Hypothalamic Astrocyte Development and Physiology for Neuroprogesterone Induction of the Luteinizing Hormone Surge

Neural circuits in female rats sequentially exposed to estradiol and progesterone underlie so-called estrogen positive feedback that induce the surge release of pituitary luteinizing hormone (LH) leading to ovulation and luteinization of the corpus hemorrhagicum. It is now well-established that gonadotropin releasing hormone (GnRH) neurons express neither the reproductively critical estrogen receptor-α (ERα) nor classical progesterone receptor (PGR). Estradiol from developing ovarian follicles acts on ERα-expressing kisspeptin neurons in the rostral periventricular region of the third ventricle (RP3V) to induce PGR expression, and kisspeptin release. Circulating estradiol levels that induce positive feedback also induce neuroprogesterone (neuroP) synthesis in hypothalamic astrocytes. This local neuroP acts on kisspeptin neurons that express PGR to augment kisspeptin expression and release needed to stimulate GnRH release, triggering the LH surge. In vitro and in vivo studies demonstrate that neuroP signaling in kisspeptin neurons occurs through membrane PGR activation of Src family kinase (Src). This signaling cascade has been also implicated in PGR signaling in the arcuate nucleus of the hypothalamus, suggesting that Src may be a common mode of membrane PGR signaling. Sexual maturation requires that signaling between neuroP synthesizing astrocytes, kisspeptin and GnRH neurons be established. Prior to puberty, estradiol does not facilitate the synthesis of neuroP in hypothalamic astrocytes. During pubertal development, levels of membrane ERα increase in astrocytes coincident with an increase of PKA phosphorylation needed for neuroP synthesis. Currently, it is not clear whether these developmental changes occur in existing astrocytes or are due to a new population of astrocytes born during puberty. However, strong evidence suggests that it is the former. Blocking new cell addition during puberty attenuates the LH surge. Together these results demonstrate the importance of pubertal maturation involving hypothalamic astrocytes, estradiol-induced neuroP synthesis and membrane-initiated progesterone signaling for the CNS control of ovulation and reproduction.