GROWTH HORMONE REGULATION OF PUBERTY & FERTILITY

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Studies were continued to determine how the growth hormone (GH) - insulin-like growth factor-I (IGF-I) axis is regulated in juveniles and adults and how resulting changes in GH and IGF-I affect reproductive maturation and adult fertility. A comparison of ovariectomized adolescent (n = 11) to adult (n = 11) females revealed that a constant subcutaneous infusion of IGF-I effectively elevated serum levels of its major carrier protein (IGFBP-3) at all ages, thereby slowing degradation of the administered peptide. Estradiol replacement augmented IGF-I secretion in adolescent females prior to puberty but actually suppressed serum IGF-I in post-adolescent and adult females. Although GH secretion was also diminished in the older females, its decrease could not account for the suppressive action of estradiol on IGF-I. In contrast, estradiol increased IGFBP-3 at all ages. These data suggest that the effect of estradiol on hepatic IGF-I secretion changes as a function of growth an d development. Additional studies indicated that estradiol and GH status interact to regulate the IGF-I axis. Estradiol replacement to these females decreased serum IGF-I. Although treatment with either a somatostatin analog or a GH receptor antagonist significantly decreased serum IGF-I, the combined treatment of either with estradiol significantly elevated serum IGF-I. These data suggest that GH status determines the effect of estradiol on hepatic IGF-I synthesis and release. In another study, the effects of IGF-I were compared to an IGF-I analog that has a reduced affinity for the IGF-I carrier proteins with no compromise in binding to the IGF-I receptor. IGF-I infusion effectively elevated serum IGFBP-3 whereas the analog had no such effect. Since binding to the receptor is not compromised with the analog, these data suggest that IGF-I may increase IGFBP-3 by slowing degradation of the carrier protein. Functional studies revealed that the chronic infusion with IGF-I advances first ovulation in monkeys (n = 6) and this effect is associated with an earlier activation of luteinizing hormone releasing hormone (LHRH) neurons as treated animals were more responsive to the excitatory amino acid analog, n-methyl d,l aspartic acid than untreated females (n = 6). However, this effect is dependent upon the corresponding ability of exogenous IGF-I to elevate serum IGFBP-3. If IGFBP-3 does not show a corresponding rise, administered IGF-I is quickly degraded, unable to have its tissue specific effects. In contrast, treatment of adult monkeys with IGF-I (n = 6) or a somatostatin analog (n = 5) did not affect the parameters of an ovulatory cycle. These data suggest that the effects of the GH - IGF-I axis may be limited to puberty and are not involved in the maintenance of normal ovulatory function.