The small amount of progesterone (P) released by human follicles at their very final stage of maturation plays a central role in the human reproduction. It may anticipate the expansion of the cumulus even before the LH peak and, once the oocyte-cumulus complex has been released into the fallopian tube, it attracts the sperms toward the oocyte ¹allowing its fecundation. While facilitating the fecundation process, follicular P also plays as the main trigger of the mid-cycle gonadotropin surge. Indeed, under raising estradiol concentration, hypothalamic cells expose P receptors (PR). These P receptors are extremely sensitive and may react to the very small amounts of hormone, either synthesized within the brain or released from the end stage follicle. The activation of hypothalamic PR triggers the release of a peak of GnRH, which in turn triggers the midcycle gonadotropin surge ².

The above mechanism opens the opportunity to modulate the release of the midcycle surge within controlled ovarian hyperstimulation (COH) cycles by administering a receptorial progesterone inhibitor, namely mifepristone (M). In early clinical studies an M dose as small as 1 mg administered by the oral route to normally cycling women when their dominant follicle had reached the size of 14-16 mm inhibited the release of the peak in all the treated women. The follicles continued to develop normally and a spontaneous surge appeared 2-3 days after discontinuing the drug. In alternative, the spontaneous surge blocked by M occurred 1 day after the injection of small doses of P ³.

However, in a later study a 5 mg oral dose of M, besides inhibiting the surge, also caused an arrest of the development of the follicles ⁴indicating that the possible therapeutic window is narrow. Indeed, although quite selective for the PR, M also inhibits glucocorticoid receptors and partial recognition of other steroid receptors is possible.  Thus, M may act as a surge modulator without negative effects on the follicles only given at very small doses and at the very end of follicular phase.

The therapeutic window for M as a surge modulator might be further enlarged by using the nose-to brain delivery of M. Indeed, it has a small molecular size and is very well soluble in lipids and is therefore a perfect candidate to such a route of administration. The expected in-brain bioavailability of M by the nasal route is larger than 10% whereas the IC ₅₀for M-induced inhibition of the wild-tape PR is as low as 0.01 nM ⁵, therefore the mechanism would be saturated at a nasal M dose lower than 0.5 mg.

This new strategy for the inhibition of the mid cycle peak would carry several advantages.  First, the pituitary would be active during the cycle and thus regulating the endocrine background, which means i) timed release of the proper LH pulses and, ii) better coordination with the endometrium. Second, once the follicles are ready, a pituitary-generated LH peak would induce the final maturation without the need of an artificial boost with the too long acting hCG. Last but not least, the new schedule is definitely more physiology friendly and very likely to be cost-effective.

In summary, P plays a central role in folliculogenesis and fecundation just like it is known to do during pregnancy. The understanding of P actions in pre-fecundation phases and of their possible modulation might allow the development of new treatment strategies in COH.

1. Teves MA et al., PLoSone 2009; 4(12): e8211
2. Micevych P & Sinchak K, Mol. Cell. Endocrinol. 2008 Aug 13; 290(1-2): 44-50
3. Batista MC et al., J. Clin. Endocrinol. Metab. 1002; 74(3): 565-570
4. Croxatto HB et al., Hum. Reprod. 1995; 10(8): 1987-1991
5. Delabre K et al., Proc. Natl. Acad. Sci. USA 1993; 90: 4421-4425

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