Clomiphene citrate has been the most widely used treatment for fertility enhancement for the past 40 years. Clomiphene was a revolutionary advance in reproductive medicine and quickly became popular for induction of ovulation because of its ease of administration and minimal side effects. Ironically, it was initially synthesized as a synthetic estrogen for possible use as a contraceptive.
The pharmacology, indications, and administration of clomiphene citrate will be reviewed here. Other drugs for induction of ovulation are discussed elsewhere. (See "Overview of ovulation induction" and "Strategies for improving the efficacy of clomiphene induction of ovulation".)
Clomiphene is a triphenylethylene derivative distantly related to diethylstilbestrol. It acts as a selective estrogen receptor modulator, similar to tamoxifen and raloxifene. All three drugs are competitive inhibitors of estrogen binding to estrogen receptors and have mixed agonist and antagonist activity, depending upon the target tissue. (See "Mechanisms of action of selective estrogen receptor modulators".)
The commercially available form of clomiphene is the dihydrogen citrate salt (clomiphene citrate). It contains two stereoisomers: zu-clomiphene (38 percent) and en-clomiphene (62 percent), which were originally called the cis-isomer and trans-isomer, respectively. En-clomiphene is cleared rapidly, while zu-clomiphene has a long half-life. The two clomiphene isomers have mixed estrogenic and antiestrogenic effects that vary among species. Zu-clomiphene appears to have greater estrogenic activity than en-clomiphene .
14C-labeled clomiphene citrate is absorbed by the gastrointestinal tract. Fifty percent of the oral dose is excreted after five days, but radioactivity from labeled clomiphene appears in the feces up to six weeks after administration. However, the pharmacologic effect of clomiphene citrate is brief .