The studies outlined in this proposal are designed to test the HYPOTHESIS that the continuous, repetitive influence of estrogen (E) on the brain during the reproductive life of the animal ultimately causes hypothalamic reproductive failure.
The AIMS of the studies proposed are two-fold; first, to gain a better insight into the biochemical changes underlying the loss of reproductive function in the aging female rat; and second, to determine whether E induced reproductive failure can be regarded as a valid model of hypothalamic aging. The following QUESTIONS will be addressed: 1. Is E induced reproductive failure accompanied by the same progressive, predictable anatomical and functional changes as age-related reproductive failure? 2. Are there similar disturbances of LH secretion in aging and E treated animals? 3. What are the regional changes in brain E and progestin receptor concentrations during E induced and age-related hypothalamic reproductive failure? 4. What are the regional changes in monoamine neurotransmitter concentrations and turnovers, and in tyrosine hydroxylase and monoamine oxidase activities during E induced and age-related hypothalamic reproductive failure? These studies will utilize microdissection techniques coupled with sensitive steroid binding assays, high performance liquid chromatography systems and the assessment of key enzyme activities. These procedures will be used to determine the biochemical mechanisms underlying age-associated and E induced anatomical hypothalamic degeneration in the rat. The biochemical and morphological events accompanying the E induced arcuate lesion will be correlated with changes in vaginal smear patterns and ovarian morphology which also accompany the age and E induced lesions. This will validate the use of vaginal smears as a guide to these hypothalamic events. The methodical comparison of endocrine, biochemical, morphological, and genital events surrounding the development of E induced and age induced hypothalamic failure will allow better interpretation of the events occuring in both syndromes. In addition, these studies will allow the evaluation of E induced hypothalamic failure as a model for hypothalamic senescence in aging. Although no direct evidence exists indicating the generality of E induced aging effects in non-rodent species, we believe that this information has implications for understanding steroid action and the aging process in all species.
| Brown, T J; MacLusky, N J; Shanabrough, M et al. (1990) Comparison of age- and sex-related changes in cell nuclear estrogen-binding capacity and progestin receptor induction in the rat brain. Endocrinology 126:2965-72 |
