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Ovulation induction with clomiphene citrate

Emre Seli, MD
Aydin Arici, MD
Section Editor
Robert L Barbieri, MD
Deputy Editor
Kathryn A Martin, MD


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 "Ovulation induction with letrozole".)


Clomiphene is a nonsteroidal triphenylethylene derivative distantly related to diethylstilbestrol. It acts as a selective estrogen receptor modulator (SERM), similar to tamoxifen and raloxifene. All three drugs are competitive inhibitors of estrogen binding to estrogen receptors (ERs) and have mixed agonist and antagonist activity, depending upon the target tissue. (See "Mechanisms of action of selective estrogen receptor modulators and down-regulators".)

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 [1]. The two clomiphene isomers have mixed estrogenic and antiestrogenic effects that vary among species. En-clomiphene is the more potent isomer with greater antiestrogenic activity and the one primarily responsible for inducing follicular development [2].

Clomiphene is cleared through the liver and excreted in feces. Over 50 percent of an oral dose of 14C-labeled clomiphene citrate is excreted after five days, but traces of radioactivity from the labeled clomiphene appear in the feces up to six weeks after administration. Although this observation raises concerns about fetal exposure to clomiphene, most studies suggest that the frequency of congenital malformations is not increased [3]. (See 'Perinatal outcome' below.)

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Literature review current through: Sep 2017. | This topic last updated: Mar 07, 2016.
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