes (H)
and others
Your Environment; Your Fertility—Is There a Link?
Cigarette smoke Reduced fertility‡ (H) Reduced fertility‡ (H)

Active and/or passive smoking Fetal loss (H) Decreased semen quality (H)
Early menopause (H) Hormonal changes (H)
Hormonal changes (H)
(H) Data from human studies. (A) Data from human studies. *, Decreased semen quality may include decreased sperm concentration, sample
volume, motility or percent normal morphology. ‡, Reduced fertility may include infertility, increased time to pregnancy (reduced fecundity),
greater proportion with failure to conceive in 12 months. Δ, Menstrual irregularities may include altered cycle length, irregular cycles, abnormal
bleeding, anovulation in humans, estrous cycle irregularities in animals. ^, Fetal loss may include spontaneous abortion (clinical or sub-clinical
and stillbirth). Table modified with permission from: Challenged Conceptions: Environmental Chemicals and Fertility. Carlson A, Eddy E, Giudice
L et al, eds. A Report of the Fertility/Pregnancy Compromise Working Group of the Collaborative on Health and the Environment. 2005.
205
19
19
206
Table 19.2. In utero exposures that may alter fertility-related endpoints

Bisphenol A (BPA) Altered puberty onset (A) Altered prostate development (A)
Monomer used to make polycarbonate Obesity (A) Decreased semen quality* (A)
plastic, resins Hormonal changes (A)
Chlorinated hydrocarbons Malformations of the Malformations of the
Dioxins/furans, PCBs reproductive tract≠ (A) reproductive tract≠ (H,A)
Altered estrous cycle (A) Decreased semen quality* (H,A)
Reduced fertility‡ (A) Altered sex ratio (H,A)
Hormonal changes (H, A) Altered puberty onset (H)
Altered sex ratio (H,A)
Altered puberty onset (H)
Organochlorine pesticides Delayed time to pregnancy (H) Malformations of reproductive tractΔ (A)
DDT/DDE, linuron, others
Pesticides Altered sex ratio (H,A) Altered sex ratio (H,A)
Includes insecticides, fungicides, Altered puberty onset (A) Altered puberty onset (A)
herbicides, rodenticides, and fumigants Malformations of reproductive tract≠ (H,A)
Reduced fertility (A)
Cigarette smoke Decreased semen quality* (H)
Maternal smoking
Diethylstilbestrol (DES) Malformations of reproductive tract≠ (H,A) Malformations of reproductive tract≠ (H,A)
Pharmaceutical thought (erroneously) to Altered hormone response (A) Altered hormone response (A)
prevent recurrent or threatened Menstrual irregularitiesΔ (H,A)
spontaneous abortion Reduced fertility≠ (H,A)
Uterine fibroids (A) ]
Fetal loss (H)

Heavy metals Hormonal changes (A)
Lead, mercury, manganese, cadmium Altered puberty onset (H)
Phthalates Shortened anogenital distance (H)
Plasticizers added to soften plastics; Malformations of reproductive tract≠ (A)
also found in cosmetics, toys, Hormonal changes (A)
pharmaceuticals, and medical devices Decreased semen quality* (A)
Perfluorinated compounds (PFOS, PFOA) Hormonal changes (A) Hormonal changes (A)
Used to make fabrics stain-resistant/
water-repellant; in coating of cooking pans,
floor polish, insecticides
Polybrominated diphenyl ethers (PBDEs) Decreased semen quality* (A)
Flame retardants found infurniture foam,
mattresses, textiles, and electronics
Your Environment; Your Fertility—Is There a Link?
Octylphenol/nonylphenol Hormonal changes (A) Hormonal changes (A)

Surfactants Altered puberty onset (A) Decreased semen quality*(A)
Decreased testes size (A)
*, Decreased semen quality may include decreased sperm concentration, sample volume, motility or percent normal morphology. ‡, Reduced
fertility may include infertility, increased time to pregnancy (reduced fecundity), greater proportion with failure to conceive in 12 months. Δ,
Menstrual irregularities may include altered cycle length, irregular cycles, abnormal bleeding, anovulation in humans, estrous cycle irregularities
in animals. ^, Fetal loss may include spontaneous abortion (clinical or sub-clinical and stillbirth). ≠, malformations of the reproductive tract: In
males, may include shortened anogenital distance, undescended testicles (cryptorchidism), and abnormalities of the testicles or epididymis. In
females, may include hypoplastic ovaries, reduced number of follicles, and structural abnormalities of the oviducts, uterus, cervix, and/or
vagina. Table modified with permission from: Challenged Conceptions: Environmental Chemicals and Fertility. Carlson A, Eddy E, Giudice L et
al, eds. A Report of the Fertility/Pregnancy Compromise Working Group of the Collaborative on Health and the Environment. 2005.
207
19
Factors That May Alter a Couples’ Fertility

