Doi:10.1016/j.fertnstert.2006.08.023

Use of clomiphene citrate in women
The Practice Committee of the American Society for Reproductive Medicine American Society for Reproductive Medicine, Birmingham, Alabama Ovulatory dysfunction is one of the most common causes of over consecutive cycles of treatment, but there is no evi- reproductive failure in sub-fertile and infertile couples. In the dence of any important clinical consequence absence of other significant infertility factors, successfulovulation induction often will restore normal fertility. Clo-miphene citrate (CC) is the best initial treatment for the large MODE OF ACTION
majority of anovulatory infertile women. The first clinical Structural similarity to estrogen allows CC to bind to estro- trial of CC therapy demonstrated successful ovulation induc- gen receptors (ER) throughout the reproductive system.
tion in 80% of women, half of whom achieved pregnancy However, in contrast to estrogen, CC binds nuclear ER for an during treatment In subsequent years, results of CC extended period of time and ultimately depletes ER concen- treatment have not changed appreciably, despite the advent trations by interfering with the normal process of ER replen- of modern immunoassays for steroid hormones, advances in ishment The drug’s effectiveness in ovulation induction ultrasound technology for cycle monitoring, and the intro- can be attributed to actions at the hypothalamic level. De- duction of commercial test kits that allow detection of the pletion of hypothalamic ER prevents correct interpretation of midcycle luteinizing hormone (LH) surge in urine.
circulating estrogen levels. Reduced levels of estrogen neg-ative feedback trigger normal compensatory mechanisms This guideline will first describe the pharmacology, mode that alter pulsatile hypothalamic GnRH secretion to stimu- of action, and indications for CC treatment. Second, it will late increased pituitary gonadotropin release that, in turn, outline the pretreatment evaluation, standard and combina- drives ovarian follicular activity. In ovulatory women, CC tion treatment regimens, and alternative strategies for the treatment increases GnRH pulse frequency In anovula- CC-resistant patient. Lastly, it will summarize the methods tory women with polycystic ovary syndrome (PCOS) in for monitoring therapy and review the results, side effects, whom the GnRH pulse frequency is already abnormally high, CC treatment increases pulse amplitude, but not fre-quency During CC treatment, levels of both LH and FSH PHARMACOLOGY
rise, falling again after the typical 5-day course of therapy is Chemically, CC (like tamoxifen) is a nonsteroidal triphenyleth- completed In successful treatment cycles, one or more ylene derivative that exhibits both estrogen agonist and antag- dominant follicles emerge and mature, generating a rising onist properties In general, estrogen agonist properties are tide of E that ultimately triggers the midcycle LH surge and manifest only when endogenous estrogen levels are extremely low. Otherwise, CC acts solely as a competitive estrogen Not surprisingly, tamoxifen also has been used success- antagonist. Clomiphene citrate is cleared through the liver fully to induce ovulation in anovulatory infertile women and excreted in stool. About 85% of an administered dose is Given its structural similarity to CC, its mechanism of action eliminated after approximately 6 days, although traces may presumably is also similar Recent evidence suggests remain in the circulation for much longer As currently that letrozole, an orally active aromatase inhibitor, may have manufactured, CC is a racemic mixture of two distinct ste- potential as an ovulation-inducing agent In contrast reoisomers, enclomiphene and zuclomiphene. Available ev- to the central actions of CC and tamoxifen, letrozole acts in idence indicates that enclomiphene is the more potent isomer the periphery to inhibit ovarian follicular E production, but and the one primarily responsible for the ovulation inducing the end result is similar—a decrease in central estrogen actions of CC Enclomiphene levels rise rapidly after feedback action that stimulates a compensatory increase in administration and fall to undetectable concentrations soon thereafter. Zuclomiphene is cleared far more slowly. Levelsof this less active isomer remain detectable in the circulationfor more than a month after treatment and may accumulate INDICATIONS
Anovulation
The causes of anovulation are many and varied. Whenever Committee Opinion
Reviewed June 2006.
possible, treatment should be directed at correcting the un- Received June 20, 2003; and accepted June 20, 2003.
