Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Chronically reduced inhibin production is associated with age-related decline in Sertoli and Leydig cell function in mice. (#152)

Amanda Bielanowicz 1 , Mark Hedger 2 , James Doery 3 , Kate Loveland 4 , Catherine Itman 1
  1. University of Newcastle, Callaghan, NSW, Australia
  2. MIMR-PHI, Clayton, Victoria, Australia
  3. Department of Medicine, Monash University, Clayton, Victoria, Australia
  4. Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia

Deteriorating physical function in ageing men is postulated to involve reduced testosterone levels and is estimated to affect 6-39% of men over 40 and up to 50% of men over 85.  Although age-related reductions in Leydig cell steroidogenic capacity and altered hypothalamic-pituitary-gonadal (HPG) communication have been described, little is known about mechanisms triggering these changes.  Inhibin is produced predominantly in the testis and circulating inhibin-B concentrations decline from ~30 years.  Inhibin is a potent activin inhibitor, hence reduced inhibin implicates upregulated activin signalling in age-related testicular decline.  We used mice lacking one copy of the inhibin alpha gene to investigate the consequences of an altered inhibin:activin ratio on testicular ageing.  Testicular and circulating inhibin-α subunit concentrations were 30% lower in Inha+/- mice compared to wildtype, but activin A, activin B, follicle stimulating hormone and testosterone concentrations were not different (n>6).  Inha+/- mice displayed an age-related decline in daily sperm production between 8 and 26 weeks (-27%, P<0.05), whereas sperm production in wildtype mice increased during this period (+31%, P<0.01).  Flow cytometric ploidy analysis confirmed that Inha+/- mice had a significantly lower testicular haploid cell content compared to wildtype, correlating with somatic cell changes.  Sertoli cell flow cytometry identified ~30% of Sertoli cells in S-phase in both Inha+/+ and Inha+/- mice at 8 weeks.  By 26 weeks, the proportion of S-phase Inha+/+ Sertoli cells had declined to 19% (P<0.001) but remained elevated in Inha+/- mice (35.8%).  Testosterone is necessary for optimal spermatogenesis and for Sertoli cell terminal differentiation and cell cycle quiescence. Immunohistochemical analysis of steroidogenic enzymes identified that expression of CYP11A1 (p450scc), the rate-limiting enzyme upstream of testosterone synthesis, was reduced in some Inha+/- Leydig cells at 26 weeks.  Suggestive of focal regions of androgen deficiency, these findings correlate inhibin insufficiency with Leydig cell failure and age-related testicular decline.