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Differential Sex Steroid Negative Feedback Regulation of Pulsatile Follicle-Stimulating Hormone Secretion in Healthy Older Men: Deconvolution Analysis and Steady- State Sex-Steroid Hormone Infusions in Frequently Sampled Healthy Older Individuals¹

Division of Endocrinology, Department of Internal Medicine, University of Virginia Health Sciences Center, National Science Foundation Center for Biological Timing (J.D.V.), Charlottesville, Virginia 22908; the Endocrine Section, Medicine Service, Salem Veterans Affairs Center (A.I.), Salem, Virginia 24153; the Endocrine and Metabolism Laboratory, Department of Medicine, New Jersey School of Medicine and Dentistry (E.S.), Princeton, New Jersey 07039; and the Department of Internal Medicine, University of Texas Medical Branch (R.J.U.), Galveston, Texas 77550

Address all correspondence and requests for reprints to: Dr. Johannes D. Veldhuis, Department of Medicine/Endocrinology & Metabolism, University of Virginia Health Sciences Center, NSF Center for Biological Timing, Box 202, Charlottesville, Virginia 22908.

The healthy aging male reproductive axis tends to exhibit a progressive decline in serum concentrations of biologically available testosterone with gradual concomitant reciprocal increases in both LH and FSH concentrations. However, relatively little is known about the sex steroid-mediated negative feedback regulation of physiologically pulsatile gonadotropin release in general, and episodic FSH release in particular, in older males. To examine the steroid hormone negative feedback control of pulsatile FSH secretion in healthy older men, we applied multiparameter deconvolution analysis to serum FSH (immunoradiometric assay) profiles obtained by sampling every 10 min over 24 h during steady state (4.5-day) infusions of estradiol (E₂; 48 µg/day), 5-dihydrotestosterone (DHT; 7.0 mg/day), or 5% dextrose in water in five healthy older men, aged 60–73 yr. We observed the following principal responses: 1) both E₂ and DHT significantly suppressed mean and 24-h integrated serum FSH concentrations (P < 0.032); 2) the calculated daily secretion rate of FSH fell significantly in all five individuals during DHT infusion; 3) the apparent half-life of FSH decreased during E₂ (but not DHT) infusion; 4) DHT infusion reduced the mass and frequency of FSH secretory bursts significantly; 5) neither E₂ nor DHT treatment significantly attenuated the release of FSH stimulated by consecutive iv injections of GnRH (10 and 100 µg); and 6) integrated 24-h serum LH (immunoradiometric assay) concentrations decreased significantly during both DHT and E₂ infusions, whereas mean LH release after the serial GnRH injections was not altered. Compared to younger men studied earlier in an identical fashion, older men had significantly reduced FSH intersecretory burst intervals, reflecting a higher FSH pulse frequency at baseline and during the steroid infusions and a significantly lower mass of FSH secreted per burst during E₂ infusion.

We conclude that healthy older men maintain intact negative feedback responsiveness of the hypothalamo-pituitary gonadotroph unit to exogenously delivered sex steroid hormones, and that individual sex steroid hormones differentially regulate specific features of pulsatile FSH release and half-life in older men.

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