Induction of Ovulation with Clomiphene Citrate

Ovulatory dysfunction is one of the most common causes of reproductive failure in subfertile and infertile couples. Although the therapeutic armamentarium has expanded significantly in recent years, clomiphene citrate(CC) remains the most commonly prescribed ovulation-inducing medication and is the most appropriate initial choice in the largest majority of anovulatory infertile women.

This chapter provides a brief historical perspective, describes the pharmacology, mode of action, and indications for use of CC, outlines pretreatment evaluation and alternative treatment strategies for the CC-resistant anovulatory woman, discusses methods for monitoring therapy, and reviews the results, side effects, and risks of CC treatment.

Initial studies of the therapeutic potential of CC, conducted more than 40 years ago, focused on its adverse effects on fertility in animal models. In 1960, Kistner and Smith performed the first clinical trials for ovulation induction in women.¹ Soon afterward, Greenblatt and colleagues reported successful induction of ovulation in nearly 80% of a group of amenorrheic anovulatory women, half of whom conceived during treatment.² Since that time, results of CC 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 (OPK) that allow accurate identification of the midcycle luteinizing hormone (LH) surge.

Chemically, CC is a nonsteroidal triphenylethylene derivative and, like other such compounds (e.g., tamoxifen), exhibits both estrogen agonist and antagonist properties, depending on the prevailing levels of endogenous estrogen (Fig. 1).³ Estrogen agonist properties are manifest only when endogenous estrogen levels are extremely low. Otherwise, CC acts solely as an antiestrogen.

Clomiphene is cleared through the liver and excreted in stool; approximately 85% of an administered dose is eliminated after approximately 6 days, although traces may remain in the circulation for much longer.⁴ As currently prescribed, CC is a racemic mixture of two distinct stereoisomers, enclomiphene and zuclomiphene, having different properties. Available evidence indicates that enclomiphene is the more potent isomer and the one primarily responsible for the ovulation-inducing actions of CC.^3,5 Levels of enclomiphene rise rapidly after administration and fall to undetectable concentrations soon thereafter. Zuclomiphene 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.⁶ As discussed below, however, there is no evidence that this accumulation has any important clinical consequence.

Structural similarity to estrogen allows CC to bind to estrogen receptors(ER) throughout the reproductive system; however, in contrast to estrogen, CC binds nuclear ER for an extended period of time, weeks rather than hours, and ultimately depletes ER concentrations by interfering with the normal process of ER replenishment.³ Its effectiveness in ovulation induction can be attributed to actions at the hypothalamic level. Depletion of hypothalamic ER prevents correct interpretation of circulating estrogen levels; estrogen concentrations are falsely perceived as low. Reduced levels of estrogen negative feedback trigger normal compensatory mechanisms that alter the pattern of pulsatile hypothalamic gonadotropin-releasing hormone(GnRH) secretion to stimulate increased secretion of pituitary gonadotropins that, in turn, serve to drive ovarian follicular activity. In normally cycling women, CC treatment increases GnRH pulse frequency.⁷ In anovulatory women with polycystic ovarian syndrome, in whom the GnRH pulse frequency is already abnormally high, CC treatment increases pulse amplitude, but not frequency.⁸ The weight of experimental evidence suggests that CC induces ovulation primarily through the effects on the hypothalamic GnRH pulse generator, but actions at the pituitary level may also be involved. During CC treatment, levels of both LH and follicle-stimulating hormone (FSH) rise, then fall again after the typical 5-day course of therapy is completed.⁹ 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.

Anovulation

The causes of anovulation are many and varied. Whenever possible, treatment should be directed at correcting the underlying cause because correct diagnosis may suggest specific treatment and many of these conditions may have longer-term health consequences. Thyroid disease, pituitary tumors, eating disorders, extremes of weight loss and exercise, hyperprolactinemia, polycystic ovary syndrome, and obesity may be identified, but very often the immediate cause of anovulation cannot be confidently defined. CC is the initial treatment of choice for most anovulatory or oligo-ovulatory infertile women who are euthyroid and euprolactinemic and have normal circulating levels of estrogen.

