The overall aim of this proposal is to gain insight into the neuroendocrine factors associated with the occurrence of hypothalamic amenorrhea. This is a heterogeneous syndrome, in which several types of patients with three contributing lifestyle variables may be identified: 1) exericse, 2) nutritional deprivation, and 3) depression. We hypothesize that in all these cases inputs to the GnRH pulsatile secretory mechanism have been modified with a resulting failure of normal pituitary release of gonadotropin. We further propose that the modification in hypothalamic-pituitary function may involve an alteration of pulsatile and circadian hormone release and an altered set-point of the stress system involving CRF, ACTH and related peptides and cortisol. Differences in these modifications are anticipated in different types of hypothalamic amenorrhea associated with the lifestyle variables outlined above. We intend to define such differences in Three Stages of descriptive and experimental observations. FIRST, we propose to screen prospective subjects for their ovulatory, physical, dietary, and psychological status to properly select and assign them to experimental groups. SECOND, we propose to differentiate the 24-hour hormonal rhythms associated with the lifestyle variables and their interactions. THIRD, we propose to conduct four experiments to identify the neuroendocrine mechanisms responsible for the observed 24-hour hormonal rhythms. We will investigate how the lifestyle variables are associated with altered hypothalamic-pituitary mechanisms involving 1) CRF, 2) endogenous opioids, 3) dopamine, and 4) the amino acid neurotransmitter precursors tyrosine and tryptophan. These observations may provide valuable clinical and pathophysiological information concerning the influences of lifestyle on reproduction.
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