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Age Attenuates Testosterone Secretion Driven by Amplitude-Varying Pulses of Recombinant Human Luteinizing Hormone during Acute Gonadotrope Inhibition in Healthy Men

Endocrine Research Unit, Department of Internal Medicine, General Clinical Research Center, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Endocrine Research Unit, Department of Internal Medicine, General Clinical Research Center, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

Context: Whether testosterone (Te) depletion in aging men reflects deficits in the testis, hypothalamus, and/or pituitary gland is unknown.

Objective: Our objective was to quantify the impact of age on gonadal Te secretion driven by amplitude-varying pulses of recombinant human LH (rhLH) in the absence of confounding by endogenous hypothalamo-pituitary signals.

Design: This was a double-blind, placebo-controlled study.

Setting: The setting was an academic medical center.

Subjects: Fifteen healthy community-dwelling men ages 22–78 yr were included in the study.

Intervention: Saline or four separate rhLH doses were each infused twice iv in randomized order as one pulse every 2 h over 20 h to stimulate Te secretion, after LH secretion was suppressed by a GnRH-receptor antagonist, ganirelix.

Main Outcome: LH and Te concentrations were determined in blood samples collected every 5 min. Maximal and minimal (as well as mean) Te responses were regressed linearly on age to reflect LH peak and nadir (and average) effects, respectively.

Results: The ganirelix/rhLH paradigm yielded serum LH concentrations of 4.6 ± 0.22 IU/liter (normal range 1–9). By regression analysis, age was associated with declines in rhLH pulse-stimulated peak and nadir (and mean) concentrations of total Te (P = 0.0068), bioavailable Te (P = 0.0096), and free Te (P = 0.013), as well as lower Te/LH concentration ratios (P < 0.005). Deconvolution analysis suggested that the half-life of infused LH increases by 12%/decade (P = 0.044; R² = 0.28).

Conclusions: Infusion of amplitude-varying pulses of rhLH during gonadal-axis suppression in healthy men unmasks prominent age-related deficits in stimulated total (39%), bioavailable (66%), and free (63%) Te concentrations, and a smaller age-associated increase in LH half-life. These data suggest that age-associated factors reduce the efficacy of LH pulses.