Androgen synthesis in the gonadotropin-suppressed human testes can be markedly suppressed by ketoconazole.
BACKGROUND
The concentration of intratesticular testosterone (IT-T) required for human spermatogenesis is unknown because spermatogenesis can persist despite the markedly reduced IT-T concentrations observed with LH suppression. Methods to lower IT-T further are needed to determine the relationship between IT-T and spermatogenesis.


OBJECTIVE
The objective of the study was to determine the effect of inhibiting the synthesis and metabolism of testosterone (T) on IT-T in gonadotropin-suppressed human testes.


METHODS
Forty normal men participated in a blinded, placebo-controlled, randomized trial at an academic center. INTERVENTION/OUTCOME MEASURES: All men were first administered the GnRH antagonist acyline to suppress LH. Forty-eight hours after acyline administration, subjects were randomly assigned to placebo, ketoconazole (to inhibit T synthesis) at 400 or 800 mg, dutasteride (to inhibit T metabolism) 2.5 mg, or anastrazole (to inhibit T metabolism) 1 mg, daily for 7 days (n = 8/group). Intratesticular steroid concentrations were measured 48 hours after acyline administration alone and again after 7 days of combination treatment.


RESULTS
After 7 days of combination treatment, the median IT-T (25th, 75th percentile) in the placebo group was 14 (8.0, 21.2) ng/mL. IT-T was reduced to 3.7 (2.5, 7.1) ng/mL in the ketoconazole 400 mg group and 1.7 (0.8, 4.0) ng/mL in the ketoconazole 800 mg group (P < .001 vs placebo for both comparisons). IT-T concentrations in the dutasteride and anastrazole groups were similar to placebo.


CONCLUSIONS
Combining inhibition of steroidogenesis with gonadotropin suppression lowers IT-T more than gonadotropin suppression alone. This combination might be useful to determine the minimum IT-T concentration necessary for human spermatogenesis, information essential for developing male hormonal contraceptives.
Departments of Internal Medicine, University of Washington, 1959 NE Pacific Street, Box 357138, Seattle, Washington 98195, USA. mylang@u.washington.edu
M Y
MY
Roth
J J S
JJ
Nya-Ngatchou
K
K
Lin
S T
ST
Page
B D
BD
Anawalt
A M
AM
Matsumoto
B T
BT
Marck
W J
WJ
Bremner
J K
JK
Amory
D058888:14-alpha Demethylase Inhibitors / Q000008:administration & dosage; D019326:17-alpha-Hydroxyprogesterone / Q000097:blood; D000293:Adolescent; D000328:Adult; D000728:Androgens / Q000096:biosynthesis* / Q000097:blood; D000735:Androstenedione / Q000096:biosynthesis / Q000097:blood; D003267:Contraception / Q000379:methods*; D003687:Dehydroepiandrosterone / Q000096:biosynthesis / Q000097:blood; D015195:Drug Design; D004357:Drug Synergism; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage*; D010919:Placebos; D013091:Spermatogenesis / Q000187:drug effects / Q000502:physiology; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D013739:Testosterone / Q000096:biosynthesis / Q000097:blood; D055815:Young Adult
D058888:14-alpha Demethylase Inhibitors; D000728:Androgens; D009842:Oligopeptides; D010919:Placebos; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D019326:17-alpha-Hydroxyprogesterone; D007654:Ketoconazole; C109238:acyline