Factors affecting serum testosterone levels in elderly men Influence of physiological factors and lifestyle

The physiological basis underlying the large inter-individual variation in serum testosterone levels seen at any age is not yet fully elucidated, but several physiological variables and factors related to lifestyle have been identified accounting for part of the wide range of normal values observed in healthy men (Kaufman and Vermeulen 1999). The apparent inter-individual variability of testosterone levels is not merely artefactual as a result of the cross-sectional design of the clinical studies, as single-point plasma testosterone estimates reflect longer-term androgen status in healthy men fairly well (Vermeulen and Verdonck 1992). The circadian variation of serum testosterone, with highest levels in the early morning and lowest levels in the late afternoon, should not play an important role in the wide range of normal testosterone levels if they are regularly evaluated in the morning (preferably before 10 a.m.). The ultradian pattern of episodic testosterone secretion undoubtedly contributes to the variability of testosterone levels (Naftolin etal. 1973; Spratt et al. 1988; Veldhuis et al. 1987). Therefore, although single time point estimates are a valid approach for clinical studies, the existence of fluctuations in serum testosterone should be taken into account when assessing the androgen status of individual elderly subjects (Morley etal. 2002).

Heredity appears to play an important role, with Meikle et al. (1986; 1988) concluding from the study of monozygotic and dizygotic twins that up to 60% of the variability of serum testosterone and up to 30% of the variability of SHBG, after normalization for body surface area, may be attributable to genetic factors. Nevertheless, also according to the same authors, non-genetic factors still have a substantial impact on testosterone serum levels.

The genetic basis for the heredity of serum (free) testosterone and SHBG is presently unknown. Reports of ethnic differences in serum testosterone levels have been inconsistent with small differences tending to disappear if adjustments are made for differences in body composition, especially for abdominal adiposity (Gapstru etal. 2002; Heald etal. 2003; Winters etal. 2001).

Recently there has been considerable interest in a possible role of a polymorphic trinucleotide CAG-repeat contained in exon 1 of the AR (see Chapter 3). It has been suggested that a shorter AR CAG-repeat length maybe associated with a more rapid decline of serum (bio-available) testosterone levels in middle-aged men (Krithivas et al. 1999), but the same study and other studies failed to establish a relationship between CAG-repeat length and prevalent serum androgen levels in middle-aged or elderly men (Harkonen etal. 2003; Van Pottelbergh et al. 2001; Zitzmann et al. 2001; 2003).

Several metabolic and hormonal factors influence SHBG serum levels. Insulin and insulin-like factor-I (IGF- I) inhibit SHBG production by hepatoma cells in vitro and in clinical studies insulin was found to be inversely correlated with serum SHBG and testosterone levels (Haffner et al. 1988; Heald et al. 2003; Simon et al. 1996; Vermeulen etal. 1996).

In clinical studies, body mass index (BMI) emerges as an important determinant of SHBG levels (Demoor and Goossens 1970). For the whole range of BMI values encountered clinically there is a highly significant negative correlation with SHBG and testosterone serum levels, explained at least in part by increased insulin levels (Giagulli etal. 1994; Khaw and Barrett-Connor 1992; Plymate etal. 1988). In elderly men this inverse relationship between BMI and SHBG levels can be clearly demonstrated notwithstanding the background of an age-related rise of SHBG levels (Vermeulen et al. 1996). Similarly, a negative association of serum SHBG and total testosterone with leptin levels has been observed in elderly men (Haffner et al. 1997; Van den Saffele et al. 1999). Negative associations with serum testosterone levels tend to be most pronounced for indices of abdominal fat (Couillard et al. 2000; Haffner et al. 1993; Khaw and Barrett-Connor 1992; Vermeulen et al. 1999a). Whereas moderate obesity affects mainly total serum testosterone by lowering SHBG binding capacity, in morbid obesity (BMI>35-40) free testosterone levels are decreased as well as a result of neuroendocrine disturbances (Giagulli etal. 1994).

It has long been known that alterations in thyroid hormone levels can have a marked effect on SHBG levels, with thyreotoxicosis resulting in a several-fold increase of SHBG levels and marked increase of total serum testosterone (Vermeulen etal. 1971). In this regard, it is interesting to note that more subtle changes in thyroid hormone levels within the "normal range" can also affect SHBG and testosterone levels, with subclinical hyperthyroidism, characterized by suppressed serum levels of thyroid-stimulating hormone without clinical symptoms of hyperthyroidism or elevation of thyroid hormone levels above normal, resulting in a significant increase of SHBG and testosterone levels (Faber etal. 1990; Giagulli etal. 1992).

As to factors related to lifestyle, reports on the effects of diet on serum testosterone levels do not always agree, but available data suggest that diet influences testosterone levels mainly indirectly through changes in SHBG levels, fiber-rich, vegetarian diets being associated with higher SHBG and testosterone levels than western-type diets and more particularly those diets with high fat content (Adlercreutz 1990; Belanger et al. 1989; Key et al. 1990; Meikle et al. 1990; Reed et al. 1987). It is not clear to what extent changes in SHBG related to diet might be mediated through changes in insulin secretion, vegetarians having generally lower fasting insulin levels than omnivores. In men aged 40 to 70 years in the Massachusetts Male Aging Study fiber intake and protein intake but not carbohydrate, fat or total caloric intake were independent positive and negative determinants, respectively, of serum SHBG (Longcope etal. 2000).

Smokers tend to have higher testosterone levels than non-smokers (Barrett-Connor and Khaw 1987; Dai etal. 1988; Deslypere and Vermeulen 1984; Field etal. 1994). This is observed in both young and elderly men, the difference amounting to 5-15% of the levels in non-smokers for both total and free testosterone levels (Vermeulen et al. 1996). Alcohol abuse, also in the absence of liver cirrhosis, may accentuate the age-associated decrease of testosterone levels, estradiol serum levels being increased (Cicero 1982; Ida et al. 1992; Irwin et al. 1988); moderate alcohol consumption has no adverse effect (Longcope etal. 2000; Sparrow etal. 1980).

