Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Female Infertility


Fertility is defined as the capacity to conceive and produce offspring. Infertility is the state of a diminished capacity to conceive and bear offspring. In contrast to sterility, infertility is not an irreversible state. In the past, infertility was defined as the inability to conceive after 12 months of frequent coitus. A recent and more inclusive definition of infertility is a disease characterized by the failure to establish a clinical pregnancy after 12 months of regular, unprotected sexual intercourse or due to the impairment of a person’s capacity to reproduce either as an individual or with his/her partner. This expanded definition supports fertility treatment of unpartnered individuals, same-sex couples, and transgender persons. , Infertility prevalence is approximately 13% among women and 10% among men. An estimated 48.5 million couples worldwide are infertile. Among women and men with infertility, 57% and 53%, respectively, were reported to seek infertility treatment. Women with higher income, higher education level, medical insurance, and more frequent use of the healthcare system are more likely to seek infertility treatment. , In the United States, non-Hispanic Asian or white women are more likely to seek infertility care than non-Hispanic black and Mexican-American women.

The prevalence of infertility rises as female age increases. In one study, at 32 and 38 years of age, 12% and 21% of women reported infertility. Since the fertility potential of the female partner decreases after 35 years of age, most authorities recommend initiating an infertility evaluation after 6 months of attempting conception in women 35 to 40 years of age and after 3 months in women over 40 years of age. , Women with known causes of infertility, such as amenorrhea, should immediately start an evaluation to assess the cause of the endocrine disorder.

A Statistical Model of Infertility

  • The cumulative probability of conception, F, through month N is calculated as follows: F = 1 − (l–f) N , where f is the per-cycle pregnancy rate .

The clinical definition of infertility is relatively crude because it does not reflect the wide range of fertility potential in couples that have not conceived after 12 months. The clinical definition of infertility implies the existence of a dichotomous state, either a pregnancy is achieved in 12 months and infertility is not present, or a pregnancy is not achieved in 12 months and, by definition, infertility is present. The current clinical definition of infertility is similar to analyzing a continuous variable, such as height, by using a dichotomous variable: “short” and “tall.” Height is clearly much better described by a continuous measure, such as centimeters, rather than by using a dichotomous variable like “short” and “tall.”

Our clinical approach to fertility and infertility would be advanced by increased use of the statistical concept of fecundability in the fertility literature. Fecundability is the probability of achieving a pregnancy in one menstrual cycle. Fecundability is approximately 0.25 in healthy young couples just beginning attempts at conception and decreases steadily with age, falling by 60% among women aged 40 to 45 years. A related concept, fecundity , is the ability to achieve a pregnancy that results in a live birth based on attempts at conception in one menstrual cycle. Fecundability, a population estimate of the probability of achieving pregnancy in one menstrual cycle, is a valuable clinical and scientific concept because it creates a framework for the quantitative analysis of fertility potential. Based on the clinical characteristics of a population of infertile couples, the estimated fecundability may range from 0.00 in couples with an azoospermic male partner to approximately 0.04 in couples where the female partner has early-stage endometriosis.

Fecundability provides a convenient quantitative estimate of the efficacy of various fertility treatments. An infertile couple with an estimated fecundability of 0.04 if left untreated, may have the choice of two approaches to the treatment of their fertility: a low-cost treatment (clomiphene plus intrauterine insemination) that will increase fecundability to 0.08, or an expensive treatment ( in vitro fertilization) that will increase fecundability to 0.30. A clear quantitative presentation of the potential effect of each treatment on fecundability should assist the couple in choosing an optimal treatment plan. A practical problem with using fecundability as a central concept in infertility care is that the prediction models for estimating the fecundability of a couple are not well developed or validated. Factors that are important in estimating fecundability of a couple are the age of the female partner, number of motile sperm, duration of subfertility, and presence of primary or secondary infertility.

The concept of fecundability can be used to derive a simple statistical description of the fertility process. Fecundability (f) is defined as the probability of conceiving during any one cycle. The probability of failing to conceive during any one cycle is 1–f. Over a short period of time, the fecundability of a population is often stable.

For a large group of couples, the probability of conception is f for the first month, f × (1–f) for the second month, f × (1–f) 2 for the third month, and f × (1–f) N−1 for the Nth month. Using this model, the mean number of months required to achieve conception is 1/f. The cumulative probability of conception, F, through month N is calculated as follows: F = 1–(l–f) N . Based on this simple statistical model, assuming a normal menstrual cycle fecundability of 0.25 and starting with 100 couples, approximately 98 couples should conceive within 13 cycles. If each cycle is 28 days, then 98% of couples should conceive within one calendar year (13 cycles × 28 days/cycle = 364 days).

Over short periods of follow-up, a population of couples attempting pregnancy behaves in a statistically stable manner, with a fixed proportion of the cohort becoming pregnant with each additional cycle of follow-up. As the follow-up is extended, however, the fecundability of the nonpregnant couples declines, and the cumulative pregnancy rate approaches an asymptote, which is less than 100%. Conceptually, this issue can be managed by assuming that there is an asymptote to the cumulative pregnancy rate of the population, or by using complex mathematical modeling of the population fecundability based on the assumption that couples in the population have a range of per-cycle pregnancy rates. This issue is of special importance in the analysis of fertility rates in populations over long periods of time, such as 2 years. This issue is of less practical importance in studies where the time period for analysis is 3 to 6 cycles.

Many studies report that the observed fecundability of a population diminishes with long-term follow-up. For example, Guttmacher assessed the number of months to conception in 5574 women who achieved pregnancy between 1946 and 1956. During the first 3 months of observation, the fecundability was 0.25. During the next 9 months of observation, the fecundability was 0.15. studied 200 healthy couples who desired to conceive. During the first 3 months of observation, the fecundability was 0.25. During the next 9 months of observation, the fecundability was 0.11 ( Table 23.1 ). Other investigators have reported similar results.

Table 23.1
Observational Studies Often Demonstrate That the Fecundability of the Cohort Decreases as Follow-up Progresses
From Zinaman MJ, Clegg ED, Brown CC, et al. Estimates of human fertility and pregnancy loss. Fertil Steril. 1996;65:503–509.
Cycle Number of Women Available for Study at Start of Cycle Number of Pregnancies in Cycle Per-Cycle Pregnancy Rate
1 200 59 0.30
2 137 41 0.30
3 95 16 0.17
4 78 12 0.15
5 66 14 0.21
6 52 4 0.08
7 48 5 0.10
8 43 3 0.07
9 40 2 0.05
10 38 1 0.03
11 37 2 0.05
12 35 1 0.03

The decrease in fecundability with time suggests that each large population consists of a heterogeneous mixture of couples. Some couples have completely normal fertility and achieve pregnancy at a high rate (0.25 per cycle). The remaining couples have a lower fecundability (ranging from 0.00 to 0.15). Some of the couples in this pool will eventually present to a clinician for the treatment of infertility. At the end of 12 months of attempting conception, the couples that have not achieved conception have a fecundability in the range of 0.00 to 0.04 if left untreated ( Table 23.1 ). Successful interventions to improve fertility must increase the per-cycle pregnancy rate over the spontaneous pregnancy rate.

Unfortunately, not all pregnancies produce a live birth. Many pregnancies are lost soon after implantation. The terms occult pregnancy and chemical pregnancy are often used to describe these early pregnancy losses. Occult pregnancy was defined by Bloch as a pregnancy that terminates so soon after implantation that there was no clinical suspicion of its existence. Estimates of the incidence of occult pregnancy vary with hCG detection techniques and range from approximately 10% to 20% following IVF and spontaneous pregnancies, respectively. , Unlike occult pregnancies, a chemical pregnancy typically occurs in the presence of a clinical suspicion that a pregnancy may exist. A blood or urine human chorionic gonadotropin (hCG) assay demonstrates the presence of a pregnancy, but no clinical evidence of the pregnancy is detectable by ultrasound.

