FSH concentrations must exceed a certain level before follicular development will proceed.⁷ When this FSH threshold is surpassed in the normal cycle, the growth of a cohort of small antral follicles is stimulated and ensures ongoing preovulatory follicular development (Fig. 37-1).⁸ The duration of this period in which the threshold is exceeded (the FSH window) is limited in the normal cycle by a decrease in FSH, which occurs in the early to mid-follicular phase because of negative feedback from rising estrogen levels.

Figure 37-1 The intercycle rise in serum follicle-stimulating hormone (FSH) concentrations exceeds the threshold for recruitment of a cohort of follicles for further development. The number of follicles recruited is determined by the time (FSH window) for which the serum FSH is above the threshold at which recruitment occurs.

Adapted from Fauser BC, van Heusden AM: Manipulation of human ovarian function: Physiological concepts and clinical consequences. Endocr Rev 18:71, 1997.

Extending this window would allow the continuous development of more follicles. In the normal cycle, one follicle continues developing despite falling FSH levels because of an increased sensitivity to FSH ⁸ while the remaining follicles respond to falling FSH levels by undergoing atresia, as shown in Figure 37-1.

When the follicle reaches a certain level of development, sustained high circulating levels of estradiol produced by the preovulatory follicle will initiate the midcycle surge in luteinizing hormone (LH) that will trigger ovulation. The surge initiates a gene cascade in granulosa cells, the products of which initiate luteinization, signal the egg to commence meiotic maturation, and lead to rupture of the follicle wall.⁹

Corpus Luteum Development

The preovulatory surge of gonadotropins induces ovulation and differentiation of residual follicular cells that form the corpus luteum and begin to produce progesterone and estrogen at high rates. Theca cells express the enzymes necessary to convert cholesterol to androgens but lack the enzymes necessary to convert androgens to estrogens. Conversely, granulosa cells produce progesterone but are unable to convert pregnenolone or progesterone to androgens.

The preovulatory LH surge results in luteinization of granulosa and theca cells and alters the steroidogenic pathway so that progesterone is the primary steroid hormone produced after luteinization. However, the corpus luteum retains the ability to produce estrogen. Adequate luteal progesterone is secreted to allow maintenance of pregnancy until a conceptus-derived source of progesterone, the placenta, can produce adequate amounts of this steroid to support pregnancy.¹⁰

OVULATION INDUCTION

Indications

Normal follicular development culminates in ovulation of a mature oocyte, followed by the development of a corpus luteum producing adequate amounts of progesterone. This sequence of events is orchestrated by the interaction of local ovarian factors and endocrine factors from remote tissues, including the pituitary and hypothalamus. In addition, adequate functioning of other endocrine glands such as the thyroid and adrenal glands is important in orchestrating the interaction between the hypothalamus, pituitary, and ovaries that results in ovulation.

Any derangement of any of these systems may result in dysfunctional ovarian follicular development or even the complete failure of ovulation. The presence of subtle abnormalities despite the occurrence of ovulation is believed to be responsible, at least in part, for what is thought to be unexplained infertility in some women and perhaps for endometriosis-related infertility.

Ovulatory Dysfunction Classification

Clinically obvious anovulation or oligo-ovulation has been traditionally classified into three groups: World Health Organization (WHO) group I, II, and III anovulation.¹¹

Women in WHO group I suffer from a defect at the level of the hypothalamus/pituitary. They are estrogen deficient with normal or low FSH or prolactin levels and have no space-occupying lesion in the hypothalamic/pituitary region. They typically have amenorrhea and do not bleed in response to progestin challenge.

Women in WHO group II are not estrogen deficient. Their FSH and prolactin levels are normal. They typically experience oligomenorrhea, but they may have anovulatory cycles or amenorrhea with bleeding in response to a progestin challenge. Included in this group are women with polycystic ovary syndrome (PCOS).

Women in WHO group III include those with elevated gonadotropins secondary to primary ovarian failure mainly due to diminished ovarian reserve and the loss of ovarian follicles. These women are resistant to various methods of ovarian stimulation, and the best approach for their anovulation-associated infertility is oocyte donation.

Medications for Ovarian Follicle Stimulation

The available medications for stimulating ovarian follicular development include oral agents, mainly antiestrogens, better termed selective estrogen receptor modulators (SERM), and medications delivered by injections: gonadotropins and GnRH agonists. For more than four decades, an oral agent, clomiphene citrate, and injectable gonadotropins have almost been exclusively used for stimulating ovarian follicular development.

Gemzell and his coworkers announced the first successful induction of ovulation using human pituitary gonadotropins in 1958 and the first pregnancy in 1960.^12,¹³ One year later, Bettendorf and his group reported a similar experience.¹⁴ In 1961, Greenblatt and his coworkers published the first results of ovulation induction achieved by the use of clomiphene citrate (at that time known as MRL/41).¹⁵

In the past decade, insulin sensitizers have been introduced into clinical practice for ovulation induction for patients with PCOS and significant insulin resistance. Most recently, aromatase inhibitors have been used as an alternative to clomiphene citrate for ovulation induction or to improve the outcome of controlled ovarian stimulation with gonadotropins.

CLOMIPHENE CITRATE

For more than 40 years, clomiphene citrate has been the most commonly used oral agent for induction of ovulation. Since the early 1960s, results of clomiphene citrate treatment have not changed appreciably, despite the advent of modern immunoassays for steroid hormones, advances in ultrasound technology for cycle monitoring, and the introduction of commercial ovulation predictor kits that allow accurate identification of the midcycle LH surge.

It is interesting to note that clomiphene citrate is considered pregnancy risk category X. Studies in rats and mice have shown a dose-related increase in some types of malformations and an increase in mortality. This is particularly important when considering the relatively long half-life of about 5 days to 3 weeks (depending on the isomer) and that clomiphene citrate may be stored in body fat.¹⁶^–¹⁸ Fortunately, studies in humans have not found an association between clomiphene citrate and congenital defects.

Structure and Pharmacokinetics

Chemically, clomiphene citrate is a nonsteroidal triphenylethylene derivative and is chemically related to diethylstilbestrol and tamoxifen. Like the latter of these compounds, clomiphene can be considered to be a SERM that can exhibit both estrogen agonist and antagonist properties depending on the prevailing levels of endogenous estrogen. Estrogen agonist properties are manifest only when endogenous estrogen levels are extremely low. Otherwise, clomiphene citrate acts mainly as an antiestrogen.¹⁶

Clomiphene citrate is cleared through the liver and excreted in the stool. About 85% of an administered dose is eliminated after approximately 6 days, although traces may remain in the circulation for much longer.¹⁷ Clomiphene citrate is a racemic mixture of two distinct stereoisomers, enclomiphene and zuclomiphene, having different properties. Available evidence indicates that enclomiphene is the more potent antiestrogenic isomer and the one primarily responsible for the ovulation-inducing actions of clomiphene citrate.¹⁶^–¹⁸

Levels of enclomiphene rise rapidly after administration and fall to undetectable concentrations after few days. Zuclomiphene, the transisomer of clomiphene citrate, is cleared far more slowly; levels of this less active isomer remain detectable in the circulation for more than 1 month after treatment and may actually accumulate over consecutive cycles of treatment.¹⁸

Pharmacodynamics and Mode of Action

Clomiphene binds to estrogen receptors throughout the body due to its structural similarity to estrogen. However, unlike natural estrogen, which only binds estrogen receptors for a period of hours, clomiphene citrate binds estrogen receptors for an extended period of time, weeks rather than hours. Such extended binding ultimately depletes estrogen receptor concentrations by interfering with the normal process of estrogen receptor replenishment.¹⁵

The antiestrogenic effect of action of clomiphene citrate on the hypothalamus, and possibly the pituitary, is believed to be its main mechanism for ovarian stimulation. Depletion of hypothalamic estrogen receptors prevents correct interpretation of circulating estrogen levels; estrogen concentrations are falsely perceived as low, leading to reduced estrogen-negative feedback on GnRH production by the hypothalamus and gonadotropin (FSH and LH) production by the pituitary.

