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Combined Inhibition of Types I and II 5 -Reductase Selectively Augments the Basal (Nonpulsatile) Mode of Testosterone Secretion in Young Men

Endocrine Service, Research and Development (A.I.), Salem Veterans Affairs Medical Center, Salem, Virginia 24153; and Endocrine Research Unit, Department of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center (J.D.V.), Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Endocrine Research Unit, Department of Internal Medicine, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

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 -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 -reduced steroids.

Setting/Design/Intervention: In a university setting, nine young men received placebo and a dual (type I/type II) 5 -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 -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 -reductase preferentially drives nonpulsatile Te secretion in healthy men. The concomitant stability of LH outflow could indicate that intragonadal 5 -reduced androgens repress basal Leydig-cell steroidogenesis.