Luteal Phase Deficiency

Luteal phase deficiency is a controversial disorder that is perhaps best regarded as a subtle form of ovulatory dysfunction in which ovulation occurs, but corpus luteum progesterone production is inadequate in amount and/or duration to support implantation or the normal progress of early pregnancy. Given that the corpus luteum derives from the follicle that ovulates, its functional capacity is, at least in part, dependent on the quality of preovulatory follicle development. In that context, CC is one logical treatment option for luteal phase deficiency.¹⁰ Progesterone levels are typically higher after CC treatment than in spontaneous cycles, reflecting improved preovulatory follicle and corpus luteum development and/or the hormone production from more than one corpus luteum.¹¹

Unexplained Infertility

In couples whose infertility remains unexplained after careful and thorough evaluation, empirical treatment with CC may be justified, particularly in young couples with relatively brief duration of infertility and in those unwilling or unable to pursue more aggressive therapies involving greater costs, risks, and logistic demands. The efficacy of empirical CC treatment may be attributed to correction of subtle and unrecognized ovulatory dysfunction and/or “superovulation” of more than a single ovum.¹² Treatment is most effective when it is combined with properly timed intrauterine insemination (IUI), all in an effort to bring together more than the usual numbers of ova and sperm at the optimal time. Recent studies have demonstrated that cycle fecundity in couples with unexplained infertility treated with CC and IUI is twofold higher than in those who receive no treatment.¹³

Infertile women with amenorrhea or oligomenorrhea (cycles longer than 35 days) are candidates for CC treatment. Basal body temperature (BBT)recordings, serum progesterone determinations, or other means of demonstrating ovulatory dysfunction (OPK, endometrial biopsy, serial transvaginal ultrasound examinations) are unnecessary when menstrual history alone is diagnostic. All patients merit preliminary evaluation to identify any underlying systemic illness that may require additional tests, counseling, or an alternative or specific treatment.

A detailed medical history and physical examination may reveal evidence of other endocrine or metabolic disease (e.g., insulin resistance/diabetes, hyperandrogenism, hyper-/hypothyroidism, hyperprolactinemia). Acanthosis nigricans is often observed in women with underlying insulin resistance or frank diabetes and merits a formal evaluation to exclude these diagnoses. Screening may be limited to a fasting glucose and insulin determination (a glucose/insulin ratio less than 4.5 demonstrating overt insulin resistance), although a glucose challenge (75 g) with repeated determinations at 2 hours offers greater diagnostic sensitivity.¹⁴ Severe hirsutism is indication for measurements of serum 17-hydroxyprogesterone (17-OHP), testosterone, and dehydroepiandrosterone sulfate (DHEA-S). Markedly elevated follicular phase 17-OHP concentrations (>8 ng/mL) establish the diagnosis of congenital adrenal hyperplasia, whereas more modest elevations(2 to 8 ng/mL) require provocative testing with adrenocorticotropic hormone(ACTH) stimulation to exclude that diagnosis.¹⁵ Grossly elevated levels of testosterone (>2 ng/dL)¹⁶ or DHEA-S (>700 μg/dL),¹⁷ or signs of virilization (temporal balding, deepening of the voice, increased muscle mass, and/or clitoromegaly) warrant further evaluation to exclude androgen-producing tumors of the ovary or adrenal glands. Screening for thyroid disorders (serum thyroid-stimulating hormone [TSH]) and hyperprolactinemia (serum prolactin [PRL]) is prudent before beginning CC treatment because both require additional preliminary evaluation and both are most effectively treated with medications other than CC.

Amenorrheic patients require additional evaluation to determine whether circulating estrogen levels are normal or frankly low. This can be accomplished by administering an oral progestin (e.g., medroxyprogesterone acetate, 10 mg daily for 5 days)or by measuring the serum estradiol level. Those who menstruate in response to a progestin challenge or have normal levels of circulating estrogen (estradiol >30 pg/mL)may be expected to respond to CC treatment. Those who fail to menstruate or have a grossly low estrogen level will not and require further evaluation with a serum FSH measurement to determine whether ovarian failure (FSH >20 IU/L) or hypothalamic/pituitary dysfunction (FSH normal or low) is the cause. Any attempt at ovulation induction is generally futile in patients with elevated serum FSH levels. Those with hypothalamic/pituitary dysfunction will rarely respond to CC and typically require treatment with exogenous gonadotropins or a pulsatile GnRH pump to achieve ovulation. To be effective, CC depends on normal operation of the hypothalamic-pituitary-ovarian feedback mechanism. In patients with low circulating estrogen levels and low or normal FSH concentrations, that feedback mechanism is clearly not operating normally; if it were, FSH levels would be frankly elevated. Consequently, successful ovulation induction will require exogenous pulsatile GnRH treatment to reestablish normal communication between the hypothalamus and pituitary, or exogenous gonadotropins to stimulate the ovary directly.

