Male reproductive ageing using the Brown Norway rat as a model for man

Christina Wang*, Amiya Sinha Hikim*, Monica Ferrinif, Juan J. Bonavera*, Dolores Vernetf, Andrew Leung*, Yan-He Lue*, Nestor F. Gonzalez-Cadavidf and Ronald S. Swerdloff*

Divisions of * Endocrinology and {Urology, Departments of Medicine and Surgery, Harbor-UCLA Medical Center and Research and Education Institute, 1000 West Carson Street, Carson, CA 90509, USA

Abstract: 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.

2002 Endocrine facets of ageing. Wiley, Chichester (Novartis Foundation Symposium 242) p 82-97

Cross-sectional and longitudinal studies in men showed that serum testosterone declined with ageing (Vermeulen 1991). Even though serum total testosterone may be in the normal range, the free or bioavailable testosterone levels are frequently lower in elderly men (Gray et al 1991, Korenman et al 1990, Baker et al 1976, Harman & Tsitouras 1980). Low testosterone levels in older men are associated with sexual dysfunction, loss of bone, decreased muscle mass and strength, increased body fat, frailty, and poorer quality of life (Swerdloff & Wang 1993). The low circulating serum testosterone levels are usually associated with elevated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in aged men. However, such increases in LH may be inappropriately low compared to those of young men with similar low serum testosterone levels. In search of an animal model to examine the process and mechanisms of reproductive ageing, we and others have defined the BN rat as the most suitable model for male reproductive ageing (Zirkin et al 1993, Wang et al 1993, Gruenewald & Matsumoto 1991). The BN rat is a better model to study male reproductive ageing than other strains because these rats have a longer lifespan, do not develop pituitary or testicular tumours, are not excessively obese, and manifest both testicular and hypothalamic-pituitary dysfunction with ageing. In this chapter, we will describe the work in our laboratory using the BN rat as a model for studying human male reproductive ageing.

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