Androgen synthesis in the gonadotropin-suppressed human testes can be markedly suppressed by ketoconazole

Abstract

Context: 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.

Design/setting/patients: 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.

Conclusion: 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.

Figures

Figure 1.

Study design. SC, subcutaneous.

Figure 2.

A–D, Box plots of IT-T (A), IT-DHT (B), IT-ADD (C), and IT-DHEA (D) in gonadotropin-suppressed subjects on day 3 and day 10 by treatment group. Baseline median (25th and 75th percentiles) IT-T concentration for normal men is 715 (486, 1000) ng/mL (19). The baseline median IT-DHT concentration for normal men is shown in gray shaded area (19). The baseline median IT-ADD and IT-DHEA concentrations for normal men are 179 (88, 246) ng/mL and 162 (118, 253) ng/mL, respectively (23). K400, ketoconazole 400 mg; K800, ketoconazole 800 mg; * P < .05 compared with day 3 and all nonketoconazole treatment groups;**P < .05 compared with day 3 and all other treatment groups; †P < .05 compared with day 3.

Figure 3.

A–D, Serum T (A), DHT (B), E2 (C), and 17-OHP (D) at baseline, 48 hours after acyline administration (day 3), and 1 week after oral medication administration (day 10) by treatment group. Dashed lines represent the normal reference range. Ana, anastrazole 1 mg; Dut, dutasteride 2.5 mg; K400, ketoconazole 400 mg; K800, ketoconazole 800 mg; Pla, placebo. *P < .05 compared with baseline; **P < .05 compared with all other treatment groups at day 10.