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Inhibition of Luteinizing Hormone Secretion by Testosterone in Men Requires Aromatization for Its Pituitary But Not Its Hypothalamic Effects: Evidence from the Tandem Study of Normal and Gonadotropin-Releasing Hormone-Deficient Men

Reproductive Endocrine Unit of Department of Medicine (N.P., A.A.D., S.D., P.A.B., W.F.C., F.J.H.) and Department of Biostatistics and General Clinical Research Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Frances Hayes, MB, FRCPI, Reproductive Endocrine Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: Hayes.Frances{at}MGH.Harvard.edu.

Context: Studies on the regulation of LH secretion by sex steroids in men are conflicting.

Objective: Our aims were to determine the relative contributions of testosterone (T) and estradiol (E₂) to LH regulation and localize their sites of negative feedback.

Design: This was a prospective study with three arms.

Setting: The study was conducted at a General Clinical Research Center.

Patients or Other Participants: Twenty-two normal (NL) men and 11 men with GnRH deficiency due to idiopathic hypogonadotropic hypogonadism (IHH) participated.

Intervention: Medical castration and inhibition of aromatase were achieved using high-dose ketoconazole (KC) for 7 d with 1) no sex steroid add-back; 2) T enanthate 125 mg im starting on d 4; or 3) E₂ patch 37.5 µg/d starting on d 4. Blood sampling was performed every 10 min for 12 h at baseline, overnight on d 3–4 and d 6–7.

Main Outcome Measures: Mean LH levels, LH pulse amplitude, and GnRH pulse frequency were assessed at baseline, d 3–4, and d 6–7.

Results: In NL men, KC caused a 3-fold increase in mean LH on d 3–4, which was stable on d 6–7 with no add-back. Addition of T reduced LH levels (34.6 ± 3.9 to 17.4 ± 3.6 IU/liter, P < 0.05) by slowing GnRH pulse frequency (13.3 ± 0.4 to 6.7 ± 1.0 pulses/12 h, P < 0.005). LH amplitude increased (6.9 ± 1.0 to 12.1 ± 1.4 IU/liter, P < 0.005). E₂ add-back suppressed LH levels (36.4 ± 5.6 to 19.0 ± 2.4 IU/liter, P < 0.005), by slowing GnRH pulse frequency (11.4 ± 0.2 to 8.6 ± 0.4 pulses/12 h, P < 0.05) and had no impact on LH pulse amplitude. In IHH men, restoring normal T levels caused no suppression of mean LH levels or LH amplitude. E₂ add-back normalized mean LH levels and decreased LH amplitude from 14.7 ± 1.7 to 12 ± 1.5 IU/liter (P < 0.05).

Conclusions: 1) T and E₂ have independent effects on LH. 2) Inhibition of LH by T requires aromatization for its pituitary, but not hypothalamic effects. 3) E₂ negative feedback on LH occurs at the hypothalamus.

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