!DOCTYPE html>
Treatment of WHO 2: Aromatase Inhibitors
Introduction
Worldwide, approximately 49 million couples have difficulty conceiving, of which about 20 million couples have primary infertility, and 29 million couples have secondary infertility (1). The estimated proportion of patients having an ovulatory disorder out of this population is 15%, most of them classified as WHO class 2 anovulation (PCOS prototype). A simple, safe method of ovulation induction is important because there are millions of women with anovulatory infertility around the world, many without access to ultrasound monitoring or even access to an infertility specialist. An inexpensive, oral agent for ovulation induction that has few side effects and that requires very little if any monitoring to prevent multiple pregnancies is urgently needed. We believe that the use of aromatase inhibitors fulfills these criteria. In this chapter, we describe the use of aromatase inhibitors for ovulation induction in the subset of patients with WHO 2 ovulatory problems.
Overview of Existing Evidence
Letrozole is a potent, nonsteroidal, aromatase inhibitor (AI), originally used for postmenopausal breast cancer therapy, which, at present, is its only registered indication. Unlike the selective estrogen receptor modulators (SERMs), such as clomiphene citrate and tamoxifen, letrozole’s mechanism of action does not involve depletion of estrogen receptors nor estrogen receptor antagonism with subsequent anti-estrogenic effects.
Aromatase is the catalyzing enzyme for the rate-limiting step in estrogen biosynthesis. It is expressed in the ovary as well as in other tissues, such as fat, muscle, liver, brain, and breast. Letrozole, a third-generation AI, effectively blocks the production of estrogen from the androgen precursors without disturbing other steroidogenic pathways. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme. Following oral administration, which is not affected by food, letrozole is rapidly absorbed and extensively distributed to tissues. The half-life (t1/2) for letrozole elimination is approximately 2 days. It is metabolized to an inactive metabolite and cleared mostly through renal excretion.
When letrozole was first introduced for ovulation induction, it was hypothesized that it could result in release of the hypothalamic–pituitary axis from estrogenic negative feedback, leading to an increase in gonadotropin secretion and the stimulation of ovarian follicle development. Its relatively short half-life, compared with CC, enables rapid elimination from the body. In addition, because ER downregulation does not occur, no adverse effects on estrogen target tissues are expected.
In the first report of letrozole as a potential ovulation induction agent (2), letrozole was shown to result in successful ovulation in 75% of PCOS patients, and pregnancies were achieved in 25% of them (LOE 3). The initial protocol, which has been most commonly used ever since, included a dose of 2.5 mg on days 3–7 after menses. Since then, accumulated data of randomized clinical trials suggest a clinical pregnancy rate of 32% and a live birth rate of 29.1%. A 5-day versus a 10-day administration protocol for letrozole in the dose of 2.5 mg or increasing the dose to 5 mg or 7.5 mg did not demonstrate a difference in the clinical pregnancy rate (LOE 2a). In early studies, the 2.5 mg daily dose was compared with a 5 mg daily dose in a selected PCOS population, and the results supported a higher number of mature follicles and a higher pregnancy rate for the 5 mg dose (LOE 2b). Comparison to placebo has been rarely performed, for understandable reasons, but the medical literature includes sufficient evidence to support the effectiveness of aromatase inhibitors in terms of ovulation induction efficiency and live birth rates. In particular, there is now high-level evidence (LOE 1a, LOE 1b) that letrozole is more effective than clomiphene citrate in ovulation induction and clinical and live birth rates in PCOS patients (but letrozole is still not licensed for ovulation induction) (3,4). The latest multicenter clinical trial addressed this question by randomly assigning 750 women, in a 1:1 ratio, to receive letrozole or clomiphene citrate for up to five treatment cycles. The cumulative ovulation rate was significantly higher with letrozole than with clomiphene citrate (61.7% of treatment cycles vs. 48.3%, respectively, <0.001), and the risk ratio for live birth was 1.44 in favor of letrozole (95% confidence interval, 1.10 to 1.87). A meta-analysis surveying nine clinical randomized trials summarized birth rates for letrozole compared to clomiphene citrate followed by timed intercourse. The birth rate was higher in the letrozole group (OR 1.64, 95% CI 1.32 to 2.04, n = 1783, LOE 1a).
Even when used in a PCOS population with significant resistance to clomiphene citrate (failed ovu-lation after six cycles, up to 150 mg/day), a 54.6% response rate was achieved with letrozole, and out of these cycles, 25% resulted in conception. No specific characteristics were found to differentiate the letrozole responsive group in terms of age, period of infertility, body mass index (BMI), waist or hip circumference, waist/hip ratio, LH, FSH, or LH/FSH ratio (LOE 3).
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
