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Testosterone’s Short-Term Positive Effect on Luteinizing-Hormone Secretory-Burst Mass and Its Negative Effect on Secretory-Burst Frequency Are Attenuated in Middle-Aged Men

Endocrine Research Unit (P.Y.L., P.D.R., J.N.B., J.D.V.), and Department of Internal Medicine (P.Y.T.), Mayo Medical School, Mayo School of Graduate Medical Education, Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905; and Department of Statistics (D.M.K.), University of Virginia, Charlottesville, Virginia 22904

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Endocrine Research Unit, Mayo Medical School, Mayo School of Graduate Medical Education, Center for Translational Science Activities, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

Background: Testosterone (T) production declines and LH pulses become smaller and more frequent in middle-aged men. The mechanisms underlying these changes are not known.

Rationale: Small frequent LH pulses in middle-aged men could reflect impaired feedback by systemic T.

Hypothesis: Middle age disrupts negative feedback by T on selected facets of LH secretion.

Subjects and Setting: Healthy men were studied at an academic medical center.

Methods: The protocol comprised blockade of gonadal steroidogenesis and graded transdermal addback of T doses of 0, 2.5, 5, or 7.5 mg/d designed to span the castrate to physiological range of T concentrations in each of 23 healthy men ages 19–71 yr (interquartile range, 28–53 yr). We quantified 12-h basal and pulsatile LH secretion (92 time series) using a mathematically justified deconvolution method.

Results: Stepwise T supplementation from the hypogonadal through the eugonadal range repressed mean (12-h) LH concentrations (P = 0.001). By regression analysis, age attenuated the capabilities of increasing T concentrations to 1) increase LH secretory-burst mass (P < 0.0001); and 2) decrease LH secretory-burst frequency (P = 0.025). Age did not alter T’s feedback on basal LH secretion, interpulse regularity, the waveform of LH secretory bursts, or the slow half-life of LH.

Conclusion: Middle age impairs both the positive and negative actions of systemic T on pulsatile LH secretion in healthy men, thus potentially explaining earlier inconsistencies in feedback studies based upon single-sample mean LH concentrations. Longitudinal studies will be required to elucidate the precise age dependence of inferred dual feedback failure.