Of all clinically recognized pregnancies, approximately 20% result in a spontaneous abortion. Of all pregnancies, approximately 30% are lost, either as occult, chemical, or clinical spontaneous abortions ( Table 23.2 ). Women older than 40 years of age who become pregnant have a spontaneous abortion rate more than double that observed in women younger than 30 years of age. The miscarriage rate is as high as 75% among women aged 45 years and older.

Table 23.2
Pregnancy Occurrence and Outcome During Three Consecutive Menstrual Cycles in 200 Healthy Couples Desiring Pregnancy
From Zinaman MJ, Clegg ED, Brown CC, et al. Estimates of human fertility and pregnancy loss. Fertil Steril. 1996;65:503–509.
Cycle Numbers
Cycle Outcome 1 2 3 Total
Not pregnant at start of cycle 200 137 95
Pregnant during cycle 59 41 16 116
Chemical pregnancy 7 7 1 15
Spontaneous abortion 12 5 4 21
Live births 40 29 10 79
Dropped out, not pregnant 4 1 1 6
Lost to follow-up 1
Age of female partner, 30.6 ± 3.3 (mean ± standard deviation [SD]).

Diseases Associated with Infertility

  • The most common causes of female infertility are anovulation, tubal disease, pelvic adhesions, and endometriosis. Many women with infertility (up to 30%) do not have an identifiable cause, referred to as unexplained infertility if there is no male factor .

Pregnancy is the result of the successful completion of a complex series of physiological events occurring in both the male and female that allows for the implantation of an embryo in the endometrium ( Fig. 23.1 ). At a minimum, pregnancy requires the production of a competent oocyte and ovulation, production of competent sperm, proximity of the sperm and oocyte in the reproductive tract, transport of the embryo into the uterine cavity, and implantation of the embryo into the endometrium.

Fig. 23.1, Schematic representation of the transport of the oocyte, sperm, and embryo in the female reproductive tract.

Some diseases, such as those that cause azoospermia, clearly have a cause-effect relationship with infertility. For other disease processes, such as stage I endometriosis as defined by the revised American Society for Reproductive Medicine criteria, there is no clear cause-effect relationship between the disease and the infertile state. In these situations, it is preferable to state that there is an association between the disease condition and the infertile state but that causality has not been definitively established. Due to the limits of our current understanding of fertility in humans, it is often difficult to categorize disease conditions as either causing infertility (e.g., azoospermia) or associated with infertility (e.g., stage I endometriosis). Consequently, a discussion of the distribution of reproductive diseases that are diagnosed in infertile couples is not necessarily based on hard scientific data but rather on descriptive observations and assumptions about diseases that cause or might be associated with infertility.

Most tabulations of the medical conditions that “cause” infertility divide the problem into male factors and female factors. The World Health Organization (WHO) task force on Diagnosis and Treatment of Infertility conducted a study of 8500 infertile couples using a standardized diagnostic protocol. In developed countries, diseases that were identified as contributing to the infertile state were attributed to the female partner in 37% of couples, to the male partner in 8% of couples, and to both partners in 35% of couples. Five percent of the couples had no identifiable cause of infertility (unexplained infertility) and 15% of the couples became pregnant during the investigation. The diseases in the female most often identified were ovulatory disorders (25%), pelvic adhesions (12%), tubal occlusion (11%), other tubal abnormalities (11%), hyperprolactinemia (7%), endometriosis (15%), and no identifiable disease in 20%. In another data set of 2198 infertile couples treated at 11 Canadian clinics, the distribution of primary diagnoses was: unexplained (26%), abnormal semen parameter (24%), tubal disease (23%), ovulatory disorders (18%), endometriosis (6%), and other (3%). , ,

In developing countries, the reported distribution of infertility diagnoses often includes a higher rate of female infertility associated with pelvic infections and tubal disease. In a meta-analysis of 21 studies of African nations including 9244 couples, female infertility was identified in 54%, male infertility in 22%, combined male and female infertility in 21%, and unexplained infertility in 10%. Among women with female infertility, identified causes included pelvic inflammatory disease and tubal factors (39%), ovulatory dysfunction (31%), uterine factors (18%), and endometriosis (2%). In a review of 21 published reports containing 14,141 infertile couples, Collins reported that the primary diagnoses in the couples were: ovulatory disorders (27%), abnormal semen parameter (25%), tubal defect (22%), endometriosis (5%), unexplained (17%), and other (4%), as shown in Fig. 23.2 . These observations can be broadly grouped into five major conditions that influence fecundability:

  • 1.

    Abnormalities in the production of a competent oocyte (anovulation, depletion of the oocyte pool, or poor oocyte function/quality)

  • 2.

    Abnormalities in reproductive tract transport of the sperm, oocyte, and embryo (tubal, uterine, cervical, and peritoneal factors)

  • 3.

    Abnormalities in the implantation process, including early defects in embryo development and embryo–endometrial interaction (embryo–endometrial factors)

  • 4.

    Abnormalities of sperm production (male factor)

  • 5.

    Other conditions, including immunological factors that can affect multiple components of the process

Fig. 23.2, Primary clinical diagnoses in infertile couples.

The initial infertility evaluation focuses on these five major processes ( Box 23.1 ). Abnormalities of embryo–endometrial interaction are reviewed in Chapter 10 . Male infertility is reviewed in Chapter 24 .

Box 23.1
Initial Laboratory Approach to the Infertile Couple

Primary tests for infertility

  • Documentation of competent ovulation

    • Regular menses (21–35 days) by patient report

    • Luteinizing hormone (LH) surge by urine or blood testing

    • Midluteal progesterone > 3 ng/mL

  • Consider documentation of ovarian reserve

    • Day 3 FSH and estradiol

    • Anti-müllerian hormone

    • Antral follicle count

  • Semen analysis

    • Volume ≥ 1.5 mL

    • Concentration ≥ 15 million/mL

    • Total motility ≥ 40%

    • Progressive motility ≥ 32%

    • Morphology ≥ 4% (using “strict” criteria)

    • Terminology used to describe abnormal semen analysis: low sperm concentration, oligospermia; low sperm motility, asthenospermia; sperm morphology abnormal, teratospermia; elevated white blood cells, leukocytospermia

  • Documentation of tubal patency

    • Hysterosalpingogram or hysterosalpingo-contrast sonography

  • Assessment of the uterine cavity

    • Hysterosalpingogram, hysterosalpingo-contrast sonography, or hysteroscopy

  • Secondary tests for infertility

    • Laparoscopy

    • Hysteroscopy

Initial Infertility Evaluation

  • Three tests should be completed early in the infertility evaluation: semen analysis, documentation of ovulation, and test of tubal patency .