It is believed that the hypothalamus is the main site of action because in normally ovulatory women, clomiphene citrate treatment was found to increases GnRH pulse frequency.¹⁹ However, actions at the pituitary level may also be involved because clomiphene citrate treatment increased pulse amplitude, but not frequency in anovulatory women with PCOS, in whom the GnRH pulse frequency is already abnormally high.²⁰

During clomiphene citrate treatment, levels of both LH and FSH rise, then fall again after the typical 5-day course of therapy is completed. In successful treatment cycles, one or more dominant follicles emerge and mature, generating a rising tide of estrogen that ultimately triggers the midcycle LH surge and ovulation.^19,²⁰

Indications

The two main indications for clomiphene citrate treatment in women are (1) induction of ovulation in women with anovulatory infertility, and (2) stimulation of multifollicular ovulation or enhancing ovulation in ovulatory infertile women (e.g., unexplained infertility).

Clomiphene citrate is the initial treatment of choice for most anovulatory or oligo-ovulatory infertile women who are euthyroid and euprolactinemic while having adequate circulating levels of estrogen (WHO group II anovulation; e.g., PCOS). For anovulatory infertility, clomiphene citrate is effective only in conditions in which adequate levels of circulating estrogen exist to exert estrogen-negative feedback on gonadotropin production, and that could be antagonized by the antiestrogenic effect of clomiphene citrate. Women who do not respond to clomiphene citrate are those with very low circulating estrogen levels such as WHO groups I and III or women with defective hypothalamic-pituitary axis such as those with Sheehan’s syndrome and Kallmann syndrome.

For “unexplained” infertility, clomiphene citrate enhances the chance of achieving pregnancy apparently by stimulating multifollicular development as well as alleviating possible subtle ovulation dysfunction. The downside is an increased risk of multiple pregnancy, primarily twins.

Clomiphene Citrate Administration

Clomiphene citrate is administered orally for 5 days, starting on any day from the second to fifth day after the onset of spontaneous or progestin-induced menses. In anovulatory women, ovulation rates, conception rates, and pregnancy outcome are similar regardless of whether treatment is started on cycle day 2, 3, 4, or 5. Starting on day 5 has the theoretical advantage of giving more time to verify normal menses (and hopefully decreasing the chance of being pregnant) before starting therapy.

Treatment typically begins with a single 50-mg tablet daily for 5 consecutive days, increasing by 50-mg increments in subsequent cycles until ovulation is induced. Once the effective dose of clomiphene citrate is established, there is no indication for further increments unless the ovulatory response is lost. Higher doses will not improve the probability of conception, but the risk of hyperstimulation and multiple pregnancy might increase.

Although the dose required for achieving ovulation is correlated with body weight, there is no reliable way to predict accurately what dose will be required in an individual woman. Consequently, clomiphene citrate induction of ovulation amounts to an empirical incremental titration to establish the lowest effective dose for each individual.

The effective dose of clomiphene citrate for most women ranges from 50 to 250 mg/day, although some women will be found to be sensitive to clomiphene citrate and only require doses as low as 12.5 to 25 mg/day. Most women will ovulate at the lower doses, with 52% ovulating after 50 mg/day and another 22% after treatment with 100 mg/day. Although higher doses are sometimes required, the ovulation rates are usually low at these doses, with only 12% ovulating after 150 mg/day, 7% after 200 mg/day, and 5% after 250 mg/day. Most women who fail to respond to 150 mg/day of clomiphene citrate will ultimately require alternative or combination treatments.^21,²²

After the lowest ovulatory dose is determined, the same dose is repeated until pregnancy is achieved or a maximum number of approximately six cycles is reached. Pregnancy rates are highest during the first three cycles of clomiphene citrate treatment. The chances of achieving pregnancy are significantly lower beyond the third treatment cycle and uncommon beyond the sixth treatment cycle (Fig. 37-2). Therefore, it is rarely advisable to continue clomiphene citrate treatment beyond six treatment cycles.²¹

Figure 37-2 Cumulative pregnancy rates with clomiphene citrate and intrauterine insemination in patients with ovulatory and anovulatory infertility by Kaplan-Meier life table analysis. A, Filled circles, age <= 30; closed squares, age 31–35; open circles, age 36–40; open squares, age >= 41. B, Groups collapsed into two: closed circles, age <= 35; open squares, age >35.

From Agarwal SK, Buyalos RP: Clomiphene citrate with intrauterine insemination: Is it effective therapy above the age of 35 years? Fertil Steril 65:759–763, 1996.

The recommendation regarding which dose to apply is clear in cases of anovulatory infertility (increments of 50 mg until ovulation is achieved, then the dose is maintained). However, this is not clear in cases with ovulatory infertility. There are no adequate studies regarding which dose or what response (number of mature follicles) would be optimal in these women. This uncertainty is related to the individual variability in response to clomiphene citrate treatment irrespective of the dose and to the absence of a clear correlation between pregnancy rates and the number of mature follicles or amount of clomiphene citrate administered. Moreover, the value of clomiphene citrate treatment in enhancing the chance of achieving pregnancy in cases with ovulatory infertility has been questioned ²² and has not been proven by large controlled studies.

Treatment Monitoring

Monitoring is required to ensure that ovulation is occurring during a clomiphene citrate treatment cycle. For most patients treated with clomiphene citrate, ovulation monitoring can often be done with any one of a number of low-cost, highly convenient methods conducted in the setting of a general obstetrician and gynecologist practice. Objective evidence of ovulation and normal luteal function are keys to successful treatment. The choice may vary and should be tailored to meet the needs of the individual patient.²³

Basal Body Temperature

Basal body temperature (BBT) recordings provide a simple and inexpensive method for evaluating response to treatment. For this test, the woman takes and graphs her temperature every morning. A midcycle phase shift indicates that ovulation has occurred.

Urinary LH Detection Kit

An ovulation prediction kit can identify the midcycle LH surge in urine and more precisely defines both the interval of peak fertility (day of surge detection and the next 2 days).²⁴ Usually the LH surge is observed from 5 to 12 days after the last clomiphene citrate tablet.²⁵ Ovulation will generally follow within 14 to 26 hours of detection of an LH surge. Consequently, timed coitus or intrauterine insemination (IUI) on the day after the first positive urinary LH test will have the highest pregnancy rates.

Midluteal Progesterone

BBT charts and urinary LH detection kits can confirm that ovulation has occurred but do not document the quality of luteal function, which requires further tests—classically, a serum progesterone determination or endometrial biopsy.

