• Seifer, David (PI)

Project: Research project

Project Details


The overall goal of this research is to develop a more complete
understanding of the interactions of components of the
hypothalamic-pituitary-ovarian axis as they contribute to the aging of the
reproductive system. Examination of the interaction of specific organs
should provide insight into the basis of reproductive aging and may allow
development of means of deferring natural reproductive senescence, as well
as understanding the mechanisms involved in the aging of other
endocrine-dependent systems. Specifics regarding training in cell and
molecular biology are outlined in this proposal. Phase I research will attempt to clarify the respective roles of
hypothalamic-pituitary and ovarian factors in the reproductive aging of the
female rat. The working hypothesis is that aging of the
hypothalamic-pituitary-ovarian axis is an endocrine-dependent process.
Assessment of the neuroendocrine and ovarian contributions to aging of the
female rat's reproductive system will be done by comparing the results of
selective, reversible inhibition of the hypothalamus and ovaries. The
intent is to assess concurrently the effects of these interventions in the
hypothalamic arcuate nucleus and ovarian follicles, which are critical to
preovulatory LH surges and ovarian steroidogenesis, respectively. To test the working hypothesis, two organ-specific questions will be
addressed. 1) Is aging of the hypothalamus a function of (ovarian) estrogen
exposure? The presence of gonadotrophin positive feedback and morphologic
hypothalamic changes in rats given placebo, 17 Beta-estradiol, or the
antiestrogen, keoxiphene will be examined. Following discontinuation of
each treatment, rats will be examined for the extent of arcuate nucleus
gliosis as evidence of synaptic remodeling in addition to an assessment of
estradiol-induced daily LH surges and reproductive function. 2) Is aging of
the ovary a function of repetitive stimulation by gonadotropins? Whether
blocking repetitive stimulation with gonadotropins affects the primordial
oocyte pool will be investigated. The number and diameter of ovarian
follicles will be assessed in rats given GNRH agonist, GNRH agonist plus 17
Beta-estradiol and compared with placebo-treatment controls. Following
discontinuation of each treatment rats will be examined for ovarian
follicular depletion, the ability of E2 to induce daily LH surges, arcuate
nucleus lesions, and reproductive function. Phase II research will focus upon determining possible genetic markers of
aging of the female rat reproductive system as well as the investigation of
interventions which affect the expression of such markers.
Effective start/end date9/24/919/1/96


  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)

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