Effects of the neuropeptidase thimet oligopeptidase on testicular development and testosterone production

The endopeptidase thimet oligopeptidase (TOP) is found throughout the body, but is most catalytically active in the testes and brain. One of its important substrates is the hypothalamic peptide gondadotropin‐releasing hormone (GnRH), which acts in the hypothalamus‐pituitary‐gonadal axis to regulate steroid hormone production in gonads. We have previously demonstrated that TOP is itself regulated by steroid hormones in the hypothalamus of female mice. The current study was designed to test whether TOP also has a local effect on the gonads of male mice. We injected male mice subcutaneously with a specific inhibitor of TOP (N‐[1‐(R,S)‐carboxy‐3‐phenylpropyl]‐Ala‐Aib‐Tyr‐p‐aminobenzoate) or vehicle from post‐natal day 7 weekly until 6 weeks of age. This time period was chosen so that the first injection would occur before the onset of spermatogenesis and treatment would continue through maturation of spermatozoa. Animals were sacrificed at 6 weeks; blood, testes, and brain samples collected. Animals treated with the inhibitor displayed larger testes weight:body weight ratio than untreated animals. In addition, there was a trend towards higher circulating testosterone levels in the inhibitor‐treated animals. Because the inhibitor is not thought to cross the blood‐brain barrier, these results suggest that TOP acts peripherally in control of gonadal function in males.