The relative role of gonadal sex steroids and gonadotropin-releasing hormone pulse frequency in the regulation of follicle-stimulating hormone secretion in men

Abstract

Objective: Our objective was to determine the importance of testosterone (T), estradiol (E(2)), and GnRH pulse frequency to FSH regulation in men.

Design: This was a prospective study with four arms.

Setting: The study was performed at the General Clinical Research Center.

Patients or other participants: There were 20 normal (NL) men and 15 men with idiopathic hypogonadotropic hypogonadism (IHH) who completed the study.

Intervention: Medical castration and inhibition of aromatase were achieved using ketoconazole x 7 d with: 1) no sex steroid addback, 2) T addback starting on d 4, and 3) E(2) addback starting on d 4. IHH men in these arms received GnRH every 120 min. In a further six IHH men receiving ketoconazole with no addback, GnRH frequency was increased to 35 min for d 4-7. Blood was drawn every 10 min x 12 h at baseline, overnight on d 3-4 and 6-7.

Main outcome measures: Mean FSH was calculated from the pool of each frequent sampling study.

Results: In NL men FSH levels increased from 5.1 +/- 0.7 to 8.7 +/- 1.3 and 9.7 +/- 1.5 IU/liter (P < 0.0001). T caused no suppression of FSH. E(2) reduced FSH from 12.4 +/- 1.8 to 9.3 +/- 1.3 IU/liter (P < 0.05). In IHH men on GnRH every 120 min, FSH levels went from 6.0 +/- 1.6 to 9.0 +/- 3.0 and 11.9 +/- 4.3 (P = 0.07). T caused no suppression of FSH. E(2) decreased FSH such that levels on d 6-7 were similar to baseline. Increasing GnRH frequency to 35 min had no impact on FSH.

Conclusions: The sex steroid component of FSH negative feedback in men is mediated by E(2). Increasing GnRH frequency to castrate levels has no impact on FSH in the absence of sex steroids. When inhibin B levels are NL, sex steroids exert a modest effect on FSH.

Figures

Figure 1

Serum T and E2 levels in healthy male volunteers (A and C) and GnRH-deficient men on GnRH therapy (B and D) during acute biochemical castration for 7 d with either no sex steroid addback 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).

Figure 2

Mean FSH levels in healthy male volunteers (A) and GnRH-deficient men on GnRH therapy (B) during biochemical castration for 7 d with either no sex steroid addback or replacement with T or E2 from d 4–7. P value shown represents overall change using repeated measures ANOVA. a, Significant difference from BL (P < 0.005). b, Significant difference from BL (P < 0.05). c, Significant difference between d 3–4 and 6–7 (P < 0.05).

Figure 3

Mean FSH levels in GnRH-deficient men on GnRH therapy during biochemical castration for 7 d with no sex steroid addback. The GnRH pulse frequency (Freq) was increased from 1 pulse every 120 min to 1 pulse every 35 min for d 4–7. Values represent a study pool from the mean of samples drawn every 10 min for 12 h. P value shown represents overall change using repeated measures ANOVA.*Significant difference from BL (P < 0.05).