The hypothalamic-pituitary complex (H-P) loses the ability to orchestrate ovulation by middle age in many female laboratory animals. The gradual loss in cyclicity correlates to alterations in the preovulatory LH surge, the signal that induces ovulation. Beginning at a time when the ovaries contain significant numbers of oocytes, the malady is believed independent of the aging process in the ovary, but dependent upon long-term exposure of the H_P to ovarian steroids, especially estradiol (E2). Because the anterior pituitary (AP) and the hypothalamus are closely linked, both anatomically and chemically, it is difficult to determine how each component contributes to the aging process. The present approach taken by may laboratory is to study each component separately. The question is where to begin. Current research indicates that much of the neuroendocrine impairment lies centrally in the hypothalamic control over the AP. There is evidence, however, that alterations in LH function and cyclicity also involves inherent changes in the AP. These alterations are dependent upon E2 influences and occurs by middle age. For example, the AP of aging mice are unable to sustain LH release following prolonged pulsatile stimulation with LHRH, a necessity during the preovulatory LH surge. At the pituitary level, such episodic releases rely on synchronization of cell membrane and intracellular events of the gonadotropes. therefore, the specific aim of this proposal is to test the hypothesis: Exposure to E2 alters LH function of the AP with age. Pituitary involvement will be tested by measuring AP changes in LH secretory ability, LHRH receptor dynamics and turnover of key mRNAs for the biosynthesis of LH (LHbeta) and cytoskeletal elements (alpha- tubulin). Our standard aging model, the C57BL/6 female mouse, will be tested under conditions that challenge the ability of the AP for sustained release of LH, specifically, 1) during the preovulatory period, 2) following short-and long-term ovariectomy (OVX), and 3) after OVX plus ovarian steroid manipulation and priming. Experiments are also planned to pin point the age at which impairment occurs, and whether various ovarian steroid regimes can accelerate or attenuate the aging effects of E2. Lastly, chemicals that modify cytoskeletal mediated events will be used to clarify the role of tubulin and actin in pituitary aging. These studies will aid in characterizing what LH secretory mechanisms are affected by age and the role of estradiol in the aging process.
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