Neuroendocrinology of Aging in Humans: Attenuated Sensitivity to Sex Steroid Feedback in Elderly Postmenopausal Women

Abstract

Studies in experimental animals have shown that the sensitivity of the hypothalamic-pituitary system to ovarian sex steroid feedback declines while aging progresses. Since similar observations are lacking in humans, we studied the gonadotropin secretion of postmenopausal women (PMW) of different ages before and following a 7-day course of oral clomiphene citrate (CC, 100 mg daily). For serial determinations of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, blood was sampled frequently from 5 younger PMW (mean age 55.2 years) and 6 older PMW (mean age 80.3 years) for 10 h. Eight hours after initiation of blood sampling, gonadotropin-releasing hormone (GnRH, 25 µg) was administered. Compared to untreated conditions, CC administration did not significantly change the serum concentrations of the estrogens (estrone, estradiol) and androgens (testosterone; androstenedione, dehydroepiandrosterone sulfate). However, CC increased the sex hormone-binding globulin levels in both younger and older PMW, suggestive of the estrogenic effects of this compound. In the unstimulated secretory profiles of younger PMW, mean LH levels decreased (p < 0.05) in response to CC, presumably a consequence of decreased (p < 0.05) pulse frequencies, but not pulse amplitudes. Likewise, by virtue of decreased (p < 0.05) FSH pulse amplitudes, FSH levels declined (p < 0.05) in younger PMW. In contrast, both the LH and FSH levels and their pulsatility remained virtually unaltered following CC administrations to older PMW. The GnRH-mediated gonadotropin release was uneffected by CC administrations in either group of PMW. Thus, the use of an anti-estrogen as a pharmacological probe revealed that the sensitivity of the hypothalamic-pituitary axis to negative feedback is attenuated with advanced age in PMW. Since the gonadotropin responsiveness to GnRH stimulations remained unaltered during CC administrations, we infer that the age-related attenuation of feedback sensitivity rather relates to a hypothalamic decline than to a pituitary hypofunction.

Female Pituitary Size in Relation to Age and Hormonal Factors

“…This relationship has also been described by other investigators [9,10,11]. The loss of volume is generally attributed to the decreasing levels of gonadal steroids after puberty [3]; furthermore, a loss of sensitivity of the hypothalamic-pituitary system to ovarian sex steroid feedback has been described, which might display a reason for this [12]. Although less close than pituitary volumes, cranio-caudal diameters of pituitary glands also decreased with age, as shown in the present study and prior ones [10].…”

Activation and degeneration during aging: A morphometric study of the human hypothalamus

“…The sensitivity of LH to LHRH did not decrease in elderly males (Giusti et al, 1990;Kaufman et al, 1990Kaufman et al, , 1991. On the other hand, a decreased sensitivity to sex steroid feedback was found in elderly (80 years) postmenopausal women as compared to younger postmenopausal women (55 years) (Rossmanith et al, 1994). No data on changes in the exact number of Fig.…”

Metabolic and Non-Cognitive Manifestations of Alzheimer’s Disease: The Hypothalamus as Both Culprit and Target of Pathology

“…While age-related changes in the HPG axis have focused on the sharp decline in estrogen and testosterone, loss of the hypothalamic negative feedback from the sex hormones has also been implicated in AD (Rossmanith et al, 1994). Furthermore, hypothalamic dysfunction leading to gonadotropin releasing factor (GnRH) signaling deficits could also play a role.…”