derlying cause. Correct diagnosis may suggest specific treat- ment, and many conditions may have longer-term health Correspondence to: Practice Committee, American Society for Repro- consequences. Thyroid disease, pituitary tumors, eating dis- ductive Medicine, 1209 Montgomery Highway, Birmingham, Alabama35216.
orders, extremes of weight loss and exercise, hyperpro- Fertility and Sterilityா Vol. 86, Suppl 4, November 2006 S187
Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc.
lactinemia, PCOS, and obesity may be identified, but very Acanthosis nigricans is often observed in women with un- often the immediate cause of anovulation cannot be confi- derlying insulin resistance or frank diabetes and merits for- dently defined. CC is the initial treatment of choice for most mal evaluation to exclude these diagnoses Screening anovulatory or oligo-ovulatory infertile women. However, for hypothyroidism (serum TSH) and hyperprolactinemia given its hypothalamic site of action, CC is often ineffective (serum prolactin) is reasonable since both disorders are best in women with hypogonadotropic hypogonadism (hypotha- treated with medications other than CC Hirsutism lamic amenorrhea). Women with other demonstrable endo- that is severe or rapid in progression warrants specific addi- crinopathies (diabetes mellitus, thyroid disorders, hyperpro- tional evaluation to exclude non-classic congenital adrenal lactinemia, congenital adrenal hyperplasia) should first hyperplasia (CAH) and androgen-producing tumors of the receive specific treatment and be offered CC only when that therapy fails to restore regular ovulatory cycles.
Attempts at ovulation induction are generally futile in women with elevated serum FSH levels. Those with hypothalamic/ Luteal Phase Deficiency
pituitary dysfunction are also unlikely to respond to CC as its Given that the corpus luteum derives from the follicle that mechanism of action requires a functional hypothalamic/ ovulates, its functional capacity is, at least in part, dependent pituitary/ovarian feedback axis. Alternative treatments that on the quality of preovulatory follicle development. In that will reestablish normal hypothalamic/pituitary communication context, CC is one logical treatment option for luteal phase (pulsatile exogenous GnRH) or stimulate the ovary directly deficiency (LPD) Progesterone levels are typically (exogenous gonadotropins) will generally be required.
higher after CC treatment than in spontaneous cycles, re-flecting improved preovulatory follicle and corpus luteum Ovulation induction has little value when severe male, development and/or the combined hormone production of uterine, or tubal factors are also present. Semen analysis should be performed to identify seminal abnormalities thatalso may require treatment. Hysterosalpingography is indi-cated when clinical history raises suspicion of uterine or Unexplained Infertility
tubal pathology (pelvic infection or surgery, ectopic preg- In couples whose infertility remains unexplained after care- nancy, inflammatory bowel disease), but may otherwise be ful and thorough evaluation, empiric treatment with CC may reserved for those who fail to conceive within three to six be justified, particularly in young couples with a short du- ovulatory treatment cycles. An HSG is also prudent in older ration of infertility and in those unwilling or unable to pursue women (over 35 years) to avoid ineffective treatment at a more aggressive therapies involving greater costs, risks, and time when fertility is steadily declining.
logistical demands The efficacy of empiric CCtreatment may be attributed to correction of subtle and un-recognized ovulatory dysfunction and/or “superovulation” of TREATMENT REGIMENS
more than a single ovum CC treatment is most effective Standard Therapy
when it is combined with properly timed intrauterine insem- CC is administered orally, typically starting on the third to fifth ination (IUI), all in an effort to bring together more than the day after the onset of spontaneous or progestin-induced menses; usual numbers of ova and sperm at the optimal time ovulation rates, conception rates, and pregnancy outcome aresimilar regardless whether treatment begins on cycle day 2, PRETREATMENT EVALUATION
3, 4, or 5 Although the dose required to achieve Infertile women who rarely or never ovulate are candidates ovulation correlates with body weight, there is no reliable for CC treatment. Diagnosis of ovulatory dysfunction may way to accurately predict what dose will be required in an individual woman Consequently, CC induction of ovu-lation amounts to an empiric incremental titration in efforts to establish the lowest effective dose for each individual.
