moisturizers and lubricants.
When considering hormonal treat- cystic fibrosis, and Klinefelter disease may also lead to inability or
ment options for these patients there is good evidence that vaginal
and topical estrogen is quite safe when used appropriately. The
lowest possible dose for shortest duration is recommended in
these patients and often providers will feel more comfortable con-
sidering hormonal therapies in consultation with the patient’s
oncologist. Be aware that many patients that are breastfeeding
or are taking combination oral contraceptives may also experi-
ence atrophic changes that cause pain during sexual encounters.
For these patients, topical vulvar hormones are often quite effec-
tive in relieving symptoms.
References
Coady D: Chronic sexual pain: a layered guide to evaluation, Contemporary OB/
GYN 60:18–28, 2015.
Goldstein AT, Belkin ZR, Krapf JM, et al: Polymorphisms of the androgen receptor
gene and hormonal contraceptive induced provoked vestibulodynia, J Sex Med
11:2764–2771, 2014.
Goldstein A, editor: Female Sexual Pain Disorders Evaluation and Management,
Hoboken, 2009, Wiley-Blackwell.
Shifren JL, Monz BU, Russo PA, et al: Sexual problems and distress in United States
women: prevalence and correlates, Obstet Gynecol 112:970–978, 2008.
Stein A: Heal Pelvic Pain: A proven stretching, strengthening, and nutrition program
for relieving pain, incontinence, IBS, and other symptoms without surgery,
New York, 2009, McGraw Hill, pp 785-802.
INFERTILITY
Method of
Jessica Kanter, MD; and Michael P. Diamond, MD
17 Women's Health
CURRENT DIAGNOSIS
• Infertility is defined as the inability to conceive with regular
intercourse after 12 months in couples in which the female part-
ner is younger than 35 or after 6 months in couples in which the
female partner is older than 35.
• The incidence of infertility is increasing.
1102
CURRENT THERAPY
• Assisted reproductive technologies are being used with
increasing frequency and with increasing success rates.
Epidemiology
Infertility is defined as the failure to conceive after 12 months of
regular, unprotected intercourse. In couples where the female part-
ner’s age exceeds 35 years, evaluation may begin after just 6 months
of infertility owing to the time-sensitive nature of the problem. In
some circumstances, diagnostic evaluation and therapeutic inter-
vention is warranted at an earlier time. Infertility affects approxi-
mately 15% of couples. Many of these patients present to their
primary care physician. Timely evaluation and potential referral
to an infertility subspecialist is prudent.
Risk Factors
There are numerous risk factors that contribute to infertility. The
most common is age. However, it is necessary to evaluate other
potential contributing factors to infertility as these may lead to nar-
rowing of the differential diagnosis and a more targeted subsequent
treatment plan. For example, a history of sexually transmitted
infections, especially chlamydia, and episodes of pelvic inflamma-
tory disease have been associated with tubal factor infertility in
women. Metabolic disorders such as obesity and polycystic ovar-
ian syndrome, which may lead to anovulation, are an increasingly
more prevalent concern and a major risk factor for infertility.
Finally, certain genetic diseases such as fragile X, Turner syndrome,
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difficulty in conceiving.
Pathophysiology
The pathophysiology of infertility should be grouped first by male
and female factors and then by components of their respective
reproductive tracts. One must not discount the fact that multiple
factors may coexist. Unexplained infertility is accountable for
8% to 28% of infertility in couples.
Prevention
Some etiologies of infertility may be preventable. Many cases of
tubal factor infertility may be prevented by protecting against
transmission of sexually transmitted infections (STIs). Barrier con-
traception is essential to prevent STIs, particularly in high-risk indi-
viduals with an early age of coitarche and/or those with multiple
sexual partners. Even with highly efficacious forms of contracep-
tion such as intrauterine devices, long-acting injectable progestins,
and progestin-containing subdermal implants, providers must
counsel their patients that barrier contraception is still of the
utmost importance in preventing STI transmission.
There are various medical therapies, particularly those related to
cancer treatments, that may be detrimental to fertility. In these
cases, oncofertility consultation prior to treatment is paramount
for fertility preservation. For men, sperm cryopreservation is a rel-
atively easy, noninvasive option. For women, oocyte or embryo
preservation, experimental approaches to medically induced ovar-
ian suppression, and ovarian transposition are all tools to have in
the arsenal for women undergoing gonadotoxic chemotherapy or
radiation therapy.