While we have focused here on environmental exposures, a wide range of envi-
ronmental, infectious, endocrine, lifestyle and genetic factors may play a role in
infertility. These factors may result in a range of clinical endpoints including fetal
loss (both subclinical and clinical), menstrual dysfunction, endometriosis, uterine
fibroids, and hormonal irregularities. Clearly, a full discussion of all factors and their
influence on each of these endpoints is beyond the scope of this brief discussion.
However, several general comments may be helpful.
Exposure to factors that can alter fertility may occur at any time from gestation
to adulthood. Adults today carry an enormous body burden of chemicals of which
we are likely unaware since these exposures are “invisible” except by examining lev-
els in human samples (such as blood and urine). In a study led by Mount Sinai
School of Medicine in New York, in collaboration with the Environmental Working
Group and Commonweal, researchers at two major laboratories found an average of
91 industrial compounds, pollutants, and other chemicals in the blood and urine of
nine volunteers, with a total of 167 chemicals found in the group (http://
www.ewg.org/reports/bodyburden/). Like most of us, the people tested do not work
with chemicals on the job and do not live near an industrial facility.
While it is not possible to provide full toxicological profiles of the chemicals
that are prevalent today, an overview of the contaminants found most frequently
in the Mt. Sinai survey may be useful. PCBs, which were used as industrial insu-
lators and lubricants prior to being banned in the US in 1976, persist for decades
in the environment and accumulate up the food chain, to man. A recent study
found PCBs to be associated with reduced semen quality. There are 210 different
19 dioxins and furans, which are by-products of PVC production, industrial bleach-
ing, and incineration. These chemicals can also persist for decades in the environ-
ment and are found in air, water, soil and food. Dioxins are developmental toxicants
affecting the developing endocrine (hormone) system. For example, a significant
deficit of male babies was reported among couples exposed to high levels of di-
oxin. Organochlorine pesticides (such as DDT and chlordane) also accumulate
up the food chain to man and have been shown to cause cancer and numerous
reproductive effects. There are a range of organophosphate insecticide metabo-
lites, such as breakdown products of chlorpyrifos and malathion which are potent
nervous system toxicants found most commonly as residues in food. Metals, in-
cluding lead, mercury, arsenic and cadmium, have long been shown to cause low-
ered IQ, developmental delays, behavioral disorders and cancer at doses found in
the environment. Most exposures to lead are from lead paint. Most exposures to
mercury are from fish, particularly canned tuna. The main sources of arsenic ex-
posures are from arsenic (CCA) treated lumber and contaminated drinking water.
Sources of cadmium exposure include pigments and bakeware. Phthalates, plasti-
cizers found in a wide range of cosmetic and personal care products, have recently
been associated with reduced semen quality and in animal models cause birth
defects of male reproductive organs.
Unfortunately, we cannot reduce our body burden of past exposures, most of
which persist in the body for decades. Work place exposures, which may be avoid-
able, can be far higher, and it is in those settings that we have learned much of what
we know about human reproductive risks. Workers, particularly those attempting
to conceive, should be provided with full information on the reproductive risks of

