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.

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.

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.

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.

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.

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.

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. 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.