A progesterone level above 3 ng/mL is evidence of ovulation.²⁶ Midluteal phase progesterone concentration (7 days after BBT shift or 7 to 9 days after urinary LH surge) offers more information. Levels exceeding 10 ng/mL are usually suggestive of an adequate luteal phase.²⁷ Endometrial biopsy and “secretory” histology that results from the action of progesterone also provides evidence of ovulation. Endometrial “dating,” using established histologic criteria, has been traditionally suggested for diagnosing luteal phase adequacy.²⁸ However, there is still much uncertainty about the importance of luteal phase defects diagnosed by serum progesterone levels or by endometrial biopsies, reflecting our poor state of knowledge regarding the actual mechanisms involved in endometrial receptivity and implantation.^29,³⁰

More sophisticated measures to monitor the outcome of clomiphene citrate treatment, including transvaginal follicular ultrasound scans and measurements of serum estradiol and LH levels, can usually be conducted in a subspecialist reproductive endocrinology practice. Because of the cost and logistic requirements involved, the method is generally reserved for patients in whom less complicated methods fail to provide the necessary information and for women who are at a high risk for developing serious complications such as severe ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy.²³

In the past, it was generally recommended that patients receiving clomiphene citrate treatment be examined before starting each new treatment cycle to ensure that there was no significant residual ovarian enlargement or ovarian follicular cysts. However, it appears that small residual follicular cysts usually do not expand during continued treatment.³¹ Consequently, it is unnecessary to perform “baseline” ultrasound examinations before each new treatment cycle. However, it is reasonable to withhold treatment when symptoms suggest the presence of a large cyst or gross residual ovarian enlargement.²³

Outcome of Clomiphene Citrate Treatment

Clomiphene citrate treatment has been reported to successfully induce ovulation in 60% to 80% of properly selected women. More than 70% of those who ovulate respond at the 50-mg or 100-mg dosage level. In young anovulatory women in whom anovulation is the sole reason preventing them from conceiving, cumulative conception rates between 60% and 70% are observed after up to three successfully induced ovulatory cycles, and 70% to 85% after five cycles. Overall, cycle fecundity is approximately 15% in women who ovulate in response to treatment.²¹

In the reality of daily clinical practice, clomiphene citrate induction of ovulation usually results in much lower pregnancy rates, particularly in a subspecialty referral infertility practice. Important factors that adversely affect treatment outcome are increased age (particularly older than age 35), presence of other treated or untreated infertility factors, and increasing duration of infertility.³² Amenorrheic women are more likely to conceive than oligomenorrheic women, probably because those who already ovulate, albeit inconsistently (oligomenorrheic), are more likely to have other coexisting infertility factors. Generally speaking, failure to conceive within six clomiphene citrate-induced ovulatory cycles is a clear indication to expand the diagnostic evaluation to exclude other factors, change the overall treatment strategy, or both.²³

Adverse Effects and Risks of Clomiphene Citrate

Clomiphene citrate is generally well-tolerated. Some side effects are relatively common, but rarely are they persistent or severe enough to threaten completion of treatment. Although clomiphene citrate treatment does have intrinsic risks, they are typically modest and manageable. Adverse effects are generally divided into the side effects related to clomiphene citrate itself and the adverse effects related to induction of ovulation in general.

Side Effects

Hot flashes due to the antiestrogenic property of clomiphene citrate are dose-dependent and occur in approximately 10% of clomiphene citrate-treated women. Symptoms are transient, rarely severe, and typically resolve soon after treatment ends.

Visual disturbances, including blurred or double vision, scotomata, and light sensitivity, are generally uncommon (<2% prevalence) and reversible. However, there are isolated reports of persistent symptoms long after treatment is discontinued with more severe complications such as optic neuropathy. Whenever visual disturbances are identified, treatment should be stopped and alternative methods of ovulation induction should be considered.

Less specific side effects include breast tenderness, pelvic discomfort, and nausea, all observed in 2% to 5% of clomiphene citrate-treated women.³³ In addition, there are relatively common reports of premenstrual syndrome-type symptoms in women on clomiphene citrate.³⁴

Congenital Anomalies

There is no evidence that clomiphene citrate treatment increases the overall risk of birth defects or of any specific malformation. Several large series have examined the question and have drawn the same conclusion.^35,³⁶ Earlier suggestions that the incidence of neural tube defects might be higher in pregnancies conceived during clomiphene citrate treatment have not been confirmed by more recent studies.³⁷ A small study of pregnancy outcome in women inadvertently exposed to clomiphene citrate during the first trimester also found no increase in the prevalence of congenital anomalies.³⁸

Pregnancy Loss

More than one study has suggested that pregnancies resulting from clomiphene citrate treatment are at increased risk of spontaneous abortion compared to spontaneous pregnancies. A study reviewed outcomes of 1744 clomiphene pregnancies compared to outcomes of 3245 spontaneous pregnancies.³⁹ In this study, pregnancy loss was classified as either clinical if a sac was seen on ultrasound or if it occurred after 6 weeks’ gestation, or preclinical if a quantitative human chorionic gonadotropin (hCG) was greater than or equal to 25 IU/L and no sac was seen or abortion occurred earlier. In this study, when preclinical and clinical were considered together, the overall incidence of spontaneous abortion was slightly higher for clomiphene pregnancies than for spontaneous pregnancies (23.7% versus 20.4%). When considered separately, preclinical spontaneous abortions were also increased by clomiphene citrate overall (5.8% versus 3.9%) and for women at least 30 years old (8.0% versus 4.9%), but not for those younger than age 30 (3.7 versus 3.0%). In contrast, when clinical abortions were considered separately, clomiphene citrate did not increase the overall rate (18.0% versus 16.4%), but the rate was increased for women younger than age 30 (15.9% versus 11.2%).

More recent studies looking at rate of spontaneous miscarriage in 62,228 clinical pregnancies resulting from ART procedures initiated in 1996 to 1998 in U.S. clinics also found that spontaneous miscarriage risk was increased among women who used clomiphene citrate.^40,⁴¹ However, the results of these studies are not considered to be conclusive. The pregnancy loss seen in women after clomiphene treatment may actually be related to other comorbidities in these patients, such as insulin resistance, other genetic factors related to PCOS or unexplained infertility, endometriosis, and advancing maternal age.⁴²

Antiestrogenic Effects and Fertility

Clomiphene citrate treatment is associated with antiestrogenic effects that might have adverse effects on fertility. Because of the relatively long half-life of clomiphene citrate isomers, clomiphene citrate exerts undesirable and unavoidable antiestrogenic effects on the endocervix, endometrium, ovary, ovum, and embryo. Numerous studies in women and in various model systems have described adverse effects on the quality or quantity of cervical mucus, endometrial growth and maturation, follicular or corpus luteum steroidogenesis, ovum fertilization, and embryo development.

These adverse effects are believed to explain the “discrepancy” between the ovulation and conception rates observed in clomiphene citrate-treated patients. These effects appear to be more apparent at higher doses or after longer durations of treatment. It has been suggested that treatment with exogenous supplemental estrogen may help to minimize or negate these effects.^43,⁴⁴ However, there is little compelling evidence to support any beneficial effect of estrogen replacement to reverse these peripheral antiestrogenic effects.²³

Clomiphene citrate treatment has been shown to affect the quality and quantity of cervical mucus production as well as the structure of the endometrium.⁴⁵^–⁴⁷ However, cervical mucus score (based on quantity and quality) has not been found to be of proven prognostic value on the treatment outcome (i.e., achievement of pregnancy).

