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W1981476069 abstract "Western populations represent an ageing society with continuing gains being made in life expectancy; a male born in Australia has a healthy life expectancy of 70 years with slightly lower expectations for those born in the UK and USA (WHO, 2001). The search for ways to maintain and enhance physical health and well-being is endless. Rather than aiming to simply live longer, people aspire to undertake ‘active ageing’ (WHO, 2002), with an emphasis on quality of life. Attention has been focussed on the possibility that testosterone replacement therapy may be beneficial to the quality of life of men in middle age and beyond, akin to that of the role of oestrogen replacement for symptomatic peri- and postmenopausal women (Hlatky et al., 2002). Although the clinical presentation of androgen deficiency in men with primary or secondary testicular failure is well recognized and the benefits of treatment well established (Allan & McLachlan, 2003), whether testosterone replacement therapy is beneficial for older men with more subtle age-associated declines in serum testosterone levels is beneficial remains uncertain. Ill-defined terms such as ‘andropause’ or ‘partial androgen deficiency of ageing men’ have been popularized and underscore the increasing use of testosterone treatment for a range of ailments prevalent in older men. In the USA, the market for testosterone therapies has increased from US$49 million to almost US$400 million between 1997 and , with the majority of prescribing being for men 40 years and older. No matter how well-intentioned, such treatment cannot escape evaluation according to the modern principles of evidence-based medicine. Recent experiences in the field of female HRT (Hulley et al., 1998; Rossouw et al., 2002) serve to remind us of the need for properly designed and powered randomized, placebo-controlled data, and for caution in extrapolating cross-sectional or surrogate end-point data. We will discuss the extent of age-related decline in testosterone and the confounding effects of concomitant illness, the physiology of the changes in the hypothalamo–pituitary–testicular (HPT) axis, and the approaches to the laboratory assessment of hypoandrogenism in older men. The effects of androgens on key target tissues and the existing data from the limited number of placebo-controlled trials regarding the benefits and potential risks of its usage will be discussed. Unlike the predictable 90% fall in serum oestradiol across the menopause (Burger et al., 2002), testosterone levels in men begin to decline in the late third or early fourth decade and diminish at a constant rate thereafter (Baker et al., 1976b; Leifke et al., 2000; Harman et al., 2001). Many cross-sectional and several longitudinal studies have now documented significantly lower total testosterone levels in older men when compared to their younger counterparts (Feldman et al., 2002; Zumoff et al., 1982; Gray et al., 1991a, 1991b; Tenover & Bremner, 1991; Simon et al., 1992; Morley et al., 1997; Zmuda et al., 1997; Ferrini & Barrett-Connor, 1998; Harman et al., 2001). Those studies that have failed to identify this fall in testosterone have been criticized for the timing of sample collection (Harman & Tsitouras, 1980), the small numbers of subjects (Nankin & Calkins, 1986), or because of unexpectedly low testosterone levels in the younger subjects (Sparrow et al., 1980; Nieschlag et al., 1982). The absolute rate of decline in total testosterone levels in longitudinal studies varies threefold – from 0·11 nm (Harman et al., 2001) to 0·29 nm (Feldman et al., 2002) to 0·38 nm (Morley et al., 1997) per year. As a percentage of baseline values, cross-sectional studies estimate the rate of decline to be 0·5–0·8% per year (Davidson et al., 1983; Gray et al., 1991b; Simon et al., 1992), while longitudinal studies suggest a greater rate of decline, e.g. 1·6% per annum in the Massachusetts Male Ageing Study (MMAS; Feldman et al., 2002). Concomitant with the fall in total testosterone is a rise in SHBG levels with ageing (Field et al., 1994; Harman et al., 2001), estimated to be 1·3% per year in a cohort aged 40 years and over (Feldman et al., 2002). As a result of the combined effects of a rise in SHBG and a fall in total testosterone, calculated free testosterone levels decrease by approximately 2–3% per year (Feldman et al., 2002). The relationship between the changes in total testosterone and SHBG is unclear. Excluding obese men, in whom SHBG levels are reduced as a function of adiposity (Field et al., 1994), one group has described a fall in total testosterone from the age of 30 years with SHBG levels rising only from the age of 50 years (Leifke et al., 2000), whereas others have identified an earlier rise in SHBG with total testosterone levels falling only from the age of 55 years (Vermeulen et al., 1996). Ageing and obesity have opposing effects on SHBG levels. Given the increasing prevalence of obesity (Ball et al., 2002; 65% of Australian men