the agents with which they are working. If economics permit, it would be prudent
for those of reproductive age to avoid occupational exposure to reproductive toxins.
Setting aside fetal and childhood exposures and occupational setting exposures,
we are left with exposure to currently used chemicals in the home and the surround-
ing environments. The routes of these exposures (i.e., water, air, food, skin) are
limited. There are steps that one can take to limit exposure via each of these routes.
There are several nongovernmental organizations that have produced excellent
web-based facts sheets for consumers that provide practical information based on
good science. These are provided below.
Key Points
Though data suggest causal links between environmental exposures and
fertility-related endpoints, many uncertainties remain, particularly with respect to
human fertility. Fertility and the related endpoint, impaired fecundity, can be caused
by female, male, couple-dependent factors, or some combination of these. Identify-
ing the role of environmental factors, on the clinical level, will seldom be possible,
except for extreme examples, such as pharmaceuticals (e.g., DES), or some occupa-
tional exposures (such as DBCP). Nonetheless, environmental factors may well be
having adverse effects on population fertility. An awareness of the emerging evi-
dence can help clinicians educate their patients about potential exposures to avoid
(pesticides, heavy metals, phthalates). Unraveling the extent of these effects, and the
principal agents of concern, are the challenges now faced by researchers in this field.
Web-Based Resources
19
General Information on Fertility and the Environment
An excellent overview, used extensively in this review, Challenged Conceptions:
Environmental Chemicals and Fertility, Carlson A, Eddy E, Giudice L et al, eds. A
report of the Fertility/Pregnancy Compromise Working Group of the Collaborative
on Health and the Environment, October 2005. Proceeding of February 2005
Vallombrosa Workshop Understanding Environmental Contaminants and Human
Fertility Compromise: Science and Strategy (http://www.healthandenvironment.org/
working_groups/fertility).
The Collaborative for Health and the Environment (CHE) maintains a web page
that provides accurate and timely information on the environment and fertility (http:/
/www.healthandenvironment.org/infertility) and more general information on envi-
ronment and health http://www.healthandenvironment.org.
Infertility and Related Reproductive Disorders by Ted Schettler includes an excel-
lent discussion of the role of the environment (http://www.healthandenvironment.org/
infertility/peer_reviewed).
Food
Food News, an affiliate of the Environmental Working Group (EWG) has com-
piled a Shoppers Guide for Pesticide in Produce. The report suggests substituting
organic for conventional produce that is consistently contaminated with pesticides
and, when organic products are not a choice, to consume fruits and vegetables with
consistently low pesticide loads (http://www.foodnews.org/walletguide.php).
Water
The EWG has conducted an extensive survey of drinking water sources by state
and compiled the Clean Water Report Card (that will help consumers evaluate the
quality of their own drinking water (http://www.ewg.org/reports/reportcard/
home.html)
Personal Care Products
The EWG has conducted an extensive, chemical-by-chemical evaluation of per-
sonal care products called Skin Deep (http://www.ewg.org/reports/skindeep/).
Fish Consumption
A report with a pocket size shopping guide on contaminants in fish, Healthy
Fish, Healthy Families has been compiled Physicians for Social Responsibility (http:/
/www.mercuryaction.org/fish/).
Suggested Reading
1. Bonde JP, Ernst E, Jensen TK et al. Relation between semen quality and fertility: A
population-based study of 430 first-pregnancy planners. Lancet 1998; 352:1172-1177.
2. Challenged Conceptions: Environmental Chemicals and Fertility. In: Carlson A, Eddy
E, Giudice L et al, eds. A Report of the Fertility/Pregnancy Compromise Working
Group of the Collaborative on Health and the Environment. 2005 (http://
www.healthandenvironment.org/working_groups/fertility)
3. Carlsen E, Giwercman A, Keiding N et al. Evidence for decreasing quality of semen
during past 50 years. BMJ (Clinical Research Ed) 1992; 305:609-613.
4. Centers for Disease Control and Prevention. Tracking the Hidden Epidemics: Trends
in STDs in the United States 2000. Atlanta: Centers for Disease Control and Preven-
tion, 2001.
19 5. Chandra A, Stephen EH. Impaired fecundity in the United States: 1982-1995. Fam
Plann Perspect 1998; 30:34-42.
6. Duty SM, Silva MJ, Barr DB et al. Phthalate exposure and human semen parameters.
Epidemiology 2003; 14:269-277.
7. Evenson DP, Jost LK, Perreault SD et al. Application of the sperm chromatin structure
assay to the Teplice Program semen studies: A new method for evaluating sperm nuclear
