Male reproductive ageing: using the brown Norway rat as a model for man.

The Brown Norway (BN) rat is an excellent model for male reproductive ageing. We and others have shown that with ageing, the BN rat exhibits low serum testosterone, low Leydig cell steroidogenic capacity, decreased Sertoli cell function and number, marked reduction in seminiferous tubule volume and sperm content, and accelerated germ cell apoptosis. These testicular changes are the result of a combination of a primary testicular defect and a secondary hypothalamic dysfunction. Leydig cell dysfunction results from decreased activities of the steroidogenic enzymes and Leydig cell secretory capacity and is not corrected by daily administration of replacement luteinizing hormone (LH), suggesting a primary testicular defect. However ageing in male BN rats is associated with decreased LH pulse amplitude, reduced gonadotropin releasing hormone (GnRH) and gonadotropin responsiveness to excitatory amino acids, and decreased GnRH mRNA and peptide in the hypothalamus. We have further shown in the hypothalamus of ageing BN rats that while the excitatory amino acid receptor content is reduced, nitric oxide synthase (NOS) activity is increased which is due to increased inducible (iNOS) but not neuronal NOS (nNOS). The increased iNOS protein in the hypothalamus is associated with increased peroxynitrite formation and neuronal cell apoptosis. We conclude that increased hypothalamic levels of iNOS may result in neurotoxicity in the hypothalamus leading to loss of hypothalamic GnRH secretory cells and impaired GnRH pulsatile secretion that contributes to the abnormal Leydig cell function characteristic of male reproductive ageing.