Introduction: Balanced, antagonistic actions of activins and inhibins regulate testis development, fertility and follicle stimulating hormone (FSH) production.  Whereas progress has been made in understanding the activin:inhibin axis during development, little is known of the effects of altered activin signaling on the ageing testis.  To address this, we measured sperm production and reproductive hormone levels in adult mice lacking either one copy of the Inhibin alpha (Inha) gene or the transcription factor SMAD3, which transduces activin signals.

Methods: Testis weight and daily sperm production (DSP) were determined at 8 and 26 weeks (n>5/genotype).  FSH, activins A, B and inhibin were measured by radioimmunoassay.

Results: At 8 and 26 weeks, FSH and serum and testicular activin A and B levels were not different between Inha+/+ and Inha+/- mice, whereas inhibin concentrations were half wildtype levels.  At 8 weeks, Inha+/- testes were 10% larger than wildtype and DSP was 50% greater, apparently due to increased spermatogenic efficiency.  By 26 weeks of age, testes of wildtype mice had grown by 20% and DSP increased by 35%.  Testes of adult Inha+/- mice, however, did not grow and by 26 weeks, spermatogenic efficiency had sharply declined (33% DSP reduction compared to 8 weeks).  Adult testis growth was Smad3-dependent; Smad3+/+ and Smad3+/- testes increased in size by 20% between 8 and 26 weeks but Smad3-/- testes did not grow.  At 8 and 26 weeks, serum and testicular activin concentrations in Smad3-/- mice were 1.5-2 times greater than in wildtype mice.  In contrast, differences in inhibin concentrations were found only at 26 weeks - serum inhibin in Smad3-null mice was half wildtype levels, yet testicular inhibin was 1.5-fold greater.

Conclusion: Altered activin signalling influences adult testis growth and age-related testicular decline in mice, providing insight into changes in testicular and endocrine function in men during ageing.