The standard components of the infertility evaluation include a thorough history and physical examination ( Table 23.3 ), a semen analysis ( Box 23.1 ), documentation of competent ovulation, documentation of the female reproductive tract and tubal patency, and assessment of the uterine cavity. , The evaluation of the semen analysis is discussed in Chapter 24 , Male Infertility. As discussed in more detail below, ovulation may be presumptively detected based on a history of regular menses every 28 days on average (range 21–35 days) or observation of a luteinizing hormone (LH) surge in the urine using an immunochemical method, and definitively diagnosed by a serum progesterone >3 ng/mL or the histological demonstration of secretory changes on an endometrial biopsy. Particularly in women ≥ 35 years of age, a test of the size of the ovarian follicle pool, also known as ovarian reserve, is warranted. Tests to assess the ovarian follicle pool include measurement of 1) anti-müllerian hormone (AMH), 2) follicle-stimulating hormone (FSH) and estradiol on menstrual cycle day 3, 3) ovarian antral follicle count by ultrasound, and 4) FSH and estradiol in a clomiphene citrate challenge test (CCCT), though the use of this last test has declined in contemporary practice due to relative ease of these other tests.

Table 23.3
History and Physical Examination Findings Relevant to the Infertility Evaluation in the Female Partner
History Physical Exam Findings
Duration of infertility and results of previous tests and treatments. Prior pregnancies and outcomes. Pubertal milestones: adrenarche, thelarche, and menarche. Menstrual cycle history from menarche to present. Evidence for cycle irregularity. Previous gynecological and abdominal surgery. Past contraceptive use. Coital frequency and sexual function. Relevant medical history of male partner. Current medications and allergies. History of hirsutism, pelvic or abdominal pain, dyspareunia, thyroid disease, galactorrhea. Current occupation and exposure to environmental toxins. Use of tobacco, alcohol, and drugs. Exercise history and current pattern of exercise. History of stress, anxiety, depression. Weight, height, body mass index. Evidence for hirsutism, acanthosis nigricans. Thyroid size. Presence of thyroid nodules. Breast exam including palpation for breast masses and expression of nipple secretion. Tanner stage of the breasts. Assessment of the anatomy of the clitoris, hymenal ring, vagina, and cervix. Assess for a vaginal septum. Assess for cervical stenosis or displacement of cervix from midline. Examination of position of the uterus and uterine size and mobility. Examination of adnexae for a mass or tenderness. Examination of the uterosacral ligaments and cul-de-sac.

Documentation of tubal patency should be accomplished early in the infertility evaluation by a hysterosalpingogram (HSG), a hysterosalpingo-contrast sonogram (HyCoSy), or a laparoscopy with chromopertubation. An HSG has high sensitivity and few false positives for the detection of distal tubal disease, but it is associated with an approximately 15% false positive rate for diagnosis of proximal tubal occlusion. This means that if the HSG demonstrates that there is a proximal tubal blockage, the finding should be confirmed by a second test (selective interventional radiology catheterization of each tube, hysteroscopic cannulation, or laparoscopy with tubal lavage). The HSG also provides evidence of the shape of the uterine cavity and will identify large intrauterine defects. As noted below (anatomical factors in the female), the hysterosalpingo-contrast sonogram is gaining in popularity as an initial test in the fertility workup because it can detect tubal occlusion and is very sensitive to identifying small defects in the uterine cavity. ,

Detection of uterine abnormalities can be accomplished by an HSG, HyCoSy, saline infusion sonogram (SIS), 3-dimensional ultrasonography, magnetic resonance imaging, or hysteroscopy. For the detection of uterine abnormalities, hysteroscopy remains the gold standard, though hysteroscopy does not show the outer uterine contour, and bicornuate and septate uteri cannot be sufficiently differentiated by hysteroscopy alone.

Infertility tests that are probably unnecessary as part of the initial infertility evaluation include the postcoital test, endometrial biopsy for luteal phase dysfunction, the hamster egg penetration test, routine Mycoplasma culture, and antisperm antibody testing. A major problem with the postcoital test is that it has low reproducibility, low interobserver reliability, and has not been reliably shown to help guide treatment recommendations. In addition, there is little consensus on what constitutes an abnormal postcoital test. Given these limitations, there is little scientific rationale for performing a postcoital test.

The endometrial biopsy is abnormal in many infertile women, and in the past clinicians believed that it was the gold standard for documenting ovulation and assessing endometrial competence for implantation. However, studies have demonstrated that the rates of abnormal (out-of-phase) endometrial histology are similar in fertile and infertile. Given the weak correlation between abnormal (out-of-phase) biopsies and fertility, most clinicians are not performing endometrial biopsy as a first-line fertility diagnostic test.

The fertility evaluation also presents an opportunity for general preconception testing and counseling. Women considering pregnancy should start a folic acid supplement (at least 400 mcg) to reduce the risk of birth defects, especially spina bifida, and receive an influenza vaccination. Prior to attempting pregnancy, women should complete preconception testing including measurement of antibody titers against the rubella, varicella, hepatitis B, and human immunodeficiency (HIV) viruses, a complete blood count to assess for hemoglobinopathies, and appropriate genetic testing. The minimum genetic screening recommended for a woman planning pregnancy includes spinal muscular atrophy and cystic fibrosis; screening for fragile X syndrome is recommended for women with a family history of fragile X–related disorders or intellectual disability potentially related to fragile X, and for Tay-Sachs, if either member of a couple is of Ashkenazi Jewish, French–Canadian, or Cajun descent. Further testing should be considered in the Ashkenazi population, including Canavan disease, among others. “Expanded carrier screening,” which may include hundreds of recessive conditions, is also available. While these expanded panels are not currently recommended by professional obstetrical organizations, the increasingly multiethnic nature of society and couples may limit the efficacy of targeted genetic screening. Patients should be counseled that these genetic screening tests constitute risk reduction, not risk elimination, and rarely may homozygosity be detected or heterozygosity with clinical implications for the individual.

Abnormalities in Oocyte Production

Disorders of oocyte production are a common cause of female infertility. The most common disorders of oocyte production are anovulation, oligoovulation, depletion of the follicle pool, and aging of the ovarian follicle resulting in poor oocyte quality. Depletion of the follicle pool and aging of the ovarian follicle result in poor oocyte quality, thereby also resulting in diminished ovarian reserve. Anovulation is typically associated with amenorrhea or severe oligomenorrhea. Oligoovulation is typically associated with oligomenorrhea (cycle lengths greater than 35 days). A depleted ovarian follicle pool is usually detected by measurement of AMH, FSH, and estradiol on day 3 of the menstrual cycle, ovarian antral follicle count by ultrasound, and/or measurement of FSH in a CCCT.

There are no readily available clinical tests of oocyte quality. Instead, poor oocyte quality should be suspected when the age of the female partner is older than 37 years of age, even if tests of the ovarian follicle pool indicate good ovarian reserve. The correlation of diminishing oocyte quality with increasing age has been demonstrated through the aneuploidy rates of embryos produced during in vitro fertilization (IVF), as most embryonic aneuploidy derives from the oocyte. The embryo aneuploidy rate rises steadily with age: 35% at age 35, 43% at age 37, 58% at age 40, 75% at age 42, and 88% at age 44.

Among women with regular monthly menses (roughly every 21–35 days), a majority (96%) are typically ovulatory. In low-resource settings, the basal body temperature (BBT) measurement can be used to identify ovulation. For most women, the morning basal temperature obtained prior to rising from bed is less than 98°F before ovulation and over 98°F after ovulation. Progesterone production from the ovary appears to raise the hypothalamic set-point for basal temperature by approximately 0.6°F. The temperature rise occurs 1 or 2 days following ovulation and is therefore not helpful in identifying the fertile window for conception in a given cycle. The normal luteal phase is typically associated with a temperature rise, above 98°F, for at least 10 days in length. Occasionally BBT recordings may appear monophasic even in the presence of ovulation. A biphasic pattern is almost always associated with ovulation. If the pattern is biphasic, coitus can be recommended every other day for a period including the 5 days prior to and the day of ovulation ( Fig. 23.3 ). In most developed countries, sequential daily home measurement of urine LH in the periovulatory interval is the most common approach to detecting impending ovulation. A surge in urine LH is detected one or two days before ovulation.

