This project tests the hypothesis that insulin-like growth factor-1 (IGF-1) and its receptor are essential comediators of critical reproductive actions of estradiol (E2) in the neuroendocrine hypothalamus (HYP). We have shown that chronic intracerebroventricular infusion of an IGF-1 receptor antagonist suppresses estrous cycles, an effect that is not attributable to impaired food intake or reduced body weight. Therefore, the proposed experiments test the hypothesis that IGF-1 receptor signaling in the HYP is essential for neuroendocrine regulation of female reproductive function by E2. We will identify the mechanisms and neural sites of IGF-1 regulation of the hypothalamic-pituitary-gonadal axis by determining whether IGF-1 acts directly on the gonadotropin releasing hormone (GnRH) neurons, their afferent inputs, and/or their responsiveness to E2. Finally, we will test the hypothesis that the delayed and attenuated luteinizing hormone (LH) surge that characterizes female rats making the transition to reproductive senescence is causally related to reduced IGF-1 receptor signaling in the aging brain.
Specific Aim 1 tests the hypothesis that IGF-1 regulation of the E2-dependent LH surge is mediated at the level of the HYP rather than the pituitary.
Specific Aim 2 tests the hypothesis that IGF-1 regulates E2-dependent afferent signals to GnRH neurons. We will determine the effects of brain IGF-1 receptor blockade on GnRH neuronal activation under hormonal conditions that should generate LH surges. We will also determine the effects of brain IGF-1 receptor blockade on E2 regulation of progestin receptors and kisspeptin gene expression in the HYP and on the release of excitatory (glutamate) and inhibitory (GABA) neurotransmitters in medial preoptic area (HYP site of GnRH cell bodies).
Specific Aim 3 tests the hypothesis that IGF-1 regulates GnRH neuronal responsiveness to E2 afferent input. We will determine the effects of brain IGF-1 receptor blockade on glutamate, kisspeptin and a1-adrenergic activation of LH release in hormone-primed females.
Specific Aim 4 tests the hypothesis that declining levels of bioavailable IGF-1 are causally related to the delayed and attenuated LH surges in middle-aged females undergoing the transition to reproductive senescence. We will determine whether elevating brain IGF-1 restores hormone-dependent LH surges in middle-aged rats, and if so, whether this manipulation also restores E2 regulation of amino acid neurotransmission and of kisspeptin gene expression. These findings may provide insight into the mechanisms underlying premature ovarian failure and reproductive neuroendocrine dysfunction that accompanies diabetes and polycystic ovarian syndrome (PCOS). This could suggest new therapeutic strategies for treating reproductive disorders associated with altered IGF-1 levels, such as PCOS. They could also identify factors whose manipulation might prolong exposure of middle-aged women to the physiological benefits of ovarian steroids

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DSR-L)
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Albert Einstein College of Medicine
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Kuokkanen, Satu; Polotsky, Alex J; Chosich, Justin et al. (2016) Corpus luteum as a novel target of weight changes that contribute to impaired female reproductive physiology and function. Syst Biol Reprod Med 62:227-42
Al-Safi, Zain A; Liu, Huayu; Carlson, Nichole E et al. (2016) Omega-3 Fatty Acid Supplementation Lowers Serum FSH in Normal Weight But Not Obese Women. J Clin Endocrinol Metab 101:324-33
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Wang, Yuxiang; Zhu, Liyin; Kuokkanen, Satu et al. (2015) Activation of protein synthesis in mouse uterine epithelial cells by estradiol-17β is mediated by a PKC-ERK1/2-mTOR signaling pathway. Proc Natl Acad Sci U S A 112:E1382-91
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Neal-Perry, Genevieve; Yao, Dachun; Shu, Jun et al. (2014) Insulin-like growth factor-I regulates LH release by modulation of kisspeptin and NMDA-mediated neurotransmission in young and middle-aged female rats. Endocrinology 155:1827-37
Ross, Lauren A; Polotsky, Alex J; Kucherov, Alexander et al. (2014) Profound reduction of ovarian estrogen by aromatase inhibition in obese women. Obesity (Silver Spring) 22:1464-9
Roth, Lauren W; Bradshaw-Pierce, Erica L; Allshouse, Amanda A et al. (2014) Evidence of GnRH antagonist escape in obese women. J Clin Endocrinol Metab 99:E871-5
Meek, Thomas H; Matsen, Miles E; Damian, Vincent et al. (2014) Role of melanocortin signaling in neuroendocrine and metabolic actions of leptin in male rats with uncontrolled diabetes. Endocrinology 155:4157-67

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