are now considered to be overweight or obese) and the lack of understanding about the biological importance of indices of free testosterone, determining the prevalence of hypoandrogenism in ageing men is complex. Observational data on total testosterone levels across ages, reported in 1984 (Deslypere & Vermeulen, 1984), 1992 (Simon et al., 1992), 1996 (Vermeulen et al., 1996) and 2000 (Leifke et al., 2000), are reasonably consistent (Fig. 1). This 20–40% decrease in total testosterone levels is consistent with the decline reported in other cross-sectional and longitudinal work (Harman et al., 2001). Importantly, however, these data represent only cohorts of healthy nonobese men. In a community context, the MMAS suggests that only 26% of men aged 40 years and over are in ‘apparent good health’, defined by the absence of chronic illness, prescription medication, obesity or excess alcohol consumption (Feldman et al., 2002), and after 7–10 years of follow-up, only 18% of men remained in good health. The effects of such factors on serum testosterone are discussed in more detail below. Total testosterone (nm) levels (mean ± SD) in healthy, nonobese men aged 20–100 years. The number of subjects is listed at the base of each column. Deslypere & Vermeulen, 1984 (top left panel), Simon et al. (1992) (top right panel), Vermeulen et al. (1996) (bottom left panel), Leifke et al. (2000) (bottom right panel). Given the high prevalence of disorders that concomitantly lower serum testosterone levels in typical Western ageing male populations, it is difficult to know which ‘normal’ reference range to apply. One could consider ranges derived from reproductively normal healthy young men, from age-stratified healthy nonobese men (as in Fig. 1) or from the general ageing population, despite the majority having concomitant illnesses. Whether one uses young or age-related ranges from healthy older men, there is a need to look critically at the risks and benefits of treatments that seek to return serum testosterone levels to these reference ranges and, importantly, at whether such reference values should be equally applied to the many older men with concomitant illness. If one uses a healthy ageing reference range, one will advocate treatment for a smaller number of men than when using the higher standard set from fit young men. This issue has yet to be settled. Ageing is associated with changes both within the testes and at the level of the pituitary and hypothalamus. Leydig cell number is reduced (Neaves et al., 1984), serum LH levels rise (Baker et al., 1976b) and the testosterone response to stimulation with hCG (used in this context as an LH substitute) is reduced (Harman & Tsitouras, 1980). An age-related rise in LH levels of 0·9% per year was demonstrated in the MMAS (Feldman et al., 2002). The only other longitudinal study of LH in ageing (Morley et al., 1997) also found an LH rise but without the expected inverse correlation with falling testosterone, suggesting an alteration in the feedback mechanisms within the HPT axis. Several changes in neuroendocrine pathways controlling testosterone production in healthy older men are consistent with a degree of secondary testicular failure (Veldhuis, 1999), including a decrease in the amplitude of endogenous LH pulses (Veldhuis et al., 1992). Older men display asynchrony between LH release and testosterone secretion suggesting disruption of neuroendocrine control mechanisms (Veldhuis et al., 2000) and appear more sensitive to the negative feedback effects of testosterone on LH secretion (Winters & Atkinson, 1997). A full understanding of the changes in the HPT axis with ageing is lacking; however, it is important to appreciate that falling testosterone levels in ageing men may not elicit a compensatory LH response (Kaufman & Vermeulen, 1997). There is no agreed biomarker of testosterone and therefore clinical judgement must be supported by laboratory confirmation. The literature on male ageing and testosterone generally report in terms of total testosterone levels. Although a single value correlates well with the mean value of multiple samples across 12 months (Vermeulen & Verdonck, 1992), there is sufficient intraindividual variability over weeks to months to warrant at least two samples to confirm a suspected diagnosis of hypoandrogenism (Morley et al., 2002). Serum testosterone has a circadian rhythm in normal young men, with peak levels in the order of 22–25 nm at 06·00–08·00 h and a nadir of 15–18 nm in the early evening (Bremner et al., 1983; Gupta et al., 2000; Diver et al., 2003). This diurnal pattern may be attenuated as a function of ageing (Bremner et al., 1983; Gupta et al., 2000) but as the loss is not universal (Diver et al., 2003), testosterone levels should be taken in the morning. Testosterone circulates 98% protein-bound (54% with low affinity to albumin and other proteins, and 44% with high affinity to SHBG; Sodergard et al., 1982) with only 2% as free testosterone. By analogy with other steroid hormones it has been proposed that free