Anovulatory women with a long history of oligomenorrhea or amenorrhea merit preliminary evaluation of the endometrium to ensure that they have not developed hyperplasia or neoplasia as a consequence of long-term unopposed estrogen stimulation, regardless of their age. Endometrial biopsy is diagnostic, but is not always necessary. Transvaginal ultrasound examination and measurement of endometrial thickness is a useful screening tool for identifying those having an abnormally thickened endometrium. In the absence of any data to define the thickness that should be regarded as an indication for biopsy in the asymptomatic individual, thickness greater than 10 mm(e.g., maximum distance between the anterior and posterior endometrial/myometrial interfaces in the midsagittal plane) is a conservative, but reasonable, threshold. Although successful ovulation induction and cyclic endogenous progesterone production will normalize the hyperplastic endometrium within one to three cycles, preliminary treatment with progestational agents is generally recommended before attempts at ovulation induction with CC begin in earnest.

Before CC treatment begins, other important causes of infertility should be excluded. Ovulation induction will achieve little purpose if significant male, uterine, or tubal factors are also present. Preliminary semen analysis is always wise. The test is relatively inexpensive, poses no risk, and when clearly abnormal, often will signal the need for a change in treatment strategy. Evaluation of uterine and tubal factors, typically accomplished by performing a hysterosalpingogram (HSG), should also be considered. A preliminary HSG is clearly indicated in women with past history of pelvic infection, inflammatory bowel disease, or previous pelvic surgery (e.g., myomectomy, ovarian cystectomy, neosalpingostomy). It is also prudent in older women (e.g., 35 years or older) to help avoid ineffective treatment at a time when fertility is steadily declining. It is reasonable to begin CC treatment without preliminary HSG in young asymptomatic anovulatory women with an entirely normal past gynecologic history, but if conception is not achieved within 3 to 6 ovulatory treatment cycles, further evaluation is clearly necessary.

Standard Therapy

CC is administered orally, starting on the 3rd to 5th day after the onset of spontaneous or progestin-induced menses. In anovulatory women, ovulation rates, conception rates, and pregnancy outcome are similar regardless whether treatment begins on cycle day 2, 3, 4, or 5.¹⁸ Although the dose required to achieve ovulation correlates with body weight, there is no reliable way to predict accurately what dose will be required in an individual woman.¹⁹ Consequently, CC induction of ovulation amounts to an empirical incremental titration in efforts to establish the lowest effective dose for each individual (Fig. 2).

Treatment typically begins with a single 50-mg tablet daily for 5 consecutive days (e.g., cycle days 3 to 7 or 5 to 9), increasing by 50-mg increments in subsequent cycles until ovulation is induced (see Fig. 2). The effective dose of CC ranges from 50 to 250 mg/day. Lower doses (e.g., 12.5 to 25 mg/day) deserve a trial in women who demonstrate exquisite sensitivity to CC or consistently develop large ovarian cysts that interfere with efficient cyclic treatment.²⁰ Most women respond to treatment with 50 mg (52%) or 100 mg (22%). Higher doses are sometimes required but also less often successful (150 mg, 12%; 200 mg, 7%; 250 mg, 5%) (Fig. 3).²¹ Most who fail to respond to 150 mg will ultimately require alternative or combination treatments. Once the effective dose of CC is established, there is no indication for further increments unless the ovulatory response is lost. Higher doses will not improve the probability of conception, only the risk of hyperstimulation and multiple pregnancy.

Alternative and Combination Treatment Regimens

Many women who prove resistant or refractory to standard CC treatment regimens will ovulate in response to alternative or combination treatment regimens. These involve longer durations of CC treatment (e.g., an 8-day treatment regimen), the use of “insulin sensitizing” agents (e.g., metformin) or other adjuncts (e.g., exogenous human chorionic gonadotropin [hCG], glucocorticoids), and combinations (e.g., sequential treatment with CC and exogenous gonadotropins). A choice among them should not be arbitrary, but based on specific elements of the patient's history, the results of laboratory evaluation, and/or observations in previous unsuccessful CC treatment cycles. These regimens also should not be considered as a prerequisite for use of more aggressive treatment strategies(e.g., exogenous gonadotropins). They are simply useful alternatives that merit consideration, depending on the patient's age, goals, available resources, and risk tolerance.

