Neuroprogesterone: Key to estrogen positive feedback?

In the cycling female rat, estradiol and progesterone induce reproductive behavior and the surge of luteinizing hormone (LH) needed for ovulation. Circulating estradiol of ovarian origin induces progesterone receptors in the preoptic area and hypothalamus. Sequential activation of estrogen receptors (ER) and progesterone receptors coordinates reproductive physiology and behavior. In ovariectomized and adrenalectomized (ovx/adx) rats, administration of estradiol alone is sufficient to initiate an LH surge, and central infusion of aminoglutethimide (AGT), a blocker of the P450 side chain cleavage enzyme, disrupted the estrous cycle of intact rats without affecting peripheral estradiol levels, suggesting that an endogenous source of progesterone remains in these animals. In ovx/adx rats, progesterone levels in the hypothalamus increase prior to the LH surge, and inhibition of progesterone synthesis prevents the LH surge, suggesting that hypothalamic neuroprogesterone is necessary for estrogen positive feedback. In support of the idea that estradiol induces neuroprogesterone, estradiol increased expression of the progesterone-synthesizing enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) in the hypothalamus before the LH surge. Further, in vitro experiments demonstrate that estradiol stimulates progesterone synthesis in astrocytes, considered to be the most active steroidogenic cells in the CNS. To stimulate neurosteroidogenesis, estradiol acts through membrane ER and type 1a metabotropic glutamate receptors (mGluR1a) to increase free cytoplasmic calcium ([Ca2+]i) via activation of the PLC-IP3 pathway. Estradiol-induced progesterone synthesis is mimicked by thapsigargin-induced release of IP3 receptor-sensitive Ca2+ stores in astrocyte cultures. Thus, estradiol-induced progesterone synthesis is dependent on membrane ERs that act through mGluR1a to activate the PLC-IP3 pathway. This neuroprogesterone also facilitated proceptive behavior. Blocking either progesterone synthesis or progesterone receptor in estrogen-primed ovx/adx prevented proceptive but not receptive behaviors.