testosterone will relate to biological effect on tissue more than the total testosterone, and a number of methods for estimating this free fraction have been described (Morley et al., 2002). The clinical utility of this ‘free hormone hypothesis’ is unproven and no consensus exists on the optimum serum marker for testosterone (Anonymous, 2001). Although it is intrinsically appealing to suggest that free testosterone is a better index of androgen action (akin to the measurement of free rather than total thyroid hormone levels), direct evidence for this proposition is minimal. Limited observational data suggest a better correlation between muscle strength and either bioavailable testosterone (Perry et al., 2000) or a calculated free testosterone index (Roy et al., 2002) than with total testosterone. One prospective controlled study (Kenny et al., 2001) reported that bioavailable testosterone correlated better with the effect of testosterone supplementation on lean body mass (LBM) than did total testosterone levels. Nonetheless, the vast majority of data relate to total testosterone and it is this measure that primarily serves as the basis for making clinical decisions. The measurement of the free testosterone fraction by equilibrium dialysis is considered to be the ‘gold standard’ (Vermeulen et al., 1999) but it is time-consuming and expensive, and requires an estimation of total testosterone levels. Direct estimations by an analogue ligand radioimmunoassay (RIA) technique correlate poorly with equilibrium dialysis, significantly underestimating the actual free testosterone level, and their use cannot be recommended (Rosner, 2001). Bioavailable (also called ‘non-SHBG bound’ and comprising free and albumin-bound fractions) testosterone measurements are determined by RIA of the supernatant obtained after precipitation of SHBG-bound testosterone with 50% ammonium sulphate (O’Connor et al., 1973), and correlate well with estimates obtained by equilibrium dialysis (Vermeulen et al., 1999). These measures cannot be automated. Bioavailable testosterone values also show a circadian rhythmicity that is blunted with ageing (Plymate et al., 1989) and are subject to the same week-to-week variability seen with total testosterone levels (Morley et al., 2002). Calculations have been devised to determine the free component of testosterone based on the total levels of testosterone, SHBG and albumin, and make the reasonable assumption that the affinity constants for testosterone binding to both proteins are constant (Vermeulen et al., 1999). These values are usually described as the ‘calculated free testosterone’ levels and show a very good correlation with equilibrium dialysis measures. They are readily performed using standard assays and a computer algorithm. To date, however, there are no published data of population-based reference ranges. It should be noted that the free androgen index (FAI) is a derived unit-less calculation based on the formula FAI = (total testosterone/SHBG) × 100% and although validated for use in women is not applicable in men (Kapoor et al., 1993). The usefulness of serum LH as an ‘internal’ marker of androgen sufficiency is limited. Elevated levels support the diagnosis of testosterone deficiency in primary testicular failure, but many older men will have a serum LH within the young reference range along with a borderline low serum testosterone. Whether or not such older men are in fact eugonadal, as opposed to having a deficiency in hypothalamo–pituitary ‘recognition’ of actual deficiency (potentially implying benefit from testosterone therapy), is not clear. Testosterone treatment of the symptomatic ‘low-normal testosterone/normal LH men’ may seem attractive to some but lacks an evidence base and an understanding of its safety. Investigation of secondary testosterone deficiency (i.e. actual LH deficiency) must be considered as pituitary tumours and haemochromatosis (in particular) may occur in older men, and whilst rare, require specific evaluation (anterior pituitary hormone assessment, serum iron studies, and imaging) and treatment. The prevalence of androgen deficiency in the ageing male population is difficult to estimate due to the heterogeneity of the studied populations, the differing methods of estimating testosterone levels (total, free estimates) and the lack of consistency of nominal values for defining biochemical hypoandrogenism. Prevalence estimates are often based on the assumption that ageing men should be regarded as hypoandrogenic (synonymous with deserving of replacement therapy) when their testosterone measures fall below the lower limit of the healthy young adult male reference range. However, the latter is also subject to variability due to differences in assay platforms and reference ranges. Using differing and somewhat arbitrary cut-off points, one can obtain widely differing prevalence rates. The characteristics of the cohort of older men studied are critical in determining the reported prevalence of hypoandrogenism. In a study of institutionalized men