Project: Research project

Project Details


Alteration in neuroendocrine function is a major cause of reproductive
aging processes in females. Reduced sensitivity to estrogen appears to
play an important role in this dysfunction. Chronic exposure to estrogen
and possibly other ovarian secretions is in turn implicated in the etiology
of reduced estrogenic sensitivity, since long-term withdrawal from ovarian
hormones during adult life lessens these age-related reductions in
sensitivity. This proposal aims to elucidate the molecular basis for these
estrogen dependent aging processes in the hypothalamus-preoptic area (HPOA)
of the female C57BL/6J mouse, a well characterized model of female
reproductive aging. Three major questions are addressed. First, studies
are proposed to elucidate the molecular and cellular basis for reduced
concentrations and altered intracellular dynamics of estrogen receptor
during aging. The role of altered expression of the gene encoding the
estrogen receptor in its age-related reduction and altered intracellular
dynamics will be determined using a solution hybridization/RNAse protection
assay for mouse estrogen receptor mRNA. The relative contributions of
reduced intraneuronal concentrations of the estrogen receptor versus loss
of neurons that actively produce estrogen receptor will be assessed. These
studies will use immunocytochemistry and in situ hybridization to map the
age-related changes in the distribution and intraneuronal density of
estrogen receptor and estrogen receptor mRNA. The second major question
concerns the effect of aging on estrogen-modulated gene expression in the
hypothalamus-preoptic area. Because estrogen receptor levels are only
partially reduced in brain and because of the prevalence of selective age
related changes, the hypothesis will be tested that genes responsive to
estrogen exhibit variable impairment in responsiveness during aging:
specifically, genes most sensitive to estrogenic modulation show the least
age-related reduction in sensitivity to estrogen; whereas less sensitive
genes show greater impairment. These studies will involve exposing young
and old mice to variable concentrations of circulating estradiol and
measuring the relationship between plasma estradiol, cell nuclear occupancy
of the estrogen receptor and level of induction (or suppression) of the
estrogen modulated mRNA. Finally, studies will determine whether the age-
related alterations in estrogen receptor parameters and in estrogen-
responsive genes that are identified in the aforementioned studies are
attenuated by long-term ovariectomy, and thus may mediate some of the
protective effects of hormonal withdrawal on reproductive aging processes.
The proposed studies should contribute to understanding the molecular
mechanism and cellular targets for altered responsiveness to estrogen in
the aging brain. In addition to advancing understanding of an important
reproductive aging process, this knowledge has implications for post-
menopausal hormone withdrawal and for estrogen replacement therapy, the
most common steroid hormone replacement regimen in women.
Effective start/end date2/1/911/31/96


  • National Institutes of Health: $174,668.00


  • Medicine(all)


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