Hypothalamic Insulin-Like Growth Factor-I Receptors Are Necessary for Hormone-Dependent Luteinizing Hormone Surges: Implications for Female Reproductive Aging

Abstract

Brain IGF-I receptors are required for maintenance of estrous cycles in young adult female rats. Circulating and hypothalamic IGF-I levels decrease with aging, suggesting a role for IGF-I in the onset of reproductive senescence. Therefore, the present study investigated potential mechanisms of action of brain IGF-I receptors in the regulation of LH surges in young adult and middle-aged rats. We continuously infused IGF-I, the selective IGF-I receptor antagonist JB-1, or vehicle into the third ventricle of ovariectomized young adult and middle-aged female rats primed with estradiol and progesterone. Pharmacological blockade of IGF-I receptors attenuated and delayed the LH surge in young adult rats, reminiscent of the LH surge pattern that heralds the onset of reproductive senescence in middle-aged female rats. Infusion of IGF-I alone had no effect on the LH surge but reversed JB-1 attenuation of the surge in young females. In middle-aged rats, infusion of low doses of IGF-I partially restored LH surge amplitude, and infusion of JB-1 completely obliterated the surge. Intraventricular infusion of IGF-I or JB-1 did not modify pituitary sensitivity to exogenous GnRH or GnRH peptide content in the anterior or mediobasal hypothalamus in either young or middle-aged rats. These findings support the hypothesis that brain IGF-I receptor signaling is necessary for GnRH neuron activation under estrogen-positive feedback conditions and that decreased brain IGF-I signaling in middle-aged females contributes, in part, to LH surge dysfunction by disrupting estradiol-sensitive processes that affect GnRH neuron activation and/or GnRH release.