The objective of this proposal is to establish whether thyroid hormone is required for the neurobiological processes that dictate the ontogeny of pulsatile hypothalamic GnRH release from birth until puberty in the male rhesus monkey (Macaca mulatta). The applicant?s Specific Aims will be to: 1) determine the effect of juvenile thyroidectomy in the male rhesus monkey on the timing and progression of the pubertal reaugmentation of hypothalamic GnRH pulse generator activity, and if pubertal reinitiation of pulsatile GnRH release is delayed or prevented; 2) determine whether thyroid hormone replacement restores a pubertal pattern of GnRH pulse generator activity, or if reaugmentation of the GnRH pulse generator is unaffected, then examine whether the thyroid hormone deficit has subtle effects on the GnRH pulse frequency; 3) confirm that neonatal thyroidectomy fails to influence the turn off of pulsatile GnRH release during the transition from infancy to the juvenile period; and 4) assess the effect of hypothyroidism during infancy (birth to 8 months of age) on the timing and progression of the pubertal reinitiation of pulsatile GnRH release. The agonadal monkey will be employed as the experimental paradigm to facilitate the tracking of the ontogeny of GnRH pulse generator activity, and to eliminate the confounding influence of thyroid hormone action on the testis. Circulating LH concentration will be used as an indirect index of changes in GnRH secretion. If necessary, monkeys will be implanted with venous catheters and housed in remote sampling cages to determine the pattern of GnRH release during the peripubertal period. Thyroid hormone status will be manipulated by thyroidectomy and thyroid hormone replacement. Studies of sexual development of the monkey are particularly relevant to the human situation because the control systems regulating the timing of puberty exhibit marked species differences. Most notable, the prepubertal brake that holds the hypothalamic-pituitary- gonadal axis in check throughout prepubertal development in man and other higher primates is not observed in rodents. Thus, the present proposal will lead to a better understanding of the mystery of human puberty and disorders of sexual development in boys and girls.
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