EXTENDED COURSE CLOMIPHENE TREATMENT.

Some CC-resistant anovulatory women who fail to respond to a standard 5-day treatment regimen, even at higher dosage levels, may respond to longer courses of CC treatment. An 8-day, high-dose treatment regimen (e.g., 200 to 250 mg/day) can be effective when shorter courses of therapy fail.²²

INSULIN SENSITIZING AGENTS.

Insulin resista nce and hyperinsulinemia are now recognized as a common feature of polycystic ovary syndrome (PCOS) and an important contributing cause of the hyperandrogenism and chronic anovulation that characterize the disorder.²³ Most women with PCOS will respond to CC treatment, but many prove resistant and ultimately require alternative treatment. Among these, a large majority will have demonstrable insulin resistance.

A number of recent studies have demonstrated that treatment with insulin-sensitizing agents (e.g., metformin) alone can restore menses and cyclic ovulation in many amenorrheic PCOS women.^24,25 Some advocate metformin as primary therapy inanovulatory infertile PCOS women with insulin resistance (1000 to 2000 mg/day in divided doses) and add CC only in those who fail to respond. Given the greater costs and complexity of metformin treatment and the frequency of severe gastrointestinal side effects (e.g., nausea, vomiting, diarrhea), others prefer to reserve metformin treatment for those who first prove resistant to CC. In either case, many who fail to ovulate in response to either alone will respond when the two are used in combination.²⁵

CLOMIPHENE AND hCG.

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 CC alone.²⁶ Although this treatment can be successful, relatively few women will clearly benefit, and the method does have distinct potential disadvantages and consequences.

The underlying premise for the use of exogenous hCG must be that CC treatment can promote development of a preovulatory follicle that, for some reason, cannot or does not stimulate the LH surge necessary to achieve ovulation. Physiologically, and in practice, these circumstances are relatively rare. In any event, they could be documented only if follicular development were monitored with serial transvaginal ultrasound examinations that are costly and generally unnecessary. Should these observations be made, serial ultrasound monitoring is again required whenever hCG treatment is anticipated to ensure that the ovulatory stimulus is delivered at or very near the peak of follicular maturity. If administered prematurely, before the follicle is mature enough to respond, hCG is more likely to induce atresia than ovulation.

It is difficult to determine when best to administer exogenous hCG, even in carefully monitored cycles. Clinical studies in anovulatory infertile women have demonstrated that on the day of the spontaneous LH surge in successful CC-induced ovulatory cycles, mean diameter of the lead follicle ranges between 19 and 30 mm (median diameter, 25 mm).²⁷ Given that the average growth rate of the preovulatory follicle over the days immediately preceding ovulation (2 mm/day), that range in peak follicular diameter spans an interval 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 to induce 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.

Occasionally, a couple may require both CC treatment and IUI (with partner or donor sperm) to overcome both anovulation and a coexisting male factor. Clearly, accurate timing of the insemination is crucial to the success of treatment. Ideally, IUI should be performed on the morning after the spontaneous LH surge is detected using an OPK. Use of adjunctive hCG to stimulate ovulation is justified when efforts to detect the LH surge prove unreliable or troublesome. In those cases, the cycle should be monitored and hCG administered as described above, with IUI performed approximately 36 hours thereafter. To be effective, IUI must be timed to coincide with the anticipated time of ovulation. Normally, ovulation occurs between 24 and 48 hours after initiation of the LH surge.²⁸ An OPK detects the LH surge only when urinary LH concentration exceeds the test threshold, necessarily sometime well after initiation of the surge; IUI is therefore best performed 12 to 24 hours later. In contrast, when hCG is used as a surrogate, the “surge” begins at the time of injection with ovulation then expected 24 to 48 hours later. For convenience in scheduling, hCG is generally best administered in the evening hours (i.e., 10:00 p.m.) and IUI performed 2 days later (i.e., 10:00 a.m.).

CLOMIPHENE AND GLUCOCORTICOIDS.