Finally, fertility should also be considered when managing tubal
ectopic pregnancy in women. Medical therapy, when not contrain-
dicated, is an excellent option in the compliant patient with an
ectopic pregnancy. When surgery is necessary, salpingostomy
may be considered when possible in lieu of salpingectomy in an
attempt to preserve tubal function.
Clinical Manifestations
Infertile patients generally present with failure to conceive after a
variable time of home intercourse. The definition of infertility is
subdivided into primary and secondary infertility. Primary infertil-
ity means the patient has not borne children in the past. Secondary
infertility means the patient has successfully procreated in the past.
Diagnosis
The diagnosis of infertility begins with a thorough history and
physical examination. It is important to remember that a history
must be obtained from both partners during this evaluation.
The male partner assessment begins with a semen analysis. Text-
books often suggest two semen analyses, preferably separated in
time by at least 1 month.
Female partner assessment can include determination of ovarian
reserve by hormonal evaluation of antim€ ullerian hormone (AMH)
or cycle day 3 follicle-stimulating hormone (FSH). Frequently, pro-
lactin and thyroid-stimulating hormone (TSH) are also obtained,
as is a measure of ovulation such as a midluteal progesterone level.
Other labs may be ordered if clinically indicated, such as androgens
in women with hirsutism. Tubal patency is assessed by sonohyster-
ogram or hysterosalpingogram. These imaging tests also allow
assessment of the uterine cavity for uterine contour and any abnor-
malities including fibroids or polyps. Sonography may also be use-
ful in identifying m€ ullerian anomalies or anomalies of the basic
structure of the uterus; the gold standard for identifying these
anomalies is magnetic resonance imaging. In cases where other pel-
vic pathology such as endometriosis and adhesions are suspected,
diagnostic laparoscopy may be considered. Chromotubation dur-
ing laparoscopy may be empirically performed. Finally, for both
partners, karyotype analysis may be considered.
Differential Diagnosis
When determining a differential diagnosis, both male and female
factors must be considered.
Male Factors
The most common etiologies of male factor infertility are oligosper-
mia and azoospermia. The etiologies leading to these diagnoses are
broad and varied, and include genetic conditions such as cystic
fibrosis (leading to congenital absence of the vas deferens).
Female Factors
Female factors for infertility are numerous and most easily subdi-
vided by system.
Ovulatory Dysfunction
Inability to produce a viable oocyte each month can be related to
several factors. First, anovulation may occur, meaning oocytes are
present in the ovaries but none are released on a regular basis. This
can be related to hormonal ovarian suppression (e.g., hyperprolac-
tinemia) and metabolic disturbances (e.g., polycystic ovarian syn-
drome). Alternatively, an oocyte may not be produced secondary
to a paucity of oocytes owing to age, genetic factors, or prior insults
to the ovaries such as radiation therapy. In addition to the afore-
mentioned AMH and day 3 FSH and serum estradiol to assess
ovarian function, ultrasound may be employed to evaluate antral
follicle count, another marker of ovarian reserve.
Tubal Factor
The fallopian tubes are responsible for transporting the oocyte
from the ovaries to the uterine cavity. For this to occur, at least
one fallopian tube must be patent. Perhaps the most common eti-
ology of tubal factor infertility is a history of pelvic inflammatory
disease, with one of the most common inciting agents being Chla-
mydia trachomatous. C. trachomatis is particularly problematic in
women as the initial infection may be asymptomatic. Other tubal
infertility may arise from prior tubal ligation, other tubal surgery,
history of ectopic pregnancy with salpingectomy or salpingostomy,
or scarring of the tubal lumen.
Uterine Factor
Any irregularities within the uterine cavity may also lead to infer-
tility, generally secondary to poor implantation of the fertilized
embryo. Some such etiologies may be present from birth, namely
m€ ullerian anomalies and uterine septae. The abnormally shaped
uterine cavity in these anomalies reduces the opportunity for nor-
mal implantation and embryo growth.
During the course of a woman’s life, she may develop benign
intrauterine growths including polyps and leiomyomas that can
reduce the opportunity for normal embryo implantation. Finally,
prior uterine surgery may damage the endometrium and myome-
trium, as in Asherman syndrome, or cause uterine cavity scarring,
called synechiae.
Combined
One must not forget that multiple etiologies in a wide variety of
combinations may be at play in female factor infertility.