Fig. 23.3, Probability of conception on specific days near the day of ovulation.

A serum progesterone level greater than 3 ng/mL is diagnostic of ovulation. In the midluteal and late-luteal phases, progesterone secretion is pulsatile due to the pulsatile nature of luteinizing hormone secretion. At a conceptual level, the pulsatile nature of progesterone secretion may make it difficult to reliably use a single progesterone measurement as a marker for the adequacy of ovulation. However, in most clinical situations, a single midluteal progesterone measurement appears to be a useful marker of the adequacy of ovulation. Hull and colleagues have suggested that a midluteal progesterone concentration less than 10 ng/mL is associated with a lower per-cycle pregnancy rate than progesterone levels above 10 ng/mL.

Sonographic examination of the ovary and serial measurement of LH or estrone-3-glucuronide can be used to demonstrate the growth of a dominant follicle, which is a necessary precondition to ovulation. During menses, the follicles in the ovary are approximately 4 to 9 mm in diameter. Prior to ovulation, the dominant follicle reaches a diameter in the range of 20 to 25 mm. Demonstration of follicle growth and rupture of the dominant follicle is presumptive evidence that ovulation has occurred. Ovulation typically occurs about 36 hours after the onset of the urine LH surge and approximately 24 hours after the urine LH peak. In one large prospective study, the detection of a urine LH surge by patients using a home detection kit was associated with ovulation, as demonstrated by a secretory endometrial biopsy in 93% of cycles.

An endometrial biopsy with histological secretory changes is a definitive test demonstrating ovulation. Although not currently widely used in infertility evaluation, it is likely that the endometrial biopsy could be used to detect endometrial proteins that might serve as useful markers of endometrial receptivity for implantation. Validation of the detection of implantation markers in endometrial biopsy specimens awaits future research.

Many diseases can cause anovulatory infertility. The most common causes of adult-onset anovulation are hypothalamic dysfunction (35% of cases), pituitary disease (15%), and ovarian dysfunction (50%). , The most common causes of hypothalamic dysfunction are abnormalities in weight and body composition, stress, and strenuous exercise (see Chapter 18, Chapter 19 ). Less common causes of hypothalamic dysfunction are infiltrating diseases of the hypothalamus, such as lymphoma and histiocytosis. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism have been reported to be associated with hypothalamic anovulation including fibroblast growth factor receptor 1, prokineticin receptor 2, GnRH receptor , and Kallmann syndrome 1 sequence . The pituitary disorders that cause anovulation (see Chapter 3, Chapter 21 ) are prolactinoma, empty sella syndrome, Sheehan syndrome, Cushing disease, acromegaly, and other pituitary tumors. Other brain tumors in the region of the hypothalamus or pituitary gland (such as craniopharyngioma) and their surgical excision can also disrupt central reproductive function. The most common ovarian causes of anovulation are ovarian failure (depletion of the oocyte pool) and ovarian hyperandrogenism (e.g., polycystic ovary syndrome [PCOS]). Occasionally, thyroid disease can be associated with anovulation.

Evaluation of the various causes of anovulation can be complex. Typically, measurement of body weight and height, and measurement of serum FSH, prolactin, thyroid-stimulating hormone (TSH), and androgens, if indicated, can help identify the cause of the anovulation. A progestin withdrawal test may be helpful to evaluate the degree of hypogonadism present and may help guide treatment choices.

Patients with anovulation generally have the greatest success with infertility therapy. Treatment of anovulatory disorders can result in fecundability similar to that observed in normal couples (0.15–0.25). The choice of treatment is dependent on the cause of the anovulation. Common treatment choices include:

  • 1.

    Interventions to modulate weight

  • 2.

    Letrozole

  • 3.

    Clomiphene citrate

  • 4.

    Clomiphene plus other hormone adjuvants

  • 5.

    Gonadotropin treatment (see Chapter 34 )

  • 6.

    Ovarian surgery

  • 7.

    Pulsatile administration of gonadotropin-releasing hormone (GnRH)

  • 8.

    Bromocriptine and cabergoline

  • 9.

    Correction of thyroid dysfunction

Interventions to Modulate Weight and Induce Ovulation

  • Many obese anovulatory infertile women can achieve pregnancy by lifestyle changes including calorie restriction and moderate exercise. Many excessively lean anovulatory infertile women can achieve pregnancy by gaining weight, especially by increasing body fat .

Anovulation, oligoovulation, and subfertility are commonly observed in women above or below their ideal body weight (see also Chapter 19 ). In one study of 597 cases of women with anovulatory infertility and 1695 fertile controls, overweight women (body mass index [BMI] greater than 27 kg/m 2 ) had a relative risk of anovulatory infertility of 3.1 compared with women with BMI 20 to 25 kg/m 2 . Excessively thin women with a BMI less than 17 kg/m 2 had a relative risk of anovulatory infertility of 1.6. The investigators concluded that the risk of ovulatory infertility is highest in overweight women but is also increased in underweight women. In a retrospective study of more than 2.3 million couples in China, underweight (BMI < 18.5 kg/m 2 ) and obesity (BMI ≥ 28.0 kg/m 2 ), compared with normal weight (BMI 18.5–23.9 kg/m 2 ) were associated with a decrease in the rate of pregnancy achieved within one year, by 4% and 14%, respectively.

For women who are far below or far above their ideal body weight, appropriate management of dietary intake may be associated with the resumption of ovulation and pregnancy. For example, Pasquali and colleagues demonstrated that anovulation in obese women with PCOS could be successfully treated with weight loss. Obese women with anovulation and PCOS were placed on a 1000-calorie to 1500-calorie diet for 6 months, resulting in a mean weight loss of 10 kg. After weight loss, there was a 45% decrease in basal LH concentration and a 35% decrease in serum testosterone. Most studies of the impact of weight loss on reproductive function have not included a control group. Guzick and colleagues reported the results of a randomized, controlled trial of the impact of weight loss on reproductive function. Twelve obese, hyperandrogenic, oligoovulatory women were randomized to either a weight reduction program or a “waiting list” observation control group. The six women randomized to the weight reduction program had a mean decrease in weight of 16 kg, a significant decrease in circulating testosterone, a decrease in fasting insulin, and no change in LH pulse frequency and amplitude. In the women who were randomized to the weight reduction program, four of six resumed ovulation. All of the women in the control group who were anovulatory before the study remained anovulatory during the period of study observation.

Elevated BMI and a sedentary lifestyle decrease fecundability and poor reproductive outcomes. In addition to anovulation, overweight and obesity are associated with reduced oocyte quality, an increased risk of spontaneous abortion, congenital anomalies, gestational diabetes, hypertensive disorders of pregnancy, and stillbirth. Weight loss and increased activity are the first-line recommended management for elevated BMI and can increase fertility potential. In one study of 574 infertile women with a BMI ≥ 29 kg/m 2 (median BMI of 36 kg/m 2 ), the women were randomized to receive a 6-month lifestyle intervention or to a control group. The lifestyle intervention included a reduction in calorie intake by 600 kcal daily with the goal of reducing body weight by ≥5% and increased activity including 10,000 steps daily plus 30 minutes of moderate exercise 2 to 3 times weekly. Natural conception was achieved by 26% of the women in the lifestyle intervention and 16% of the women in the control group (relative risk 1.61, 95% confidence interval 1.16–2.24). Weight loss prior to ovulation induction may result in a greater live birth rate in women with polycystic ovary syndrome (PCOS).

