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 microg/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.

Trial registration: ClinicalTrials.gov NCT00386022.

Figures

Figure 1

Serum LH during the 28-h study in a representative subject. Beginning at 0800 h, blood was sampled every 30 min for 4 h to assess baseline secretion. The subject then received a sc injection of the NAL-GLU GnRH antagonist. Beginning 8 h after GnRH receptor blockade, GnRH doses of 25, 75, 250, and 750 ng/kg were administered iv at 4-h intervals. LH is expressed in IU/liter, as equivalents of the 2nd International Reference Preparation of human menopausal gonadotropins.

Figure 2

Decrease in LH responsiveness to GnRH with aging in PMW. LH amplitude is expressed in absolute values (top) or as percentage change from baseline (bottom) in response to increasing doses of GnRH (25, 75, 250, and 750 ng/kg) in younger and older PMW after administration of a GnRH antagonist. LH is expressed in IU/liter, as equivalents of the 2nd International Reference Preparation of human menopausal gonadotropins.

Figure 3

Decrease in FSH responsiveness to GnRH with aging in PMW. FSH amplitude is expressed as absolute values (top) or as percentage change from baseline (bottom) in response to increasing doses of GnRH (25, 75, 250, and 750 ng/kg) in younger and older PMW after administration of a GnRH antagonist. FSH is expressed in IU/liter, as equivalents of the 2nd International Reference Preparation of human menopausal gonadotropins.