● Timed serum P determinations● Monitoring urinary LH excretion Treatment typically begins with a single 50-mg tablet daily for 5 consecutive days, increasing by 50-mg incre- ● Serial transvaginal ultrasound examinations ments in subsequent cycles until ovulation is induced. Theeffective dose of CC ranges from 50 mg/day to 250 mg/day, However, specific tests of ovulation are unnecessary when although doses in excess of 100 mg/day are not approved by menstrual history alone is diagnostic (amenorrhea, oligo- the Food and Drug Administration (FDA). Lower doses menorrhea). Once identified, anovulatory infertile women (e.g., 12.5 mg/day to 25 mg/day) deserve a trial in women merit additional pretreatment evaluation to identify any un- who demonstrate exquisite sensitivity to CC or consistently derlying systemic illness that may require additional tests, develop large ovarian cysts that interfere with efficient cyclic treatment Most women ovulate in response to treatment A detailed medical history and physical examination may with 50 mg (52%) or 100 mg (22%); higher doses have been reveal evidence of other endocrine or metabolic disease.
used, but also are less often successful (150 mg, 12%; 200 Use of clomiphene citrate in women
mg, 7%; 250 mg, 5%) Some CC-resistant anovulatory domized trials have demonstrated that IUI after exogenous women who fail to respond to a standard 5-day treatment hCG-triggered ovulation in CC-induced cycles is no more regimen may respond to longer courses (8 days) of CC effective than IUI performed after detection of the endoge- treatment but such treatment should be considered only nous LH surge Therefore, use of exogenous hCG is when alternative treatment with exogenous gonadotropins is perhaps best limited to those women who require IUI and in whom a midcycle LH surge cannot reliably be detected.
Clomiphene and Glucocorticoids In some CC-resistant
Alternative and Combination Treatment Regimens
PCOS women, addition of glucocorticoids (e.g., dexameth-asone 0.5 mg or prednisone 5 mg hs) to the CC treatment Many women who prove resistant or refractory to standard regimen may induce ovulation when CC alone has failed CC treatment may ovulate in response to alternative treat- Adjunctive glucocorticoid treatment may be based on ment regimens. A choice among them should not be arbi- the serum DHEAS concentration (Ͼ200 ␮g/dL) or trary, but based on specific elements of the patient’s history, empiric Treatment may be continued (three to six results of laboratory evaluation, and/or observations in pre-vious unsuccessful CC treatment cycles. These regimens cycles) when it is successful and should be promptly discon- also should not be considered as a prerequisite for use of tinued when it is not. There is no evidence that glucocorti- more aggressive treatment strategies (e.g., exogenous gonad- coid treatment has any important side effects or risks when otropins). They are merely useful alternatives that merit used in the doses or for the duration indicated.
consideration, depending on the patient’s age, goals, avail- Clomiphene and Gonadotropins CC-resistant anovulatory
women who ultimately require exogenous gonadotropins to Insulin Sensitizing Agents Insulin resistance and hyperinsu-
achieve ovulation and those with unexplained infertility might linemia are common features in women with PCOS. Most benefit from a trial of sequential CC/gonadotropin therapy women with PCOS will respond to CC, but many prove using either traditional menotropins (hMG) or purified or re- resistant and ultimately require alternative treatment. Among combinant FSH Given the costs and risks of exogenous these, a large majority will have demonstrable insulin resis- gonadotropin therapy, treatment should be offered only by tance Insulin sensitizing agents (e.g., metformin) alone those having the requisite training or experience. The typical can restore menses and cyclic ovulation in many amenor- cycle includes a standard CC treatment regimen (50 mg/day to rheic PCOS women although they are not currently 100 mg/day, cycle days 5–9), followed by low-dose hMG or approved by the FDA for this indication. Based on observa- FSH (75 IU/day, cycle days 9 –12). Treatment is individual- tions from open trials, some advocate metformin as primary ized thereafter, in the same way as with traditional gonado- therapy in anovulatory infertile PCOS women (1,000 mg/day tropin therapy, based on transvaginal ultrasound examina- to 2,000 mg/day in divided doses) and add CC only in those tions. Cycle fecundity with this approach is similar to that who fail to respond Given the greater costs and com- achieved with gonadotropins alone, but the dose and dura- plexity of metformin treatment and the frequency of severe tion of treatment and the associated costs of monitoring may gastrointestinal side effects (e.g., nausea, vomiting, diar- be significantly reduced. Treatment with exogenous gonad- rhea), others prefer to reserve metformin treatment for those otropins alone is the obvious alternative. CC-resistant anovu- who first prove resistant to CC. In either case, many who fail latory women are often very sensitive to low doses of go- to ovulate in response to either alone will respond when the nadotropins and treatment should be aimed at achieving two are used in combination Because metformin ovulation of but a single mature follicle if possible. There is therapy may have hepatic toxicity or be complicated by no indication for purposeful superovulation in the anovula- lactic acidosis, liver and renal functions must be evaluated before treatment and monitored periodically thereafter. Al- Ovarian “Drilling” A contemporary version of the classic