chromatin damage. In: Sram RJ, ed. Teplice Program: Impact of Air Pollution on
Human Health. Prague: Academia, 2001:167-180.
8. Faroon O, Kueberuwa S, Smith L et al. ATSDR evaluation of health effects of chemi-
cals. II. Mirex and chlordecone: Health effects, toxicokinetics, human exposure, and
environmental fate. Toxicol Ind Health 1995; 11:1-203.
9. Fenster L, Waller K, Windham G et al. Trihalomethane levels in home tap water and
semen quality. Epidemiology 2003; 14:650-658.
10. Glebatis DM, Janerich DT. A statewide approach to diethylstilbestrol—the New York
program. N Engl J Med 1981; 304:47-50.
11. Goldsmith JR. Dibromochloropropane: Epidemiological findings and current ques-
tions. Ann N Y Acad Sci 1997; 837:300-306.
12. Hauser R, Chen Z, Pothier L et al. The relationship between human semen parameters
and environmental exposure to polychlorinated biphenyls and p,p’-DDE. Environ
Health Perspect 2003; 111:1505-1511.
13. Jensen TK, Jorgensen N, Punab M et al. Association of in utero exposure to maternal
smoking with reduced semen quality and testis size in adulthood: A cross-sectional
study of 1,770 young men from the general population in five European countries.
Am J Epidemiol 2004; 159:49-58.
14. Mocarelli P, Brambilla P, Gerthoux PM et al. Change in sex ratio with exposure to
dioxin. Lancet 1996; 348:409.
15. Schettler T, Solomon G, Valenti M et al. Generations at risk: Reproductive Health and
the Environment. Cambridge: MIT Press, 1999.
16. Schrader SM, Turner TW, Ratcliffe JM. The effects of ethylene dibromide on semen
quality: A comparison of short-term and chronic exposure. Reproductive Toxicology
1988; 2:191-198.
17. Seibel MM. Infertility: A comprehensive text. In: Seibel MM, ed. Diagnostic Evalua-
tion of an Infertile Couple. Stamford: Appleton and Lange, 1997:3-28.
18. Slutsky M, Levin JL, Levy BS. Azoospermia and oligospermia among a large cohort of
DBCP applicators in 12 countries. Int J Occup Environ Health 1999; 5:116-122.
19. Swan SH, Elkin EP, Fenster L. Have sperm densities declined? A reanalysis of global
trend data. Environ Health Perspect 1997; 105:1228-1232.
20. Swan SH, Hertz-Picciotto I. Reasons for infecundity. Fam Plann Perspect 1999;
31:156-157.
21. Swan SH, Kruse RL, Liu F et al. Semen quality in relation to biomarkers of pesticide
exposure. Environ Health Perspect 2003a; 111:1478-1484.
22. Swan SH, Brazil C, Drobnis EZ et al. Geographic differences in semen quality of
fertile U.S. males. Environ Health Perspect 2003b; 111:414-420.
23. United Nations Population Information Network (POPIN) dictionary of demographic
and reproductive health terminology (1990). Retrieved 2002, (from http://www.un.org/
popin/).
24. Ventura SJ, Abma JC, Mosher WD et al. Estimated pregnancy rates for the United
States, 1990-2000: An update. National Vital Statistics Report 2004; 52:1-9.
25. Whorton D. The effect of occupation on male reproductive function. In: Spira A,
Jouannet P, eds. Human Fertility Factors. Paris: Editions INSERM, 1981:339-348.
19
Index 213
INDEX
A C
Acupuncture 100, 189, 190, 192 Calcium supplement 100, 105, 115
Index
Adenoma 15, 32, 68, 70, 90-92, 136, Cardiovascular disease 51, 56-59, 62,
148, 149, 165, 171 71, 77, 108, 115, 116
Adhesiolysis 150, 154 Cervical factor 145, 146
Adrenarche 10, 12 Chaste berry 191
Age 3, 10-15, 17, 20, 21, 23, 33, 48, Chemicals 120, 196, 202-205,
56, 57, 62, 65, 71, 82, 84, 88, 207-210
107, 108, 113, 115, 116, 118, Classification of endometriosis 84,
137, 138, 145, 149, 151, 153, 156
159, 163, 168, 179, 184-186, Clomiphene citrate (CC) 137, 149,
191, 196, 201, 202, 209 151, 166, 168-171, 176
Alternative/complementary treatment Combined oral contraceptive (COC)
100, 105, 110, 115 67, 70-75, 78-82
Amenorrhea 4, 17, 18, 20, 21, 23-25, Contraception 7, 35, 44, 53, 65, 66,
28, 29, 31-35, 39, 45, 47, 49, 67, 68, 69, 70, 71, 72, 73, 74,
50, 65, 68-70, 85, 92, 107, 110, 76, 77, 78, 79, 80, 81, 82, 145,
121, 124-126, 146, 147, 149, 147, 201
162, 165 Contraceptive vaginal ring 66, 68, 73,
Androgen excess 47, 48, 50, 51, 53, 74, 82, 109, 111, 112
55 Controlled ovarian hyperstimulation
Androgen insensitivity syndrome (AIS) (COH) 165, 167, 168, 176, 178
16, 20, 31, 35, 121 Craniopharyngioma 19, 32, 91
Antifibrinolytic agent 44
Antral follicle count (AFC) 34, 129, D
138, 181
Appetite suppressant 59 Delayed puberty 15-17, 21
Aromatase inhibitor 15, 87, 166, 170 Depo-Provera 76, 77, 82
Ascorbic acid 191 Depressive disorder 97, 98, 100
Asherman’s syndrome 29, 31, 35, 162 Diet 54, 58-63, 96, 100, 101, 105,
Asthenospermia 197, 198 111, 115, 191-193
Azoospermia 19, 184, 194, 196-198 Distal tubal occlusion 128, 156, 158
Dopamine 3, 19, 35, 59, 89, 90, 91,
B 92, 93, 94, 104, 111, 149, 166,
171, 172
Bariatric surgery 61, 62 Dysfunctional uterine bleeding (DUB)
Bisphosphonate 115 36-41, 43-45
Body mass index (BMI) 10, 19, 51,
56, 57, 59-62, 146, 149, 179,
190
Breast cancer 19, 56, 70, 71, 75, 77,
80, 111, 114, 116, 117, 168
E Gonadotropin 3-6, 8-11, 14-17, 19,