Unexplained
Perhaps the most frustrating of all diagnoses is unexplained infer-
tility. In couples who have had a negative fertility workup, a spe-
cific etiology of infertility is never revealed. There is new,
burgeoning research in the area of sperm microRNA that may iden-
tify male factor infertility in men with otherwise normal semen ana-
lyses. Although not currently in wide use, such studies may be of
great utility in the future.
Prior Diagnosis
As the field of infertility is becoming understood to an increasingly
greater degree, there are prior diagnoses that have fallen out of
favor. One such diagnosis is cervical factor insufficiency. It was
previously evaluated by the postcoital test, in which a sample of
cervical mucus would be taken after intercourse and evaluated
for the presence of motile sperm. This test has fallen out of favor
owing to subjectivity, lack of reproducibility, and poor correlation
with future fertility.
Also out of favor is the prior diagnosis of luteal phase deficiency
(LPD), previously defined as inadequate endogenous progesterone
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production during the luteal phase of the menstrual cycle. No clin-
ical tests have proven reliable for LPD, nor have any treatments
demonstrated any significant improvement in fertility.
Treatment
The mainstay of therapy is first treating underlying disorders such
as obesity, thyroid disease, hyperprolactinemia, and so forth. Life-
style modifications should be recommended to all women, includ-
ing folate supplementation (at least 400 mcg daily), caffeine
reduction, and weight loss for those who are overweight or obese.
Other known causes of infertility that require surgical management
may include intrauterine pathology (e.g., polyps, fibroid tumors) or
repair of a hydrosalpinx, a distally blocked fallopian tube filled
with serous fluid.
With a normal male partner semen analysis, the first step in inter-
vention is generally an oral agent to induce ovulation combined
with intrauterine insemination. Options for induction include clo-
miphene citrate (Clomid) and off-label use of letrozole (Femara), an
aromatase inhibitor. If this fails, therapy can proceed to treatment
with injectable gonadotropins (i.e., FSH and luteinizing hormone)
to stimulate development of ovarian follicles and ovulation with
intrauterine insemination or in vitro fertilization. Various addi-
tional procedures may include assisted hatching of the embryo with
the hope to increase implantation rates; intracytoplasmic sperm
injection to increase fertilization rates of the oocytes, particularly
in the setting of male factor infertility; and preimplantation genetic
screening to evaluate for embryo genetic anomalies, particularly in
women of advanced maternal age.
Monitoring
To reduce risks associated with ovulation induction and ovarian
stimulation, monitoring of serum estradiol and follicular develop-
ment is performed. Monitoring provides the ability to minimize the
occurrence of multiple gestation and complications associated with
ovarian hyperstimulation syndrome.
Menopause
References
Gelbaya TA, Potdar N, Jeve YB, Nardo LG: Definition and epidemiology of unex-
plained infertility, Obstet Gynecol Surv 69(2):109–115, 2014.
Jodar M, Sendler E, Moskovtsev SI, et al: Absence of sperm RNA elements correlates
with idiopathic male infertility, Sci Transl Med 7(295):295–296, 2015. https://doi.
org/10.1126/scitranslmed.aab1287.
Practice Committee of American Society for Reproductive Medicine: Diagnostic eval-
uation of the infertile female: A committee opinion, Fertil Steril 98(2):302–307,
2012. 1103
Practice Committee of American Society for Reproductive Medicine: Current clinical
irrelevance of luteal phase deficiency: A committee opinion, Fertil Steril 103(4):
e27–e32, 2015.
Sharlip ID, Jarow JP, Belker AM, et al: Best practice policies for male infertility, Fertil
Steril 77(5):873–882, 2002.
MENOPAUSE
Method of
Andrew M. Kaunitz, MD; and JoAnn E. Manson, MD, DrPH
CURRENT DIAGNOSIS
• In women who meet clinical criteria for menopause who present
for management of vasomotor symptoms (VMS), checking
follicle-stimulating hormone (FSH) and estradiol levels is not
necessary. However, if no recent level available, checking a
thyroid-stimulating hormone (TSH) level to rule out thyroid dis-
ease is appropriate.
• Occasionally, nonmenopausal conditions can masquerade as
menopausal VMS.
• Although genitourinary syndrome of menopause (GSM) can be
presumptively diagnosed based on a characteristic history, a pel-
vic examination can help exclude other vulvovaginal conditions
that can present with similar symptoms.