aged 46–89 years almost 30% were classified as testosterone-deficient (defined as total testosterone levels below 10·4 nm; Swartz & Young, 1987). Conversely, several groups have reported that only approximately 20% of ambulant healthy men 60 years or older are testosterone deficient (defined as total testosterone < 11 nm; Kaufman & Vermeulen, 1997; Harman et al., 2001; Tenover, 2000). If the definition of hypoandrogenism is restricted to a total testosterone level < 8·7 nm, then only approximately 8% of these healthy cohorts would be classified as deficient (Tenover, 2000). If, however, free testosterone, as measured by equilibrium dialysis, is taken as the biological meaningful parameter, almost 1/3 of men classified as normal according to their total testosterone levels would be incorrectly labelled (Morley et al., 2002). The effects of ageing on testosterone levels may be confounded by other variables that must be considered in the assessment of androgen status. Older men recruited from medical clinics have lower testosterone levels than community-dwelling populations, suggesting that concurrent ill health depresses testosterone levels (McKinlay et al., 1989). Chronic illness, prescription medication, obesity or excessive alcohol were associated with a reduction in testosterone of 10–15% in all age cohorts in the MMAS men aged 40 years or over during 7–10 years of follow-up (Feldman et al., 2002). A direct effect on serum testosterone levels may be seen with medications such as opiates (change in LH pulsatility) or anticonvulsants (hepatic enzyme induction) (Zitzmann & Nieschlag, 2001). Acute systemic illness will affect steroidogenesis in addition to spermatogenesis, regardless of age (Hudson et al., 1970; Dong et al., 1992; Handelsman, 1994). In a group of men aged 75 years or over admitted to hospital with acute illness, testosterone levels were 30% lower than matched controls and returned to normal upon recovery (Impallomeni et al., 1994). Both benign and malignant lung disease reduce testosterone levels irrespective of age, the effect being more marked in those with lung cancer (Blackman et al., 1988). Untreated diabetic men aged 50 years and over have also been found to have 15% lower testosterone levels than their body mass index (BMI)-matched, nondiabetic counterparts (Barrett-Connor, 1992). The effects of cardiovascular disease, depression and malignant prostate disease upon serum testosterone levels are dealt with below. The MMAS identified obesity as the most important determinant of total testosterone over time, with levels 25% lower in obese men when compared to their nonobese counterparts (Gray et al., 1991b). In this cohort, controlling for age, there was a 33% reduction in testosterone levels in the highest quintile BMI group when compared to the lowest (Field et al., 1994). Over 9 years of follow-up in these men obesity predicted a greater decline in total testosterone and SHBG with ageing (Derby et al., 2002). Whilst the lower SHBG levels associated with obesity contribute to low total testosterone levels, free testosterone levels may also be lower in obese as compared to nonobese men (Vermeulen et al., 1996). The effects of smoking on total testosterone levels are contradictory and the precise mechanisms of any effect are unclear. Elevated levels in current smokers in the order of 9–25% have been reported in middle-aged and older men (Deslypere & Vermeulen, 1984; Field et al., 1994; Vermeulen et al., 1996) but others have identified an inverse relationship between cigarette smoking and testosterone levels (Zmuda et al., 1997; Hsieh et al., 1998) while no effect was seen in current smokers comprising 18% of a cohort followed longitudinally in the Baltimore Ageing Study (Harman et al., 2001). The effects of alcohol upon testosterone are dependent upon the pattern and duration of usage. Acutely alcohol inhibits testosterone production (Gordon et al., 1976; Frias et al., 2002) whilst sustained stable alcohol intake in healthy older men does not influence total testosterone levels (Harman et al., 2001; Sparrow et al., 1980). Chronic alcoholic liver disease may effect androgen metabolism (Lester & Van Thiel, 1977) and elevate SHBG levels (thereby raising total testosterone levels) (Gluud, 1988) in addition to its well-known association with hypogonadism (Baker et al., 1976a). No correlation between exercise patterns and testosterone levels has been proven in population-based studies (Svartberg et al., 2003) perhaps related to the inaccuracies of self-reporting. Elderly men undertaking endurance training over a period of 15–20 years have similar baseline (Tissandier et al., 2001) and GnRH-stimulated (Struder et al., 1998) testosterone levels when compared to their more sedentary peers, but importantly data regarding BMI was not provided. Short-term resistance training in healthy older men has been shown to transiently increase testosterone (Zmuda et al., 1996), but to a lesser degree than seen in younger men (Kraemer et al., 1998), and this effect appears to be lost