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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 10 4789-4796
Copyright © 2004 by The Endocrine Society

Clinical Review 171

The Rationale, Efficacy and Safety of Androgen Therapy in Older Men: Future Research and Current Practice Recommendations

Peter Y. Liu, Ronald S. Swerdloff and Johannes D. Veldhuis

Division of Endocrinology, Department of Internal Medicine, Endocrine Research Unit, Mayo Clinic, Mayo Medical and Graduate Schools of Medicine (P.Y.L., J.D.V.), Rochester, Minnesota 55905; and Division of Endocrinology, Department of Medicine, Harbor-University of California-Los Angeles, Research and Education Institute (R.S.S.), Torrance, California 90502

Address all correspondence and requests for reprints to: Dr. Peter Y. Liu, Division of Endocrinology, Department of Internal Medicine, Endocrine Research Unit, Mayo Clinic, Mayo Medical and Graduate Schools of Medicine, 200 First Street SW, Rochester, Minnesota 55905. E-mail: liu.peter{at}mayo.edu.


   Abstract
Top
 Abstract
Introduction
 Muscle, fat, and bone
 Prostatic disease,...
 Current recommendations and...
 References
 
Epidemiological studies indicate that normal male aging is associated with a gradual and variable decline in blood testosterone concentrations and unfavorable changes in muscle, bone, and fat that mimic those of androgen deficiency in young men. These age-related reductions in muscle and bone mass and increased fat mass may be responsible for other age-related changes, including decreased muscle strength and physical function, changes in metabolic function, and increased falls, fractures, and disability. Whether age-related relative androgen deficiency truly causes any of these features requires interventional studies specifically in older men, because aged tissues may not remain androgen sensitive nor is such treatment necessarily safe. A Medline search (years 1966 through January 2004, using search terms random and androgen), supplemented by subsequent reference searches of retrieved articles, identified randomized placebo-controlled studies of androgen therapy. These studies show that androgen replacement in older men increases muscle and reduces fat mass to a small degree, but to date has not improved muscle strength, physical function, or insulin sensitivity, nor does it convincingly improve bone density, although the latter effect is particularly dose responsive. However, idiosyncratic adverse effects, such as disordered sleep and breathing as well as polycythemia, are also dose responsive, suggesting that dose escalation to increase efficacy may create or aggravate undesirable side effects. Furthermore, the clinical safety of androgen therapy for cardiovascular and prostatic disease is uncertain. Under these circumstances, androgen supplementation is not recommended in healthy older men. However, interim recommendations are available to help guide appropriate and curb unnecessary androgen prescription for symptomatic older men with low serum testosterone levels.


   Introduction
Top
 Abstract
 Introduction
Muscle, fat, and bone
 Prostatic disease,...
 Current recommendations and...
 References
 
BOTH THE ABSOLUTE number and the proportion of men over 60 yr of age will increase during the next 50 yr in a diverse range of countries, including the U.S., China, and Australia (1). Safe and effective medical interventions to promote healthy aging are therefore potentially valuable. Hormonal methods are promising, because testosterone (T) is inexpensive, and androgens have anabolic effects on muscle, fat, and bone (2) as well as muscular mass and strength, all of which are known determinants of physical function, disability, and quality of life. Nevertheless, the safety and benefit of androgen therapy in older men require substantiation by randomized placebo-controlled studies to evaluate efficacy and safety, specifically in that population. This is because the longitudinally estimated modest annual decrement (3, 4) in systemic T exposure of 1–2% may not be sufficient to warrant replacement, older tissues may hypothetically have diminished androgen responsiveness, and absolute cardiovascular and prostate risk are higher due to rising age-related background rates of these androgen-dependent disorders. Estimates of the rate of fall in T concentrations may differ by as much as 2-fold when the same data are analyzed cross-sectionally or longitudinally (3). This distinction emphasizes the need for longitudinal, population-based studies to obtain accurate effect size estimates.

Longitudinal studies indicate that key functional determinants, such as muscle strength and bone mineral density, decline by 1–2% and less than 1%/yr between the fifth and ninth decades, respectively, and furthermore, that aging is associated with increased fat, insulin resistance, falls and fractures, and decreased muscle mass, muscle strength, physical performance, physical activity, bone mineral density, and libido (5, 6, 7, 8, 9, 10, 11). These clinical features, although individually nonspecific, are reminiscent of organic androgen deficiency when considered as a whole. However, determining whether aging is really a functional state of relative androgen deficiency and therefore potentially responsive to androgen therapy requires careful evaluation of efficacy and safety (Table 1Go). Based on known androgen actions, the greatest benefits lie in improvements in muscle, fat, and bone mass and function, whereas the greatest safety concerns arise from putative sleep-related, prostatic, and cardiovascular effects. To highlight these issues, this review will concentrate on outcomes of randomized placebo-controlled androgenic interventional studies of at least 3-month duration in older men over 60 yr of age. Studies of combined GH and androgenic supplementation have been excluded, although conclusions are congruent.