For women with refractory obesity, surgical interventions for weight reduction may be pursued, which have been associated with the resumption of ovulatory menstrual cycles and improved fertility. In a series of 12 women with PCOS with a mean BMI of 50 kg/m 2 who underwent bariatric surgery, the mean weight loss was 41 kg within 12 months, with improvements in hyperandrogenism and insulin resistance and restoration of regular menses in all twelve. In a meta-analysis of 13 studies including 2130 patients undergoing various types of bariatric surgery, patients lost on average more than 50% of their excess weight, and the prevalence of irregular menstrual cycles fell from 56% preoperatively to 8% one year after surgery. Infertility also declined from 18% to 4%. Clinicians should be aware that women with prior bariatric surgery are at increased risk for nutritional deficiencies, including iron, folate, vitamin D, calcium, and vitamin B12.

Weight loss is difficult to achieve. Consultation with a nutritionist, encouragement from a physician, a hypocaloric diet, and initiation of an exercise program may be the most effective nonsurgical interventions that can help a woman lose weight. A realistic starting goal can be considered 5% to 10% weight loss within 6 months. Surgical methods of weight reduction can be very effective, especially in women with a BMI over 40 kg/m 2 , and may be considered in women who are not successful with more conservative weight loss methods. Devoting time to weight loss before fertility treatment should be considered in the context of a woman’s age, as advantages of weight loss may be lost to advancing reproductive aging and resulting reductions in oocyte quantity and quality.

Excessively lean women are at increased risk for anovulatory infertility. In experimental models, oligoovulation ensues following interventions that result in daily energy expenditure greater than daily calorie intake. In the captive female monkey, regular ovulatory cycles are observed with routine activity and a steady calorie intake of 300 kcal daily. When calorie intake is maintained at 300 kcal daily, but activity is increased to include 6 miles of additional ambulation daily, anovulation and amenorrhea ensue. Increasing calorie intake to up to 600 kcal daily while maintaining 6 miles of exercise daily results in the resumption of ovulation and menses. In the exercising monkey, resumption of ovulation can also be initiated without an increase in calorie intake by administering pulses of GnRH. In a study of sedentary women assigned to exercise plus calorie restriction or exercise plus a eucaloric diet, the exercise plus calorie restriction group produced greater declines in ovarian steroid production than exercise plus a eucaloric diet.

Hormones that help the brain assess the relative levels of calorie intake and energy expenditure include leptin, insulin, thyroid hormones (thyroxine and triiodothyronine), growth hormone, insulin-like growth factor 1 (IGF1), cholecystokinin, glucagon-like peptide-1, and ghrelin. Women with hypothalamic amenorrhea (hypothalamic hypogonadism) often have low levels of leptin. Two clinical trials reported that the administration of exogenous leptin or a decapeptide leptin peptide (metreleptin) to lean women with hypothalamic amenorrhea, resulted in the resumption of ovulatory menses in some of the subjects. , In addition, metreleptin administration for 36 weeks increased free triiodothyronine, IGF1, and osteocalcin. Leptin may exert its effect on GnRH secretion through signal transduction pathways including kisspeptin-releasing neurons.

Lean women with anovulatory infertility are often reluctant to gain weight, alter their diet, or reduce their exercise regimen. However, in one study of 26 underweight women who practiced strict dieting and were infertile, the subjects were counseled by a dietician and given physician-directed advice to increase their BMI. After the intervention, the women gained a mean of 3.7 kg and 73% of the women became pregnant. Interpersonal psychodynamic psychotherapy or cognitive behavior therapy may help WHO I anovulatory women resume ovulating. It is important to try to achieve a normal BMI prior to initiating ovulation induction in excessively lean anovulatory women because pregnancy in women with a low BMI may be associated with an increased risk of pregnancy loss, as shown in a large meta-analysis including 265,760 women (relative risk 1.08, 95% CI 1.05–1.11) . Underweight women also appear to be at increased risk of preterm birth and delivering infants with low birth weight. Maternal eating disorders are associated with an increased risk of small neonatal head circumference and microcephaly.

Specific dietary factors may influence the risk of anovulatory infertility. For example, in one prospective study, women who consumed iron supplements were reported to have a 40% lower risk of anovulatory infertility. In another prospective study, dietary patterns characterized by high consumption of monounsaturated rather than trans fats, vegetable rather than animal protein, low glycemic carbohydrates, high-fat dairy, and multivitamins were associated with a reduced risk of ovulatory infertility. Myoinositol, a dietary supplement, is a precursor of D-chiro-inositol, which is involved in the control of glucose metabolism and cell response to insulin stimulation. In one small observational study without a control group, oligoovulatory women with PCOS who took myoinositol, 2 g twice daily, reported an increase in spontaneous menstrual cycles. Forty percent of the subjects became pregnant during 6 months of myoinositol treatment. In a trial of 120 women with PCOS, participants were randomized to 1500 mg of metformin per day or metformin plus myoinositol 1800 mg per day. Women attempted spontaneous conception for 3 months, after which they initiated ovulation induction with clomiphene and low-dose gonadotropins with IUI, for a maximum of 3 cycles. At the study’s conclusion, 55% of patients receiving both agents were pregnant, as compared to 27% receiving metformin only, suggesting combination therapy with myoinositol is more effective than metformin alone in patients with PCOS. In a meta-analysis of 10 randomized trials, including 362 women taking inositols (257 on myo‐inositol, and 105 on di‐chiro‐inositol), the use of inositols was associated with a sixfold increase in the frequency of menstrual cycles compared with placebo among women with oligoovulatory or anovulatory PCOS.

Letrozole

  • For the treatment of anovulatory infertility caused by polycystic ovary syndrome, letrozole has largely replaced clomiphene as the first-line treatment .

Aromatase inhibitors including letrozole and anastrozole block estradiol synthesis, reduce estradiol feedback, and increase the production of FSH in premenopausal women. Letrozole at doses of 2.5 mg to 7.5 mg daily for 5 days and anastrozole at a dose of 1 mg daily for 5 days have been demonstrated to induce ovulation in women with PCOS. In addition, clinical trials have reported that letrozole is superior to clomiphene for ovulation induction, but anastrozole is NOT superior to clomiphene. These data suggest that letrozole may be a first-line treatment for anovulatory infertility due to PCOS, but anastrozole should generally not be used for this indication. The FDA has approved letrozole for the treatment of breast cancer in postmenopausal women but it is not approved for ovulation induction. Infertile women using letrozole for ovulation induction should be aware of the off-label use of letrozole.

Legro and colleagues randomized 750 women with anovulatory infertility and PCOS to clomiphene or letrozole for ovulation induction. The medications were used in a step-wise dose escalation protocol. The doses of clomiphene were 50 mg, 100 mg, and 150 mg per day. The doses of letrozole were 2.5 mg, 5 mg, and 7.5 mg per day. The lowest dose that induced ovulation as determined by measurement of progesterone was utilized in up to 5 cycles. The medications were given for 5 days on cycle days 3 to 7 following spontaneous menses or a medroxyprogesterone acetate withdrawal bleed. The ovulation rates for letrozole and clomiphene were 62% and 48%, respectively ( P < .001). The live birth rates for letrozole and clomiphene were 28% and 19%, respectively ( P < .007). Among women with a BMI of ≤ 30.3 kg/m 2 , both letrozole and clomiphene resulted in a similar live birth rate; 35% and 30%, respectively. Among women with a BMI ≥ 30.3 kg/m 2 , the live birth rates with letrozole and clomiphene were 20% and 10%, respectively. For letrozole and clomiphene, the spontaneous abortion rate (32% and 29%) and the twinning rate (3.4% and 7.4%) were not statistically different. This study indicates that letrozole is superior to clomiphene for ovulation induction in PCOS, especially in women with a BMI ≤ 30.3 kg/m 2 .