21, 28, 32-34, 38, 45, 86, 98,
Ectopic pregnancy 37, 38, 40, 68, 69, 99, 104, 107, 108, 125, 138,
125, 147, 158, 159, 182, 186 146, 149-151, 155, 161,
Emergency contraception (EC) 59, 165-168, 171-176, 179, 183,
72-75, 79-82 186, 189-191
Index
Endometrial ablation 44, 45 Gonadotropin therapy 151, 171, 172,

Endometrial cavity 7, 31, 84, 125, 176
126, 128-130, 135, 141, 150 Gonadotropin releasing hormone
Endometriosis 37, 45, 72, 76, 84-88, (GnRH) 3-14, 19, 21, 29, 32,
128, 129, 139-141, 145-147, 33, 45, 48, 85-88, 98, 99, 104,
149, 150, 152-156, 163, 165, 141, 146, 155, 161, 165, 171,
166, 176, 179, 181, 182, 203, 173, 189, 190
204, 208 analog 86, 88, 161
Environment 6, 84, 112, 120, 137, pulse generator 4, 8, 10, 12, 48,
153, 180, 196, 201-203, 205, 189
207-209
Estrogen 3-6, 8-10, 13-16, 18-21, 23, H
25, 27, 29, 32, 35, 38, 43, 53,
67, 70, 72, 75, 76, 82, 84-87, Heavy menstrual bleeding 36
90, 99, 108-118, 124, 146, 148, Herbal medicine 60, 100, 101, 105,
149, 151, 161, 162, 165, 112, 191, 192, 196
168-170, 172, 191, 195 Hormone replacement therapy (HRT)
Estrogen replacement therapy (ERT) 39, 109, 110, 112, 116-119, 149
110, 111, 112, 115-118 Hot flashes 68, 86, 98, 107-112, 170
Etiology 12, 13, 21, 25, 28, 89, 96, Human chorionic gonadotropin
99, 165, 166, 189, 191, 199 (hCG) 8, 9, 14, 20, 38, 125,
Eugonadal 25, 28, 29, 31 167, 170-176, 185, 186
Extended use contraception 70 Hydrosalpinx 126, 128-130, 135,
150, 158
F Hyperandrogenism 44, 48, 49, 121,
136, 183
Fecundity 20, 145, 146, 151, 152, Hypergonadotropic hypogonadism
165, 201-203, 205, 207, 209 17-19, 32-34
Fertility 19, 20, 35, 43, 45, 76, 86, Hypogonadism 15-20, 23, 25, 27, 29,
108, 141, 146, 150, 152-154, 30, 32-35, 86, 91-93, 146, 166,
159, 165, 180, 182, 189, 171, 175, 176, 195, 197
190-192, 194, 196, 201-209 Hypogonadotropic hypogonadism 17,
Fimbrioplasty 158 19, 20, 32, 33, 171, 175, 176,
Follicular phase 4-8, 49, 97, 98, 103, 195, 197
161, 181, 203 Hysterectomy 45, 87, 97, 116, 184
Hysterosalpingogram 41, 42, 126,
G 129, 141, 148, 151, 153, 162,
165, 181
Galactorrhea 32, 90-92, 111, 149, Hysteroscopy 41-45, 129, 135, 150,
179 161, 162, 181
Index 215
I Laparoscopy 85-87, 128, 129,

