Aromatase Inhibition Improves Ovarian Response to Follicle-Stimulating Hormone in Poor Responders

Abstract

Up to one fourth of women undergoing controlled ovarian hyperstimulation may have an inadequate ovarian response to follicle-stimulating hormone (FSH), and they are probably less likely than normal responders to become pregnant. In most instances the cause is unknown. The present investigators believed that blocking estrogen synthesis using an aromatase inhibitor during the early part of the menstrual cycle would reduce negative feedback centrally and lead to increased gonadotropin secretion. At the same time, accumulating androgens within the ovary may increase follicle sensitivity by amplifying the expression of FSH receptor genes. This pilot study evaluated the aromatase inhibitor letrozole in 12 women with unexplained infertility (primary in 9 cases, secondary in 3) and low responses to FSH in two or more cycles. In all, there had been 25 cycles of stimulation with FSH only. In each case, fewer than three follicles larger than 1.8 cm in diameter were present on the day of the luteinizing hormone surge or human chorionic gonadotropin administration. Letrozole was given in a dose of 2.5 mg from cycle day 3 to day 7, followed in most cases by FSH on day 7 in a dose of 50 to 225 IU daily. Recombinant FSH was administered in most instances. The dose of FSH was adjusted until three adequate-sized follicles were obtained. Although no pregnancies had occurred previously with FSH alone, four women conceived after receiving letrozole plus FSH. There were three clinical pregnancies. The number of mature follicles averaged 3.3, compared with 1.9 with FSH alone. Significantly less FSH was required when letrozole was also given. Letrozole had no apparent antiestrogenic effect on the endometrium. Adding an aromatase inhibitor such as letrozole to FSH stimulation seems to improve the chance of pregnancy in women who formerly responded poorly to FSH alone. These drugs have relatively brief half-lives and therefore should no longer be present at the time of embryogenesis. They may even be eliminated before implantation.