Role of Aromatase Inhibitors-

Aromatase Inhibitors---

Mode of action: - AI may increase the responsiveness of follicular FSH receptors and sensitivity to FSH by further rising androgens Aromatase inhibitors were first used as OI by team of Casper and Mitwally (Fertil Steril, 2001; 75:305-9.). Letrozole mostly act at ovarian level and hypothalamus remains free to act as negative feedback effect of decreasing FSH by rising serum E2 in late follicular phase.

 Aromatase enzyme usually converts androstenedione to active oestrogens. & AI decreases the level of oestrogens. So rise of GnRH pulse frequency. Increase the flow of FSH from the Pit. As such by exerting primary action in hypothalamus by increasing the GNRH pulsatility.  

Though both CC & AI acts primarily in the same site (hypothalamus) but mechanism of action is different. The use of AI causes accumulation of androgens in the ovaries as because the conversion of thecal androgens is blocked by ingested AI. Theoretically it seems paradoxically because there is already a considerable amount of androgen excess in the ovaries in cases of PCOS. What happens in nature is something contrary. That is a further accumulation of androgens augments follicular receptors expression-and thereby augments /amplifying FSH action as FSH surge occurs after 2-3 days of Letroz ingestion.

Adv of AI over CC? AI does not case thinning ET or adverse change in cervical mucus. No estrogen receptor blockade & depletion at hypothalamus.  The third adv of AI is that as estrogen receptors at hypo are not depleted, therefore, a rising FSH at midfollicular time: the negative feedback mechanism will be operational. This persistence of negative feedback mechanism will hopefully modify/ control the overzealous FSH secretion in midcycle as happens in CC where the negative feedback mechanisms blocked by CC due to estrogen receptor depletion at hypothalamus.. Some believe that it will be wiser to continue the letrozole for 7 days / eight days so that window of FSH s prolonged.

Possible adverse effects: - Increased rate of congenital locomotor malformations and cardiac malformations. But later it was established that the prevalence of CM is less than that induced by CC.

What will be pregnancy rate? A comparison with CC? It appears that it will be wise to think of enhancing the sensitivity to FSH receptors by increasing the follicular androgen content (priming the of FSH receptors by increasing the follicular androgen contents).

Some use as much as 10mg OD schedule. And both Casper and Lergo et al (Fertil Steril 2013; 100(3 suppl), 0-167.     ) confirmed that the preg rate was much higher with letrozole than CC. A RCT confirmed that preg rate was 27.5% in letrozole group than 19.5% in CC group.

Can Letrozole be added along with FSH -more so in IUI cycles?  The addition of AI may increase the responsiveness of follicular FSH receptors and sensitivity to FSH by further rising androgens. In fact, some believes in cases who were unresponsive to FSH alone should be given a fair trial with AI & FSH - before other procedures are considered. Similarly letrozole may be prescribed along with conventional IVF protocolà with the idea that in some cases there may be high expression of aromatase P450 expression at endometrial level. This adverse effect of high Aromatase present at endometrium may be counter effected if AI are Co prescribed.