though the safety of metformin treatment in pregnancy has ovarian wedge resection is another treatment option in CC- not been established, preliminary evidence suggests that it resistant, hyperandrogenic, anovulatory women (e.g., PCOS).
may reduce the incident risk of spontaneous abortion and The technique involves laparoscopic cautery, diathermy, or laser vaporization of the ovaries at multiple sites, the objective Clomiphene and hCG Although exogenous hCG has been
being to decrease circulating and intraovarian androgen lev- used to trigger ovulation and define the optimal time to els by reducing the volume of ovarian stroma. Data derived perform IUI in CC-induced cycles, the practice is difficult to from randomized controlled trials suggest that initial ovula- justify on a routine basis. Treatment requires costly moni- tion and pregnancy rates after ovarian drilling are similar to toring with serial transvaginal ultrasound examinations that those achieved by treatment with exogenous gonadotropins, are otherwise unnecessary. The mean peak diameter of the and the risk of multiple pregnancy is lower When it preovulatory follicle in successful CC-induced ovulatory does not result in spontaneous ovulation, ovarian drilling cycles ranges between 19 and 30 mm (median diameter: 25 may help to restore sensitivity to CC treatment. Ovarian mm) and the optimum time to administer hCG is drilling is a reasonable option for clomiphene-resistant therefore difficult to determine. Most importantly, two ran- anovulatory women, but the temporary effects of treatment FERTILITY & STERILITYா
and the risks of postoperative adhesions or diminished ovar- Results of Treatment
ian reserve should be carefully considered.
CC treatment will successfully induce ovulation in approx-imately 80% of properly selected candidates. Likelihood ofresponse declines with increasing age, body mass index Treatment Monitoring
(BMI), and free androgen index Overall, cycle fecun- Objective evidence of ovulation and normal luteal function dity is approximately 15% in anovulatory women who re- is key to successful treatment. Ovulation can be documented spond to treatment. In the absence of any other infertility using any one of a number of methods. The choice may vary factors, cycle fecundity is higher (22%), and comparable to and should be tailored to meet the needs of the individual that seen in fertile women after discontinuation of diaphragm contraception (25%) and in those with male factor infertilitywho receive inseminations with donor sperm. Approxi- Basal body temperature (BBT) recordings provide a simple mately 70% to 75% of anovulatory women who respond to and inexpensive method for evaluating response to treatment, CC (50 mg/day to 150 mg/day, as required) may be expected but may be tedious. Test kits that can identify the midcycle LH to conceive within six to nine cycles of treatment surge in urine more precisely define both the interval of peak Amenorrheic women are more likely to conceive than oli- fertility and luteal phase duration The surge is typically gomenorrheic women, probably because those who already observed between 5 and 12 days after treatment is completed, ovulate albeit inconsistently, are more likely to have most often on cycle day 16 or 17 when CC is administered on other co-existing infertility factors. In infertile women with days 5–9 Whereas any P level greater than 3 ng/mL luteal phase deficiency, CC treatment increases luteal phase provides presumptive evidence of ovulation a midluteal phase concentration offers more information regarding the quality of luteal function. Best results are observed when con-centrations exceed 10 ng/mL Fecundability declines with advancing age; and prolonged treatment with CC is unjustified in women in their latter Endometrial biopsy revealing a secretory endometrium reproductive years. The failure to conceive within a maxi- also provides evidence of ovulation. Endometrial “dating” mum of six CC-induced normal ovulatory cycles is a clear using established histologic criteria may reveal evidence of indication to expand the diagnostic evaluation to exclude LPD although controversies persist regarding the ac- other infertility factors or to change the overall treatment curacy of traditional diagnostic criteria. Serial transvaginal strategy if evaluation is already complete.