The endometrium is believed to be one of the most important targets of the antiestrogenic effect of clomiphene citrate and may explain a large part of the lower pregnancy rate and the possible higher miscarriage rate with clomiphene citrate. Successful implantation requires a receptive endometrium, with synchronous development of glands and stroma.⁴⁸

Studies have reported conflicting effects of clomiphene citrate on the endometrium 45–47,⁴⁹^–⁵¹ possibly due to different methodology used for endometrial assessment. However, a recent study has prospectively applied morphometric analysis of the endometrium, a quantitative and objective technique to study the effect of clomiphene citrate on the endometrium in a group of normal women. In this study, clomiphene citrate was found to have a deleterious effect on the endometrium, demonstrated by a reduction in glandular density and an increase in the number of vacuolated cells.⁵¹ In addition, a reduction in endometrial thickness below the level thought to be needed to sustain implantation was found in up to 30% of women receiving clomiphene citrate for ovulation induction or for unexplained infertility.⁴⁵ This observation has been confirmed by other studies.^46,⁴⁷

Decreased uterine blood flow during the early luteal phase and the peri-implantation stage has been suggested to explain, at least in part, the poor outcome of clomiphene citrate treatment.⁵¹ Other investigators have suggested the presence of other unrecognized factors associated with clomiphene citrate treatment failure.⁵²^–⁵⁴ Moreover, there is some evidence for a direct negative effect of clomiphene citrate on fertilization, and on early mouse and rabbit embryo development.^55,⁵⁶ In addition, there have been reports of low-quality oocytes associated with clomiphene citrate treatment. However, the negative effects of clomiphene citrate in some animal studies have not been confirmed by others,^53,⁵⁴ and at present it is unclear if there are adverse direct effects of clomiphene citrate on human oocytes and human embryo development.

Because of the above-mentioned evidence for adverse peripheral antiestrogenic effects of clomiphene citrate treatment, several investigators tried to reverse these effects by administering estrogen concomitantly with clomiphene citrate treatment. Some investigators have reported increased endometrial thickness and improved pregnancy rates with this approach ^57,⁵⁸; others have reported no benefit⁴⁴ or even a deleterious effect of estrogen administration.⁵⁹ Another approach has been to administer clomiphene citrate earlier during the menstrual cycle rather than starting on day 5,⁶⁰ in the hopes of allowing the antiestrogenic effect to wear off to some extent before ovulation and implantation. In view of the long half-life of clomiphene citrate isomers, this approach is unlikely to be successful. A third method has been to combine another SERM such as tamoxifen, which has more estrogen agonistic effect on the endometrium with clomiphene citrate or to use tamoxifen as an alternative to clomiphene citrate.⁶¹ However, none of these strategies have proved to be completely successful in avoiding the peripheral antiestrogenic effects of clomiphene citrate. A more recent publication has suggested that high-dose soy isoflavones may be able to overcome the antiestrogenic effect of clomiphene citrate on the endometrium.⁶² This report remains to be confirmed by other investigators.

To summarize, from the available evidence and accumulated clinical experience, it is difficult to conclude the exact significance of adverse antiestrogenic effects on pregnancy outcome in clomiphene citrate-treated women. It seems that individual variability exists regarding sensitivity to the peripheral antiestrogenic effects of clomiphene citrate, likely because of the complexity of estrogen receptor replenishment and activation, and individual differences in the pharmacokinetics of clomiphene citrate. The discrepancy in the success rates in achieving pregnancy between women with unexplained infertility and women with PCOS in response to clomiphene citrate treatment (higher rates in PCOS women) suggests that PCOS women may be less vulnerable to the antiestrogenic effects of clomiphene citrate on peripheral tissues. Recent findings of differences in the expression levels of receptors (androgen receptor, estrogen receptor α and β, progesterone receptor) and cofactors in human endometrium and myometrium in PCOS patients support this hypothesis.⁶³ For example, the p160 family of steroid receptor coactivators, known to facilitate the action of steroid receptors throughout the menstrual cycle, was found to be overexpressed in the endometrium of women with PCOS.⁸⁰ However, the presence of infertility factors, rather than an increased sensitivity to the antiestrogenic effects of clomiphene citrate, in non-PCOS women may explain the less favorable outcome of clomiphene citrate treatment.

FAILURE OF CLOMIPHENE CITRATE TREATMENT

Etiologies

When considering clomiphene citrate treatment we can define two groups of treatment failures. The first group, clomiphene ovulation failure (clomiphene resistance), includes patients who fail to ovulate with clomiphene citrate treatment. The second group, clomiphene pregnancy failure, includes patients who ovulate with clomiphene citrate treatment but fail to achieve pregnancy. This second group also includes women with ovulatory infertility who do not achieve pregnancy after clomiphene citrate treatment.

Clomiphene Ovulation Failure

The two main reasons for clomiphene ovulation failure are insulin resistance (women with PCOS) and inappropriate indication for clomiphene citrate (e.g., use in women with WHO group I or III anovulation or women with ovulatory dysfunction due to medical disorders that require specific treatments, such as thyroid disorders, congenital adrenal hyperplasia [CAH], and hyperprolactinemia).

Clomiphene Pregnancy Failure

The reasons for clomiphene pregnancy failure (women who ovulate in response to clomiphene citrate but do not achieve pregnancy) may be related to a wide variety of underlying infertility factors, such as male factor infertility, endometriosis, undiagnosed tubal factor, or endometrial receptivity factors. However, the success of many of these women in achieving pregnancy with alternative ovarian stimulation protocols using injectable gonadotropins or aromatase inhibitors supports the hypothesis that persistent antiestrogenic effects associated with clomiphene citrate might play a major role in the discrepancy between ovulatory rates and pregnancy rates.⁶⁴^–⁶⁶

ALTERNATIVE APPROACHES FOR CLOMIPHENE FAILURES

Some women who are refractory to standard clomiphene citrate treatment regimens will ovulate in response to alternative regimens of clomiphene citrate, including longer duration or higher doses of clomiphene citrate treatment. For example, an 8-day treatment regimen or doses of 200 to 250 mg/day can be effective when shorter courses of therapy fail. However, longer treatment and higher doses are expected to be associated with more antiestrogenic effects and reduced chances for achieving pregnancy even though ovulation is achieved.²³

Several adjunctive treatments have been suggested to overcome resistance to clomiphene citrate, including the use of insulin-sensitizing agents (e.g., metformin), exogenous hCG and combinations (sequential treatment with clomiphene citrate and exogenous gonadotropins), and laparoscopic ovarian drilling. Steroids are no longer used for ovulation induction except for properly diagnosed CAH. It is obvious that the choice of treatment should not be arbitrary, but rather should be based on the patient’s history, the results of laboratory evaluation, and observations in previous unsuccessful clomiphene citrate treatment cycles. We provide a brief overview of the use of these agents in conjunction with ovulation induction in PCOS patients in this chapter.

Insulin-Sensitizing Agents

Insulin resistance and hyperinsulinemia are recognized features of PCOS. Hyperinsulinemia contributes significantly to hyperandrogenism and chronic anovulation. It is logical that agents that improve insulin action in the body (insulin sensitizers) will help infertile PCOS women with insulin resistance to achieve ovulation by lowering their hyperinsulinemia. This is particularly true in PCOS patients who fail to ovulate with clomiphene citrate treatment. De Leo and colleagues reviewed the use of insulin-lowering agents in the management of PCOS,⁶⁷ with extensive discussion of the effect of these agents on endocrine, metabolic, and reproductive functions.