In some CC-resistant PCOS women, addition of glucocorticoids (e.g., dexamethasone 0.5 mg or prednisone 5 mg hs) to the CC treatment regimen will achieve ovulation when CC alone has failed.²⁹ Adjunctive glucocorticoid treatment is perhaps most useful in those having serum DHEA-S levels greater than 200 μg/dL, but can also be empirical, continued if successful and promptly discontinued when it is not.³⁰ Given the potential side effects and risks of chronic glucocorticoid administration, continued treatment should be limited to those who respond and extended durations of treatment avoided.

CLOMIPHENE AND GONADOTROPINS.

CC-resistant anovulatory women who ultimately require exogenous gonadotropins to achieve ovulation might benefit from a trial of sequential CC/gonadotropin therapy using either traditional menotropins (hMG) or newer preparations of purified recombinant FSH (rFSH).³¹ Those in whom CC stimulates significant but only transient follicular growth are the logical candidates. In a typical cycle, CC treatment (e.g., 50 to 100 mg/day, cycle days 5 to 9) is immediately followed by low dose rFSH (e.g., 75 IU/day, cycle days 9 to 12). Monitoring(e.g., transvaginal ultrasound, serum estradiol determinations) begins on cycle day 13, and treatment is individualized thereafter, in the same way as with traditional gonadotropin therapy. Cycle fecundity with this approach is similar to that achieved with gonadotropins alone, but the dose and duration of treatment and the associated costs of monitoring are significantly reduced.

OVARIAN “DRILLING”

A contemporary version of the classical ovarian wedge resection is another treatment option in CC-resistant, hyperandrogenic, anovulatory women (e.g., PCOS). 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. Serum testosterone concentrations typically fall by approximately 40% to 50%, at least for a period of months.³² Data from a number of published series indicate that 70% to 90% of properly selected candidates will ovulate after drilling, and 50% to 80% of those will conceive.^33,34 If not spontaneous ovulation, the procedure may restore sensitivity to CC treatment.³³ Postoperative adhesions that may compromise fertility are a concern and must be considered. Consequently, ovarian drilling is perhaps best reserved for CC-resistant women in whom costs or logistic considerations effectively preclude alternative treatments (e.g., exogenous gonadotropins).

To ensure that ovulation induction is efficiently achieved and maintained, the results of CC treatment must be monitored. Objective evidence of ovulation and normal luteal function is key to successful treatment. Ovulation can be documented using any one of a number of methods. The choice may vary and should be tailored to meet the needs of the individual patient.

BBT recordings provide a simple and inexpensive method for evaluating response to treatment. The method helps to determine the approximate time of ovulation (the 3-day interval immediately before the thermal shift) and length of the luteal phase. Ideally, the thermal shift should occur between cycle days 13 and 21 with menses beginning 12 to 15 days thereafter in a cycle of no greater than 35 days' duration. An OPK 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),³⁵ and luteal phase duration; onset menses should be observed 14 to 17 days after the LH surge. The surge may be observed from 5 to 12 days after treatment is completed, most often on cycle day 16 or 17 when CC is administered on days 5 to 9.²⁸

A BBT or OPK can provide presumptive evidence of ovulation, but neither alone can confirm the quality of luteal function; that requires a serum progesterone determination or endometrial biopsy. Any progesterone level greater than 3 ng/mL is evidence of ovulation,³⁶ but a midluteal phase concentration offers more information. For greatest accuracy, it is best obtained 7 days after the thermal shift in BBT or 7 to 9 days after detection of the midcycle urinary LH surge. Best results are observed when concentrations exceed 10 ng/mL.³⁷ Endometrial biopsy and “secretory” histology that results from the action of progesterone also provides evidence of ovulation. Endometrial “dating” using established histologic criteria is the traditional method for diagnosis of LPD,³⁸ although controversies persist regarding the accuracy of these diagnostic criteria.³⁹ Those controversies, and the cost and discomfort of biopsy, are arguments against the use of biopsy as the means to monitor response to CC treatment. Serial transvaginal ultrasound can reveal the size and number of developing follicles and provide presumptive evidence of ovulation (e.g., progressive follicular growth, sudden collapse of the preovulatory follicle, and an increase in cul-de-sac fluid volume)and luteinization (e.g., loss of clearly defined follicular margins and appearance of internal echoes).⁴⁰ Because of the cost and logistical requirements involved, the method is generally reserved for patients in whom less complicated methods fail to provide the necessary information. A recent study that compared cycle fecundity in CC-induced cycles monitored with BBT, an OPK, or serial ultrasound examinations could demonstrate no clear advantage for any one of these methods.⁴¹