In contrast to letrozole, anastrozole is not superior to clomiphene. In clinical trials, anastrozole at doses of 1 mg, 5 mg, and 10 mg daily for 5 days was less effective for ovulation induction in the first cycle of treatment than clomiphene at a dose of 50 mg. ,

Letrozole and anastrozole are not approved by the FDA for ovulation induction. Pregnancy and birth registries indicate that pregnancy outcome following ovulation induction with aromatase inhibitors is good. In one registry, the risk of congenital cardiac malformations was greater with clomiphene-induced pregnancy than with letrozole-induced pregnancy. However, concern remains about the potential adverse effects of these agents on pregnancy, especially given known adverse effects on rabbit and rodent pregnancy.

Aromatase inhibitors may be an effective monotherapy option for women who are clomiphene resistant. In one trial, 250 anovulatory women with PCOS who did not ovulate with standard doses of clomiphene were randomized to treatment with letrozole 2.5 mg daily for 5 days or metformin 1500 mg plus clomiphene 150 mg daily for 5 days. The ovulation rate was 65% in the letrozole group and 70% in the metformin-clomiphene group. The pregnancy rate was 15% and 14% in the letrozole and clomiphene groups, respectively.

Ovulation induction and ovarian stimulation in women with estrogen-sensitive tumors, such as breast cancer, is another clinical scenario in which the use of aromatase inhibitors may be prioritized. Aromatase inhibitors increase FSH levels but block estradiol production resulting in folliculogenesis with relatively reduced levels of circulating estradiol compared with clomiphene or gonadotropin treatment. In women with a history of estrogen-sensitive tumors, inducing folliculogenesis and ovulation while maintaining relatively low levels of circulating estradiol has a theoretical advantage. This effect may be especially advantageous in women with a history of breast cancer planning on undergoing an IVF cycle.

Given the superiority of letrozole compared to clomiphene or anastrozole, first-line therapy with letrozole is recognized as a reasonable option, even though it is not FDA-approved for this purpose.

Clomiphene

  • Clomiphene or letrozole ovarian stimulation is useful in combination with intrauterine insemination in the treatment of unexplained infertility .

The emergence of reproductive endocrinology and infertility as a unique subspecialty was catalyzed by the discoveries that clomiphene and urinary human menopausal gonadotropins were effective agents for the induction of ovulation in anovulatory infertile women. In modern fertility practice, letrozole is generally used to induce ovulation for infertile women with PCOS. Clomiphene and letrozole ovarian stimulation in combination with intrauterine insemination is often used for the treatment of unexplained infertility. Clomiphene, a nonsteroidal triphenylethylene derivative estrogen agonist-antagonist related to tamoxifen and diethylstilbestrol, was first synthesized in 1956. In 1961, Greenblatt and colleagues reported clomiphene to be effective in the induction of ovulation, and the drug was approved by the Food and Drug Administration (FDA) in 1967 (see also Chapter 34 ). Clomiphene citrate is marketed as a racemic mixture of enclomiphene (E, trans) and zuclomiphene (Z, cis) in a ratio of approximately 3 to 2. The Z-isomer may have greater ovulation-inducing properties than the trans isomer. An important recent observation is that nonsteroidal triphenylethylene compounds like tamoxifen and clomiphene may require bioactivation by the liver cytochrome P450 enzyme 2D6. In one study, liver microsomes containing active CYP2D6 , metabolized clomiphene to two potent estrogen antagonist compounds, (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene. These two compounds demonstrated 50% inhibition of estrogen receptor function at concentrations of 2.5 and 1.4 nM, respectively. The activity of CYP2D6 shows significant variation among women, suggesting that allelic variation in this enzyme may contribute to the variability in the response to clomiphene.

Clomiphene has a half-life of approximately 5 days. It is metabolized by the liver and excreted in the feces. Fecal clomiphene can be detected up to 6 weeks after discontinuing the drug. In normally cycling women , the administration of clomiphene citrate, 150 mg daily for 3 days, resulted in an increase of serum concentration of LH and FSH of 40% and 50%, respectively. In addition, LH pulse frequency increased from 3.3 to 6.8 pulses per 8 hours. The clomiphene-induced increase in LH pulse frequency indicates that clomiphene has an action in the hypothalamus. In women with PCOS who already have a high LH pulse frequency, clomiphene does not further increase LH pulse frequency, but it does increase LH pulse amplitude and serum levels of LH and FSH. Successful induction of ovulation with clomiphene requires an intact hypothalamic-pituitary-ovarian axis. In contrast, exogenous gonadotropin treatment is effective even in the absence of a functional hypothalamus or pituitary.

Evidence that clomiphene has central nervous system effects includes the observation that clomiphene induces vasomotor symptoms, increases LH pulse frequency, and partially blocks the contraceptive potency of estrogen. Studies in laboratory animals demonstrate that clomiphene can decrease estrogen-stimulated hypothalamic tyrosine hydroxylase and that clomiphene increases GnRH secretion from the rat medial basal hypothalamus.

In addition to a hypothalamic site of action, clomiphene also has biological effects on the pituitary, ovary, endometrium, and cervix. In incubations of rat pituitary cells, both estradiol and clomiphene augmented GnRH-induced release of FSH and LH. Zhuang and colleagues demonstrated that clomiphene, estradiol, and diethylstilbestrol all augmented gonadotropin induction of aromatase activity in rat granulosa cells. In hypoestrogenic women receiving exogenous estrogen, clomiphene can cause endometrial atrophy. Clomiphene can diminish estrogen-induced cervical mucus quantity and quality, as demonstrated by decreased ferning and spinnbarkeit formation. ,

Clomiphene is most effective in inducing ovulation in women with euestrogenic anovulation, including women with PCOS. In women with severe hypoestrogenism and hypogonadotropic hypogonadism, clomiphene is typically ineffective in the induction of ovulation. In contrast, women with hypogonadotropic hypogonadism respond well to gonadotropin injections or pulsatile GnRH treatment. Failure to have a withdrawal uterine bleed following the administration of progesterone is presumptive evidence of severe hypoestrogenism in women with anovulation and an anatomically normal uterus. , Clomiphene is unlikely to effectively induce ovulation in this setting. Maruo and colleagues have reported that clomiphene induction of ovulation has a low chance of success in women with triiodothyronine levels below 80 ng/mL, levels sometimes seen in hypothyroidism or with eating disorders. Clomiphene citrate is also unlikely to be effective in women with a consistently elevated FSH concentration (depletion of oocyte pool). Although clomiphene is relatively contraindicated in women with pituitary tumors, it has been reported to be effective in the induction of ovulation in women with a prolactinoma who did not ovulate with bromocriptine treatment alone.

The FDA-approved dosages for clomiphene are 50 or 100 mg daily for a maximum of 5 days per cycle. After spontaneous menses, or the induction of menses with a progestin withdrawal, clomiphene is started on cycle day 3, 4, or 5 at 50 mg daily for 5 days. Starting clomiphene on cycle day 3 or 5 does not appear to influence the per-cycle pregnancy rate. In properly chosen women, approximately 50% will ovulate at the 50 mg daily dosage; another 25% will ovulate if the dose is increased to 100 mg daily. During each cycle, determination of ovulation should be attempted. In most patients, ovulation occurs approximately 5 to 12 days after the last dose of clomiphene. Measurement of the urinary LH surge is recommended to assist the couple in prospectively determining the preovulatory interval, which is the optimal time for achieving pregnancy.