139-141, 147, 153, 154, 158,
Impaired glucose tolerance 51 159, 163, 178, 181
Implanon 75, 77 Levonorgestrel-releasing intrauterine
Implantable contraception 77 system (LNG-IUS) 44, 45, 78,
Implantation 3, 8, 9, 67, 79, 80, 126, 79, 81, 82
Index
150, 151, 158, 159, 163, 178, LH surge 6-8, 148, 149, 167,
179, 184, 185, 190, 192 170-173, 180
In vitro fertilization (IVF) 18, 19, Luteal phase 4, 7-9, 96-98, 103-106,
129, 135, 138, 140, 141, 148, 171, 180, 191
149-154, 156, 158, 159, 162, Luteal phase dosing of serotonin
163, 165, 166, 169, 173, 176, reuptake inhibitors 103, 104,
178, 179, 181-187, 190-192, 106
198
Infertility 8, 25, 28, 31, 39, 42, 56, M
79, 82, 84, 88, 92, 93, 124, 126,
128, 135-139, 141, 145-154, Male infertility 181, 194, 195,
158, 161-163, 165-167, 176, 198-200
179-185, 187, 189-202, 205, McCune-Albright syndrome (MAS)
207-209 12, 13, 15
Infertility treatment 56, 138, 145, Menarche 3, 10, 11, 15, 21, 23, 33,
176, 181, 182, 190-193 36, 39, 47, 49, 147
Inhibin 4, 5, 8, 11, 12, 107 Menopause 3, 12, 36, 41, 45, 57, 85,
Injectable hormonal contraception 74 86, 99, 107-113, 115-118, 138,
Insemination 19, 129, 135, 149, 151, 165, 172, 178, 184, 205
162, 163, 166, 167, 174, 175, Menorrhagia 36, 38-41, 72, 141
183, 195 Menstrual irregularity 48, 50-53, 55,
Insulin resistance 31, 35, 48, 51, 93, 191, 204-207
53-55, 180, 181, 183 Menstruation 4, 9, 11, 20, 31, 32, 38,
Intracytoplasmic sperm injection 84, 86, 107
(ICSI) 19, 151, 178, 183, 185, Metabolic syndrome 31, 35, 51, 57,
187, 198 58
Intrauterine contraception (IUC) Metaplastic theory 84
78-80, 82 Metformin 52, 54, 60, 149, 161, 166,
Intrauterine device (IUD) 37, 44, 65, 170, 171, 176, 183
66, 69, 78, 87, 147 Metrorrhagia 36
Mifepristone 87
K Mind/body technique 192
Mirena 44, 78, 82
Kallman syndrome 20, 32, 195, 197 Mullerian anomalies 20, 21, 35, 121,
Klinefelter syndrome 19, 180 122, 124, 125, 135, 136, 180,
184
L Multiple gestation/pregnancy 125,
185-187
L-arginine 192
Laparoscopic ovarian diathermy N
(LOD) 171, see also Ovarian
drilling Nonsteroidal anti-inflammatory drug
Laparoscopic uterosacral nerve ablation (NSAID) 44
(LUNA) 87 NuvaRing 73
O Pituitary 3, 5, 9-12, 14, 17, 19-21,

25, 32, 48, 53, 86, 89-92, 94,
Obesity 39, 43, 50, 51, 56-63, 70, 96, 95, 107, 108, 136, 146, 148,
117, 146, 195, 206 149, 151, 159, 165, 169-173,
Oligospermia 194, 196-198 189-191, 195-199
Oocyte donation 18, 149, 152, 165, Polycystic ovary syndrome (PCOS)
Index
166, 187 12, 15, 21, 29, 31, 35, 40, 41,
Operative hysteroscopy 150, 162 47-55, 58, 136, 148, 149, 152,
Oral contraceptive 18, 21, 43, 53, 67, 159, 165, 167-171, 173, 174,
70, 79, 81, 85, 88, 96, 104, 147 176, 180, 181, 183
Ortho Evra 72 Precocious puberty 12-15, 21
Osteoporosis 19, 35, 77, 82, 93, 108, Pregnancy 5, 7-9, 16, 18, 19, 21, 25,
113-115, 119, 149, 168 33-35, 37-41, 43-45, 52-54, 56,
Ovarian drilling 159, 161, see also 62, 65, 68, 69, 72, 75-77, 79-82,
Laparoscopic ovarian diathermy 89, 90, 92-94, 121, 124, 125,
Ovarian failure 17, 18, 21, 29, 33-35, 128, 129, 135, 138, 141, 145-147,
50, 137, 146, 149, 152, 159, 149-151, 153-156, 158, 159,
178, 179, 181, 184, 187 161-163, 167-176, 178, 179,
Ovarian hyperstimulation syndrome 182-187, 190, 196, 198, 199,
(OHSS) 152, 167, 168, 170, 201-203, 205-207, 209
173-176, 183, 186 Preimplantation genetic diagnosis
Ovarian reserve 137, 138, 148, 151, (PGD) 179, 184, 187
181, 184, 185 Premenstrual dysphoric disorder
Overweight 54-57, 72, 76, 168 (PMDD) 72, 96-106
Ovulation 4-8, 18, 20, 21, 29, 35, 38, Premenstrual syndrome (PMS) 68,
40, 41, 43-45, 47, 54, 67, 70, 96-105
74, 76, 79, 86, 94, 107, 122, Presacral neurectomy 87
146, 148-153, 159, 165-176, Primary amenorrhea 23, 29, 31, 32,
179, 180, 183, 187, 190, 191, 121, 124
194, 195, 203, 205, 207 Progesterone 3, 4, 7-9, 12, 13, 16, 18,
Ovulation induction 18, 20, 21, 35, 21, 25, 35, 38, 40, 41, 43, 49,
44, 149, 150, 152, 159, 53, 74, 76, 86, 99, 104, 109,
165-176, 183, 187, 190 110, 116, 117, 122, 146, 148,
Ovulatory dysfunction 39, 41, 47, 56, 167, 169, 172, 180, 181, 191
146, 148, 152, 165, 185, 192 Progestin 16, 18, 19, 21, 25, 35, 43,
44, 52, 53, 66-68, 70, 72, 74-77,
P 79-82, 86, 110, 111, 115, 117,
165, 174
Pelvic inflammatory disease (PID) 66, Progestin challenge test 16, 25, 165
68, 69, 79, 80, 82, 125, 126, Progestin only pill (POP) 66, 74, 75,
130, 147, 149, 154, 156, 163, 77, 79, 81, 82
179, 180, 187 Prolactin (PRL) 14, 15, 19, 21, 25,
Pelvic magnetic resonance imaging 32, 33, 49, 50, 89-95, 99, 136,
(MRI) 41, 42 146, 148, 149, 165, 171, 181,
Pelvic ultrasound 49, 167 191, 195, 197-199
Perimenopause 98, 107, 108 Prolactinoma 19, 29, 32, 34, 90-95
Phytoestrogen 111, 191 Proliferative phase 6, 8, 38, 130
Prospective daily rating 97
Psychotherapy 101
Index 217
R Tubal catheterization 159

