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Infertility

Christopher P. Montville MD, MS


Michael A. Thomas MD
Basics
Description
Inability to conceive after 12 months of regular, unprotected, intercourse.
85% of general population will conceive without medical assistance in this
time period.
Fecundability: Probability of conception within 1 menstrual cycle

Fecundity: Probability of pregnancy resulting in live birth during 1 menstrual


cycle

Chemical pregnancy: Positive blood or urine pregnancy test with clinical


suspicion of pregnancy

Age-Related Factors
Ability to conceive decreases as maternal age increases.
Oocyte number and quality decrease with time.

Accelerated loss after age 35.

Oocytes less sensitive to FSH stimulation

Oocyte chromosomal abnormalities

Increased rate of aneuploidy in embryos

Decreased IVF success rates:


o

Pregnancy rates

SAB: Age <40 (1820%), Age >40 (>35%)

Epidemiology
Fecundability of general population approximately 20%. In general, declines
in populations with time.
Diagnoses in infertile couples:
o

Ovulatory disorder: 2527%

Tubal disease/defect: 2235%

Male factor: 2540%

Endometriosis: 5%

Other: 4%

Unexplained: 17%

Risk Factors
Any etiology that can cause abnormalities in gamete production, gamete
transport, or embryo implantation

Infectious:
o

PID

Endometritis

Epididymitis

Pelvic adhesive disease:


o

PID

Prior pelvic/abdominal surgery

D&C (septic abortion)

Chemical exposure:
o

Smoking

Work environment (semen parameters)

Genetics
Genetic defects associated with infertility are primarily associated with chromosomal
abnormalities in the oocytes and embryos of women of advanced maternal age.
Maternal genetic defects include:
Turner syndrome (45 XO) or Turner mosaicism
X chromosome translocations/deletions (premature ovarian failure)

Identified mutated genes affecting:


o

FSH receptor; LH receptor

FMR1 (Fragile X syndrome)

Pathophysiology
Abnormal gamete (oocyte/sperm) production
Reproductive tract defects resulting in abnormal gamete/embryo transport

Dysfunctional implantation

Abnormal embryo development

Other: Genetics, immunologic factors, lifestyle

Associated Conditions
Iatrogenic causes of infertility with cytotoxic chemotherapy or pelvic radiation for
malignancy
Diagnosis
Signs and Symptoms
Menstrual irregularities most common. Absence of 2235 day cycles, breast
tenderness, dysmenorrhea or bloating (moliminal symptoms) suggests ovulatory
dysfunction.
History

Complete history, female and male:


Obstetric, menstrual, surgical (especially history of pelvic/abdominal surgery).
Infectious disease; GYN (pap smear, endometriosis, etc)

Endocrinologic (thyroid; prolactin)

Male partner: Chemical exposure, history of mumps, testicular trauma,


inguinal hernia, past paternal history, family history (genetic and
reproductive), sibling history

Review of Systems
Menstrual cycle characteristics:
Moliminal symptoms, dysmenorrhea, menorrhagia, vasomotor symptoms
Abnormal nipple discharge

Palpitations, constipation, diarrhea

Dyspareunia

Male:
o

Erectile dysfunction, testicular lesions

Physical Exam
Particular attention to thyroid, breasts, abdomen, and pelvis:
o BMI

Hirsutism, acanthosis nigricans

Thyroid size and contour

Nipple discharge

Pelvic exam:
o

Size of uterus and adnexa

Utero-sacral ligament/cul-de-sac nodularity

Male:
o

Usually defer to urologist

Hernia and varicocele evaluation

Tests

Goal is to identify cause of infertility.


Ovulatory dysfunction
o

Basal body temperature (biphasic normal)

Ovulation predictor assay:

Urine LH assay for presence of LH surge

>3 ng/mL: Positive ovulation

>10 ng/mL: Correlates with in-phase endometrium

Clomiphene citrate challenge:

FSH cycle day #3 100 mg PO cycle days 59 day 10


FSH

Elevated FSH on day 3 or 10 (1020 ng/mL) indicates poor


ovarian reserve

Anatomic factors (see Imaging):


o

Serum progesterone:

Postcoital test and endometrial biopsy rarely performed.

