Aromatase inhibition in the human male reveals a hypothalamic site of estrogen feedback.
Level 3 - non-randomized controlled study
Non-randomized controlled interventional study comparing normal men with IHH controls.
PubMed 10999781 · doi:10.1210/jcem.85.9.6795
What was done
Fourteen normal men and seven men with idiopathic hypogonadotropic hypogonadism (IHH) receiving long-term pulsatile GnRH replacement were studied to map estrogen feedback sites using anastrozole (10 mg/day orally for 7 days). In Experiment 1, daily morning blood samples were drawn in 9 normal and 7 IHH men. In Experiment 2, 9 normal men underwent frequent blood sampling (every 10 minutes for 12 hours) at baseline and on day 7 of anastrozole; a subset of 5 normal men then received the GnRH antagonist Nal-Glu (5 microg/kg) followed by frequent sampling for 8 hours to evaluate endogenous GnRH secretion.
What was found
Anastrozole suppressed estradiol equivalently in normal men (136 +/- 10 to 52 +/- 2 pmol/L, P < 0.005) and IHH men (118 +/- 23 to 60 +/- 5 pmol/L, P < 0.005). Testosterone rose significantly in both groups (53 +/- 6% in normal vs. 56 +/- 7% in IHH men, P < 0.005). The rise in gonadotropins was greater in normal than IHH men (LH: 100 +/- 9 vs. 58 +/- 6%, P = 0.07; FSH: 85 +/- 6 vs. 41 +/- 4%, P < 0.002). Frequent sampling in normal men revealed increases in LH pulse frequency (10.2 +/- 0.9 to 14.0 +/- 1.0 pulses/24 h, P < 0.05) and pulse amplitude (5.7 +/- 0.7 to 8.4 +/- 0.7 IU/L, P < 0.001). Acute LH suppression by GnRH antagonist was unchanged by anastrozole (69.2 +/- 2.4 vs. 70 +/- 1.9%).
Why it matters
By demonstrating that aromatase inhibition accelerates LH pulse frequency in intact men but produces blunted gonadotropin increases in men with fixed GnRH pulses, this study establishes that estrogen exerts negative feedback at both the hypothalamic and pituitary levels in men.
Limits
The total sample size was small (14 normal men and 7 IHH men; only 5 received the GnRH antagonist challenge), the intervention lasted only 7 days, there was no placebo control, and hypothalamic GnRH dynamics were inferred indirectly through peripheral pulse analysis and receptor blockade.
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.