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1 Endocrine Research Unit, Department of Internal Medicine, Mayo Clinic, Mayo School of Graduate Medical Education, General Clinical Research Center, Rochester, MN, USA
2 Departments of Bioethics and Statistics, University of Virginia, Charlottesville, VA, 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.
Testosterone (Te) concentrations fall gradually in healthy aging men. Postulated mechanisms include relative failure of GnRH, LH and/or gonadal Te secretion. Available methods to test Leydig-cell Te production include pharmacological stimulation with hCG. We reasoned that physiological lutropic signaling could be mimicked by pulsatile infusion of rh LH during acute suppression of LH secretion. To this end, we studied 8 young (ages 19-30 y) and 7 older (ages 61-73 y) men in an experimental paradigm comprising: (i) inhibition of overnight LH secretion with a potent selective GnRH-receptor antagonist (ganirelix, 2 mg sc); (ii) iv infusion of consecutive pulses of rh LH (50 IU every 2 h); and (iii) chemiluminometric assay of LH and Te concentrations sampled every 10 min for 26 h. Statistical analyses revealed that: (a) ganirelix suppressed LH and Te equally (> 75% median inhibition) in young and older men; (b) infused LH pulse profiles did not differ by age; and (c) successive iv pulses of rh LH increased concentrations of: (i) free Te (ng/dL) to 4.6 ± 0.38 (young) and 2.1 ± 0.14 (older) [P < 0.001]; and (ii) bioavailable Te (ng/dL) to 337 ± 20 (young) and 209 ± 16 (older) [P = 0.002]. Thus, controlled pulsatile rh LH drive that emulates physiological LH pulses unmasks significant impairment of short-term Leydig-cell steroidogenesis in aging men. Whether more prolonged pulsatile LH stimulation would normalize this inferred defect is unknown.
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