Male factor:
o

Semen analysis (see Labs)

Labs

Day 3 FSH (if age >35 or question of ovarian reserve)


Midluteal progesterone

TSH; prolactin

Total testosterone (if hyperandrogenism/PCOS suspected)

LFTs, renal panel (if considering metformin)

Semen analysis:
o

Normal: >50% motile; >20 million; >14% normal forms

Imaging
Pelvic US and hysterosalpingogram mainstays of diagnostic imaging
Pelvic US:

Appearance of ovaries; follicular development

Corpus luteum formation

Adnexal mass/endometrioma

Hydrosalpinx

Uterine leiomyoma; endometrial stripe measurement

Sonohysterogram (saline infusion sonography):


o

Distention of uterine cavity with saline with concomitant pelvic US.


Valuable for identification of uterine leiomyoma/polyps

Hysterosalpingogram (HSG):
o

Hysteroscopy:
o

Office-based or in operating room. Evaluation of uterine cavity, tubal


ostia

Potential for cannulation of ostia

Laparoscopy:
o

Fluoroscopy with contrast dye injected into uterus. Evaluation of tubal


patency, tubal lumen diameter, peritubal adhesions, endometrial
contour, presence of endometrial adhesions

Direct visualization of pelvic anatomy and peritoneal structures.


Advised in women with unexplained infertility, history of
endometriosis, prior pelvic surgery and/or infection; tubal occlusion on
HSG.

Chromopertubation:
o

Injection of methylene blue or indigo carmine through cervix into


uterus to evaluate tubal patency

Concomitant adhesiolysis and tubal surgery

MRI is useful to delineate uterine leiomyoma prior to myomectomy.

Differential Diagnosis
Ovulatory dysfunction:
Anovulation/Oligo-ovulation:
o PCOS most common (70%)
P.119
Infection
Tubal disease (occlusion/adhesions):
PID/STDs
Ruptured appendix
Metabolic/Endocrine
Ovulatory dysfunction/oligo-ovulation:
o PCOS most common (70%)

Thyroid dysfunction

Hyperprolactinemia

Hypothalamic dysfunction:
o

Eating disorders

Athletic induction amenorrhea

Hypothalamic hypogonadism

Poor oocyte quality:

POF

Prior ovarian surgery

Age-related factors

Extremes in BMI (<20; >27)

Immunologic
Ovarian insufficiency/POF
Trauma
Tubal occlusion/adhesions
Pelvic surgery
Drugs

Cytotoxic chemotherapy with ovarian failure


Drug induced hyperprolactinemia

Other/Miscellaneous
Endometriosis (tubal damage, inflammation)
Male factor (azoospermia/oligospermia)

Uterine anomalies (fibroids, polyps, septum)

Asherman's syndrome

Treatment
General Measures
Treatment should be centered on specific diagnosis, patient safety, and patient
preference. Adequate counseling and informed consent of vital importance.
Ovulatory Dysfunction
Weight loss (if PCOS), smoking cessation, timed intercourse
Clomiphene citrate:
o

50100 mg PO for 5 days (cycle day 37)

50% will ovulate with 50 mg dose:

In PCOS, 825% fecundability with 36 cycles

Metformin 500 mg t.i.d. improves success in PCOS

Antiestrogen effect on endometrium possible

Aromatase inhibitor: Controversial; off label

Gonadotropin therapy:

Indications: Hypothalamic hypopituitarism; PCOS following failed


clomiphene therapy; decreased ovarian reserve; IVF:

Multifollicular development and ovulation

80% ovulation rate; 1040% fecundability

Risk of multiple gestation and OHSS

Tubal Factor
Tubal surgery (See Fallopian Tube Surgery.):
o Adhesiolysis; fimbrioplasty; salpingotomy (hydrosalpinx); tubal
cannulation (proximal occlusion):

Success rates depend on indication and severity of disease

If significant tubal disease IVF

Endometriosis
Adhesiolysis; endometrioma resection:
Pretreatment with GnRH agonists/antagonists helpful prior to ovulation
induction
Uterine Factors
Myomectomy (abdominal/hysteroscopic):
o Success dependent on leiomyoma size; proximity to endometrium,
iatrogenic endometrial damage.

