Neuroestrogen restraint of GnRH in juvenile female primates

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 DESCRIPTION (provided by applicant): Juvenile development is characterized by pronounced suppression of reproductive hormone release, a mechanism that maintains gonadal quiescence until the onset of reproductive maturation. In primates, this juvenile "brake" is believed to be mediated by signals that arise within the brain and actively suppress hypothalamic neurosecretion of the major neural effector of reproductive hormone release, gonadotropin- releasing hormone (GnRH). Diminishment of this central restraint is believed to contribute to the acceleration of pulsatile GnRH release that, in turn, initiates pubertal maturation. Premature lifting of this restraint may underlie the pathogenesis of true precocious puberty, as well as earl pubertal onset within the range of normal variation. The neural signals that impose the juvenile brake remain unclear. In adulthood, the "GnRH pulse generator" is homeostatically suppressed by negative feedback actions of gonadal steroids, principally estradiol in females. Recent studies have demonstrated that estrogens produced in the brain itself may modulate GnRH release, and we have obtained preliminary evidence to suggest that extra-gonadal estrogens may contribute to the suppression of the GnRH pulse generator. The proposed studies are therefore designed to test the novel hypothesis that neuroestrogens mediate the prepubertal restraint of GnRH release during the juvenile period of development in female primates. In Aim 1, prepubertal female rhesus macaques will be ovariectomized and treated with a vehicle or letrazole, an inhibitor of the estrogen synthesizing enzyme, aromatase (CYP19A1). We will monitor secretion of pituitary gonadotropins, LH and FSH, to determine if systemic inhibition of aromatase in non-gonadal tissues results in a premature activation of GnRH release. In Aim 2, a viral vector expressing shRNA corresponding to aromatase, or a vector expressing a scrambled RNA sequence, will be injected into the hypothalamic areas critical for negative feedback regulation of GnRH release. Gonadotropin levels will be monitored to determine if localized hypothalamic inhibition of aromatase expression likewise results in premature activation of GnRH release. We predict that the results obtained in Aim 1 will demonstrate that non-gonadal estrogens exert some or all of the juvenile restraint on the GnRH pulse generator, and that Aim 2 will confirm neuroestrogens as specific mediators of this important physiological process.