with longer-term (6 months) training (Hakkinen et al., 2000). The perimenopause is often marked by a well-defined group of symptoms (Dennerstein et al., 2000) that prompts women to seek advice from their General Practitioner. For men, the relationship between ageing, declining sex steroids and symptomatology is more complex. The age-related decline in serum testosterone tend to be associated with nonspecific symptoms (Vermeulen, 1993). Quantification of these symptoms (quality-of-life, sexual and physical performance and mood/behavioural) has been attempted (Morley et al., 2000), and questionnaires developed which employ both objective and subjective variables (Smith et al., 2000). Unfortunately the specificity and sensitivity of these questionnaires for predicting low testosterone levels is low and neither has been properly validated. There remains a lack of practically useful and validated screening tools for identifying men most likely to be testosterone deficient. The clinician must consider whether some or all of the symptoms are potentially due to testosterone deficiency, as opposed to other co-morbidities, and consider these in conjunction with the testosterone levels. The diagnosis may be straightforward with unequivocally low testosterone levels in an appropriate clinical setting. However, the testosterone levels are often low-normal and the clinical diagnosis of androgen deficiency in the older man then prompts consideration of the benefits and potential short- and longer-term risks from testosterone therapy. Despite the increasing prescription of testosterone for a wide range of symptoms in ageing men very few properly conducted randomized, double-blinded, placebo-controlled studies have been performed (Gruenewald & Matsumoto, 2003) involving cumulatively approximately 900 men. These studies are summarized in Table 1. Comparing the outcomes of these trials is limited by the different doses and formulations of testosterone administration, the varying duration of treatment (usually only for short periods), and the inclusion of cohorts with a wide range of baseline testosterone levels. The effects of testosterone on key tissues of interest in men are outlined below. The prescribing of testosterone in ageing men to achieve pharmacological effect for specific benefits (e.g. increased muscle mass and strength, improved bone strength) has not been rigorously studied with regard to long-term safety or functional end-points (fracture, quality of life) and cannot be advocated. However, one must keep in mind the concept that, with testosterone therapy, one can imperceptibly blend replacement physiology into pharmacology. As demonstrated in recent data (Bhasin, 2003), body composition parameters can be similarly modified in both young and older eugonadal men by testosterone treatments yielding serum levels across the hypogonadal into the supraphysiological range. The relationship between the development of cardiovascular disease and serum testosterone levels remains uncertain. It is possible that testosterone supplementation poses a risk for the development of coronary heart disease (CHD) but data also support the notion that it may improve the cardiovascular risk status of ageing men. The basis for the long held belief that androgens have a detrimental effect is derived from the strong epidemiological association between male sex and premature onset of cardiovascular risk (Lerner & Kannel, 1986) and case reports linking the use of anabolic steroids with cardiac toxicity (Sullivan et al., 1998). Prospective epidemiological studies have failed to identify a relationship between serum testosterone and the development of CHD in middle-aged and older men (Alexandersen et al., 1996) but testosterone was only measured at baseline and the impact of other recognized cardiovascular risk factors on outcomes could not be determined. Recent observational data (Hak et al., 2002) and short-term studies of testosterone supplementation on surrogate markers of cardiovascular risk (Kenny et al., 2002b) suggest that lower testosterone levels may actually confer greater risk. Two thorough reviews of the associations between androgens and CHD has recently been published (Liu et al., 2003a; Wu & Von Eckardstein, 2003). These critical analyses of the available human and animal studies of the effects of endogenous and exogenous androgens confirm the contradictory nature of our current knowledge but suggest that the use of testosterone in androgen-deficient older men should not be limited by fear of increasing cardiovascular risk (Wu & Von Eckardstein, 2003). We shall therefore focus this discussion on the clinical data pertaining to older men with age-associated declines in testosterone levels. Cross-sectional studies of total testosterone in men with CHD (as determined by clinical events – AMI, angina and/or angiography) have either failed to show a relationship or suggested a negative association (Wu & Von Eckardstein, 2003). Such a negative association was shown for both total and bioavailable testosterone