Androgen effects

The 20th century saw dramatic prolongation of life expectancy in developed countries. More people living longer in retirement creates a premium on strategies to promote healthy ageing (meaning, in this context, maintenance of enjoyable and independent living for the longest time with compression of morbidity into the shortest timeframe at the end of life). A focus on gainful coexistence with chronic ailments supplants the eradication of disease. Ameliorating disabilities that accrue during age could enhance quality of life regardless of its prolongation. Among strategies to improve health and well-being of the elderly, the judicious evidence-based use of hormonal therapy clearly warrants exploration. An important caveat is that since the best available evidence suggests that androgen replacement therapy does not influence life-expectancy (Handelsman 1998), beneficial effects of physiological androgen dosages are likely to be restricted to quality of life, for which instrumental measures remain inadequate.

'You can't make a piggrow by weighing it': observational studies

As testicular endocrine function can be evaluated from blood samples, large community-based epidemiological studies were feasible since the advent of radioimmunoassay in the 1960s. The now accepted consensus that blood testosterone concentrations decline gradually after mid-life (Gray et al 1991a) was secured by decisive evidence from the population-based Massachusetts Male Ageing Study (Gray et al 1991b). This decline of * 1% per annum, accompanied by rising blood sex-hormone-binding globulin (SHBG), luteinizing hormone (LH) and FSH concentrations, is accelerated by concomitant medical disorders which accumulate with age. It is sobering that three generations of observational studies using various convenience samples had not achieved definitive conclusions, generating futile controversy for two decades, before the pivotal importance of representative sampling was fully appreciated. Key aspects of the descriptive epidemiology of androgenic status of older men still requiring clarification include (a) whether androgenic thresholds, sensitivity and effects differ between ethnic groups, individuals and tissues, and (b) which older men and what biological effects are the best targets for androgen therapy.

'The Emperor's New Clothes': measuring testosterone

Like most steroids and drugs, testosterone binds with varying affinity to circulating proteins notably SHBG and albumin. It is often stated or assumed that various measures of 'free' testosterone are superior markers of androgen supply to, and/or net effects upon, androgen sensitive tissues than measurement of total testosterone, the gold standard for biochemical confirmation of androgen deficiency. The so-called 'free hormone' hypothesis has a long and tortuous history (Edwards & Ekins 1988, Pardridge 1988, Mendel 1989). Regarding testosterone, claims of superiority for derived testosterone assays are based exclusively on theoretical arguments without clinical validation; yet even in theory, freer movement of unbound testosterone into tissues would be just as likely a priori to result in faster metabolic inactivation as enhanced biological effects on target tissues.

Derived testosterone assays include direct measurement of free (non-protein-bound) testosterone by equilibrium dialysis, centrifugal ultrafiltration or analogue immunoassay, or indirect measures of 'bioavailable' (non-SHBG bound) testosterone. 'Free' testosterone can also be calculated from total testosterone and SHBG concentrations either as a simple ratio (Kapoor et al 1993) or a more complex calculation (Sodergard et al 1982). Claims of superior clinical utility have not been supported by direct empirical proof; some derived testosterone measures are invalid on theoretical (Kapoor et al 1993) and/or empirical (Winters et al 1998) grounds. Given their weak rationale, absent empirical validation of alleged superiority and less accurate measurements, there seems little to recommend such measures in routine clinical use. The curious gulf between their validation and popularity may reflect their common distinctive feature, that of demonstrating a faster fall with age than total testosterone. Clearer separation between younger and older men serves to inflate the proportion of older men defined in this manner as having biochemical 'androgen deficiency'. This circular logic however cannot evade the need to prove efficacy and safety of androgen therapy in older men. Such confusion of ends and means may be alleviated by distinguishing androgen replacement therapy, which assumes a deficiency state to be rectified by physiological testosterone doses, and pharmacological androgen therapy which aims for proof of efficacy and safety regardless of drug, dose or deficiency state.

