With aging, female rats exhibit a progressive cessation of regular estrous cyclicity and a decline in reproductive capacity. Progress from our grant project has provided evidence to suggest that, in middle-aged females, there is a decreased neuroendocrine responsiveness to the stimulatory feedback of estradiol (E2) on LH secretion, and that a delayed or diminished LH surge response to an increase in endogenous E2 in these aging females results in the prolonged, irregular estrous cycles or a persistent estrus (PE). In these spontaneous PE females, the mechanism for producing the LH surge remains intact and is responsive to male stimulation but not estrogen challenge. We also have observed that a cessation of regular cyclicity during aging occurs significantly earlier in life in virgin females than in multiparous rats, and that successive increases in circulating progesterone (P) by Silastic implants in young virgins decrease ovarian E2 production, follicular development and the loss of ovarian follicles, and result in subsequent maintenance of regular cyclicity and improved reproductive capacity at middle age. This grant proposal outlines systematic approaches: 1) To determine whether increased circulating P levels decelerate the progression of reproductive aging by reducing the E2 inhibitory actions on the CNS- neuroendocrine system and/or by maintaining sufficient numbers of ovarian follicles for regular ovulatory function; 2) To examine the effects of P, LH-releasing hormone (LHRH) administration and intraventricularly infused norepinephrine (NE) on LH secretion in middle-aged rats; 3) To explore the possibility that regular ovulatory cycles may be restored in formerly PE or irregularly cyclic females by cyclic pattern of P or LHRH administration or by pulsatile pattern of LHRH administration; 4) To determine the specific male factors responsible for the caging/mating induced LH surges in PE rats, and to assess whether this male factor(s) stimulates hypothalamic LHRH and pituitary LH release by activating the central adrenergic mechanism. The overall objectives of this proposal are to understand the endocrine mechanisms by which E2 and P influence the progression of reproductive aging, and to assess whether a functional ovarian follicular pool is an important determinant in the exhibition of regular ovulatory function. Such findings may be relevant to women during the perimenopausal age with irregular menstrual cycles.
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