Specialized Cooperative Centers Program in Reproductive & Infertility Research

Project Three - IGF-1 and Neuroendocrine Regulation of Female Reproductive Function

Research in this laboratory is focused on determining the cellular and molecular mechanisms by which ovarian steroid hormones regulate brain function. The major focus is theregulation of female reproductive physiology and behavior by the ovarian hormones, estradiol and progesterone.

We wish to understand how hormonal modulation of synaptic transmission in specific brain regions, the hypothalamus and preoptic area, coordinates the timing of ovulation with mating behavior (lordosis), thereby maximizing reproductive success. It is well known that estradiol acts via a ligand-activated transcription factor, estrogen receptor-α(ERα), to regulate female reproductive function. Recent findings from our labindicate that hypothalamic insulin-like growth factor-1 (IGF-1) receptors act in concert with ERα to control gondatropin releasing hormone (GnRH) neurons andhence female reproductive function.

We are now testing two related hypotheses:(1) that IGF-1 regulates estradiol-dependent afferent signals to GnRH neurons,and (2) that IGF-1 regulates GnRH neuronal responsiveness to afferent input. We are also working in collaboration with Genevieve Neal-Perry, M.D., Ph.D., to test the hypothesis that reduced IGF-1 receptor signaling in the aging brainmay be responsible for attenuated neural responses to ovarian steroids and hence the delayed and attenuated luteinizing hormone (LH) surge that characterizes the perimenopause.

Other experiments test the hypothesis that the delayed onset and reduced amplitude of the preovulatory LH surge in middle-aged female rats results from changes in the ability of ovarian steroids to modulate excitatory (glutamate and kisspeptin) and inhibitory (GABA) signals that regulate GnRH neurons. Recent findings suggest that intra-hypothalamic infusionof the neuropeptide kisspeptin, a potent activator of GnRH neurons, rescues LH surges in middle-aged females by enhancing local glutamate release.

Relevant Publications:

  1. Neal-Perry, G.S., Zeevalk, G.D., Shu, J. and Etgen, A.M. (2008), Restoration of the luteinizing hormone surge in middle-aged female rats by altering the balance of GABA and glutamate transmission in the medial preoptic area. Biol. Reprod. 79:878-888.
  3. Neal-Perry, G.S., Lebesgue, D., Shu, J., Zeevalk, G.D., and Etgen, A.M. Kisspeptin restores the luteinizing hormone surge by modulating amino acid neurotransmission in the medial preoptic area of middle-aged female rats. In revision.
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