Hypothalamicpituitary dysfunction

In addition to a primary testicular failure, the aged BN rat also showed features suggestive of a hypothalamic-pituitary dysfunction. Serum FSH levels were elevated in association with low serum inhibin and decreased spermatogenesis in older rats (Wang et al 1993, Gruenewald et al 1994). In contrast, despite the low serum testosterone levels, serum LH showed no change (Chen et al 1994, Gruenewald et al 1994) or a decrease in aged rats (Wang et al 1993, 1999) (Fig. 1). Moreover, the blunted rise in serum LH and FSH after castration in the old, when compared with the young animals provided further evidence for a hypofunctional hypothalamic-pituitary axis (Gruenewald et al 1994). We also showed that the pulsatile secretion of LH was characterized by a shortened pulse interval and reduced areas of the pulses in the old rats. LH pulse amplitude and total area of the LH pulses were also significantly lower in old than in young rats. In contrast, mean serum FSH levels in old rats were significantly higher than those observed in young rats. Mean areas but not amplitude of FSH pulses decreased significantly in the old rats. FSH pulse frequency increased and pulse interval decreased in the old rats (Fig. 4). Our results were corroborated by similar studies by Gruenewald et al (2000) who also demonstrated blunted circadian rhymicity of LH and testosterone secretion due to decreased gonadotropin releasing hormone (GnRH) production rather than decreased pituitary responsiveness to GnRH. These changes in the pulsatile secretion of the gonadotropins in the BN rat are similar to the human and are consistent with a hypothalamic GnRH pulse generator dysfunction. In man, high amplitude LH peaks tend to fall and frequency of low amplitude LH peaks tend to rise in older men (Veldhuis et al 1992, Mulligan et al 1995). The decreased LH secretory burst amplitude correlated with serum free testosterone in elderly men. In contrast, serum FSH showed an increase in basal secretion rate and increased FSH secretory burst mass and amplitude in old compared to young men (Veldhuis et al 1999). The neuroendocrine mechanisms underlying the discrepant LH and FSH pulsatile secretions occurring with ageing are not known.

It has been previously shown that excitatory amino acids acting through their receptors have a primary role in the regulation of the pulsatile secretion of GnRH and LH. GnRH peptide content, synthetic capacity and gene expression are reduced in aged male rats (Gruenewald & Matsumoto 1991, Gruenewald et al 2000). We hypothesize that decreased GnRH responsiveness to excitatory amino acids may occur with ageing. To test this hypothesis, we first demonstrated that in vivo serum FSH or LH responsiveness to GnRH was not altered in the old rats. We then showed that administration of an excitatory amino acid (glutamate) receptor agonist N-methyl-D-aspartate (NMDA) induced higher LH and prolactin releases in young versus old animals. Moreover, using hypothalamus fragments, we showed that the in vitro GnRH efflux in response to NMDA was lower in old rats

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Young

Young

120 240 360 480

Middle-aged

Middle-aged

120 240 360

—i—1—1—■—1—■—1 120 240 360 480 Minutes

—i—1—1—■—1—■—1 120 240 360 480 Minutes

UJ 3

10 3

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