Context: In rodents and monkeys, a combination of hormonal and physical agents accelerates germ cell death.

Objective: A "proof of concept" study to investigate whether addition of heat exposure or a progestin to an androgen induces germ cell death and more complete and rapid spermatogenesis suppression.

Design: Randomized Clinical trial.

Settings: Academic Medical Centers.

Participants: We treated 4 groups of healthy male volunteers (n=18/group) or 18 weeks: 1) testosterone undecanoate (TU) 1000 mg IM (first dose) followed by 500 mg IM every 6 weeks; 2) submersion of scrota at 43 ⁰C in water for 30 minutes/day for 6 consecutive days; 3) TU + Heat and 4) TU plus oral levonorgestrel (LNG) 250 mcg/day.

Main Outcome Measures: Semen parameters, testicular histology and germ cells apoptosis.

Results: Heat alone and TU + Heat suppressed sperm counts more than TU alone by week 6. By week 9, recovery began in the heat only group, whereas spermatogenesis remained suppressed in the TU + Heat group. Oral LNG +TU suppressed spermatogenesis earlier and more severely than TU alone. At week 2, significantly greater germ cell apoptosis occurred in Heat and Heat + TU subjects, but not in subjects without heat treatment, compared to pre-treatment subjects. By 9 weeks, markedly smaller seminiferous tubule diameters and fewer spermatocytes and spermatids were noted in all 12 biopsies from men receiving TU, TU + LNG with most dramatic differences for the TU + heat group, whereas no differences from pre-treatment biopsies were observed in men who received heat treatment only.

Conclusion: Heat causes a rapid and transient suppression of spermatogenesis. TU + Heat resulted in low sperm output that was maintained by continuous treatment with TU. Addition of an oral progestin accelerated spermatogenesis suppression by TU alone. Increased germ cell apoptosis contributed to suppression of spermatogenesis.