in men with angiographically determined coronary artery disease (English et al., 2000). Three prospective cohort studies of approximately 3500 predominantly Caucasian middle-aged and older men (Wu & Von Eckardstein, 2003) have shown no association between endogenous testosterone and CHD after a minimum 5-year follow-up period. However, an inverse association between serum testosterone and aortic atherosclerosis was found in a study of 500 men (mean age 68 years) after adjusting for age, BMI and multiple cardiovascular risk factors (Hak et al., 2002). The randomized controlled trials of testosterone supplementation have not been of sufficient duration to determine effect on development of cardiovascular disease and there is only limited information about surrogate markers for CHD risk. Vascular reactivity, a noninvasive measure of endothelial function and a recognized marker for atherosclerosis, was not influenced by either 12 months of transdermal testosterone (Kenny et al., 2002b) or 3 months of transdermal dihydrotestosterone (Ly et al., 2001) therapy in older men with baseline total testosterone levels 13·5–15 nm, although only small numbers were studied. Younger hypogonadal men (baseline total testosterone 6 nm) treated for 3 months with intramuscular testosterone or hCG did show a deterioration in endothelial function (Zitzmann et al., 2002a) but the inverse relationship between markers of vascular function and serum testosterone levels only occurred in the hypogonadal and not in the eugonadal range. The relevance of these observations in older men with low-normal testosterone levels is unclear. Several groups have reported a beneficial effect of testosterone treatment on coronary artery function in men with documented CHD and myocardial ischaemia (Pugh et al., 2000). Although some protocols employed supraphysiological doses (Webb et al., 1999), a physiological transdermal regimen (increasing serum testosterone levels from 13·6 to 22·3 nm) reduced exercise-induced angina, with the greatest benefit seen in those subjects with the lowest baseline bioavailable testosterone levels (English et al., 2000). Oral testosterone undecanoate improved symptomatic and electrocardiograph end-points in older Chinese men with CHD (Wu & Weng, 1993). These data are encouraging but are limited by small subject numbers and short duration. Of concern are the reports that supraphysiological intramuscular testosterone administration caused a transient prothrombotic state (Anderson et al., 1995). However CRP, a predictor of adverse cardiovascular outcome, was not influenced by a similar regimen (Zitzmann et al., 2002b) and markers of fibrinolysis were favourably influenced in both studies. Endogenous testosterone levels have also been shown to be positively correlated with fibrinolytic activity (Glueck et al., 1993). Treatment of men aged 60 years and over with baseline testosterone levels < 15 nm with either dihydrotestosterone or human chorionic gonadotrophin for 3 months did not alter serum inflammatory markers associated with atherosclerosis (Ng et al., 2002). Overall, the effects of androgens on haemostatic factors related to cardiovascular risk remain uncertain (Winkler, 1996) and may be affected by both the dosage (physiological vs. pharmacological) and the baseline hormonal status of the subjects. The correlation of serum testosterone levels with established cardiovascular risk factors complicates any discussion of the association of testosterone with CHD; a negative association with hypertension (Phillips et al., 1993), fasting plasma glucose (Barrett-Connor et al., 1992), hyperinsulinaemia (Simon et al., 1997) and visceral adiposity (Haffner et al., 1993), and an uncertain association with high-density lipoprotein (HDL) cholesterol (Barrett-Connor et al., 1995). A study of middle-aged men classified by total testosterone levels (10 vs. 20 nm) found that systolic blood pressure, fasting glucose and total and LDL cholesterol levels were inversely related to testosterone but after adjusting for measures of adiposity and insulin resistance, only insulin levels and triglycerides remained significantly correlated with testosterone (Simon et al., 1997). In men matched for age and BMI, 12 weeks of transdermal testosterone decreased fasting insulin and increased insulin sensitivity when compared to placebo (Simon et al., 2001) and 9 months of a similar regimen increased glucose disposal rates although fasting insulin levels were unchanged (Marin et al., 1993). On the other hand, hCG therapy for 12 weeks in an older cohort did not affect insulin sensitivity (Liu et al., 2002). The effects of testosterone therapy on lip" @default.
W1981476069 created "2016-06-24" @default.
W1981476069 creator A5080721059 @default.
W1981476069 creator A5090823385 @default.
W1981476069 date "2004-04-08" @default.
W1981476069 modified "2023-10-15" @default.
W1981476069 title "Age-related changes in testosterone and the role of replacement therapy in older men" @default.
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