TY - JOUR
T1 - 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
AU - Schnorr, J. A.
AU - Bray, M. J.
AU - Veldhuis, J. D.
PY - 2001
Y1 - 2001
N2 - The present clinical study examines the neuroregulatory hypothesis that feedback restraint of LH and FSH secretion by testosterone requires in vivo aromatization. To test this postulate, we prospectively and randomly assigned 47 healthy young men to 1 of 5 parallel short-term (5-day) double-blind interventions with: 1) placebo; 2) high-dose ketoconazole (KTCZ, 400 mg orally 4 times daily) to block both Leydig-cell and adrenal steroidogenesis; 3) KTCZ and transdermal testosterone delivery (7.5 mg daily); 4) KTCZ and transdermal estradiol (0.05 mg daily); or 5) KTCZ, testosterone, and the selective 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 to quantitate 24-h mean spontaneous and 3-h post-GnRH-stimulated (100 ng/kg iv bolus) LH and FSH release. KTCZ administration lowered the serum total testosterone 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 increased testosterone levels to 607 ± 57 ng/dL (21 ± 2.0 nmol/L). KTCZ exposure 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-specificity immunoradiometric assays. Concomitant transdermal testosterone (or estradiol) delivery repressed the elevated secretion of both LH and FSH to mid-normal baseline values. A 3-fold administration of anastrazole, KTCZ, and testosterone completely opposed exogenous testosterone's suppression of 24-h LH and FSH secretion. Anastrazole coadministration likewise abolished testosterone-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 curtails endogenously driven as well as exogenous GnRH-stimulated LH and FSH secretion conditional on its in vivo aromatization.
AB - The present clinical study examines the neuroregulatory hypothesis that feedback restraint of LH and FSH secretion by testosterone requires in vivo aromatization. To test this postulate, we prospectively and randomly assigned 47 healthy young men to 1 of 5 parallel short-term (5-day) double-blind interventions with: 1) placebo; 2) high-dose ketoconazole (KTCZ, 400 mg orally 4 times daily) to block both Leydig-cell and adrenal steroidogenesis; 3) KTCZ and transdermal testosterone delivery (7.5 mg daily); 4) KTCZ and transdermal estradiol (0.05 mg daily); or 5) KTCZ, testosterone, and the selective 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 to quantitate 24-h mean spontaneous and 3-h post-GnRH-stimulated (100 ng/kg iv bolus) LH and FSH release. KTCZ administration lowered the serum total testosterone 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 increased testosterone levels to 607 ± 57 ng/dL (21 ± 2.0 nmol/L). KTCZ exposure 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-specificity immunoradiometric assays. Concomitant transdermal testosterone (or estradiol) delivery repressed the elevated secretion of both LH and FSH to mid-normal baseline values. A 3-fold administration of anastrazole, KTCZ, and testosterone completely opposed exogenous testosterone's suppression of 24-h LH and FSH secretion. Anastrazole coadministration likewise abolished testosterone-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 curtails endogenously driven as well as exogenous GnRH-stimulated LH and FSH secretion conditional on its in vivo aromatization.
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U2 - 10.1210/jc.86.6.2600
DO - 10.1210/jc.86.6.2600
M3 - Article
C2 - 11397860
AN - SCOPUS:0034976485
SN - 0021-972X
VL - 86
SP - 2600
EP - 2606
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 6
ER -