Activins, members of the Transforming Growth Factor-β (TGF-β) superfamily of cytokines, are dimers of the inhibin βA- or βB-subunits. Functionally, the inhibins, which are heterodimers of one β-subunit and an α-subunit, are activin inhibitors. Within the male reproductive tract, expression of activin A is highest in the caput epididymis, but is extremely low in the vas deferens, while the converse is true for its binding protein, follistatin. This suggests that differential expression of activin A and follistatin may be involved in maintaining the regionalised structure and function of the male reproductive tract. The inhibin α-subunit gene knockout mouse (Inha-/-) lacks inhibin, and develops testicular tumours from about 4 weeks of age, leading to progressive testicular damage. These mice had very high levels of activin A and B, as well as elevated follistatin, in the serum and testes. At 8-10 weeks of age, Inha-/- epididymal weight was reduced by 50% compared with Inha+/+ control mice. Sperm was absent or very low in the epididymis and vas deferens of the Inha-/- mice, and the ductal epithelium of these tissues were regressed, with increased fibrosis in the stroma around the ducts. Seminal vesicle weight and serum testosterone levels were considerably reduced, but luteinizing hormone (LH) levels were paradoxically normal. Although serum inhibin was reduced by 30% in the heterozygous Inha+/- mice, serum and testicular activins, follistatin and testosterone were not altered, and the epididymis and vas deferens appeared morphologically normal. In conclusion, deletion of the inhibin α-subunit gene leads to over-expression of both activin A and B, and androgen deficiency, although with normal LH. Regression of the epididymis and vas deferens also occurs, but it is not clear whether this is a direct result of activin overexpression, or loss of testicular function associated with tumour development, or both.