AGE-RELATED LOSS OF CYCLICITY--LHRH NEURONAL DYSFUNCTION

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Reproductive cycles cease relatively early in the life-span of female mammals. Whereas alterations at all levels of the hypothalamic- pituitary-ovarian axis occur with age, considerable evidence confirms the importance of altered hypothalamic function to reproductive decline in female rodents. In contrast menopause is correlated with the loss of follicular reserves in the ovary and not routinely associated with hypothalamic dysfunction: however, recent studies reveal altered gonadotropin levels prior to the perimenopausal period and accelerated follicular loss in the 10 years prior to menopause. The potential contribution of altered patterns of gonadotropin secretion to follicular loss remains to be determined. Because luteinizing hormone releasing hormone (LHRH) is the primary signal regulating pituitary gonadotropin secretion, understanding the cause of age-related alterations in LHRH neuronal function are pivotal to unraveling the mechanisms of reproductive aging. Our studies have consistently revealed deficits in LHRH neuronal activity in aging female rats in conjunction with the spontaneous or steroid-induced LH surge, times of increased demand for LHRH secretion and biosynthesis. Alterations in excitatory and inhibitory influences on LHRH secretion have been identified with age and may be sufficient to explain the deficits observed in LHRH neuronal function. However, whether LHRH neurons in aging animals remain capable of responding to the relevant signals with significantly increased levels of gene transcription, biosynthesis and secretion remains to be determined. The studies in the present proposal test the following hypotheses: 1) LHRH gene transcription is markedly reduced in middle-aged females on the day of an LH surge; 2) reduced LHRH gene expression contributes to attenuation of the LH surge, and 3) diminished excitatory influences and / or increased inhibitory influences contribute to the marked decline in LHRH neuronal function with age. The studies proposed will determine if modulation of excitatory and inhibitory neurotransmission can enhance the normally diminished levels of LHRH neuronal activity in middle-aged females.