Sex hormone modulation of autoimmunity in NZB/NZW mice

Abstract Prepubertal castration of female NZB/NZW (B/W) hybrid mice did not influence mortality, whereas prepubertal castration of male B/W mice caused premature death and enhanced autoantibody formation. Prepubertal castration combined with the administration of sustained estradiol‐17‐β (E‐2) enhanced mortality and autoantibody development and promoted immune complex nephritis in both sexes. The enhanced mortality observed in castrated males was significantly reduced if they were treated with sustained progesterone (P). Mice of both sexes receiving P had the highest levels of autoantibodies. By contrast, sustained 5‐α‐dihydrotestosterone (DHT) and testosterone (T) suppressed these autoimmune parameters. The suppressive effect of androgens was not a nonspecific anabolic property, since danazol (a compound with attenuated masculinizing but intact anabolic properties) was ineffective in suppressing disease. AntiDNA antibody formation developed prematurely in males given cyproterone acetate, an antiandrogen. However, this metabolic blocker did not influence mortality or proteinuria. Unexpected early enhancement of mortality was observed in female and male mice castrated and given both E‐2 and DHT (when compared to sham‐operated controls or mice given E‐2 alone). When castration was combined with the administration of both E‐2 and P, mortality was enhanced in males but was similar to E‐2 alone in females. Androgen therapy was also suppressive when it was delayed and given to female mice with more advanced disease. DHT given to intact 3‐month‐old or castrated 6‐month‐old B/W females significantly improved survival without affecting the serum levels of anti‐DNA antibodies. These observations demonstrate that sex hormones significantly modify disease in B/W mice and may have therapeutic potential.