Although the combined observations of a diminished testicular reserve for testosterone secretion and increased basal gonadotropin levels may seem in line with the view that the age-related decline of Leydig cell function results from primary testicular dysfunction, closer examination of the data suggests that other mechanisms must also be involved. Indeed, the observed responses to hCG challenges in elderly men indicate that the secretory reserve of the Leydig cells, albeit diminished, should still be sufficient to allow normalization of plasma testosterone levels, provided the endogenous drive by pituitary LH is adequate. In the face of a persistent status of relative hypoandrogenism, the only modestly increased basal levels of pituitary luteinizing hormone (LH) should be regarded as inappropriately low. Furthermore, in contrast to previous reports of a delayed or diminished LH response upon stimulation with pharmacological doses of GnRH (Nieschlag etal. 1982; Rubens etal. 1974; Winters and Troen 1982), assessment of pituitary secretory capacity for (immunoreactive as well as bioactive) LH by challenges with small "physiological" doses of GnRH, clearly indicates a well preserved or even increased pituitary secretory reserve in elderly men (Kaufman etal. 1991; Mulligan etal. 1999).
It can be concluded that elderly men present not only with a primary testicu-lar defect but also with alterations of the neuroendocrine control of Leydig cell function, with failure of the feedback regulatory mechanisms to normalize the testosterone levels, notwithstanding the existence of adequate testosterone and LH secretory reserve capacity (Kaufman et al. 1990; Vermeulen and Kaufman 1992;
Winters and Troen 1982). The relative inadequacy of the gonadotropin response to hypoandrogenism in elderly men has also been shown during experimental muting of endogenous testosterone suppression by administration of an anti-androgen (Veldhuis etal. 2001).
Several changes in the neuroendocrine control of Leydig cell function have been documented in elderly men. Circadian rhythm of LH and testosterone secretion is clearly blunted in elderly men (Bremner etal. 1983; Deslypere and Vermeulen 1984; Plymate etal. 1989; Tenover et al. 1988). Furthermore, the pulsatile pattern of LH secretion is alteredwith increased irregularity (Pincus etal. 1997) and disruption of synchrony with the secretion of FSH and prolactin as well as with nocturnal penile tumescence and sleep phases (Luboshitzki et al. 2003; Veldhuis et al. 1999; 2000). The LH pulse frequency remains essentially unchanged (Tenover etal. 1987; 1988; Urban et al. 1988; Vermeulen et al. 1989a; Winters et al. 1984), but the mean LH pulse amplitude is decreased as a consequence of reduced numbers of LH pulses with larger amplitude (Veldhuis etal. 1992; Vermeulen etal. 1989a).
Indirect evidence suggests that the main neuroendocrine changes occur at the level of the hypothalamic GnRH-secreting neuronal system. Indeed, as the responsiveness of the pituitary gonadotrophs to "physiological" doses of GnRH is preserved (Kaufman etal. 1999; Mulligan etal. 1999), the decreased LH pulse amplitude is most likely due to decreased stimulation by endogenous GnRH, with reduced size of the bolus of the neuropeptide intermittently released into the pituitary portal circulation. Moreover, the LH pulse frequency, governed by the hypothalamic GnRH pulse generator and expected to increase in a state of hypoandrogenism (Plant 1986), has been found by most authors to remain unchanged and thus inappropriately low, an increased LH pulse frequency in elderly men having been reported only by one group (Mulligan etal. 1995; Veldhuis etal. 1992). Additional evidence of altered hypothalamic regulation of gonadal function in elderly men is provided by the observation of clearly increased sensitivity to the negative feedback effects of sex steroids in comparison to the situation in young adults (Deslypere et al. 1987; Winters et al. 1984; 1997). Furthermore, the LH response to opioid receptor blockade in elderly men is blunted in comparison to that in young individuals (Mikuma etal. 1994; Vermeulen etal. 1989a), the receptor blockade failing to produce the expected increase in LH pulse frequency and amplitude observed in the young.
From the latter studies it can be concluded that alteration in LH secretion in elderly men is not due to increased endogenous opioid tone, whereas the possibility of a relative leptin deficiency as underlying cause has also been excluded (Van Den Saffele etal. 1999). At present, the mechanisms underlying the apparent deficiency of GnRH secretion in elderly men remain to be fully elucidated. The observed changes in LH secretion with decreased mean LH pulse amplitude can be expected to have a significant impact on testosterone secretion as there exists a linear correlation between LH pulse amplitude and plasma testosterone levels (Veldhuis et al. 1992; Vermeulen etal. 1993).
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