Differential effects of aging on estrogen negative and positive feedback

Abstract

Recent studies have demonstrated an age-related decline in gonadotropins and a decrease in pituitary responsiveness to GnRH, indicating that aging influences the neuroendocrine components of the female reproductive axis independently of changes in ovarian function. To determine whether aging might also affect the luteinizing hormone (LH) negative and positive feedback responses to gonadal steroids, we administered a controlled, graded sex steroid infusion to 11 younger (45-56 yr) and nine older (70 -80 yr) postmenopausal women (PMW) in whom endogenous ovarian steroids and peptides are uniformly low. The doses of estradiol (E2) and progesterone (P) were chosen to mimic levels across the normal follicular phase and have been shown previously to induce negative followed by positive feedback on LH. Similar E2 and P levels were achieved in younger and older PMW (P ϭ 0.4 and 0.3, respectively) and produced a biphasic LH response in all subjects. The early decline in LH to 53% of baseline was not different in older vs. younger PMW. However, the positive feedback effect was attenuated in older compared with younger PMW (peak LH 144.4 Ϯ 19.5 vs. 226.8 Ϯ 22.3 IU/l, respectively, P ϭ 0.01). In conclusion, these studies in PMW demonstrate preservation of short-term steroid negative and positive feedback in response to exogenous E2 and P with aging. Attenuation of positive feedback in older compared with younger PMW is consistent with previous reports of declining GnRH responsiveness with aging. luteinizing hormone; neuroendocrine; postmenopausal women REPRODUCTIVE SENESCENCE IN WOMEN represents a dynamic phase of complex physiological changes in which irregular follicular development and ovulatory dysfunction eventually give way to the total loss of ovarian function. The depletion of ovarian follicles, accompanied by decreasing levels of inhibin B and anti-mullerian hormone, is the primary mechanism underlying reproductive aging in women (2,9,23,29,35). After the initial postmenopausal rise in gonadotropins, there is a progressive decline in both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in postmenopausal women (PMW) as a function of age that provides evidence for an additional neuroendocrine effect of aging in women that is independent of changes at the ovarian level (12). We have demonstrated comparable sensitivity to the negative feedback effects of chronic low-dose estrogen on LH in younger compared with older PMW (7,8,26). However, the question of whether aging attenuates the inhibitory and stimulatory effects of estrogen on LH over a time frame that more closely approximates that of the normal follicular phase has not been investigated.We have addressed this question in younger and older PMW, in whom endogenous estrogen and inhibin are uniformly low (4), by administering a controlled intravenous steroid infusion that mimics estradiol (E 2 ) and progesterone (P) levels across the follicular phase and results in negative followed by positive feedback in reproductive-aged women (20,31). This ...

The physiology of endocrine systems with ageing

“…57,58,60 The existence of direct age-related neuroendocrine changes, as revealed by the progressive decline of gonadotropin concentrations with advancing age after menopause, appears to be less physiologically relevant than the intrinsic ovarian changes. 56,61 Throughout reproductive life and menopausal transition, there is an age-related decreasing trend of adrenal production of DHEA and DHEAS, and of mixed adrenal and ovarian production of testosterone and androstenedione. However, the LH-stimulated theca cells in the postmenopausal ovaries still contribute to circulating testosterone concentrations for up to 10 years.…”

Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes

“…With increasing age after the menopause, LH secretion declines (Hall, 2007; Rossmanith et al, 1991), but many neuroendocrine functions remain intact. For example, if estrogen is administered in an appropriate regimen, positive feedback effects that stimulate LH secretion can still be demonstrated after the last menstrual cycle (Shaw et al, 2011). Furthermore, negative feedback effects of estrogen on LH secretion are not diminished with age (Gill et al, 2002a,b).…”

Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats

“…Pulsatile GnRH administration restores serum LH and gonadal function, indicating that the HH is secondary to insufficient GnRH secretion (11,56). It is not known whether these individuals will respond with an LH surge if given a regimen of steroid replacement designed to stimulate the surge (58). Because we did not ablate KNDy neurons before puberty, the full phenotype of congenital HH, in which there is abnormal pubertal progression, was not addressed in the present study.…”