Although disorders of sexual maturation are relatively rare, they are by no means trivial, nor are they well understood - primarily because the mechanisms underlying sexual maturation have not been fully revealed in the human or any other mammalian species. Elucidation of the role of the central nervous system in sexual maturation is the rather ambitious long term goal of this application. The proximate cause of ovarian activation at puberty in ferrets and several other species is a marked decrease in the efficacy of estradiol to inhibit LH secretion. This proposal is designed to pursue the implication of some exciting new data in this laboratory suggesting an important role for either dopamine, prolactin or both essential components of the peripubertal shift in negative feedback of steroids on gonadotropin secretion. The first four sections of the first specific aim use pituitary transplantation and dopamine agonist and antagonist drugs to dissect the interaction between these two hypothalamo-pituitary systems (dopamine-prolactin and GnRH-gonadotropin) and their crucial role in the regulation of sexual maturation. The fifth section of specific aim 1 will determine whether the pubertal increase in prolactin secretion also has a direct stimulatory effect on the ovary. The second specific aim examines the hyper- responsiveness of the hypothalamo-hypophyseal axis regulating gonadotropin secretion in the prepubertal female more directly. Ovariectomy, followed by timed replacement of prepubertal levels of estradiol will reveal whether the ovarian steroid participates in the maturational process in the hypothalamus. Through the use of acute treatment with specific receptor blockers of selected neurotransmitters, the neurochemical basis of this hyper-responsive period will be probed. This section also includes studies using the recently developed bioassay for FSH, to place the role of this hormone in the context of sexual maturation. The final specific aim is a look to the future. All of the endocrine regulatory changes under study are synchronized and accelerated by changes in ambient day length in this species. The studies in specific aim 3 will define the role of melatonin and circadian cycles in the induction of puberty by increased day length. Melatonin rhythm during development will be determined; melatonin rhythm will be removed by super cervical ganglionectomy, and then infusions of melatonin will test the relevance of that hormone to maturation. The use of the ferret as a model animal gives all of these studies the added component of control groups which are the same age and body weight as the pubertal females, but due to the nonstimulatory photoperiod, they are 10-12 weeks from puberty. Thus an added tool is available to allow the distinction of somatic changes from pubertal changes, and the separation of photoperiod specific changes from puberty specific ones - a truly exciting prospect.