Hysteroscopic polypectomy

Hysteroscopic septum resection

Adhesiolysis (Asherman syndrome)

Male Factor
Varicocele repair
IVF intracytoplasmic sperm injection (ICSI)
Endocrinologic
Medical treatment of hyper-/hypothyroid
Hyperprolactinemia:
o

Bromocriptine (2.57.5 mg PO daily)

Growth of microprolactinoma unlikely during pregnancy

IVF

Patient selection depends on diagnosis and prior medical therapy.


Gonadotropin ovulation induction with transvaginal oocyte aspiration

Surgery

Majority of procedures associated with tubal disease/occlusion (See Fallopian


Tube Surgery.)
Ovarian drilling:
o

In PCOS, thermal destruction of cortex and stroma associated with


increased ovulation:

Temporary improvement in ovulation

Followup
Disposition
Issues for Referral
Referral to fertility center based on past history and current treatment, duration of
infertility, extent of possible treatment. Expedited referral:
Female age >35
History of known tubal disease including PID

Known male infertility

Prior history of cancer, genetic disease, or immunologic disease

Prognosis
Success rates depend on etiology of infertility and presence of coexisting
factors
Ovulatory dysfunction: 520%

Tubal factor: 1060%:


o

Risk of ectopic (s/p surgery) 421%

Unexplained: 423%

Male factor: Success dependent on oocyte quality and female factors:


o

ICSI: ~25%

Patient Monitoring
Therapy should be tailored to patient preferences, costs, and etiologic factors.
Follicle monitoring with US should be performed with ovulation induction in
addition to:
o

Estradiol levels with gonadotropin use

Attention to development of OHSS

Increased vascular permeability due to elevated estradiol:

Risks include ascites, VTE, pulmonary edema

Treatment guidelines:
o

Clomiphene: 36 cycles

Gonadotropins: 36 cycles

Reevaluation of patient expectations and desire for further, more


intensive therapy necessary

Bibliography
ACOG Committee on Practice Bulletins. Management of infertility caused by
ovulatory dysfunction. Practice Bulletin No. 34. Obstet Gynecol. 2002;99:347358.
Adamson GD, et al. Subfertility: Causes, treatment, and outcome. Best Pract Res Clin
Obstet Gynaecol. 2003;17(2):169185.
Barbieri RL. Female infertility. In: Stauss JF, et al., eds. Yen and Jaffe's Reproductive
Endocrinology: Physiology, pathophysiology, and clinical management, 5th ed.
Philadelphia: Elsiver; 2004: 633668.
The Practice Committee of the American Society for Reproductive Medicine. Optimal
evaluation of the infertile female. Fertil Steril. 2006;86(Suppl 4):S264S267.
The Practice Committee of the American Society for Reproductive Medicine.
Effectiveness and treatment for unexplained infertility. Fertil Steril. 2004;82(Suppl
1):S160S163.
Miscellaneous
Abbreviations
BMIBody mass index
FSHFollicle-stimulating hormone
GnRHGonadotropin-releasing hormone
ICSIIntracytoplasmic sperm injection
IVFIn vitro fertilization
LHLuteinizing hormone
OHSSOvarian hyperstimulation syndrome
PCOSPolycystic ovarian syndrome
PIDPelvic inflammatory disease
POFPremature ovarian failure
SABSpontaneous abortion
STISexually transmitted infection
Codes
ICD9-CM
256.39 Polycystic ovaries (PCOS)
628.0 Infertility, anovulatory
628.2 Infertility, tubal origin
628.9 Infertility, unexplained origin
Patient Teaching
Smoking cessation, normal weight maintenance, limit chemical exposures
Effects of age on fertility. Preconception counseling in women >35
Attention to emotional health; counseling if needed
Prevention
STI prevention