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

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 microg/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.

Figures

Figure 1

Schematic of the hypothalamic-pituitary gonadal axis in normal and GnRH-deficient men. In normal men, T and E2 can exert negative feedback at both the hypothalamus and pituitary. In contrast, men with congenital GnRH deficiency lack endogenous GnRH secretion. However, their pituitary-gonadal axis can be normalized with pulsatile GnRH therapy. Because the dose and frequency of exogenous GnRH are experimentally controlled, this model represents a hypothalamic clamp. Therefore, any effect on gonadotropin secretion of altering gonadal steroids in such GnRH-deficient men can reflect only a pituitary site of action. Thus, a hypothalamic site of action of sex steroids can be inferred whenever there is a difference in the gonadotropin responses of normal and GnRH-deficient men to alterations in their sex steroid milieu.

Figure 2

Serum T and E2 levels in healthy male volunteers (A and C) and GnRH-deficient men on GnRH therapy (B and D) during medical castration for 7 d with either no sex steroid add-back or replacement with T or E2 from d 4–7. Values represent the pool of samples drawn every 10 min for 12 h. a, Significantly different from BL, P < 0.005; b, significantly different from BL, P < 0.05.

Figure 3

Mean LH levels in healthy male volunteers (A) and GnRH-deficient men on GnRH therapy (B) during medical castration for 7 d with either no sex steroid add-back or replacement with T or E2 from d 4–7. Values represent the mean of samples drawn every 10 min for 12 h. a, Significant difference from BL, P < 0.005; b, significant difference from BL, P < 0.05; c, significant difference between d 3–4 and d 6–7, P < 0.05; d, significant difference between d 3–4 and d 6–7, P < 0.005.

Figure 4

GnRH pulse frequency and LH pulse amplitude in healthy male volunteers (A and C) and IHH men on GnRH therapy maintained at a constant 2 h frequency (B and D) during medical castration for 7 d with either no sex steroid add-back or replacement with T or E2 from d 4–7. a, Significant difference from BL, P < 0.005; b, significant difference from BL, P < 0.05; c, significant difference between d 3–4 and d 6–7, P < 0.05; d, significant difference between d 3–4 and d 6–7, P < 0.005.