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

Abstract

Abstract 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.