'If I had a hammer, I'd hammer in the morning: interventional therapeutic studies

Following the adage that when one's only tool is a hammer, remarkably soon all problems turn into nails, it is an understandable that androgen administration is proposed for older men. Such proposals long pre-date the first availability of testosterone (Hamilton 1937) with many bouts of rejuvenation quackery associated with the names of Brown-Sequard, Steinach and Voronoff into the early 20th century. Standard clinical endocrine practice includes replacement therapy for unequivocal hormonal deficiencies of the pancreas (insulin), thyroid (thyroxine), adrenal (glucocorticoid, mineralocorticoid) and gonads (oestrogen, androgen). Conversely, hormone replacement is not provided for other classical hormones such as prolactin, glucagon, somatostatin, calcitonin, calcitonin-gene related peptide and adrenalin, and other hormones (thyroid-stimulating hormone, LH, FSH, parathyroid hormone) are not replaced but substituted by simpler non-peptide end products. Generally, the criteria for a treatable hormonal deficiency include (a) a well defined clinical deficiency state, (b) availability of sufficient clinical grade hormones, and (c) convincing evidence for therapeutic efficacy and safety. The flexibility of this categorization is illustrated by the changing status of adult growth hormone replacement therapy based on emerging evidence (Carroll et al 1998).

Certain features of ageing men resemble those observed in androgen-deficient younger men, notably decreased lean body mass (muscle) and bone; reduced body hair growth, skin thickness and dermal sebum secretion; impaired cognitive function and mood; increased adiposity; and reduced strength, endurance, initiative, virility and sense of well-being. Since androgen replacement in younger men can reverse muscle, bone and mental changes of androgen deficiency, it is a reasonable postulate that the partial androgen deficiency may contribute to the physical frailty and mental torpor of older men. Nevertheless, it remains unclear whether (a) blood testosterone concentrations fall far enough to warrant replenishment, (b) tissue androgenic thresholds change with age, and (c) older tissues remain sufficiently androgen responsive. In short, the biological significance of the gradual, partial and variable decline in blood testosterone concentrations in older men cannot be established from observational studies alone but requires critical evaluation by interventional therapeutic studies.

Ad hoc trials of androgen therapy in ageing men dating back to the first availability of testosterone (Heller & Myers 1944) were unconvincing as they lacked the decisive features of placebo controls and randomization. Several recent small controlled studies of at least three months' duration demonstrate inconsistent benefits of testosterone supplementation (Marin et al 1992, Tenover 1992, Morley et al 1993, Sih et al 1997) but most had significant limitations in design (inadequate masking, poorly defined clinical end-points, low power).

A major study of generally healthy men over 65 years with a low plasma testosterone (< 16.5 nmol/l) treated with daily transdermal testosterone for three years showed an improved sense of well-being, increased lean mass and decreased fat mass compared with placebo (Snyder et al 1999a,b). Crucially, however, testosterone did not consistently improve muscular function or bone density compared with placebo. Secondary analyses showed any benefits of testosterone in older men were limited to those with overt androgen deficiency. Consequently, at present androgen supplementation in ageing men is appropriate for overt androgen deficiency, but more liberal use is still best considered promising but unproven.

Future studies should aim for more powerful design, better focus on appropriate subgroups of men and end-points likely to benefit, and/or alternative hormonal regimens. Pharmacological androgen therapy, using supraphysiological doses or novel synthetic androgens, might improve muscle, bone or other androgen-dependent functions in older men regardless of androgen deficiency status, nature or dose of androgen. Viewed like any other anti-ageing treatment, this would require evidence of efficacy, safety and cost-effectiveness from controlled trials rather then relying on supposed replacement status to lighten the burden of proof for efficacy and safety. This approach would diversify androgen therapies to allow enhanced targeting of androgen therapy via exploiting variations in tissue selectivity and metabolic activation (5a reduction, aromatization) profiles (Sundaram et al 1994) that could be developed in novel potent designer androgens (Dalton et al 1998, Edwards et al 1998). Regardless of the specific androgen, the safety issues remain whether androgen therapy influences progression of prostate or cardiovascular disease or precipitates idiosyncratic effects (polycythaemia, sleep apnoea, fluid retention, behavioural disturbance). The key long-term effects on cardiovascular and prostate disorders would require large, long-term vigilance studies as were undertaken for oestrogen therapy in menopause (Handelsman 1998).

