Using aromatase inhibitors to stimulate a woman's ovaries

Ovarian stimulation, with or without IUI, is the mainstay of treatment for unexplained infertility, with pregnancy rates ranging from 10% to 17% per treatment cycle. About 85% of conceptions occur within the first four treatment cycles and the number of treatment cycles offered before moving on to assisted reproduction depends mostly on the woman's age, how long she's been infertile, and the couple's financial resources.¹

The two primary drugs used for ovarian stimulation are clomiphene citrate (CC) and follicle stimulating hormone (FSH). Despite a lack of evidence for its efficacy, CC has been the first-line treatment for unexplained infertility for almost four decades, because of its low cost and oral administration.² In fact, data collected in our center and others have shown that cycle fecundity with the drug is similar to that obtained with no treatment other than cycle monitoring for timed intercourse.^3,4 In addition, CC may have antiestrogenic effects such as hot flushes, visual disturbances, PMS-like symptoms, and more importantly from the point of view of conception, adverse effects on endometrial thickness and cervical mucus. The alternative treatment, parenteral FSH, is also fraught with side effects and requires close monitoring to prevent complications such as multiple births and ovarian hyperstimulation syndrome. FSH injections are also very costly, and only marginally increase pregnancy rates in couples with unexplained infertility.⁵

With these facts in mind, it's apparent that a new, safer treatment is needed for patients with unexplained infertility. Ideally, this treatment would be oral, have few side effects, and require little if any monitoring. We believe that aromatase inhibitors (AIs) have many of these attributes.

Aromatase inhibitors have been shown to stimulate the ovaries in anovulatory and ovulatory women, including women with unexplained infertility, with higher clinical pregnancy rates than CC.^3,4,6 Unlike CC, which depletes estrogen receptors in target tissues, there were no adverse effects observed on the endometrium or cervical mucus. Using an AI for ovarian stimulation resulted in predictable mono- or di-follicular response in most cycles, leading to a multiple birth rate of less than 5%.⁷ Of interest, pregnancy rates appear to be comparable to those resulting from FSH injections, but at a fraction of the cost.

CC and FSH injections are often combined to treat unexplained infertility, since it has long been known that the addition of CC will decrease the dose of FSH required for the development of multiple follicles, reducing the cost of therapy. In some cases this strategy turns out to be false economy, however, because the antiestrogenic effects of CC on the endometrium may still be problematic. We have shown that AIs can also be added to FSH if the goal is to achieve more than one follicle in a stimulated cycle. The addition of an AI reduces the dose of FSH by at least 50% without adversely affecting the endometrium.