Progesterone: Lessons from the progesterone receptor knockout

Progesterone has long been regarded as a pre-eminent hormone regulating female fertility, exerting diverse effects in ovarian, uterine, and mammary function to control implantation, pregnancy, and lactation (1). The major site of progesterone production is the ovary, where, in response to the leuteinizing hormone (LH) surge, production of this steroid increases in proestrous follicles and is followed by higher levels of progesterone secretion by corpora lutea during diestrous and pregnancy (2). A role for progesterone in ovulation was first demonstrated by Mori et al. (3), whose studies showed that injection of antiprogesterone antise-rum reduced the number of ovulations in the PMSG, hCG-induced rat model. Furthermore, the inhibition could be reversed by a dose of progesterone, but not by estradiol. Studies by Snyder et al. (4) and Lipner and Greep (5) showed that inhibiting 3β-hydroxysteroid dehydrogenase (the enzyme that converts preg-nenolone to progesterone) with either epostane (4) or cyanoketone (5) blocked ovulation in rats. Furthermore, the block in ovulation could be overcome by exogenous administration of progesterone (4).