Although the FDA has approved maximal clomiphene doses of 100 mg daily, many clinicians have experience prescribing clomiphene at doses of up to 250 mg daily. A woman who does not ovulate with a clomiphene dose of 100 mg daily for 5 days may ovulate if her dose is increased to 150 mg daily for 5 days. Of the women who do not ovulate at doses of 100 mg daily, up to 70% will ovulate at higher doses, but less than 30% become pregnant.

Anovulatory women have a fecundability of 0.00 without treatment. Over the first three to six cycles of clomiphene treatment, the fecundability is in the range of 0.08 to 0.25. In cases where the only fertility factor is anovulation in the female partner, fecundability with clomiphene treatment is in the range of 0.20 to 0.25 ( Fig. 23.4 ).

Fig. 23.4, Cumulative pregnancy rates in women treated with clomiphene for infertility, women discontinuing contraception with the diaphragm or oral contraceptives (OC) , and women treated with donor insemination (AID).

Women with hyperandrogenemia, markedly elevated BMI, amenorrhea, or advanced age are less likely to ovulate with clomiphene. A unique advantage of clomiphene is that few fertility treatments are available that increase fecundability from 0.00 to 0.20 at a cost in the range of $100. After 3 to 6 months of clomiphene treatment, fecundability appears to decline.

Prior to initiating a clomiphene cycle, many experts obtain a pregnancy test to rule out an ongoing pregnancy, then prescribe a progestin withdrawal, though this practice has more recently come into question. A commonly used progestin withdrawal is medroxyprogesterone acetate (Provera) 10 mg daily for 5 days, and the first day of full withdrawal flow following the cessation of the progestin treatment is day 1 of the cycle. However, in a secondary analysis of 626 women with PCOS enrolled in a randomized trial of ovulation induction agents (Reproductive Medicine Network (RMN), Pregnancy in Polycystic Ovary Syndrome I study), pregnancy rates per ovulation were lower in women with endometrial shedding induced prior to ovulation induction (anovulatory with progestin withdrawal 5.4%; anovulatory without progestin withdrawal 19.7%).

During the clomiphene treatment cycle, urine LH measurements can be measured by the patient at home to identify the preovulatory LH surge. The LH surge typically occurs 5 to 12 days after the last day of clomiphene medication. The woman’s maximal fertile time is the day before the urine LH surge, the day of the urine LH surge, and the day following the urine LH surge. Coitus should occur on at least 2 of these 3 days. Alternatively, if the woman prefers not to measure urine LH, she can have coitus with her partner every other day for 8 days beginning 5 days after the last clomiphene tablet. Evidence for successful clomiphene-induced ovulation is an appropriately drawn serum progesterone level greater than 8 ng/mL. In most clomiphene cycles resulting in successful ovulation, the serum progesterone level is >20 ng/mL. If a menses does not occur within 17 days following the LH surge, a pregnancy test can be obtained.

Some epidemiologic studies reported that clomiphene may increase the risk of ovarian tumors, including borderline tumors and ovarian cancer. However, most recent studies have not detected an increase in ovarian borderline tumors or ovarian cancer in women exposed to clomiphene.

For couples with unexplained infertility, failure to achieve pregnancy after three cycles of clomiphene plus intrauterine insemination should prompt a thorough review of the potential causes of the failure and consideration of a new approach to treatment, such as letrozole, gonadotropin therapy, or in vitro fertilization.

The role of hCG administration in enhancing the pregnancy rate associated with clomiphene treatment is controversial. Some authorities believe that the combination of clomiphene and a single dose of hCG may increase the efficacy of clomiphene induction of ovulation when women do not ovulate on standard doses of clomiphene. However, in most trials, hCG administration does not consistently improve pregnancy rate compared to women who use urinary LH testing to detect the periovulatory window.

In one study of 2369 clomiphene-induced pregnancies, 7% were twins, 0.5% were triplets, 0.3% were quadruplets, and 0.13% were quintuplets. The most common symptoms experienced by women taking clomiphene include vasomotor symptoms (20%), adnexal tenderness (5%), nausea (3%), headache (1%), and, rarely, blurring of vision or scotomata. Most clinicians permanently discontinue clomiphene treatment in women with clomiphene-induced visual changes.

Clomiphene Plus Glucocorticoid Induction of Ovulation

Women with PCOS who have failed to ovulate using standard doses of clomiphene are referred to as being “clomiphene resistant.” A consensus panel of expert fertility specialists recommended that for women with PCOS who are clomiphene-resistant, the most appropriate next steps in treatment include FSH injections or laparoscopic ovarian drilling. However, for many women, these options may be prohibitively expensive. For the clomiphene-resistant woman with PCOS, what treatment can be prescribed that is affordable?

Many clomiphene-resistant women will ovulate if they are treated with a combination of both clomiphene and dexamethasone. Before initiating combination therapy with clomiphene plus dexamethasone includes the results of the infertility workup should be reviewed to be sure that tubal and male factors are not contributing to infertility. Two randomized clinical trials have reported that, in clomiphene-resistant women, dexamethasone plus clomiphene treatment results in an increase in ovulation and pregnancy rates compared to clomiphene alone. , One regimen that has been reported to be successful is to treat the clomiphene-resistant woman with clomiphene 100 mg daily for cycle days 3 to 7, and simultaneously treat her with dexamethasone 2 mg daily for cycle days 3 to 12 ( Fig. 23.5 ). Treatment with dexamethasone reduces the serum concentration of androgens, thereby increasing the efficacy of the clomiphene. In the randomized trial that used this regimen to treat clomiphene-resistant women, the ovulation rate was 75% in the clomiphene plus dexamethasone group and 15% in the clomiphene alone group ( P < 0.001). The pregnancy rate was 40% in the clomiphene plus dexamethasone group and 5% in the clomiphene alone group ( P < 0.05). Other investigators have also reported that a glucocorticoid is an effective adjuvant to clomiphene treatment for certain women.

Fig. 23.5, Schematic outline of a combined clomiphene plus dexamethasone cycle for women who are resistant to ovulation with clomiphene monotherapy.

Many clinicians instruct their patients to take dexamethasone at night in order to maximally blunt the early morning corticotropin (ACTH) surge, which stimulates adrenal androgen production. However, experienced clinicians have found that for many women, a nighttime dose of dexamethasone energizes them and causes difficulty in falling and remaining asleep. Some experts recommend that patients take dexamethasone in the morning. If the combination of clomiphene (100 mg daily for 5 days) plus dexamethasone does not cause ovulation, a cycle with a clomiphene dose of 150 mg daily for cycle days 3 to 7 plus dexamethasone can be prescribed. If this regimen does not cause ovulation, the patient should consider other options for ovulation induction such as weight loss, FSH injections, laparoscopic ovarian drilling, or in vitro fertilization (IVF).