In the past, it was generally recommended that patients receiving CC treatment be seen and examined before each new treatment cycle began to ensure that there was no significant residual ovarian enlargement that might signal the need to postpone further treatment. Accumulated experience has demonstrated that monitoring is unnecessary. Careful studies in anovulatory infertile women receiving CC across a series of consecutive treatment cycles have demonstrated that small residual follicular cysts are relatively common, but these cysts typically do not expand during continued treatment and, if fact, usually regress.²⁸ Consequently, it is unnecessary to perform “baseline” physical or ultrasound examinations before each new treatment cycle, although reasonable to withhold treatment when symptoms lead to discovery of a large cyst or gross residual ovarian enlargement.

CC treatment will successfully induce ovulation in approximately 60% to 80% of properly selected candidates, and approximately half of these may be expected to conceive.^21,42,43 As noted earlier, more than 70% of those who ovulate respond at the 50 mg or 100 mg dosage level. Cumulative conception rates between 60% and 70% are observed after up to three successfully induced ovulatory cycles, 70% to 85% after five (see Fig. 3).²¹ Overall, cycle fecundity is approximately 15% in women who ovulate in response to treatment. In the absence of any other infertility factors, cycle fecundity is higher (22%) and comparable with that seen in fertile women after discontinuation of diaphragm contraception (25%) and in those with male factor infertility who undergo timely artificial insemination with donor sperm. Age and cycle history influence treatment results.⁴⁴ Intrinsically, fecundability (reproductive efficiency)declines with advancing age, and prolonged treatment with CC is unjustified in women in their later reproductive years. Amenorrheic women are more likely to conceive than oligomenorrheic women, probably because those who already ovulate, albeit inconsistently, are more likely to have other coexisting infertility factors. Generally speaking, failure to conceive within six CC-induced ovulatory cycles should be regarded as a clear indication to expand the diagnostic evaluation to exclude other factors or to change the overall treatment strategy when evaluation is already complete.

CC is generally very well tolerated. Some side effects are relatively common, but rarely are they persistent or severe enough to threaten completion of the usual 5-day course or next cycle of treatment. Although CC treatment does have intrinsic risks, they are typically modest and manageable.

Side Effects

Vasomotor flushes (hot flashes) occur in approximately 10% of CC treated women, prevalence being somewhat dose dependent. Given the mechanism of action of CC, they are not surprising. Symptoms are rarely severe, uniformly transient, and typically abate soon after treatment ends. Visual disturbances, including blurred or double vision, scotomata, and light sensitivity, are generally uncommon (<2% prevalence) and reversible, although there are isolated reports of persistent symptoms long after treatment is discontinued and more severe complications such as optic neuropathy.⁴⁵ Whenever visual disturbances are identified, it is prudent to stop treatment and consider alternative methods of ovulation induction. Less specific side effects include breast tenderness, pelvic discomfort, and nausea, all observed in 2% to 5% of CC-treated women.

Risks

MULITIPLE GESTATION.

Although CC induces a rise in endogenous FSH secretion that stimulates increased ovarian follicular development, the rise is only transient, and normal selection mechanisms still operate to yield but a single mature follicle in the largest majority of treatment cycles. Nevertheless, multifollicle development is relatively common and the risk of multiple gestation is clearly increased (approximately 8%).⁴⁶ The overwhelming majority of multiple pregnancies that result from CC treatment are twin gestations; triplet and higher order pregnancies are rare but may indeed occur. The risk of multiple gestation is but another reason to treat with the lowest effective dose of CC, once it is established. Higher doses cannot further improve results and only increase the risk of superovulation and multiple gestation with its attendant antenatal and neonatal complications.

CONGENITAL ANOMALIES.

There is no evidence that CC treatment increases the overall risk of birth defects or of any one anomaly in particular. Several large series have examined the question and have drawn the same conclusion.^47,48,49 Earlier suggestions that the incidence of neural tube defects might be higher in pregnancies conceived during CC treatment have not been confirmed by more recent studies.^50,51 A small study of pregnancy outcome in women inadvertently exposed to CC during the first trimester also found no increase in the prevalence of congenital anomalies.⁵²

SPONTANEOUS ABORTION.

