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

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD058155-05
Application #
8449986
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$352,738
Indirect Cost
$149,188
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Roth, Lauren W; Allshouse, Amanda A; Bradshaw-Pierce, Erica L et al. (2014) Luteal phase dynamics of follicle-stimulating and luteinizing hormones in obese and normal weight women. Clin Endocrinol (Oxf) 81:418-25
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
Kauffman, Alexander S; Sun, Yan; Kim, Joshua et al. (2014) Vasoactive intestinal peptide modulation of the steroid-induced LH surge involves kisspeptin signaling in young but not in middle-aged female rats. Endocrinology 155:2222-32
Stephens, Sahar M; Pau, Francis K Y; Yalcinkaya, Tamer M et al. (2013) Assessing the pulsatility of luteinizing hormone in female vervet monkeys (Chlorocebus aethiops sabaeus). Comp Med 63:432-8
Kundu, Mila C; May, Margaret C; Chosich, Justin et al. (2013) Assessment of luteal function in the vervet monkey as a means to develop a model for obesity-related reproductive phenotype. Syst Biol Reprod Med 59:74-81
Kulak, D; Polotsky, A J (2013) Should the ketogenic diet be considered for enhancing fertility? Maturitas 74:10-3
Wooding, Kerry M; Barkley, Robert M; Hankin, Joseph A et al. (2013) Mechanism of formation of the major estradiol product ions following collisional activation of the molecular anion in a tandem quadrupole mass spectrometer. J Am Soc Mass Spectrom 24:1451-5

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