ultrasound can reveal the size and number of developing In randomized trials, cycle fecundity in women with un- follicles and provide presumptive evidence of ovulation explained infertility treated with empiric CC has ranged (progressive follicular growth, sudden collapse of the pre- from 3.4% to 8.1% The benefits of CC treatment ovulatory follicle, and an increase in cul-de-sac fluid vol- alone are relatively small— one additional pregnancy for ume) and luteinization (loss of clearly defined follicular every 40 cycles of treatment. Based on observations in margins and appearance of internal echoes) However, clinical trials, cycle fecundity in couples with unexplained because of the cost and logistical demands involved, the infertility treated with CC/IUI is approximately 8.5% to method generally is reserved for patients in whom less 9.5%, at least twofold higher than in those who receive no complicated methods fail to provide the necessary informa- treatment CC/IUI yields one additional pregnancy tion. In CC/IUI cycles in couples with unexplained infertil- ity, transvaginal ultrasound is useful to confirm that treat-ment successfully promotes development of more than onemature follicle. A recent study that compared cycle fecundity SIDE EFFECTS AND RISKS
in CC-induced cycles monitored with BBT, urinary LH CC is generally very well tolerated. Some side effects are excretion, or serial ultrasound examinations could demon- relatively common, but rarely are they persistent or severe strate no clear advantage for any one of these methods enough to threaten completion of the usual 5-day course ornext cycle of treatment. Although CC treatment does have In the past, examination to exclude any significant residual intrinsic risks, they are typically modest and manageable.
ovarian enlargement has been recommended before eachnew treatment cycle. Although it is prudent to postponefurther treatment when symptoms lead to discovery of a Side Effects
large cyst or grossly enlarged ovaries, clinical studies Vasomotor flushes (hot flashes) occur in approximately 10% and accumulated clinical experience suggest that routine of CC-treated women, but typically abate soon after treat- “baseline” physical or ultrasound examinations are not al- ment ends. Mood swings are also common. Visual distur- ways necessary. Nevertheless, regular contact should be bances, including blurred or double vision, scotomata, and maintained to review response to treatment and to ensure light sensitivity, are generally uncommon (Ͻ2% prevalence) that any additional evaluation or alternative treatment that and reversible, although there are isolated reports of persis- tent symptoms and more severe complications such as optic Use of clomiphene citrate in women
neuropathy Whenever visual disturbances are identi- fied, it is prudent to stop treatment and consider alternative Ovarian Hyperstimulation Syndrome The incidence of ovar-
methods of ovulation induction. Less specific side effects ian hyperstimulation syndrome (OHSS) in CC-treated women include breast tenderness, pelvic discomfort, and nausea, all is difficult to determine, as definitions of the syndrome vary observed in 2% to 5% of CC-treated women.
