Aging Attenuates the Pituitary Response to Gonadotropin-Releasing Hormone

Abstract

Context: Complex changes in GnRH secretion occur with aging in women, but little is known about the effect of aging on the pituitary per se. Objective: The aim of the study was to determine whether pituitary responsiveness to GnRH is attenuated with aging. Design and Setting: A GnRH antagonist and graded doses of GnRH were used to isolate pituitary responsiveness in Clinical Research Center studies at an academic medical center. Subjects: Subjects were healthy postmenopausal women (PMW) aged 48–57 yr (n = 10) or 70–77 yr (n= 9). Interventions: A suppressive dose of the NAL-GLU GnRH antagonist (150 μg/kg sc) was administered and was followed by GnRH doses of 25, 75, 250, or 750 ng/kg iv every 4 h. Results: The LH response to GnRH was attenuated with aging (P = 0.05) with an interaction between age and dose (P = 0.01) such that the LH amplitude was less in older PMW at the higher doses (250 ng/kg, 50 ± 9 vs. 29 ± 4.9 IU/liter, for young and old PMW, respectively, P = 0.02; and 750 ng/kg, 97.7 ± 11 vs. 70.2 ± 9.3 IU/liter, P = 0.002), but not the lower doses of GnRH. The FSH response to GnRH was also attenuated with aging in PMW (P = 0.005). Conclusions: In studies that isolated the pituitary from endogenous GnRH stimulation, aging attenuated the LH and FSH responses to exogenous GnRH in PMW. These studies indicate that the pituitary plays a role in the decline in gonadotropin levels with aging, further supporting the potential contribution of age-associated changes in both hypothalamic and pituitary function to reproductive senescence. Studies using a hypothalamic clamp to isolate the pituitary from endogenous GnRH input in postmenopausal women demonstrate that the LH and FSH responses to GnRH are diminished with aging.