Ovulation induction with letrozole
- Robert F Casper, MD
Robert F Casper, MD
- Professor, Division of Reproductive Sciences
- University of Toronto, Canada
- Senior Investigator
- Samuel Lunenfeld Research Institute
- Mohamed FM Mitwally, MD, HCLD, FACOG
Mohamed FM Mitwally, MD, HCLD, FACOG
- Medical Director
- Reproductive Endocrinology & Infertility
- Baptist Medical Center
Women with polycystic ovary syndrome (PCOS) often have anovulatory infertility. Clomiphene citrate is the most commonly used pharmacologic agent to induce ovulation in these women, but some women fail to conceive with this therapy. During the past decade, aromatase inhibitors have been explored as an option for ovulation induction in women who fail to conceive with clomiphene citrate. Aromatase inhibitors are a class of drugs that block estrogen biosynthesis, thereby reducing negative estrogenic feedback at the pituitary.
This topic reviews the use of letrozole, the most effective aromatase inhibitor, for ovulation induction in women with PCOS and as an adjunct to gonadotropin therapy for controlled ovarian hyperstimulation (COH) in women with ovulatory infertility. The use of clomiphene and gonadotropins is reviewed separately. (See "Ovulation induction with clomiphene citrate" and "Overview of ovulation induction".)
PHARMACOLOGY AND PHYSIOLOGY
Aromatase is a microsomal cytochrome P450 hemoprotein-containing enzyme (P450arom, the product of the CYP19 gene) that catalyzes the rate-limiting step in the production of estrogens: the conversion of androstenedione and testosterone via three hydroxylation steps to estrone and estradiol, respectively . It is a good target for selective inhibition because estrogen production is a terminal step in the biosynthetic sequence. Aromatase activity is present in many tissues, including the ovaries, brain, adipose tissue, muscle, liver, and breast.
Aromatase inhibitors are widely used as adjuvant endocrine therapy for postmenopausal women with breast cancer. They have been used off-label in the treatment of patients with anovulatory infertility , such as polycystic ovary syndrome (PCOS), and for increasing the number of ovarian follicles recruited in ovulatory women undergoing controlled ovarian hyperstimulation (COH) [3,4]. (See "Adjuvant endocrine therapy for non-metastatic, hormone receptor-positive breast cancer" and 'Ovulation induction in PCOS' below and 'Controlled ovarian hyperstimulation' below.)
Letrozole and anastrozole are triazole (antifungal) derivatives that are potent, reversible, competitive, nonsteroidal aromatase inhibitors [5,6]. In postmenopausal women, at doses of 1 to 5 mg/day, these drugs inhibit estrogen biosynthesis by 97 to >99 percent, resulting in estrogen concentrations below the level detected by most sensitive immunoassays. They are completely absorbed after oral administration and have a mean terminal half-life of approximately 45 hours (range, 30 to 60 hours); clearance is mainly hepatic. By comparison, exemestane, a steroidal aromatase inhibitor, has a circulating half-life of approximately nine hours, but the inhibitory effect is potentially much longer because its effect on aromatase is irreversible .
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- PHARMACOLOGY AND PHYSIOLOGY
- CLINICAL USE
- Ovulation induction in PCOS
- - Regimen
- - Comparison with clomiphene
- Fetal safety
- Side effects
- - Suggested approach
- Controlled ovarian hyperstimulation
- - Poor responders
- - Women with breast cancer
- - Women with endometrial hyperplasia and endometrial cancer
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS