Combination Letrozole and Clomiphene Citrate Versus Letrozole Alone

Overview

Clomiphene citrate is a non-steroidal 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. Letrozole is a potent, nonsteroidal, aromatase inhibitor, originally used for postmenopausal breast cancer therapy.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and the most common cause of anovulatory infertility. The treatment of infertility in patients with PCOS focuses on ovulation induction. Many treatment regimens have been used, with varying success, to achieve ovulation, pregnancy, and live birth. Clomiphene citrate (CC) is a commonly prescribed pharmacologic agent used to induce ovulation in women with PCOS. It works as a selective estrogen receptor modulator by competitively attaching to nuclear estrogen receptors. As the negative feedback of estrogen is reduced, secretion of gonadotropin hormones increases, inducing ovarian follicular growth. Clomiphene citrate (CC) also has an anti-estrogenic effect on endometrial development and cervical mucus production,which has been suggested to contribute to a relatively low pregnancy rate despite a high ovulation rate. Letrozole is another commonly used oral ovulation induction agent, with a different mechanism of action. It works as a highly selective aromatase inhibitor, preventing androgen-to-estrogen conversion. One proposed mechanism is via suppressed estrogen production resulting in decreased negative feedback on the hypothalamus and increased secretion of Follicular Stimulating Hormone (FSH). An additional proposed mechanism of improved ovulatory rates with the use of letrozole is increased follicular sensitivity to FSH resulting from temporarily increased intraovarian androgens . Letrozole may offer a benefit over CC for ovulation induction because it does not block estrogen receptors in both central and peripheral target tissues, and normal central feedback mechanisms remain intact. The Pregnancy and Polycystic Ovary Syndrome (PPCOS) trial, a randomized controlled trial comparing letrozole and CC, demonstrated that letrozole was associated with a higher live birth rate (27.5% vs. 19.1%; P=007; rate ratio 1.44, 95% confidence interval \[CI\] 1.10-1.87) and cumulative ovulation rate (61.7% vs. 48.3%; P\<.001) among women with PCOS. Other than letrozole or CC for ovulation induction, there are few treatment options available to PCOS patients except proceeding to gonadotropin injections or in vitro fertilization, both of which are associated with increased cost and risk.

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