Submitted on February 24, 2005
Accepted on May 6, 2005
Age-Specific Changes in the Regulation of LH-dependent Testosterone Secretion: Assessing Responsiveness to Varying Endogenous Gonadotropin Output In Normal Men
Peter Y Liu1, Paul Y Takahashi2, Pamela D Roebuck1, Ali Iranmanesh3, and Johannes D Veldhuis1*
1 Endocrine Research Unit, Department of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, MN, USA
2 Department of Internal Medicine, Division of Primary Care Internal Medicine, Mayo Clinic, Rochester, MN, USA
3 Endocrine Service, Research and Development, Salem Veterans Affairs Medical Center, Salem, VA, USA
* To whom correspondence should be addressed. E-mail: Veldhuis.Johannes{at}mayo.edu.
Pulsatile and thus total testosterone (Te) secretion declines in older men, albeit for unknown reasons. Analytical models forecast that aging may reduce the capability of endogenous LH pulses to stimulate Leydig-cell steroidogenesis. This notion has been difficult to test experimentally. The present study used graded doses of a selective GnRH-receptor antagonist to yield 4 distinct strata of pulsatile LH release in each of 18 healthy men ages 23-72 yr. Deconvolution analysis was applied to frequently sampled LH and Te concentration time series to quantitate pulsatile Te secretion over a 16-hr interval. Log-linear regression was used to relate pulsatile LH secretion to attendant pulsatile Te secretion (LH-Te drive) across the 4 stepwise interventions in each subject. Linear regression of the 18 individual estimates of LH-Te feedforward dose-response slopes on age disclosed a strongly negative relationship (r = -0.721, P < 0.001). Accordingly, the present data support the thesis that aging in healthy men attenuates amplitude-dependent LH drive of burst-like Te secretion. The experimental strategy of graded suppression of neuroglandular outflow may have utility in estimating dose-response adaptations in other endocrine systems.
