transient scrotal hyperthermia and levonorgestrel enhance testosterone-induced spermatogenesis suppression in men through increased germ cell apoptosis

J Clin Endocrinol Metab. 2007 Aug;92(8):3292-304. doi: 10.1210/jc.2007-0367. Epub 2007 May 15.


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

Objective: A "proof of concept" study was performed 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 and settings: A randomized clinical trial was performed at academic medical centers.

Participants: We treated four groups of healthy male volunteers (18 per group) for 18 wk: 1) testosterone undecanoate (TU) 1000 mg im (first dose), followed by 500 mg im every 6 wk; 2) submersion of scrota at 43 C in water for 30 min/d for 6 consecutive days; 3) TU plus heat; and 4) TU plus oral levonorgestrel (LNG) 250 microg/d.

Main outcome measures: Semen parameters, testicular histology, and germ cell apoptosis were the main outcome measures.

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

Conclusions: Heat causes a rapid and transient suppression of spermatogenesis. TU plus 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antispermatogenic Agents / blood
  • Antispermatogenic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / physiology*
  • Azoospermia / pathology
  • Cell Count
  • Fever / physiopathology*
  • Gene Expression Regulation / physiology
  • Germ Cells / drug effects*
  • Germ Cells / physiology*
  • Hot Temperature
  • Humans
  • Immunohistochemistry
  • Levonorgestrel / pharmacology*
  • Male
  • Middle Aged
  • Oligospermia / pathology
  • Scrotum / physiology*
  • Sperm Count
  • Spermatogenesis / drug effects*
  • Spermatogenesis / genetics
  • Spermatogenesis / physiology*
  • Testis / cytology
  • Testis / pathology
  • Testosterone / blood
  • Testosterone / pharmacology*
  • Tissue Fixation


  • Antispermatogenic Agents
  • Testosterone
  • Levonorgestrel