(Applicant s abstract) Because of the greater life expectancy of today, menopause and its physiological consequences are having an enormous impact on the well-being of the older female. The present research is concerned with identifying, elucidating, and quantifying the ovarian and neuroendocrine mechanisms underlying menopause. In particular, to establish that there is a specific sequential pattern of five phases that occurs during the menopausal transition, and to construct statistical predictors of the onset age and duration of the menopausal transition. Moreover, such a predictor will also allow for the estimation of a given subject's hormonal- reproductive age, not chronological age, which has enormous implications for the infertility consequences of aging. For example, based upon certain endocrine reproductive measurements taken from say a given 40 year-old female, methods will be constructed by which to predict her age of perimenopause onset and its length, and at same time to state whether she is hormonally that of a 40 year-old, or more like a 45 or 35 year-old. The ability to predict the age and length of the menopausal transition is clinically important because early menopause has associated with it increased risk of cardiovascular disease and osteoporosis, whereas late menopause has associated with it an increased risk of breast cancer and endometrial cancer. This research consists of three components. First, five prospective and cross-sectional clinical studies specifically designed for the above aims will be conducted at the University of Virginia GCRC, using pre-, peri-, and postmenopausal subjects. Second, a biomathematical model for the aging hypothalamic-pituitary- ovarian axis will be developed which includes its several feedback/feed forward interactions, the dynamical onset and shutdown of the LH surge and ovulation, as well as its eventual cessation. Third, based upon the preceding two, hypotheses concerning the five phases will be tested, and predictors of onset age and duration constructed.
| Keenan, Daniel M; Veldhuis, Johannes D (2009) Age-dependent regression analysis of male gonadal axis. Am J Physiol Regul Integr Comp Physiol 297:R1215-27 |
| Veldhuis, Johannes D; Roelfsema, Ferdinand; Iranmanesh, Ali et al. (2009) Basal, pulsatile, entropic (patterned), and spiky (staccato-like) properties of ACTH secretion: impact of age, gender, and body mass index. J Clin Endocrinol Metab 94:4045-52 |
| Keenan, Daniel M; Roelfsema, Ferdinand; Carroll, Bernard J et al. (2009) Sex defines the age dependence of endogenous ACTH-cortisol dose responsiveness. Am J Physiol Regul Integr Comp Physiol 297:R515-23 |
| Liu, Peter Y; Pincus, Steven M; Takahashi, Paul Y et al. (2006) Aging attenuates both the regularity and joint synchrony of LH and testosterone secretion in normal men: analyses via a model of graded GnRH receptor blockade. Am J Physiol Endocrinol Metab 290:E34-E41 |
| Keenan, Daniel M; Takahashi, Paul Y; Liu, Peter Y et al. (2006) An ensemble model of the male gonadal axis: illustrative application in aging men. Endocrinology 147:2817-28 |
| Veldhuis, J D; Keenan, D M; Iranmanesh, A (2005) Mechanisms of ensemble failure of the male gonadal axis in aging. J Endocrinol Invest 28:8-13 |
| Veldhuis, Johannes D; Keenan, Daniel M; Roelfsema, Ferdinand et al. (2005) Aging-related adaptations in the corticotropic axis: modulation by gender. Endocrinol Metab Clin North Am 34:993-1014, x-xi |
| Liu, Peter Y; Pincus, Steven M; Keenan, Daniel M et al. (2005) Analysis of bidirectional pattern synchrony of concentration-secretion pairs: implementation in the human testicular and adrenal axes. Am J Physiol Regul Integr Comp Physiol 288:R440-6 |
| Liu, Peter Y; Pincus, Steven M; Keenan, Daniel M et al. (2005) Joint synchrony of reciprocal hormonal signaling in human paradigms of both ACTH excess and cortisol depletion. Am J Physiol Endocrinol Metab 289:E160-5 |
| Keenan, Daniel M; Chattopadhyay, Somesh; Veldhuis, Johannes D (2005) Composite model of time-varying appearance and disappearance of neurohormone pulse signals in blood. J Theor Biol 236:242-55 |
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