Aromatization mediates testosterone's short-term feedback restraint of 24-hour endogenously driven and acute exogenous gonadotropin-releasing hormone-stimulated luteinizing hormone and follicle-stimulating hormone secretion in young men

The present clinical study examines the neuroregulatory hypothesis that fee dback restraint of LH and FSH secretion by testosterone requires in vivo ar omatization. To test this postulate, we prospectively and randomly assigned 47 healthy young men to 1 of 5 parallel short-term (5-day) double-blind in terventions with: 1) placebo; 2) high-dose ketoconazole (KTCZ, 400 mg orall y 4 times daily) to block both Leydig-cell and adrenal steroidogenesis; 3) KTCZ and transdermal testosterone delivery (7.5 mg daily); 4) KTCZ and tran sdermal. estradiol (0.05 mg daily); or 5) KTCZ, testosterone, and the selec tive and potent. aromatase inhibitor, anastrazole (5 mg orally twice daily) . Blood was sampled every 10 min for 27 h on the last day of intervention t o quantitate 24-h mean spontaneous and 3-h post-GnRH-stimulated (100 ng/kg iv bolus) LH and FSK release. KTCZ administration lowered the serum total t estosterone concentration markedly from(mean SEM)423 +/- 57 ng/dL(15 +/- 2. 0 nmo/L)during placebo ingestion to 58 +/- 8.6 ng/dL (2.0 +/- 0.3 nmol/L) ( P < 10(-3)). Transdermal androgen addback along with KTCZ blockade increase d testosterone levels to 607 +/- 57 ng/dL (21 +/- 2.0 nmol/L). KTCZ exposur e alone drove a 3-fold increase in serum LH concentrations (P < 10(-3)) and a 2.5 fold rise in FSH secretion (P = 0.015), as assessed by high-specific ity immunoradiometric assays. Concomitant transdermal testosterone (or estr adiol) delivery repressed the elevated secretion of both LH and FSH to mid- normal baseline values. A 3-fold administration of anastrazole, KTCZ, and t estosterone completely opposed exogenous testosterone's suppression of 24-h LH and FSH secretion. Anastrazole coadministration likewise abolished test osterone-dependent inhibition of 3-h GnRH-stimulated LH and FSH release. In summary, assuming the specificity of anastrazole's inhibition of aromatase activity, we conclude that circulating testosterone in healthy men curtail s endogenously driven as well as exogenous GnRH-stimulated LH and FSH secre tion conditional on its in vivo aromatization.