Although it is believed that the endocrine and reproductive benefits observed during treatment with insulin sensitizers in PCOS women are due to improving insulin resistance, insulin sensitizers may work through other mechanisms to achieve ovulation in these patients. One such mechanism is a direct effect on ovarian steroidogenesis. There is evidence that the insulin sensitizers, metformin and thiazolidinediones, can modulate steroid production through direct suppression of steroidogenesis enzymes. Troglitazone was found to inhibit progesterone production by human luteinized granulosa cells and to reduce androgen production by rat theca cells.^68,⁶⁹ It was also found to directly inhibit 3β-hydroxysteroid dehydrogenase, leading to decreased progesterone secretion by porcine granulosa cells.⁷⁰ Troglitazone, and presumably other thiazolidinediones, inhibits cholesterol biosynthesis in Chinese hamster ovary cells⁷¹ and aromatase in human granulosa cells.⁷²

Metformin

Several studies demonstrated that treatment alone with the insulin-sensitizing agent metformin could restore menses and cyclic ovulation in many amenorrheic PCOS women.^16,⁷³ This led some to advocate metformin as primary therapy in infertile PCOS women with insulin resistance (1000 to 2000 mg/day in divided doses) and add clomiphene citrate only in those who fail to respond. However, the relatively greater costs per cycle compared to clomiphene citrate, as well as the complexity of metformin treatment and the frequency of significant gastrointestinal side effects (e.g., nausea, vomiting, diarrhea) made others prefer to reserve metformin treatment for those who first prove resistant to clomiphene citrate. Caution should be used in prescribing these drugs to women with potential renal or liver disease. It is recommended that a creatinine level and liver function tests be obtained before starting therapy.⁷³

Unfortunately, most of the studies published so far on the use of metformin in PCOS women were not randomized. Even the randomized trials included a small number of patients, which prevented definitive conclusions. However, meta-analysis of the combined results of prior clinical trials concluded that metformin is effective in achieving significant rates of ovulation and pregnancy in women with PCOS. It is important to note the difference between achieving ovulation and achieving a pregnancy.

Effectiveness of Metformin

A recent Cochrane meta-analysis showed that metformin is effective in achieving ovulation in women with PCOS with an odds ratio (OR) of 3.88 (confidence interval [CI], 2.25–6.69) for metformin versus placebo and 4.41 (CI, 2.37–8.22) for metformin and clomiphene citrate versus clomiphene citrate alone. An analysis of pregnancy rates suggests a significant treatment effect for metformin and clomiphene citrate (OR, 4.40; CI, 1.96–9.85). The authors concluded that metformin is an effective treatment for anovulation in women with PCOS, and its choice as a first-line agent seems justified.⁷³

Alternative Insulin-Sensitizing Agents

Other insulin-sensitizing agents such as the thiazolidinediones (troglitazone, rosiglitazone, and pioglitazone) and chiroinositol ⁷⁷^–⁸⁴ have been used in small clinical trials to achieve ovulation in PCOS women with insulin resistance. However, because of the higher safety profile, longer clinical experience, and lower cost of metformin, the other insulin sensitizers should be reserved for cases resistant to metformin treatment.⁸⁵ Finally, before concluding this section on the use of insulin sensitizers in infertile women with PCOS, it is necessary to stress the importance of other nonpharmacologic approaches to improve insulin action and reduce insulin resistance, including dietary factors, weight loss, and exercise. The use of insulin-sensitizing agents should be as an adjuvant to these nonpharmacologic approaches.

Human Chorionic Gonadotropin

The administration of hCG during clomiphene citrate treatment aims at either substituting (before the occurrence of the endogenous LH surge) or supporting the endogenous LH surge. This may be particularly useful for timing insemination or recommending the optimum fecundity period for intercourse.

A number of clinical studies have examined the efficacy of using exogenous hCG as a surrogate LH surge in women who fail to ovulate in response to clomiphene citrate alone.^31,^86,⁸⁷ Clinical studies in anovulatory infertile women have demonstrated that on the day of the spontaneous LH surge in successful clomiphene citrate-induced ovulatory cycles, mean diameter of the lead follicle ranges between 19 and 30 mm (median diameter, 25 mm).⁸⁷ Given that the average growth rate of the preovulatory follicle over the days immediately preceding ovulation is approximately 2 mm/day, the LH surge can occur during an interval of time of approximately 5 days. Normally, the preovulatory follicle triggers its own ovulation at the peak of maturity by generating and maintaining estrogen levels above the threshold required, inducing the LH surge. Timing of the spontaneous LH surge is therefore always optimal, and that of hCG administration can never be more than an educated guess.

In those uncommon instances in which hCG treatment may be effective and is necessary, it is probably best postponed until the lead follicle reaches or exceeds 20 mm in mean diameter.²³ Occasionally, a couple may require both clomiphene citrate treatment and IUI because of anovulation and a coexisting male factor. Clearly, accurate timing of the insemination is crucial to the success of treatment.

Effectiveness

In a review of 2000 consecutive completed ovarian stimulation cycles with timed intercourse or IUI, the occurrence of an LH surge was associated with a higher pregnancy rate compared to hCG administration with clomiphene citrate treatment, but a lower pregnancy rate compared to hCG administration with gonadotropin treatment, suggesting that awaiting occurrence of the LH surge might be associated with a better outcome with clomiphene citrate treatment.⁸⁸

Disadvantages

The administration of hCG does have distinct potential disadvantages and consequences. This is because to properly time its administration, follicular development should be monitored with serial transvaginal ultrasound examinations that are costly and generally unnecessary. This sophisticated approach contradicts the major benefit of clomiphene citrate ovulation induction (i.e., simplicity and low cost). Moreover, it is difficult to determine when best to administer exogenous hCG, even in carefully monitored cycles.

Gonadotropins

Clomiphene citrate-resistant anovulatory women who ultimately require exogenous gonadotropins to achieve ovulation might benefit from a trial of sequential clomiphene citrate and gonadotropin therapy. Sequential clomiphene citrate and gonadotropin (hMG or FSH) therapy has become increasingly used to produce ovarian superovulation for patients who fail clomiphene citrate treatment.^89,⁹⁰

The value of adding clomiphene citrate during ovarian superovulation is to decrease the FSH dose required for optimum stimulation. However, care in monitoring must be taken because clomiphene citrate use may be associated with peripheral antiestrogenic effects, offsetting the FSH dose reduction benefit.⁹¹

Laparoscopic Ovarian Drilling

Whether ovarian drilling is a valid option for clomiphene citrate-resistant women with PCOS has been a matter of intense debate. The technique involves laparoscopic cautery, diathermy, or laser vaporization of the ovaries at multiple sites, the objective being to decrease circulating and intraovarian androgen levels by reducing the volume of ovarian stroma (modern version of the classic ovarian wedge resection operation).

Ovarian drilling is reported to result in resumption of spontaneous ovulation or at least restore sensitivity to clomiphene citrate treatment. Formation of postoperative adhesions that may compromise fertility is common.⁹² Serum testosterone concentrations typically fall by approximately 40% to 50%, at least for a period of months. About 70% to 90% of properly selected candidates will ovulate after drilling, and 50% to 80% of those will conceive. Consequently, ovarian drilling is perhaps best reserved for clomiphene citrate-resistant women in whom cost or logistic considerations effectively preclude alternative treatments (e.g., exogenous gonadotropins).²³ Ovarian drilling does not seem to improve the metabolic derangement of insulin resistance and lipid dysfunction.⁹³

Aromatase Inhibitors

Clomiphene citrate is the mainstay of ovulation induction therapy as long as no other alternative is available that has the same advantages of oral administration, limited monitoring requirements, mild side effects, and a comparatively low cost and risk of multiple pregnancy. However, treatment should use the lowest effective dose, empirically determined, and should rarely exceed six cycles of therapy. Failure to conceive despite successful clomiphene citrate-induced ovulation is an indication to expand evaluation to exclude other coexisting infertility factors or to change the overall treatment strategy. In patients with PCOS, metformin is definitely an important next step and perhaps a first step. However, other drugs are available as options.

Aromatase Description

Aromatase is a microsomal member of the cytochrome P450 hemoprotein-containing enzyme complex superfamily (P450arom, the product of the CYP19 gene). Aromatase catalyzes the rate-limiting step in the production of estrogens, that is, the conversion of androstenedione and testosterone via three hydroxylation steps to estrone and estradiol, respectively.⁹⁴ Aromatase activity is present in many tissues, such as the ovaries, the brain, adipose tissue, muscle, liver, breast tissue, and in malignant breast tumors. The main sources of circulating estrogens are the ovaries in premenopausal women and adipose tissue in postmenopausal women.⁹⁵ Aromatase is a good target for selective inhibition because estrogen production is a terminal step in the biosynthetic sequence (Table 37-1).