Tubal disease 42, 128, 149, 150, 158,
Retrograde menstruation 84 167, 181, 182, 186
Tubal infertility 79, 82
S Turner’s syndrome 33, 34, 180
Type 2 diabetes 51, 53, 57, 60
Saline sonohysterogram (SSH) 41, 42,
Index
44, 45 U
Scrotal ultrasound 195, 199, 200
Secondary amenorrhea 23, 29, 34, Ultrasound 12-14, 17, 28, 42, 43, 47,
125, 126 49, 50, 85, 120-125, 130,
Secretory phase 8, 9, 38, 43, 180 135-141, 152, 153, 158, 159,
Selective estrogen receptor modulator 162, 167, 169, 170, 174-176,
(SERM) 114, 149, 151, 168 181, 186, 195, 197-200, 203
Selective serotonin reuptake inhibitor Unintended pregnancy 65, 77, 79, 80,
(SSRI) 90, 101-106 81
Semen analysis 20, 147, 148, 153,
165, 181-183, 195, 197-200 V
Serotonin reuptake inhibitor (SRI) 90,
98, 99, 101, 104, 105, 110 Vaginal maturation index 16, 21
Sonohysterogram 41, 42, 126, 129, Varicocele 180, 195, 197, 199
135, 141, 181 Vasectomy 180, 195
Spermatogenesis 20, 146, 180, 194 Vasomotor symptom 25, 45, 108,
Spironolactone 52, 53, 104 111, 119
Sterilization 69, 78, 82, 147, 156, Vitamin 41, 60, 100, 101, 105, 112,
158, 159, 182 191-193, 196
Surrogacy 178, 184, 187 von Willebrand disease (VWD) 37,
39-43
T
W
Tanner stage 10, 11
Teratozospermia 198 Waist circumference 48, 51, 57
Testosterone 11-15, 19, 20, 28, 31-34, WHO criteria 70, 71, 74, 75, 77, 80,
48-50, 52-54, 108-110, 118, 146, 165, 166, 171, 175, 176,
167, 181, 190, 194-196, 198, 182, 197, 198
199 Women’s Health Initiative (WHI)
Thelarche 10-12, 15, 21, 121 112, 114-118
Transvaginal ultrasonography 42, 45,
181
Treatment 12, 14, 18-21, 34, 35, 38,
41, 43-45, 51-61, 64, 72, 79,
84-87, 92-96, 98-107, 109-112,
114-116, 119-122, 124, 129,
137-139, 141, 145, 146,
149-151, 153-156, 158, 159,
161-163, 165-172, 176,
178-184, 187, 189-193, 196,
198-200, 202, 204
LANDES
BIOSCIENCE
V ad e me c u m V ad e me c u m
V ad eme c um
LANDES LANDES
BIOSCIENCE BIOSCIENCE
Table of contents Reproductive

