Combined inhibition of types I and II 5 α-reductase selectively augments the basal (nonpulsatile) mode of testosterone secretion in young men

Context: Testosterone (Te) is metabolized in the hypothalamus and pituitary gland, where untransformed steroid and activated products participate in feedback regulation of GnRH and LH secretion. Genetic inactivation of 5 α-reductase type I remains undescribed clinically, whereas deficiency of the type II isoenzyme elevates both LH and Te concentrations. Objective: The aim of this study was to test the combined feedback contribution of 5 α-reduced steroids. Setting/Design/Intervention: In a university setting, nine young men received placebo and a dual (type I/type II) 5 α-reductase inhibitor, dutasteride. Methods/Outcomes: LH and Te dynamics were assessed by: 1) 10-min blood sampling for 26 h; 2) GnRH stimulation (100 ng/kg iv); 3) discrete peak detection; 4) deconvolution analysis; 5) cosinor analyses of 24-h rhythmicity; and 6) pattern regularity Results: Compared with placebo, dutasteride lowered 5 α-dihydro Te concentrations by 80% (P = 0.009), but did not alter any measure of LH dynamics. Conversely, dutasteride augmented: 1) total, bioavailable and free Te concentrations (0.002 < P < 0.032) without changing estradiol or SHBG concentrations; 2) nadir Te concentrations (P = 0.025); and 3) basal (P=0.013) and thereby total (basal plus pulsatile) (P = 0.003) Te secretion. Conclusion: Combined antagonism of types I and II 5 α-reductase preferentially drives nonpulsatile Te secretion in healthy men. The concomitant stability of LH outflow could indicate that intragonadal 5 α-reduced androgens repress basal Leydig-cell steroidogenesis.