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Aromatase inhibitors (AI) block the last enzymatic step of estrogen production, the aromatization of the A-cycle of aromatizable androgens and particularly, androstenedione (delta4) and testosterone (T). Molecules designed for interfering with aromatase activity have existed for many years. Yet the activity of products of the aminogluthetimide era was unspecific and these substances carried too many side effects for being used clinically. Newer third generation AIs, however, are highly specific and essentially devoid of side effects. These molecules have recently been approved for treating breast cancer in postmenopausal women either, in advanced forms or, as part of adjuvant therapy. In women whose ovaries are active, a temporary inhibition of E2 production will raise gonadotropins and in turn, stimulate follicular growth. In cancer patients, this property precludes the use of AIs in women whose ovaries are still active, unless gonadotropins are blocked. But in infertility patients, this property of AIs has been put to play for inducing ovulation. AIs have been used both in women who do not ovulate but whose hypothalamo-pituitary-gonadal (HPG) axis is active (oligo-anovulators of PCOD type) and those who ovulate regularly but in whom multiple ovulation is sought for treating unexplained infertility or as part of IVF. Like clomiphene citrate (CC), AIs are not usable in women whose gonadotropins are suppressed, as in the case of hypothalamic amenorrhea. The sum of data available on the use of AI for inducing ovulation remains however meager to this date and is mainly constituted of pilot and non-randomized trials. Yet mounting evidence tends to support AIs' advantages over CC for induction of ovulation. Hence, we think that the likelihood that these drugs will play a key role in induction of ovulation in the future is high. AIs appear particularly interesting for treating unexplained infertility because AI-FSH/hMG regimens are lighter than FSH-only regimens while retaining the high pregnancy rates of these latter treatments.

In the long history of controlled ovarian hyperstimulation (COH), two steps stand out as being the most important ones for providing the high efficacy of current treatments: the introduction of GnRH agonists for the prevention of premature ovulation and the widespread use of pretreatment with oral contraceptives before COH for in vitro fertilization. Interestingly, the benefits of both measures resulted largely from pure serendipity, as the discovery of these advantages was mostly fortuitous and/or unintended. Today, we believe that two areas of research have the highest potential for further improving the efficacy of COH: (1) switching the follicle-stimulating hormone stimulus to that of luteinizing hormone (or small amounts of hCG) in the last stages of COH; and (2) using the benefit of the new third-generation aromatase inhibitors that have recently become available. The effects of the latter products are to enhance the endogenous production of gonadotropins (mostly FSH). This article reviews the background data and rationale that justifies each of these two new developments and summarizes data currently available.