Table 37-1 Potential Advantages of Using an Aromatase Inhibitor for Induction of Ovulation

High pregnancy rates

Monofollicular ovulation in most anovulatory patients

High safety due to short half-life and few adverse effects

Reduced rate of multiple pregnancy

Reduced risk of severe ovarian hyperstimulation syndrome

Reduced FSH dose required for controlled ovarian stimulation

Improved response to FSH in poor responders

Low cost of treatment (average, $30–$100 per cycle)

Convenience of administration: oral route, different regimens, including single-dose regimen

Types of Aromatase Inhibitors

A large number of aromatase inhibitors have been developed over the past 30 years with the most recent, third-generation aromatase inhibitors licensed mainly for breast cancer treatment in postmenopausal women.⁹⁶ Aromatase inhibitors have been classified in different ways: into steroidal and nonsteroidal and, according to the stage of development, into first-, second-, and third-generation groups.

The first aromatase inhibitor to be used clinically was aminoglutethimide, which induces a medical adrenalectomy by inhibiting many other enzymes involved in steroid biosynthesis.⁹⁷ Although aminoglutethimide is an effective hormonal agent in postmenopausal breast cancer, its use is complicated by the need for concurrent corticosteroid replacement, in addition to side effects such as lethargy, rashes, nausea, and fever that result in 8% to 15% of patients stopping treatment.⁹⁸ The lack of specificity and unfavorable toxicity profile of aminoglutethimide led to the search for more specific aromatase inhibitors. In addition, the earlier aromatase inhibitors were not able to completely inhibit aromatase activity in premenopausal patients.

The third-generation aromatase inhibitors commercially available include two nonsteroidal preparations, anastrozole and letrozole, and a steroidal agent, exemestane.⁹⁹^–¹⁰¹ Anastrozole and letrozole are available for clinical use in North America, Europe, and other parts of the world for treatment of postmenopausal breast cancer. These triazole (antifungal) derivatives are reversible, competitive aromatase inhibitors with considerably greater intrinsic potency than aminoglutethimide (more than 1000 times), and at doses of 1 to 5 mg/day, inhibit estrogen levels by 97% to more than 99% down to concentrations below detection by most sensitive immunoassays. Aromatase inhibitors are completely absorbed after oral administration, with a mean terminal half-life of approximately 45 hours (range, 30 to 60 hours) with clearance from the systemic circulation mainly by the liver. Mild gastrointestinal disturbances account for most of the adverse events, although these have seldom limited therapy. Other adverse effects including asthenia, hot flashes, headache, and back pain are based on studies in postmenopausal women.⁹⁹^–¹⁰¹

Mechanism of Action for Ovulation Induction

Recently, success in using aromatase inhibitors for induction of ovulation has been reported.¹⁰²^–¹⁰⁹ Several hypotheses have been postulated for the mechanisms underlying the effectiveness of these medications in ovulation induction.¹¹⁰

Central Hypothesis

It might be possible to mimic the action of clomiphene citrate, without depletion of the estrogen receptors, by administration of an aromatase inhibitor in the early part of the menstrual cycle. There is evidence that both circulating estrogen (produced by the ovaries) and locally produced estrogen (produced in the brain) exert negative feedback on the release of gonadotropins.¹¹¹^–¹¹⁴ Blocking estrogen production from all sources by inhibiting aromatization would release the hypothalamic-pituitary axis from estrogen-negative feedback, thereby increasing gonadotropin secretion and resulting in stimulation of ovarian follicles. The selective nonsteroidal aromatase inhibitors have a relatively short half-life (approximately 45 hours) compared to clomiphene citrate, and would be ideal for this purpose because they are eliminated from the body rapidly.^115,¹¹⁶ In addition, no adverse effects on estrogen target tissues is expected, because no estrogen receptor down-regulation occurs, in contrast to the estrogen receptor depletion observed in clomiphene citrate-treated cycles.

In addition to the primary response of gonadotropins to diminished estrogen-negative feedback during aromatase inhibitor use, another centrally mediated mechanism of action may be possible independent of GnRH-mediated gonadotropin release. Accumulating evidence suggests that estrogen can modulate the activin/inhibin/follistatin system,¹¹⁷^–¹²⁰ leading to FSH production through a direct effect on the pituitary gonadotropes. Activins are produced by a wide variety of tissues, including the pituitary gland,¹²¹ and stimulate synthesis of FSH by a direct action on the gonadotropes.¹²² Follistatin, also produced by the pituitary gland, is an activin-binding protein and may decrease FSH synthesis by sequestering activin.¹²³ Estrogen, through activin suppression,¹²⁴ was found to selectively suppress FSH, but not LH, production through a GnRH-independent mechanism.¹²⁴^–¹²⁶

In women with PCOS, relative oversuppression of FSH may be the result of excessive androgen produced from the ovary being converted to estrogen by aromatization in the brain. The aromatase inhibitors suppress estrogen production in both the ovaries and the brain. In the case of PCOS, therefore, aromatase inhibitors should result in a robust increase in FSH release and subsequent follicle stimulation and ovulation. The actual FSH release is likely to be blunted by the high circulating inhibin found in PCOS patients ¹²⁷^–¹³⁰ that would not be altered by aromatase inhibition. The raised concentrations of inhibin A and B is probably due to the increased number of small antral follicles.¹²⁹ In addition, because aromatase inhibition does not antagonize estrogen receptors in the brain, the initiation of follicle growth accompanied by increasing concentrations of both estradiol and inhibin results in a normal secondary feedback loop that limits FSH response, thereby avoiding the risk of high multiple ovulation and OHSS.

Peripheral Hypothesis

A second hypothesis to explain the mechanism of action of the aromatase inhibitors in ovarian stimulation involves an increased follicular sensitivity to FSH. This may result from temporary accumulation of intraovarian androgens, because conversion of androgen substrate to estrogen is blocked by aromatase inhibition. Recent data support a stimulatory role for androgens in early follicular growth in primates.¹³¹ Testosterone was found to augment follicular FSH receptor expression in primates, suggesting that androgens promote follicular growth and estrogen biosynthesis indirectly by amplifying FSH effects.^132,¹³³ Also, androgen accumulation in the follicle stimulates insulin-like growth factor I (IGF-I), which may synergize with FSH to promote folliculogenesis.¹³⁴^–¹³⁷ It is likely that women with PCOS already have a relative aromatase deficiency in the ovary, leading to increased intraovarian androgens,^138,¹³⁹ which leads to the development of multiple small follicles responsible for the polycystic morphology of the ovaries. The androgens may also increase FSH receptors, making these PCOS ovaries exquisitely sensitive to an increase in FSH either through exogenous administration of gonadotropins (hence the high risk of OHSS) or through endogenous increases in FSH as a result of decreased central estrogen feedback induced by aromatase inhibition. In the latter case, a relatively small rise in FSH, because of a normal inhibin/estrogen feedback loop, generally leads to monofollicular ovulation, thus avoiding the occurrence of OHSS.