widely among studies. Whereas mild OHSS (moderate ovar- Numerous studies have suggested that in addition to the ian enlargement) is relatively common, severe OHSS (mas- desirable central actions responsible for its efficacy as an sive ovarian enlargement, progressive weight gain, severe ovulation inducing agent, CC exerts undesirable and un- abdominal pain, nausea and vomiting, hypovolemia, ascites, avoidable adverse antiestrogenic effects in the periphery (endocervix, endometrium, ovary, ovum, and embryo) that Ovarian Cancer Two epidemiologic studies published early
explain the “discrepancy” between the ovulation and con- in the last decade suggested that the risk of ovarian cancer ception rates observed in CC-treated patients. However, might be significantly increased in women exposed to ovu- there is little or no compelling evidence to support these lation inducing drugs but subsequent studies have notions. The quality and quantity of cervical mucus produc- failed to corroborate those findings A recent pooled tion in CC treatment cycles may sometimes be reduced analysis of eight case-control studies concluded that neither but rarely to an extent that risks interference with the effec- fertility drug use nor use for more than 12 months was tive capture, survival, or transport of sperm. Limited endo- associated with invasive ovarian cancer Patients with metrial proliferation has been observed in some CC-treated concerns should be counseled that no causal relationship patients but the effect is minor or not at all evident in the between ovulation inducing drugs and ovarian cancer has large majority of women When reduced endome- been established and no change in prescribing practices is trial thickness is observed in CC-induced ovulatory cycles, warranted. In any case, prolonged treatment with CC is tamoxifen or letrozole may offer an alternative generally futile and should therefore be avoided.
method for ovulation induction that may avoid this effect.
Although some studies have suggested that fecundity mayrelate to endometrial thickness, others have failed to dem- SUMMARY AND CONCLUSIONS
onstrate any significant correlation. CC has indeed beenshown to inhibit steroid hormone production by cultured ● CC is the best initial treatment for the majority of women avian ovine and human granulosa/luteal cells whose infertility is associated with ovulatory dysfunction but estrogen and P levels in CC-induced cycles are typically (anovulation, luteal phase deficiency). Combined with ap- significantly higher, not lower, than in spontaneous cycles.
propriately timed IUI, CC treatment also increases cycle Adverse effects of CC on mouse ovum fertilization and fecundity in couples with unexplained infertility.
embryo development have been demonstrated in vitro ● CC treatment generally should be limited to the minimum but circulating levels of CC never reach the concentrations effective dose and to no more than six ovulatory cycles.
required to produce these effects, even after several consec- Failure to conceive after successful CC-induced ovulation utive treatment cycles Taken together, available evi- is indication for further evaluation to exclude other con- dence and accumulated clinical experience suggest that any adverse antiestrogenic effects of CC present no significant ● Combination therapies involving CC and other agents (met- obstacle in the majority of treated women.
formin, glucocorticoids, exogenous gonadotropins) may beeffective when treatment with CC alone fails to induce ovu-lation. Alternative strategies for the CC-resistant woman Risks and Complications
include treatment with aromatase inhibitors or exogenous Multiple Gestation Multifollicular development is relatively
gonadotropins and, in selected patients, ovarian drilling.
common during CC treatment and the risk of multiple ges- ● CC treatment should be monitored (BBT, serum P con- tation is clearly increased to approximately 8% overall centration, urinary LH excretion) to ensure its effective- The overwhelming majority of multiple pregnancies that result from CC treatment are twin gestations; triplet and ● Side effects of CC treatment are generally mild and well higher order pregnancies are rare but may occur.
tolerated. The principal risk of CC treatment is an in- Congenital Anomalies There is no evidence that CC treat-
creased incidence of multifetal gestation (Ͻ10%).
ment increases the overall risk of birth defects or of any oneanomaly in particular Acknowledgments: This report was developed under the direction of thePractice Committee of the American Society for Reproductive Medicine as Spontaneous Abortion Early studies suggested that the in-
a service to its members and other practicing clinicians. While this docu- cidence of spontaneous abortion in pregnancies resulting ment reflects appropriate management of a problem encountered in the from CC treatment was increased over that observed in practice of reproductive medicine, it is not intended to be the only approvedstandard of practice or to dictate an exclusive course of treatment. Other spontaneous pregnancies. However, a number of more recent plans of management may be appropriate, taking into account the needs of studies have described abortion rates that are not different the individual patient, available resources and institutional or clinical practice from those observed in spontaneous pregnancies (10% to limitations. This bulletin was approved by the Practice Committee of the FERTILITY & STERILITYா
American Society for Reproductive Medicine, and the Board of Directors of the 22. Practice Committee Report. Evaluation and treatment of androgen American Society for Reproductive Medicine.
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