Both physical and psychological stress and strenuous physical activity have been shown to result in depressed testosterone levels (Nilsson etal. 1995; Opstad 1992; Theorell et al. 1990). Acute fasting may transiently affect testosterone production through diminished gonadotropic testicular drive (Cameron et al. 1991), although elderly men may be more resistant to the metabolic stress of fasting (Bergendahl et al. 1998). Similarly, serum testosterone levels in elderly men were found to be less affected than those in young men during induced hypoglycemia and in the acute phase following myocardial infarction (Deslypere and Vermeulen 1984). Testosterone serum levels in disease

It is now generally accepted that the aging process per se adversely affects testosterone production, but it is nevertheless evident that the age-associated decline in testosterone levels may often be accentuated by intercurrent disease (Handelsman 1994; Turner and Wass 1997) (see Chapter 15).

Acute critical illness (Dong et al. 1992; Impallomeni et al. 1994; Spratt et al. 1993; Woolf et al. 1985), acute myocardial infarction (Swartz and Young 1987; Wang et al. 1978a) and surgical injury (Wang et al. 1978b) have been reported to cause profound, but generally transient decreases of (free) testosterone levels. The hypogonadism during acute critical illness involves alterations in all compartments ofthe hypothalamo-pituitary-testicular axis (Van Den Berghe etal. 2001).

A series of chronic diseases can induce more longstanding decreases in testosterone levels. Both testosterone and SHBG levels tend to be decreased in elderly men with diabetes mellitus (Barrett-Connor etal. 1990). Impaired glucose tolerance and non insulin-dependent diabetes mellitus (NIDDM), with high prevalence in elderly persons, are associated with decreased testosterone levels (Andersson et al. 1994; Chang et al. 1994), in agreement with the observations of a negative correlation between insulin levels and testosterone levels.

Coronary atherosclerosis hasbeen reported to be accompanied by lower or similar testosterone levels as compared to controls (Alexandersen etal. 1996; Hak etal. 2002; Phillips etal. 1994) and there have also been several reports of decreased testosterone levels in survivors of myocardial infarction as compared to controls (Lichtenstein et al. 1987; Mendoza et al. 1983; Poggi et al. 1976; Sewdarsen et al. 1990; Swartz and Young 1987), although it is not clear whether the decreased testosterone levels represented a consequence of atherosclerosis or rather a pre-existent risk factor for cardiovascular disease. Indeed, serum androgen levels do not predict cardiovascular events in prospective or case-control studies (see Wu and von Eckardstein 2003 for review).

In chronic obstructive pulmonary disease (COPD) and in patients with other hypoxic pulmonary diseases serum testosterone levels are often decreasedwith inappropriately low gonadotropin levels (Semple etal. 1981; 1984), also in the absence of systemic glucocorticoid treatment (Kamischke etal. 1998). Sleep apnea syndrome is accompanied by a relative hypogonadotropic hypogonadism (Luboshitzky etal. 2002; Veldhuis etal. 1993; Worstman etal. 1987), with massive obesity often being a contributing factor to the hypogonadism in these patients (Grunstein etal. 1989).

Chronic renal failure is often accompanied by hypogonadism with usually increased basal gonadotropin levels, explained at least in part by a decreased plasma clearance, whereas there is also an impaired pulsatile release of pituitary luteiniz-ing hormone (LH) (Handelsman and Dong 1993; Veldhuis etal. 1993). In chronic disease of the liver, the decreased (free) testosterone levels are accompanied by an increase of SHBG, androstenedione and estrone levels (Baker et al. 1979; Elewaut et al. 1979). Hypogonadism in hemochromatosis is multifactorially determined with a major contribution of pituitary insufficiency (Duranteau etal. 1993) besides primary testicular defects, cirrhosis of the liver and diabetes mellitus (Kelly et al. 1984).

Moderate impairment of testicular function has been observed in periarteritis nodosa, during acute flares of rheumatoid arthritis and in active ankylosing spondylitis (Gordon etal. 1988; Tapia-Serrano etal. 1991). In the elderly, as in the young, Leydig cell function may be adversely affected by endocrine diseases such as Cushing's syndrome (Luton etal. 1977;McKenna etal. 1979) and pituitary tumors, in particular prolactinomas.

Finally, among drugs not uncommonly used in the elderly and that may impair Leydig cell function, special mention should certainly be made of chronic use of glucocorticoids, which often induces a marked suppression of testosterone levels by combined actions at the testicular and at the hypothalamo-pituitary level, and by a decrease of SHBG serum levels (Kamischke etal. 1998;MacAdams etal. 1986). Opiates can induce a hypogonadotropic hypogonadism (Daniell etal. 2002; Finch etal. 2000). LH secretion and Leydig cell function maybe adversely affected by hyperpro-lactinemia during chronic use of neuroleptic drugs and related compounds (Bixler etal. 1977).

Hormonal treatment of prostate cancer is in its essence aimed at inducing a profound hypogonadism by suppression of LH and testosterone secretion with use of a GnRH analogue and/or by blockade of androgen effects with an anti-androgen (see Chapter 12). As to the use of 5a-reductase inhibitors in benign prostate hypertrophy, under treatment with finasteride testosterone levels are unchanged or modestly elevated (Vermeulen etal. 1989b), but the treatment can result in mild symptoms of hypogonadism (Thompson etal. 2003) by mitigating androgen effects in those tissues where androgenic effects are largely mediated by DHT.

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