Differential regulation of gonadotropin secretion by testosterone in the human male: absence of a negative feedback effect of testosterone on follicle-stimulating hormone secretion.
Level 3 - non-randomized controlled study
Non-randomized interventional physiological comparative study
PubMed 11231978 · doi:10.1210/jcem.86.1.7101
What was done
Sixteen healthy men (mean age 30.5 ± 2.2 years) were evaluated across two short-term pharmacologic protocols: selective aromatase inhibition with anastrozole (10 mg daily for 5 days; n = 9) to test selective estradiol withdrawal, and acute medical castration with ketoconazole (1 g loading dose, then 400 mg four times daily for 5 days; n = 12) with concurrent dexamethasone (0.5 mg twice daily) to test combined testosterone and estradiol ablation. Hormone levels (testosterone, estradiol, LH, FSH, inhibin B) were measured from single daily morning blood draws (0800–1000 h). In addition, five GnRH-deficient men (mean age 37.6 ± 3.9 years) received dexamethasone (0.5 mg twice daily) alongside GnRH dose-response testing to control for direct pituitary effects of glucocorticoids.
What was found
Anastrozole significantly lowered estradiol from 33 ± 3 to 14 ± 1 pg/mL (P < 0.0005) while increasing testosterone from 563 ± 42 to 817 ± 81 ng/dL (P < 0.05). Ketoconazole caused identical estradiol reduction (41 ± 4 to 14 ± 1 pg/mL; P < 0.0005) and suppressed testosterone to castrate levels (491 ± 28 to 40 ± 3 ng/dL; P < 0.0005). Serum LH increased nearly 3-fold more after medical castration than after selective estradiol withdrawal (275 ± 23% vs. 95.6 ± 21%; P < 0.005). Conversely, percentage increases in FSH were similar between castration and aromatase inhibition (91 ± 6% vs. 71 ± 7%; P = NS). Inhibin B did not change with anastrozole (156 ± 23 vs. 176 ± 19 pg/mL) but fell slightly with ketoconazole (156 ± 15 to 131 ± 11 pg/mL; P < 0.05). Dexamethasone had no significant effect on mean LH (19.8 ± 3.2 vs. 23.3 ± 5.4 IU/L), LH pulse amplitude (16.0 ± 2.5 vs. 19.0 ± 5.1 IU/L), or FSH (8.0 ± 1.9 vs. 9.2 ± 2.4 IU/L) in GnRH-deficient men.
Why it matters
This study shows that in men, testosterone exerts negative feedback on LH through both direct androgenic pathways and indirect estrogenic pathways via aromatization, whereas negative feedback on FSH is predominantly driven by estradiol rather than direct androgen action.
Limits
The sample size is very small (16 healthy men, 5 GnRH-deficient controls) and non-randomized. The pharmacologic intervention lasted only 5 days, precluding assessment of chronic feedback adaptation. Hormone assessments relied on single daily morning blood samples rather than frequent pulsatility profiling in the healthy cohort. Pharmacologic confounding from high-dose ketoconazole and dexamethasone cannot be completely ruled out despite the control experiments.
Cited by
- supports In males, negative feedback to the hypothalamus and pituitary regulating gonadotropin and testosterone production is primarily mediated by estradiol produced through aromatization, rather than by testosterone directly.