Clomiphene and Estrogen-Progestin Pretreatment

A risk factor for failure to ovulate with clomiphene is an elevated circulating testosterone level. Estrogen-progestin pretreatment prior to a cycle of clomiphene may improve ovulation rates by suppressing circulating testosterone prior to initiation of a clomiphene cycle. In a small case series and a randomized trial, 2 months of continuous estrogen-progestin contraceptive pill prior to treatment with clomiphene was reported to decrease circulating testosterone levels and improve ovulation and pregnancy rates in women with PCOS who had failed to ovulate with clomiphene 150 mg daily for 5 days. In the randomized trial, 48 women who had failed to ovulate with clomiphene 150 mg daily for 5 days were randomized to 42 to 50 days of pretreatment with an estrogen-progestin contraceptive (ethinylestradiol 0.03 mg plus desogestrel 0.15 mg daily with no break) followed by clomiphene 100 mg daily for 5 days, or clomiphene alone. The oral contraceptive regimen (OCP) significantly reduced circulating testosterone prior to initiation of clomiphene. The ovulation rate was 65% and 11%, respectively, in the OCP-clomiphene citrate (CC) group versus the CC group. Per cycle pregnancy rates were 54% and 4%, respectively. A regimen of OCPs followed by clomiphene may be clinically indicated in women who have failed to ovulate with clomiphene or in women known to have elevated total testosterone. A large-scale randomized trial of this sequential regimen is warranted.

Clomiphene and Nonclassical Adrenal Hyperplasia

Many authorities recommend that infertile anovulatory women with nonclassical adrenal hyperplasia (NCAH) receive glucocorticoids, such as prednisone 5 to 7.5 mg daily, for induction of ovulation. However, some women with longstanding NCAH also have evidence of ovarian hyperandrogenism and polycystic ovarian morphology on ultrasound. Clomiphene alone or clomiphene plus glucocorticoids can be used to induce ovulation and achieve pregnancy in infertile women with NCAH. ,

Clomiphene Plus Gonadotropin Induction of Ovulation

In women who do not ovulate with standard doses of clomiphene citrate, gonadotropin injections can be added to clomiphene treatment to induce ovulation. The main benefit of this approach to ovulation induction is that it tends to reduce the number of gonadotropins needed to induce ovulation during each cycle. The initial rise in LH and FSH induced by clomiphene increases the sensitivity of the follicles to respond to the gonadotropin injections. Typically, clomiphene at doses of 100 to 200 mg daily is administered for 5 days, followed by the initiation of FSH or LH-FSH injections. Investigators have reported that this regimen is associated with a 50% decrease in the dose of gonadotropin required to induce ovulation. ,

Clomiphene Plus Metformin

Hyperinsulinemia is a common endocrine abnormality observed in women with PCOS (see Chapter 22 ). The elevated insulin levels contribute to reproductive dysfunction by suppressing hepatic sex-hormone-binding globulin production and possibly by acting as a co-gonadotropin with LH in stimulating thecal cell androgen synthesis. Thus, reducing insulin levels is a therapeutic goal in women with PCOS.

Metformin is an oral biguanide antihyperglycemic agent approved for the treatment of type 2 diabetes mellitus. Metformin decreases blood glucose by inhibiting hepatic glucose production and by enhancing peripheral glucose uptake, possibly by interacting with the Peutz-Jegher syndrome tumor suppressor gene ( LKB1 ), which activates adenosine-monophosphate-activated protein kinase. It increases insulin sensitivity at the postreceptor level and stimulates insulin-mediated glucose disposal. Generic extended-release metformin is available in doses of 500, 750, and 1000 mg tablets. The target metformin dose is in the range of 1500 to 2550 mg daily. When using metformin extended-release tablets, the entire daily dose is given at dinner time. To minimize gastrointestinal adverse effects like nausea, many clinicians recommend that metformin should be started at 500 or 750 mg daily for 1 week, followed by an increase in the dose to the target range. If metformin is used as monotherapy, progesterone levels can be measured periodically on appropriate days to determine if ovulation has occurred, or the patient can keep a basal body temperature record. If ovulation has not occurred after 5 to 10 weeks of metformin monotherapy, then clomiphene, 50 mg daily for 5 days, can be administered in conjunction with metformin. If the patient becomes pregnant, metformin therapy can be discontinued. Metformin is a category B drug for pregnant women and has been used by some clinicians to treat type 2 diabetes and gestational diabetes in pregnant women.

The most common adverse effects associated with metformin are gastrointestinal disturbances, including diarrhea, nausea, vomiting, and abdominal bloating. In rare cases, metformin treatment has caused fatal lactic acidosis. In most of these cases, some degree of renal insufficiency was present. Prior to initiating treatment with metformin, the patient’s serum creatinine concentration should be measured and demonstrated to be less than 1.4 mg/dL. Other insulin sensitizers may also be effective in the induction of ovulation, either alone, or in combination with clomiphene or FSH.

Clinical trials have reported conflicting results concerning the relative efficacy of metformin versus clomiphene. In general, the majority of large-scale clinical trials have reported that both metformin and clomiphene monotherapies are effective at inducing ovulation in women with PCOS, but clomiphene results in a greater per cycle ovulation, conception, and birth rates than metformin. In one study, 626 women with anovulatory infertility caused by PCOS were randomized to receive clomiphene alone, metformin alone, or clomiphene plus metformin. The live birth rate was 27% in the clomiphene-metformin group, 23% in the clomiphene group, and 7% in the metformin monotherapy group. In contrast, other investigators have reported that single-agent treatment with clomiphene or metformin results in similar pregnancy rates. In some studies, metformin appears to be more effective in inducing ovulation in women with an above-average waist-to-hip ratio, a marker of increased visceral fat. A woman with anovulatory infertility due to PCOS who has failed to become pregnant with clomiphene, FSH treatment, or ovarian drilling, is more likely to result in pregnancy than treatment with clomiphene plus metformin. However, if FSH treatment or ovarian drilling is not available to the patient because of their high cost, adding metformin to clomiphene or switching to letrozole ovulation induction are low-cost options. Metformin may also be associated with a lower rate of spontaneous abortion in women with PCOS, though further research is needed.

Clomiphene versus Tamoxifen or Raloxifene for Ovulation Induction

Clomiphene, tamoxifen, and raloxifene are mixed estrogen agonists-antagonists with varying degrees of agonist or antagonist activity in different end organs. In a randomized trial, 371 anovulatory infertile women with PCOS were randomized to receive clomiphene citrate 100 mg daily or tamoxifen 20 mg daily for 5 days. The ovulation rate was 64% in the clomiphene group and 52% in the tamoxifen group ( P = 0.01) and the pregnancy rate was 19% and 11% in the clomiphene and tamoxifen groups, respectively ( P = 0.04). Clomiphene at a dose of 100 mg daily appears to be superior to tamoxifen at a dose of 20 mg daily for induction of ovulation in women with PCOS. In a small clinical trial, 5 days of treatment with clomiphene 100 mg daily or raloxifene 100 mg daily resulted in a similar rate of ovulation, but the pregnancy rate was not studied in this trial.

Gonadotropin Induction of Ovulation

  • The foremost risk of gonadotropin ovulation induction is the high incidence of multiple gestation pregnancy .

The use of gonadotropins, gonadotropins plus GnRH antagonists, and gonadotropins plus growth hormone to treat infertility; and the prevention and treatment of ovarian hyperstimulation syndrome are discussed in detail in Chapter 34 . Important concepts related to the use of gonadotropins to treat anovulatory infertility is that women with the best prognosis for success have hypogonadotropic hypogonadism (WHO I) ( Fig. 23.6 ) and are younger than 35 years of age ( Figs. 23.7 and 23.8 ).

Fig. 23.6, Cumulative pregnancy rates for infertile anovulatory women treated with gonadotropins for ovulation induction.

Fig. 23.7, Cumulative pregnancy rates for hypogonadotropic anovulatory women (World Health Organization WHO Croup I) treated with gonadotropins.

Fig. 23.8, Cumulative pregnancy rates following gonadotropin treatment for anovulatory women who did not respond to clomiphene induction of ovulation (WHO Croup II).

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Related Posts