Another part of the peripheral hypothesis involves estrogen receptors in the endometrium. It is possible that aromatase inhibition, with suppression of estrogen concentrations in the circulation and in peripheral target tissues, results in up-regulation of estrogen receptors in the endometrium, leading to rapid endometrial growth once estrogen secretion is restored. Estrogen has been shown to decrease the level of its own receptor by stimulating ubiquitination of estrogen receptors, resulting in rapid degradation of the receptors. In the absence of estrogen, ubiquitination is decreased, allowing up-regulation of the estrogen receptor and increasing sensitivity to subsequent estrogen administration.¹⁴⁰ This could increase endometrial sensitivity to estrogen, resulting in more rapid proliferation of endometrial epithelium and stroma and improved blood flow to the uterus and endometrium.¹⁴¹ As a result, normal endometrial development and thickness occur by the time of follicular maturation, even in the face of the observed lower than normal estradiol concentrations in aromatase inhibitor-treated cycles.¹⁰²^–¹⁰⁹

Potential Advantages Compared to Clomiphene Citrate

The significantly shorter half-life (approximately 45 hours) of the third-generation aromatase inhibitors compared to clomiphene citrate allows rapid elimination from the body.^115,¹¹⁶ Because no estrogen receptor down-regulation occurs, no adverse effects on estrogen target tissues are observed, as is frequently the case with clomiphene citrate. Aromatase inhibitors are, therefore, an interesting alternative to clomiphene citrate, particularly in cases with recurrent clomiphene citrate failure, as explained earlier in this chapter. However, in the case of clomiphene citrate resistance (failure to ovulate) due to severe insulin resistance or the use of clomiphene citrate for inappropriate indications (e.g., hypothalamic amenorrhea or ovarian failure), the use of an aromatase inhibitor is also unlikely to be successful. The correction of insulin resistance with an insulin sensitizer is the logical approach in patients with insulin resistance. Alternative treatments should be considered for other problems, such as exogenous gonadotropin injection in hypothalamic anovulation patients and oocyte donation for cases with ovarian failure.

In rcent years, evidence supporting the success of aromatase inhibitors in infertility treatment has been accumulating.¹⁰²^–¹⁰⁹ Most of the studies used letrozole. However, anastrozole, another third-generation aromatase inhibitor similar to letrozole, was used in other studies.^107,^142,¹⁴³ It is currently not known whether there are any clinically significant pharmacologic differences between letrozole and anastrozole.¹⁴⁴ Recent safety studies have found anastrozole to have no teratogenic or clastogenic effects in animal embryo development.^145,¹⁴⁶

Aromatase Inhibitors and Exogenous Gonatrotropins

Aromatase inhibitors may be used alone for induction of ovulation, or as adjuvants in conjunction with exogenous FSH or other medications to improve the outcome of ovulation induction.

A major advantage of an aromatase inhibitor used alone is the ability to achieve restoration of monofollicular ovulation in anovulatory infertility (e.g., PCOS) with either multiple ^102,^103,¹⁰⁵ or single-dose¹⁴⁷ regimens of aromatase inhibitor early in the menstrual cycle. A single-dose regimen has the benefit of convenience but the potential disadvantage of increasing side effects from administration of a larger dose. However, single doses several times higher than the doses reported for ovulation induction have been administered with no adverse effects observed.^148,¹⁴⁹

An aromatase inhibitor may also be used in conjunction with FSH injections to increase the number of preovulatory follicles that develop and to improve the outcome of treatment. Giving an aromatase inhibitor together with FSH resulted in a significant reduction in the dose of FSH required for optimum ovarian stimulation ¹⁰⁵ even in poor responders.¹⁰⁶ The additional effect of aromatase inhibitors to reduce the supraphysiologic levels of estrogen seen with the development of multiple ovarian follicles may also improve treatment outcome.¹¹⁰

To summarize, the aromatase inhibitor when used alone results in a predictable response with the development of one or two mature follicles and a significantly reduced risk for ovarian hyperstimulation and multiple gestations.¹⁵⁰ To achieve higher-order multiple ovulation, the addition of FSH to the aromatase inhibitor seems to be necessary.

Aromatase Inhibitors for Endometriosis-Related Infertility

The exciting data on the expression of aromatase enzyme in endometriotic tissues with the significant role of locally produced estrogen on endometriosis progression ^151,¹⁵² suggests a benefit of aromatase inhibitors in endometriosis-related infertility. The inhibition of local estrogen production in endometrial implants and the lower peripheral estrogen levels associated with the use of aromatase inhibition for ovulation induction are expected to protect, to some degree, against progression of endometriosis during infertility treatment.

Concerns About Aromatase Inhibitors

There are concerns about using aromatase inhibitors for induction of ovulation, including potential adverse effects of aromatase inhibitors resulting from low follicular estrogen levels and a temporary increase in ovarian androgens. In clinical use, nonsteroidal aromatase inhibitors are generally well tolerated. The main adverse events observed are hot flushes, gastrointestinal events (nausea and vomiting), and leg cramps. Overall, very few patients withdrew from first- or second-line comparative Phase III trials because of drug-related adverse events with aromatase inhibitors.^153,¹⁵⁴ These adverse effects were observed in older women with advanced breast cancer who were given the aromatase inhibitors on a daily basis over several months. Fewer adverse effects would be expected in the usually healthy younger women administered a short course of aromatase inhibitor for induction of ovulation.

The question whether low or very low intrafollicular estrogen is compatible with follicular development, ovulation, and corpus luteum formation has been reviewed before.¹⁵⁵ Markedly reduced to absent intrafollicular concentrations of estrogen are known to be compatible with follicular “expansion,” retrieval of fertilizable oocytes, and apparently normal embryo development.¹⁵⁶^–¹⁶⁰ The rapid clearance of the aromatase inhibitors, the reversible nature of enzyme inhibition, and elevated levels of FSH, which induces new expression of aromatase enzyme, are factors that limit accumulation of androgens and result in increasing estrogen production.

ADVERSE EFFECTS AND CONCERNS REGARDING ORAL OVULATION INDUCTION AGENTS

Multiple Gestations

In the past decade, the significant increase in the incidence of multiple births in most countries is almost entirely the result of the use of gonadotropins and other agents for induction of ovulation.¹⁶¹ According to the National Vital Statistics Reports for 2001, the rate of twinning has increased 33% since 1990 and 59% since 1980. Furthermore, the rate of triplets and higher-order multiples has increased more than 400% since 1980.¹⁶² In 2001, 1.6% of singletons, 11.8% of twins, 36.7% of triplets, 64.5% of quadruplets, and 78.6% of quintuplets were delivered before 32 completed weeks of gestation.¹⁶² Even more noteworthy, the incidence of extreme prematurity (delivery before 28 weeks) for both triplets and quadruplets may be as high as 14%.^163,¹⁶⁴

The increased incidence of maternal and neonatal complications associated with multiple pregnancies has been well documented.^165,¹⁶⁶ Review of data from the National Center for Health Statistics reveals that twins are 4 times more likely than singletons to die within the first month of life, and triplets are 10 times more likely to die in this time.

