Growth hormone (GH) and its primary effector, insulin-like growth factor- I (IGF-I), govern the tempo and degree of adolescent growth. In addition to anabolic effects, the OH axis may regulate the hypothalamic -pituitary - ovarian unit (HPO) during puberty and affect ovarian physiology in adults. It is not clear whether the GH axis is obligatory for the normal progression of puberty and adult fertility and, if so, whether these effects are mediated through changes in H-P regulation of luteinizing hormone releasing hormone (LHRH) and LH and/or ovarian sensitivity. The proposed studies, using a female rhesus monkey model, will not only clarify the neuroendocrine regulation of the GH axis in adolescents and adults but will also determine whether the effects of GH and IGF-I on reproduction are limited to the puberty and how these may alter the HPO function. Age-dependent changes in pulsatile GH secretion will be assessed in intact and ovariectomized (OVX) adult and adolescent females treated with varying doses of estradiol (E2) to determine if the regulation of pulsatile OH by E2 is differentially affected by age. Additional studies will test the hypothesis that IGF-I differentially regulates pulsatile GH in adult and adolescent females and under specific E2 treatment conditions. Finally, the response to GH-releasing hormone (GHRH) will be assessed to determine if the age-dependent decline in serum OH results from decreased GHRH release and if this is modified by IGF-I and E2. In situ hybridization will quantify gene expression of H - P IGF-I and hypothalamic GHRH and somatostatin (SRIF) and autoradiography will quantify H - P receptor populations of these peptides to test the hypothesis that the decline in OH secretion with aging results from decreased GHRH and increased SRIF. Additional studies of these animals will examine the specific reproductive effects of the GH axis. The effects of IGF-I, a SRIF-analog (SRIFa), and IGF-I & SRIFa together on gonadal hormone secretion during spontaneous ovulatory cycles and following LHRH agonist treatment will test the hypothesis that IGF-I is critical for normal response to LH in adults. The addition, ovarian IGF-I and II gene expression and content of IGF-I and IGF binding protein-3 in follicular fluid will be quantified in adult and adolescent females treated with saline, IGF-I, SRIFa, or IGF-I & SRIFa to determine how these are regulated by age and alterations in peripheral IGF-I levels. Pulsatile LH secretion will be assessed in these adolescent and adult, intact and E2-treated OVX females to determine if the alteration in sensitivity to E2 negative feedback on LH is restricted to the peri- pubertal period and if IGF-I mediates such effects in adults. Administration of N-methyl-D, L- aspartic acid at specific reproductive stages and under specific E2 treatment conditions will assess how IGF-I affects LHRH neuronal activity. Finally, we will test the hypothesis that IGF-I prevents the decline in pulsatile LH observed following an acute fast thus affecting LHRH neuronal activity during catabolic states. These data will further our understanding of the physiological significance of the interactive effects of the GH axis and reproduction throughout the female lifespan.
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