Early studies suggested that the incidence of spontaneous abortion in pregnancies resulting from CC treatment was increased over that observed in spontaneous pregnancies; however, a number of more recent studies have described abortion rates that are not different from those observed in spontaneous pregnancies (10% to 15%).^53,54

OVARIAN HYPERSTIMULATION SYNDROME.

The incidence of ovarian hyperstimulation syndrome (OHSS) in CC-treated women is difficult to determine as definitions of the syndrome vary widely among studies. Mild OHSS (moderate ovarian enlargement) is relatively common, but also does not require active management. When CC 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.

OVARIAN CANCER.

Two epidemiologic studies published early in the last decade suggested that the risk of ovarian cancer might be significantly increased in women exposed to ovulation-inducing drugs. The first was a case-control study and concluded that ovarian cancer risk was increased nearly threefold overall in treated women.⁵⁵ The study methodology was widely criticized for several reasons, the most important being that it compared infertile treated women to fertile women rather than 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, only in those who did not. The second was a case-cohort study and concluded that risk of ovarian tumors was increased in women treated with CC.⁵⁶ Comparisons within the CC-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) when the pathophysiology of each is very likely 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.^57,58,59,60 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. No change in prescribing practices is warranted, but prolonged treatment with CC is generally futile and may result in an unnecessary increase in risk. It should therefore be avoided, primarily because it offers little hope of success.

ADVERSE ANTIESTROGENIC EFFECTS.

Many believe that in addition to the desirable central actions responsible for its efficacy as an ovulation-inducing agent, CC exerts undesirable and unavoidable adverse antiestrogenic effects in the periphery (endocervix, endometrium, ovary, ovum, and embryo) that explain the “discrepancy” between the ovulation and conception rates observed in CC-treated patients. 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. Conventional wisdom holds that these effects have distinct clinical consequences that are most apparent at higher doses or after longer durations of treatment and that treatment with exogenous supplemental estrogen may help to minimize or negate them.^61,62 There is, however, little or no compelling evidence to support these notions.

The quality and quantity of cervical mucus production in CC treatment cycles may sometimes be reduced,⁶³ but rarely to an extent that risks interference with the effective capture, survival, or transport of sperm. Moreover, cervical mucus score (based on quantity and quality) has no proven prognostic value.^64,65 Limited endometrial proliferation has been observed in some CC-treated patients,⁶⁶ but the effect is minor or not at all evident in the largest majority of women.^67,68,69 Although some studies have suggested that fecundity may relate to endometrial thickness, others have failed to demonstrate any significant correlation. CC has indeed been shown to inhibit steroid hormone production by cultured avian,⁷⁰ ovine,⁷¹ and human granulosa/luteal cells,^72,73 but estrogen and progesterone levels in CC-induced cycles are typically significantly higher, not lower, than in spontaneous cycles. Adverse effects of CC on mouse ovum fertilization and embryo development have been demonstrated in vitro,⁷⁴ but clinical studies have revealed that circulating levels of CC never reach the concentrations required to produce these effects, even after several consecutive treatment cycles.

Available evidence and accumulated clinical experience suggest that any adverse antiestrogenic effects that CC may have present no significant obstacle in the largest majority of treated women. Moreover, even when clinical observations in an individual patient suggest the possibility, no form of treatment can reliably overcome or reverse those effects.⁶⁰ Consequently, an alternative treatment is indicated, just as it is in those who exhibit no adverse effects and do not conceive. Induction of ovulation with exogenous gonadotropins is an obvious choice. The elevated serum estrogen levels that generally accompany treatment also stimulate both cervical mucus production and endometrial proliferation maximally. Recent studies suggest that tamoxifen may be as effective as CC for ovulation induction (e.g., 10 to 20 mg/day cycle days 3 to 7 or 5 to 9).⁷⁵ Given its tendency to stimulate rather than attenuate endometrial proliferation, this option may deserve consideration before resorting to the use of exogenous gonadotropins on those few occasions when frankly poor endometrial growth is observed in CC-induced ovulatory cycles.

CC remains the mainstay of ovulation induction therapy. Advantages include oral administration, limited monitoring requirements, mild side effects, and a comparatively low cost and risk of multiple gestation. Treatment should be with the lowest effective dose, empirically determined, and rarely exceed six cycles of therapy once that is established. Failure to conceive despite successful CC-induced ovulation is indication to expand evaluation to exclude other coexisting infertility factors or to change the overall treatment strategy.