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Sex Steroid Control of Gonadotropin Secretion in the Human Male. II. Effects of Estradiol Administration in Normal and Gonadotropin-Releasing Hormone-Deficient Men^*

JOEL S. FINKELSTEIN, LOUIS ST. L. O’DEA, RANDALL W. WHITCOMB and WILLIAM F. CROWLEY, JR.

Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital Boston, Massachusetts 02114

Address requests for reprints to: William F. Crowley Jr., M.D., Reproductive Endocrine Unit, Massachusetts General Hospital, Bartlett Hall Extension 5, 40 Rear Blossom Street, Boston, Massachusetts 02114.

Although prior studies have suggested that estrogens exert their negative feedback effect at the pituitary level in men, these conclusions have been based on models that evaluate changes in LH pulse amplitude and frequency and, therefore, only provide indirect information concerning the site of action of estrogens. To assess whether estradiol (E₂) inhibits gonadotropin secretion directly and solely at the pituitary level in men, we determined the pituitary responses to physiological doses of GnRH in six men with complete GnRH deficiency, whose pituitary-gonadal function had been normalized with long term pulsatile GnRH delivery, before and during a 4-day continuous E₂ infusion (90 µg/day). To deduce whether E₂ has an additional inhibitory effect on hypothalamic GnRH secretion, their responses were compared with the effects of identical E₂ infusions on spontaneous gonadotropin secretion and the responses to a 100-µg GnRH bolus in six normal men. Both groups were monitored with 15 h of frequent blood sampling before and during the last day of the E₂ infusion. In the GnRH-deficient men, the first three GnRH doses were identical and chosen to produce LH pulses with amplitudes in the midphysiological range of values in our normal men (i.e. a physiological dose), while the last four doses spanned 1.5 log orders (7.5, 25, 75, and 250 ng/kg). The 250-ng/kg dose was always administered last because it is known to be pharmacological.

In the GnRH-deficient men, mean LH and FSH levels as well as LH pulse amplitude all decreased significantly (P < 0.02) during E₂ infusion, demonstrating a direct pituitary-suppressive effect of E₂. Mean LH (P < 0.01) and FSH (P < 0.05) levels and LH pulse amplitude (P < 0.01) also decreased significantly in the normal men. The degree of suppression of mean LH (52 ± 3% vs. 42 ± 12%) and FSH (49 ± 10% vs. 37 ± 10%) levels was similar in the two groups. These results provide direct evidence that E₂ inhibits gonadotropin secretion at the pituitary level in men and suggest that the pituitary is the most important, and possibly the sole, site of negative feedback of estrogens in men.

^* This work was supported by NIH Grants HD-15788, HD-18169, and RR-1066; FDA Grant FD-U-000523-1; and an NIH Clinical Associate Physician Award (to J.S.F.).

Current address: Endocrine Unit, Bulfinch 3, Massachusetts General Hospital, Boston, Massachusetts 02114.

Current address: Department of Endocrinology and Metabolism, Montreal General Hospital, Montreal, Quebec, Canada H3G 1A4.

Received October 29, 1990.

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