Differential Effects of Isomers of Clomiphene Citrate on Reproductive Tissues in Male Mice

BJU Int. 2016 Feb;117(2):344-50. doi: 10.1111/bju.13244. Epub 2015 Sep 7.


Objectives: To determine, in a chronic dosing study, the oral toxicity potential of the test substances, enclomiphene citrate (ENC) and zuclomiphene citrate (ZUC), when administered to male mice by oral gavage.

Materials and methods: Mice were divided into five treatment groups. Group I, placebo; Group II, 40 mg/kg body weight/day ENC; Group III, 4 mg/kg/day ENC; Group IV, 40 mg/kg/day ZUC; Group V, 4 mg/kg/day ZUC. Serum samples and tissues were obtained from each mouse for analysis and body weights were measured.

Results: In this chronic dosing study in mice, profound effects on Leydig cells, epididymis, seminal vesicles, and kidneys were seen, as well as effects on serum testosterone, follicle-stimulating hormone and luteinising hormone levels that were associated with ZUC treatment only. Treatment with the isolated enclomiphene isomer had positive effects on testosterone production and no effects on testicular histology.

Conclusions: The present study suggests that an unopposed high dose of zuclomiphene can have pernicious effects on male mammalian reproductive organs. The deleterious effects seen when administering ZUC in male mice, justifies the case for a monoisomeric preparation and the development of ENC for clinical use in human males to increase serum levels of testosterone and maintain sperm counts.

Keywords: clomiphene citrate; enclomiphene citrate; secondary hypogonadism; testosterone replacement therapy; zuclomiphene citrate.

MeSH terms

  • Administration, Oral
  • Animals
  • Clomiphene / pharmacology*
  • Disease Models, Animal
  • Epididymis / drug effects*
  • Estrogen Antagonists / pharmacology*
  • Follicle Stimulating Hormone / blood*
  • Hypogonadism / drug therapy*
  • Luteinizing Hormone / drug effects*
  • Male
  • Mice
  • Reproduction
  • Seminal Vesicles / drug effects*
  • Sperm Count
  • Spermatogenesis / drug effects*
  • Testosterone / blood*


  • Estrogen Antagonists
  • Clomiphene
  • Testosterone
  • Luteinizing Hormone
  • Follicle Stimulating Hormone