The rapid increase in popularity of physical exercise during past decades has led to the recognition of both beneficial and deleterious effects. In particular, the negative impacts of strenuous exercise on reproductive function in women, as a consequence of centrally mediated attenuations of GnRH/LH, pulsatile activities has become a common clinical problem. The management of these patients is complicated by the presence of confounding variables such as the type and intensity of exercise, body composition, psychologic background, and stress factors. In the past few years, in well controlled studies, an array of neuroendocrine-metabolic aberrations have been identified in women with functional hypothalamic amenorrhea associated with vigorous exercise and athleticism. These include changes in virtually all pituitary hormones and their target hormones as well as melatonin secretion. Although new insights with respect to the impact of chronic vigorous exercise on multitude of hormonal changes have emerged, the underlying mechanism(s) and their pathophysiological implications remain to be defined. The broad goal of this proposal is the continuation of our efforts in delineating the underlying mechanism(s) to account for these alterations in women with vigorous exercise, both cycling and amenorrheic. Experiments are designed to address five specific aims: i) that the recovery from reduced GnRH/LH pulsatility in women with exercise-associated amenorrhea is manifested by a sequence of GnRH/LH pulse patterns resembling that of a """"""""miniature puberty""""""""; and that an altered FSH circadian rhythm in athletic women with relatively normal patterns of LH pulses may be instrumental in the development of ovarian acyclicity; ii) that the development of hypercortisolemia in women athletes is mediated by increased hypothalamic CRF secondary to alpha-adrenergic activation. Increased CRF drive may account for the activation of ACTH and cortisol secretion, and the inhibition of the GnRH pulse generator; iii) that the """"""""global"""""""" reduction of circulating thyroid hormones in the presence of a normal circadian rhythm of TSH in exercise-associated amenorrhea may be related to diminished hypothalamic TRH secretion and/or changes in intrapituitary Type II 5' deiodinase; iv) that the striking increase in nocturnal melatonin secretion that occurs only in amenorrheic athletes may reflect a dysynchronization with external cues and be causally related to changes in alpha or beta adrenergic input, photosensitivity, or a response to hypothyroidemia; and v) that hypoinsulinemia and its inverse relationship to augmented IGFBP-1 levels with a consequent reduction in the bioavailability of free IGF- 1, together with hypothyroidemia, may provide a protective mechanism in response to cellular nutritional deficits. These studies will include the use of antagonists and enzymatic blockers, the characterization of pulsatile and circadian rhythmicities, nocturnal light exposures, and analyses of insulin/GH-IGF/IGFBPs circadian relationships and changes in response to the hyperinsulinemia- euglycemic clamp conditions. Insights generated should provide better understanding of this disorder (or adaptation) and strategies to its management.
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