Progesterone and ovulation.

The role of progesterone (P) in the mechanism of ovulation is controversial at best. The contraceptive application of P was established in rodents in 1936 and with orally absorbed progestogenes was put to human use. There were hints on the proovulatory actions of P administered before the time of ovulation in rats by 1948. Similarly, in 1954 the observation of high P level in the preovulatory follicle pointed to a role in ovulation. Neither of these two observations was further investigated and the positive feedback effect of P exerted on gonadotropins was described in 1968. Still the positive feedback between P and gonadotropins were not recognized as a physiologic mechanism, much less utilized pharmacologically. The apparent contradiction between these two different actions of P continues upto now. The paper sets out to expose this controversy and tries to resolve it using extensive literary data and the author's experiences with synthetic progestogenes in contraception, in the treatment of infertility and with the antigestagen mifepristone in blocking ovulation. The precise mechanisms lying behind these applications are explored and discussed in detail. The putative role of oestradiol (E2) in the mechanism of eliciting the gonadotropin surge is extensively discussed but refuted as the ovulatory signal. The time sequence between the rise of P and gonadotropins contradicts the common wisdom of LH causing luteinization. The positive feedback effect of P on the E2 sensitized ovulatory axis on the hypothalamic and pituitary level is discussed and its local role in the mechanism of follicular rupture is also taken into account. The final proof seems to be the antiovulatory effect of mifepristone, which blocked both GnRH pulsatility, pituitary sensitivity to GnRH and follicular rupture in several experiments. Thus, the dogma of LH peak causing follicular rupture and subsequent luteinization seems questionable, the putative role of E2 to initiate the ovulatory cascade has to be discarded and P's role as a trigger of the physiological mechanisms leading to ovulation should be firmly recognized.