Accelerated deaths from systemic lupus erythematosus in NZB x NZW F1 mice treated with the testosterone-blocking drug flutamide.
In the New Zealand black (NZB) x New Zealand white (NZW) (B/W) mouse model of systemic lupus erythematosus (SLE), females die prematurely and males have late onset of disease. It has been proposed that testosterone protects B/W mice from rapidly progressive SLE. The mechanisms of androgenic suppression of the immune system, however, are not understood. We tested the hypothesis that testosterone exerts protective effects in males through classic receptor-mediated actions. Flutamide, a potent and specific androgen receptor blocker, was administered continuously to B/W mice from 6 weeks of age, and the animals were monitored in a longevity study. Our supposition that flutamide treatment would accelerate disease was upheld in female B/W mice. In females, flutamide clearly accelerated mortality and reduced longevity to (median) 30 weeks as compared with 37 weeks in controls (p = 0.003). In male B/W mice, mortality was identical in treated and control animals in the early phase of the study, and deleterious effects of treatment were apparent only after the first year of treatment. Flutamide-treated males had significant elevation of serum testosterone, but their atrophied seminal vesicles strongly suggested that peripheral androgen effects were blocked. Albuminuria, blood urea nitrogen, and anti-DNA antibodies were not altered by flutamide in females or males. The receptor-mediated effects of androgens on murine autoimmune disease were dependent on gender and were noted primarily in females and in males that survived past 1 year of age.
Walker
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Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201-5297.
Besch-Williford
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Keisler
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D000419:Albuminuria / Q000453:epidemiology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D004195:Disease Models, Animal; D004958:Estradiol / Q000097:blood; D005260:Female; D005485:Flutamide / Q000494:pharmacology*; D006200:Hair Color / Q000235:genetics; D015994:Incidence; D008136:Longevity; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000401:mortality* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009026:Mortality; D011863:Radioimmunoassay; D013739:Testosterone / Q000037:antagonists & inhibitors* / Q000097:blood / Q000502:physiology
D000974:Antibodies, Antinuclear; D013739:Testosterone; D004958:Estradiol; D005485:Flutamide