Hospital costs for each twin or triplet infant can be twice or three times that of a singleton, and lifetime costs to the healthcare system and community may be 100 to 200 times that of a singleton.¹⁶⁷ After controlling for variables known to affect hospital charges, the predicted total charges to the family in 1991 for a singleton delivery were $9,845, as compared with $37,947 for twins ($18,974 per baby) and $109,765 for triplets ($36,588 per baby).¹⁶⁷ Unfortunately, there is substantial pressure from patients in infertility treatment programs to increase their success rates. Among the strategies used are increasing the number of ovarian follicles matured by the administration of exogenous gonadotropins during induction of ovulation and increasing the number of embryos or gametes transferred in cases of IVF. Each of these strategies aims at increasing the percentage of successful pregnancies but also substantially increases the likelihood of multiple pregnancies. That increase, in turn, drives obstetric and neonatal charges higher. Many fear that decreasing the number of follicles stimulated or the number of embryos transferred to reduce the number of multiple pregnancies will lead to lower success rates and an increase in the number of cycles of treatment needed to achieve a pregnancy. However, the European experience with limiting the number of embryos transferred to two or even to single embryo transfer in Scandinavia in good-prognosis patients has not demonstrated a substantial drop in pregnancy rates while reducing the twin rate to less than 10%.¹⁶⁸

More difficult is the problem of multiple pregnancy after ovulation induction with IUI. In the United States reported rates of multiple pregnancies greater than 30% result from ovarian stimulation, most commonly associated with IUI.¹⁶⁹ The incidence of multiple pregnancy ranges from 10% to 15% with gonadotropins alone and from 15% to 29% with gonadotropins and IUI.¹⁷⁰ With clomiphene citrate treatment, multifollicular development is relatively common and the risk of multiple gestation is clearly increased (approximately 8%). The overwhelming majority of multiple pregnancies that result from clomiphene citrate treatment are twin gestations; triplet and higher-order pregnancies are rare but may indeed occur.¹⁷¹ Several recent national studies of the increasing incidence of multiple pregnancies indicate that the vast majority of higher-order multiple gestations (63% to 80%) are a direct result of ovarian stimulation with gonadotropins, mainly FSH with IUI rather than with IVF with embryo transfer.^165,¹⁷² There has been a consistent decrease in the number of embryos transferred per cycle and a drop in the percentage of pregnancies with three or more fetuses since 1997 in the United States.¹⁷²

It is obvious that the best strategy is prevention of the occurrence of multiple pregnancies rather than dealing with the problem after its occurrence (e.g., multifetal pregnancy reduction). Selective fetal reduction presents an ethical problem for many couples, entails the risk of losing all fetuses being carried, and increases psychological stress for couples who have struggled through years of infertility.^173,¹⁷⁴ Other strategies that have focused on the prevention of premature delivery through intensive antenatal monitoring and interventions have been only partially successful in controlling the complications of multiple pregnancies.¹⁷⁵ Each of these proposed methods of improving the outcome of multiple pregnancies relies on post hoc measures used after multiple gestation has been established. As mentioned above, a preferable and more economical solution would be to avoid the conception of multiple fetuses.

Several studies have shown that the number of multiple pregnancies can be decreased by the more judicious use of ovarian stimulation agents, by increased monitoring,^176,¹⁷⁷ and even by the use of less common but safer agents to induce ovulation, such as pulsatile GnRH.¹⁷⁰ These strategies aim at reducing the incidence of multiple pregnancies by reducing multiple ovarian follicular development and by a more aggressive cancellation policy, or conversion to IVF.¹⁶⁹ De Geyter and coworkers used ultrasound-guided aspiration of supernumerary follicles as a way of avoiding multiple-gestation pregnancies without canceling cycles.¹⁷⁸ A study by Pasqualotto¹⁷⁹ found that the total number of follicles was not predictive of the occurrence of multiple gestation. However, another study demonstrated a relationship between multiple gestation and the number of follicles of 15 mm or more.¹⁸⁰ A safe alternative to ovarian follicular aspiration or cancellation may be to convert an IUI cycle to IVF, thereby giving clinicians control over how many embryos are introduced into the uterus. Conversion also prevents the complete financial loss and frustration of a canceled cycle by maintaining a pathway toward possible pregnancy, although the added costs of IVF are incurred.¹⁸¹ In conclusion, none of the methods suggested to reduce the risk of multiple pregnancies after ovarian stimulation and IUI proved to be effective without reducing the success rate significantly or adding significant cost by conversion to IVF. An ovulation induction agent that would achieve ovarian monofollicular development in most cycles with comparable success rate to ovarian stimulation with FSH would be an exciting approach for ameliorating the burden of multiple pregnancies after ovarian stimulation with IUI.

Ovarian Hyperstimulation Syndrome

The incidence of OHSS in clomiphene citrate-treated women and in association with mild gonadotropin stimulation for IUI is difficult to determine, because definitions of the syndrome vary widely among studies. Mild OHSS (moderate ovarian enlargement) is relatively common but does not require active management. When clomiphene citrate induction of ovulation proceeds in the recommended incremental fashion designed to establish the minimum effective dosage, the risk of severe OHSS (massive ovarian enlargement, progressive weight gain, severe abdominal pain, nausea and vomiting, hypovolemia, ascites, and oliguria) is remote.²³ This complication is discussed in more detail in Chapter 40.

Ovarian Cancer

There is an uncertain association between ovarian cancer and clomiphene citrate treatment, derived from two epidemiologic studies published early in the past decade. The first was a case-control study concluding that ovarian cancer risk was increased nearly threefold overall in women receiving various infertility treatments, including clomiphene citrate.¹⁸² The study methodology was widely criticized for several reasons, the most important being that it compared infertile treated women to fertile women rather than to infertile untreated women, even though infertility and nulliparity have long been recognized as risk factors for ovarian cancer. There was no apparent increase in ovarian cancer risk in treated women who conceived. The second study was a cohort study concluding that risk of ovarian tumors was increased in women treated with clomiphene citrate.¹⁸³ Comparisons within the clomiphene citrate-treated cohort showed no increase in risk with less than 12 cycles of treatment. This study too was widely criticized, primarily because it included cancers of varying types and tumors of low malignant potential (e.g., epithelial, germ cell, stromal); the pathophysiology of each is likely very different.

The results of subsequent studies have been reassuring, but the question of whether treatment with ovulation-inducing drugs increases risk of ovarian tumors or cancer remains unsettled and cannot be summarily dismissed.¹⁸⁴^–¹⁸⁷ Certainly, no causal relationship between ovulation-inducing drugs and ovarian cancer has been established. Patients with concerns should be counseled that an increase in risk is possible but not established. In addition, carrying a pregnancy to term and using oral contraceptives for 2 or more years have both been demonstrated to significantly reduce overall ovarian cancer risk¹⁸⁸^–¹⁹⁰ and could offset any potential increase in risk from fertility therapy. No change in prescribing practices is warranted, but prolonged treatment with clomiphene citrate is generally futile and should, therefore, be avoided, primarily because it offers little hope of success.²³

PEARLS

• Chemically, clomiphene citrate is a nonsteroidal triphenylethylene derivative and is chemically related to diethylstilbestrol and tamoxifen.

• Clomiphene citrate acts mainly as an antiestrogen.

• Clomiphene citrate binds estrogen receptors for an extended period of time, weeks rather than hours as is the case with natural estrogen.

• The antiestrogenic effect on the hypothalamus, and possibly the pituitary, is believed to be the main mechanism of action of clomiphene citrate for ovarian stimulation.

• It is believed that the hypothalamus is the main site of action because in normally ovulatory women, clomiphene citrate treatment was found to increase GnRH pulse frequency.

• During clomiphene citrate treatment, levels of both LH and FSH rise, then fall after the typical 5-day course of therapy is completed.

• Treatment typically begins with a single 50-mg tablet daily for 5 consecutive days, increasing by 50-mg increments in subsequent cycles until ovulation is induced.

• Usually the LH surge is observed from 5 to 12 days after the last clomiphene citrate tablet.

• Clomiphene citrate treatment has been reported to successfully induce ovulation in 60% to 80% of properly selected candidates.

• Clomiphene citrate treatment is associated with an increased risk of pregnancy loss, although this might be related to coexisting causes of infertility.

• Preliminary studies suggest that aromatase inhibitors may be an effective and safe alternative to clomiphene citrate for induction or augmentation of ovulation.