Testicular dysfunction

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Reproductive ageing in the BN rat is characterized by low serum testosterone levels (Zirkin et al 1993, Wang et al 1993, 1999). Low serum testosterone levels are also a hallmark of the ageing male demonstrated in both cross-sectional and longitudinal studies (Vermeulen 1991, Gray et al 1991). We studied serum testosterone levels and sperm concentration in 6, 9, 12, 15, 18 and 31 month-old BN rats. Beginning at 15 months, plasma testosterone and inhibin levels both showed a progressive decline with age (Fig. 1). Intratesticular testosterone and inhibin concentrations were not lower, and in fact appeared to be higher in testes that showed marked regression, because of the loss of seminiferous tubule content in the testis (Wang et al 1993,1999). The decrease in serum testosterone was due to decreased Leydig cell secretory capacity as demonstrated by Zirkin et al (1993), Zirkin & Chen (2000) and Chen et al (1994, 1996). The Leydig cell dysfunction resulted from reductions in the levels and activities of steroidogenic enzymes (Luo et al 1996). Leydig cells isolated from old rats produced significantly less basal and LH-stimulated testosterone in vitro. If the Leydig cells were depleted by treatment with ethane dimethanesulfonate and then allowed to regenerate, the capacity ofthe Leydig cells in the old rats to produce testosterone was similar to young animals for up to 10 weeks. Whether the capacity of these repopulated Leydig cells in old rats would continue to produce testosterone in the older BN rats was not studied (Chen et al 1996). The same investigators administered contraceptive doses of testosterone (implants) to young and old rats for 8 months. Two months after removal of testosterone implants, the Leydig cells of both the young and old rats secreted high levels of testosterone. The investigators suggest that by placing the Leydig cells in 'hibernation' the decreased Leydig cell steroidogenesis associated

FIG. 1. Plasma LH (A), FSH (B), testosterone (C), and inhibin (D) concentrations in ageing rats. Data represent mean SE of 5—10 animals per group. *Indicates p <0.05 when compared with young (6 month old) rats. Reproduced with permission from Wang et al (1999).

with ageing did not occur (Chen & Zirkin 1999). These gradual changes in serum testosterone levels in the BN rat mimicked closely the 'andropause' associated with ageing in men. Low serum testosterone levels are the cause of the low muscle mass, decreased bone density, frailty and might be partially responsible for the erectile dysfunction commonly encountered in older men as described in the chapter by Handelsman (2002, this volume).

We, as well as others (Wang et al 1993,1999, Wright et al 1993), have shown that testicular weights were reduced in 21—22 month old BN rats to about 60—70% of those of young rats. Frequently a differential decrease in testis size was observed in the same animal. One testis was often much smaller ('regressed') and the other was relatively normal in weight. By 30 months the mean testicular weights were very small: only about 25—30% of those at 6 months. Mean testicular sperm concentration and total sperm content decreased progressively from 15 months (Fig. 2). Testicular histology in the relatively normal looking testis of 21—22 month old BN rats showed active spermatogenesis with large lumina and marked variation in the appearance of the germinal epithelium from relatively normal to a flattened epithelium lined by a single layer of Sertoli cells and a few spermatogonia. Many tubules had areas consisting of normal-looking tubules intermingled with groups of damaged tubules. In the regressed testis, the seminiferous tubule showed complete cessation of spermatogenesis. By 30 months, the testes were very small and showed features similar to those of the regressed testes of the 21—22 month old rats. Testicular stereologic analysis showed a marked reduction in the volumes of seminiferous tubules and tubular diameter. In old animals, Leydig cell volume was markedly lower but their number remained unchanged. There was a marked decrease in the number of Sertoli cell per testis in the regressed testes of 21—22 and 30 month old rats (Wang et al 1993, Wright et al 1993). We also showed that the decrease in germ cells was due to accelerated germ cell apoptosis (Fig. 3) involving spermatogonia, spermatocytes and spermatids (Wang et al 1999). In addition, there was marked variability in the apoptosis rate in different tubules. Germ cell apoptosis was most evidenced in stages XII—XIV when compared with young animals. It should be noted that in the regressed testis, the seminiferous tubules were lined with Sertoli cells and few apoptotic germ cells as well as Leydig and Sertoli cells (Wang et al 1999). The variable and irregular depletion of germ cells by apoptosis in the seminiferous tubules suggests that in addition to low testosterone levels, other factors such as decreased blood supply and increased cytotoxic agents (e.g. reactive oxygen species) might also play a role in germ cell degeneration. The changes in the seminiferous tubules in the BN rats are more pronounced than those reported in men. Semen analyses of healthy active grandfathers have been reported to be relatively normal (Nieschlag et al 1982), but others reported that the daily sperm production was decreased in ageing men (Neaves et al 1984).

FIG. 2. Body weight (A), testicular parenchymal weight (B), sperm content (C), and sperm concentration (D) in ageing BN rats. Data represent mean SE of 5—10 animals per group. *Indicates significant difference, P<0.05, when compared with young (6 month old) rats. Reproduced with permission from Wang et al (1999).

FIG. 2. Body weight (A), testicular parenchymal weight (B), sperm content (C), and sperm concentration (D) in ageing BN rats. Data represent mean SE of 5—10 animals per group. *Indicates significant difference, P<0.05, when compared with young (6 month old) rats. Reproduced with permission from Wang et al (1999).

When rat LH was administered as a twice daily injection to 15 month old BN rats for 6 months, plasma hormone levels, testis weight, sperm concentration and content, and germ cell apoptosis rate remained the same as those of the untreated, control group. In the control group, three out of 10 testes were regressed whereas in the LH-treated group only one out of 12 testes was regressed. These results

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FIG. 3. Light micrographs of testicular sections from a 21 month old rat showing apoptotic germ cells (arrow) in the relatively normal looking (A) and regressed (B) testes. Visualization of apoptotic germ cells was by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL). Methyl green was used as a counterstain. Magnification

FIG. 3. Light micrographs of testicular sections from a 21 month old rat showing apoptotic germ cells (arrow) in the relatively normal looking (A) and regressed (B) testes. Visualization of apoptotic germ cells was by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL). Methyl green was used as a counterstain. Magnification suggest that impaired hypothalamic—pituitary function may not be the only cause of testicular germ cell loss associated with ageing (Wang et al 1999). However the experimental conditions cannot exclude the possibility that the LH treatment might be inadequate because it was given as twice daily doses and not in a pulsatile fashion, and the testosterone response to the dose of LH administered might be insufficient to support spermatogenesis.

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