Although studies from a variety of species indicate that a structural or functional shift in neurochemical input into gonadotropin releasing hormone (GnRH) neurons induces the developmental increase in GnRH secretion initiating puberty, the factor(s) responsible for this change are not known. Using female rhesus monkeys, this project will test the hypothesis that a signal emanating from growth, namely insulin like growth factor (IGF)-I, changes the nature of this input, increasing GnRH and pituitary gonadotropin secretion, initiating puberty. The working hypothesis is that a prepubertal increase in IGF-I stimulates the emergence of GnRH secretion as assessed from nocturnal pulsatile gonadotropin release.
Specific Aim 1 will test this hypothesis by using two different models of growth hormone (GH) insensitivity. A GH-IGF-I deficient model will be produced by treating juveniles with a GH receptor antagonist. It is predicted that the emergence of nocturnal gonadotropin secretion will be disrupted in GH antagonist-treated females compared with controls but replacement therapy with IGF-I will normalize this pattern. In the second study, reproductive maturation will be arrested by treating juveniles with an GnRH analog to prolong the prepubertal period of hypogonadotropism. Upon the cessation of analog treatment at an age equivalent to mid puberty in control females, it is predicted that co-treatment with a GH receptor antagonist will suppress the expression of the developing GnRH pulse generator, inferred from robust nocturnal pulses of gonadotropins, compared to females only treated with the analog. In contrast, this suppression of the GnRH pulse generator by GH antagonism will be reversed by co-administration of IGF-I.
Specific Aim 2 will test the hypothesis that the integrity of the GH-IGF-I axis during the neonatal period is essential for the subsequent GH-IGF-I activity, prepubertal growth and the timing of puberty. Females treated neonatally (from birth-8 mo.) with a GH receptor antagonist will be compared to controls and to females treated neonatally with a GnRH analog, a treatment known to delay puberty in monkeys and rats. It is predicted that a postnatal disruption of GH-IGF-I will produce long term deficits in the GH axis, diminishing growth, delaying the emergence gonadotropin secretion and the onset on puberty. The data derived from these studies will provide significant new information on how the GH axis regulates puberty and, thus, a better understanding of aberrations in growth and development in children.
