Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy

Nat Med. 2003 Jun;9(6):768-73. doi: 10.1038/nm878. Epub 2003 May 18.


Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease that affects males. It is caused by the expansion of a polyglutamine (polyQ) tract in androgen receptors. Female carriers are usually asymptomatic. No specific treatment has been established. Our transgenic mouse model carrying a full-length human androgen receptor with expanded polyQ has considerable gender-related motor impairment. This phenotype was abrogated by castration, which prevented nuclear translocation of mutant androgen receptors. We examined the effect of androgen-blockade drugs on our mouse model. Leuprorelin, a lutenizing hormone-releasing hormone (LHRH) agonist that reduces testosterone release from the testis, rescued motor dysfunction and nuclear accumulation of mutant androgen receptors in male transgenic mice. Moreover, leuprorelin treatment reversed the behavioral and histopathological phenotypes that were once caused by transient increases in serum testosterone. Flutamide, an androgen antagonist promoting nuclear translocation of androgen receptors, yielded no therapeutic effect. Leuprorelin thus seems to be a promising candidate for the treatment of SBMA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / therapeutic use
  • Animals
  • Disease Models, Animal
  • Female
  • Flutamide / therapeutic use
  • Humans
  • Leuprolide / therapeutic use*
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Activity / physiology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscular Disorders, Atrophic / drug therapy*
  • Muscular Disorders, Atrophic / metabolism
  • Organ Size
  • Peptides / metabolism*
  • Phenotype
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Testosterone / metabolism
  • Testosterone / pharmacology


  • Androgen Antagonists
  • Peptides
  • Receptors, Androgen
  • polyglutamine
  • Testosterone
  • Flutamide
  • Leuprolide