1. The Menstrual Cycle
2. Puberty and Its Disorders

12. Reproductive Endocrinology Diagnostic
Imaging Endocrinology
and Infertility
13. An Overview of Female Infertility

3. Amenorrhea
14. Surgical Treatment of Female Infertility
4. Dysfunctional Uterine Bleeding
15. Ovulation Induction
Ovary Syndrome 16. Assisted Reproductive Technology
6. Obesity: Recognition and Treatment in 17. Alternative Medicine and Female Infertility
Women
18. Male Infertility
7. Hormonal Contraception
19. Your Environment; Your Fertility—Is There
8. Endometriosis a Link?
9. Hyperprolactinemia
10. Premenstrual Syndrome
11. Treatment of the Menopausal Woman
The Vademecum series includes subjects generally not covered in other handbook
series, especially many technology-driven topics that reflect the increasing
influence of technology in clinical medicine.
The name chosen for this comprehensive medical handbook series is Vademecum,
a Latin word that roughly means “to carry along”. In the Middle Ages, traveling
clerics carried pocket-sized books, excerpts of the carefully transcribed canons,
known as Vademecum. In the 19th century a medical publisher in Germany, Samuel
Karger, called a series of portable medical books Vademecum.
The Vademecum books are intended to be used both in the training of physicians
Lewis
and the care of patients, by medical students, medical house staff and practicing
physicians. We hope you will find them a valuable resource.
Lewis Vivian Lewis

All titles available at ISBN 978-157059702-2
www.landesbioscience.com
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Table of contents Reproductive

2. Puberty and Its Disorders

Reproductive Endocrinology and Infertility

10. Premenstrual Syndrome

11. Treatment of the Menopausal Woman

Lewis Vivian Lewis

Vivian Lewis, M.D.

Copyright ©2007 Landes Bioscience

Please address all inquiries to the Publisher:

Cover artwork by Kristen Shumaker

Library of Congress Cataloging-in-Publication Data

Reproductive endocrinology and infertility / [edited by] Vivian Lewis.

Part II: Infertility

Victor Y. Fujimoto, M.D. Hey-Joo Kang, M.D.

William R. Phipps, M.D. Jody Steinauer, M.D., M.A.S.

Reproductive Endocrinology and Infertility provides an overview of the most

Vivian Lewis, M.D.

The Menstrual Cycle

at this stage measure 4-6 mm from the secretion of mucopolysaccharides by the

Puberty and Its Disorders

Table 2.1. Tanner staging in females with approximate ages

mid-gestation and decline at term because of negative feedback from placental

Table 2.2. Usual order of pubertal events in males and females

In patients who do not have evidence of a central cause, ovarian ultrasound or

Mc Cune-Albright syndrome is associated with precocity and is five times more

Women with hypergonadotropic hypogonadism and normal female chromo-

Figure 3.1. Evaluation of amenorrhea.

is suggestive of hypoestrogenism and hypogonadism. In addition to assisting in

Table 3.1. Progestin challenge test

Figure 3.2. Eugonadism with uterus.

Table 3.2. Gonadotropin levels

Figure 3.4. Eugonadism without a uterus.

Table 3.3. Causes of primary amenorrhea

Hypogonadism, Uterus Present

Table 3.4. Causes of secondary amenorrhea

Adapted from: Reindollar RH, Novak M, Tho SP et al. Adult-onset amenorrhea: A

Figure 3.5. Hypogonadism with a uterus.

hyperandrogenemia, and polycystic appearing ovaries. According to the 2003

illness such as poorly controlled diabetes, childhood rheumatoid arthritis and

In addition to premature ovarian failure, other stigmata of Turner’s syndrome may

slow growing and respond well to dopamine agonists such as bromocriptine or

Dysfunctional Uterine Bleeding

Table 4.1. Normal menses: Characteristics

Differential Diagnosis and Mechanisms of Bleeding

excluded with reasonable certainty prior to treatment. Accordingly, the diagnosis of

considered to be a relatively mild nongenetic form of VWD, as opposed to having

Table 4.3. Diagnostic studies in cases of abnormal vaginal bleeding

increasingly available option of performing directed biopsies or removing focal le-

ovulatory women using the LNG-IUS continue to ovulate regularly. Interestingly,

Diagnosis and Management of Polycystic

Table 5.1. Physical features of PCOS

typical is onset of menstrual irregularity at a later age. It is now recognized however

Table 5.2. Endocrine evaluation for PCOS

2 hour oral glucose Screen for glucose intolerance or diabetes.

Figure 5.1. Ultrasound of polycystic ovary. Note increased numbers of follicles in

Table 5.3. Treatment options for PCOS

Oral Contraceptives and Progestins

is a nonsteroidal, nonhormonal antiandrogenic drug, which has been demonstrated

over time and should be encouraged. Significant support is needed to encourage

Obesity: Recognition and Treatment in Women

Obesity is a component of metabolic syndrome, but it is not absolutely required

Figure 6.1. Mechanisms of action of sibtramine. Adapted from: Yanovski SZ,