Androgen-dependent disorders (prostate and cardiovascular disease)

A salient fact of ageing men's health is that cardiovascular disease is the major cause of death, and prostate disease the leading cause of both major surgery and new internal cancers. Both prostate and cardiovascular disease demonstrate distinctive hormone-dependent features, with long incubation periods during early life culminating in exponentially increasing age-related incidence during late life. These features create opportunities for novel preventive strategies (Handelsman 1998). Among promising options for future developments is the potential to develop designer androgens (Dalton et al 1998, Edwards et al 1998) that exploit tissue-selective metabolic activation of testosterone (Sundaram et al 1994) via the 5a reductase pathway, a local androgen amplification mechanism, or diversification of androgen action via aromatase which leads to effects mediated via the oestrogen receptor.

In the near future the most important developments with predictable potential for improved management of prostate disease in ageing men include (a) development of better tests to make wide-scale prostate cancer screening feasible and (b) Finasteride Prostate Cancer Chemoprevention study (Brawley & Parnes 2000) which will determine whether selective inhibition of 5a reductase can reduce prostate cancer diagnosis and mortality with great implications for development of prostate-sparing androgens for supplementation.

Arguably the most fundamental fact in cardiovascular epidemiology is that men have earlier and more severe morbidity and mortality than women of similar age. Despite prevailing orthodoxy based on retrospective case—control studies, it has long been evident that natural menopause does not accelerate cardiovascular disease (Heller & Jacobs 1978, Tunstall-Pedoe 1998), unlike breast cancer or bone density, where oestrogen dependency is clearer. This uncertainty is accentuated by the first prospective studies of oestrogen replacement therapy in menopausal women demonstrating no benefit, and even detrimental effects, on secondary prevention of cardiovascular disease (Hulley et al 1998). As life-long castration appears not to alter life-expectancy (Handelsman 1998), endogenous testosterone has at best only modest effects in promoting cardiovascular disease, perhaps only in subpopulations. While recent studies have rediscovered the vasodilatory properties of androgens (Jaffe 1977) and that low endogenous testosterone is a risk factor for cardiovascular disease (Alexandersen et al 1996), these findings need to be reconciled with the likelihood that androgens may also foster early stages of atherogenesis (McCrohon et al 1997, 1999, 2000, McCredie et al 1998).

Diagnosis and management of androgen deficiency in older men

The diagnosis of androgen deficiency, primarily a clinical diagnosis confirmed by appropriate hormone assays, is generally unambiguous in younger men with hypothalamic—pituitary or testicular disorders. Among older men the nonspecific symptoms of androgen deficiency may have other causes and biochemical diagnosis is uncertain unless blood testosterone concentrations are unambiguously low. Appropriate reference ranges for blood testosterone concentrations are controversial — adopting the reference range of healthy young men assumes age-dependent changes in blood testosterone levels are inherently pathological whereas an age-adjusted reference range might overlook rectifiable androgen deficiency. A reliable, independent marker of net tissue androgen effect would help resolve this dilemma but none exists. The androgenic threshold for sexual function is low whereas those for muscle, bone and cognitive function are unknown but likely to be higher, and may vary within and between individuals. Consequently, driven by the need for practical guidance, free of marketing hype in an environment of commercially driven disease-mongering, the Endocrine Society of Australia has recently published consensus best practice guidelines for androgen prescribing (Conway et al 2000) which were adopted by the national Pharmaceutical Benefits Scheme for subsidy of effective medicines. Revision based on further evidence and other national guidelines will undoubtedly emerge.

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