Short-term aromatase-enzyme blockade unmasks impaired feedback adaptations in luteinizing hormone and testosterone secretion in older men

The mechanisms subserving hypoandrogenemia and relative hypogonadotropism in older men are not known. The present study tests the clinical hypothesis that aging impairs hypothalamopituitary adaptations to feedback withdrawal induced by antagonism of estrogen biosynthesis. To this end, we appraised gonadal axis responses to estrogen depletion induced by anastrozole (a potent and selective aromatase inhibitor) in nine older and 11 young men vs. placebo in 17 other older and eight young men. The study design comprised a prospectively randomized, double-blind, parallel-cohort intervention. To monitor LH release, blood was sampled every 10 min for 24 h; LH concentrations were assayed by two-site monoclonal immunoradiometric assay; pulsatile LH release quantitated by a model-free discrete peak-detection technique (Cluster); feedback-dependent orderliness of LH secretion via the approximate entropy statistic; and 24-h rhythmicity of LH concentrations by cosine analysis. At baseline, older men had comparable estradiol and testosterone but lower LH concentrations than young controls. Exposure to anastrozole reduced (24-h pooled) serum estradiol concentrations by 50% (P < 0.001) and elevated mean LH concentrations by 2.1-fold (P < 0.001) in both the young and older cohorts. However, older men failed to achieve young adult augmentation of the following: 1) total testosterone concentrations (P < 0.01) or molar testosterone to SHBG ratios (P < 0.01); 2) incremental LH pulse amplitude (P < 0.001) and LH peak area (P < 0.01); 3) mean LH pulse frequency (P = 0.0044); and 4) quantifiable irregularity (approximate entropy) of LH release patterns (P < 0.001). FSH concentrations became comparable in the two age cohorts. In summary, administration of a potent and selective aromatase antagonist reduces estradiol and elevates mean LH concentrations equivalently in young and older men. The low estrogen-feedback state in elderly men unmasks diminished incremental LH pulse amplitude and area; absence of further acceleration of LH pulse frequency; impaired regulation of the orderliness of LH release; and reduced testosterone to SHBG ratios. Thus, aging alters expected hypothalamopituitary-gonadal adaptations to short-term partial estrogen depletion in healthy men.