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  		TABLE 1. Comparison of effects of androgen administration in organic androgen deficiency and aging

 

   Muscle, fat, and bone
Top
 Abstract
 Introduction
 Muscle, fat, and bone
Prostatic disease,...
 Current recommendations and...
 References
 
Nine randomized placebo-controlled studies of 3 or more months of androgen supplementation in older men with low or low normal serum T levels reporting effects on muscle and fat have been published (Table 2Go) (12, 13, 14, 15, 16, 17, 18, 19). Three other studies have not required a low baseline T for inclusion and are omitted (20, 21, 22). These studies have generally recruited healthy community-dwelling men over the age of 60 yr with baseline total serum T concentrations below 428 ng/dl (<15 nM). Interventions used standard replacement doses, except one that used supraphysiological androgen doses (18) and another that additionally employed dose titration to maintain physiological serum T concentrations, but at the expense of elevated dihydrotestosterone (DHT) concentrations due to the transdermal route of delivery (15). All studies of standard T dose therapy consistently report a 1.5- to 2.5-kg reduction in fat mass and a 1- to 2-kg increase in muscle mass even when the trial exceeded 3 months. The single high dose T study described greater changes. This suggests that the effect of standard T dosage on body composition achieves a plateau, which is modest in size and of minimal clinical significance, but that a higher plateau may be achieved with larger doses. The most comprehensive analysis in terms of sample size and duration of treatment also demonstrated that muscle and fat mass do not significantly change after 6 months, although body composition was not measured at earlier time points (15). In healthy young men, the T dose dependence of short-term changes in muscle mass and strength and fat mass has been shown unequivocally over a broad range spanning from below to above physiological T dose and blood concentrations (23). Whether these changes would persist with longer-term administration or whether similar relationships apply in older men are not yet established. Despite convincing data showing body compositional effects, few studies have additionally examined physical strength and function. Table 2Go summarizes available insights. The overall conclusion is that significant improvements have not been demonstrated and, if present, are likely to be small. For example, the effect-size estimate that global muscular strength increases by 3% with androgenic supplementation that doubles baseline blood T concentrations would mean that a sample size of thousands would be required to quantitate accurately such a relatively small effect (19). Furthermore, it remains unclear whether such a small increase in muscle strength, which would be highly important for elite sportsmen, materially improves daily living for frail older men.


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  		TABLE 2. Randomized placebo-controlled studies of androgenic supplementation on fat and muscle in older men

 
T administration may improve insulin sensitivity, because T reduces intraabdominal fat mass, and low serum T levels predict the development of noninsulin-dependent diabetes mellitus (24, 25, 26). However, few studies have used consensus methods (i.e. hyperinsulinemic euglycemic clamp or minimal model) to measure insulin sensitivity (20, 27, 28, 29, 30, 31, 32, 33, 34). When so assessed, insulin sensitivity does not change in response to either aromatizable (T) or minimally or nonaromatizable (DHT, nandrolone, or oxandrolone) androgens (Table 3Go). Whether this is true in older men is not known with certainty, because all but one study examined younger men (27). However, in young men, a T dose-responsive reduction in fat mass is not accompanied by enhanced insulin sensitivity, suggesting an uncoupling of this relationship with androgen administration (23, 29). Another important issue is the class of androgen administered. Oral 17{alpha}-alkylated androgens (oxymetholone and methandienone), possibly through known class-specific hepatotoxic effects, may induce occasional insulin resistance (35, 36, 37).


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  		TABLE 3. Effect of androgenic supplementation on insulin sensitivity in men

 
At present, no adequately powered interventional trials have explored the outcome of androgen administration on rates of long bone and vertebral fractures in men of any age. However, three randomized placebo-controlled studies have examined the impact of androgenic supplementation in older men on a widely accepted surrogate, bone mineral density (16, 38, 39) (Table 4Go). All studies treated otherwise healthy nonosteoporotic older men with transdermal T at comparable doses (16, 38) or im T injections at higher dosage (39) to examine effects on bone. Neither study of transdermal T therapy convincingly established improvement in bone density. In the larger study, bone mineral density did not differ between the T- and placebo-exposed groups because the increase in bone density observed in the T-treated group was matched by a comparable increase in the placebo group. However, in post hoc analyses, lower baseline T concentrations were correlated with a greater increase in lumbar spine bone mineral density, suggesting a concentration dependence for beneficial effects (38). In the smaller study, a between-group treatment effect was detected; however, the difference arose from a large and statistically significant reduction in femoral neck bone mineral density in the placebo group, whereas no change occurred in the cohort randomized to T (16). In contrast to these equivocal results, after the higher dose study of T enanthate (150–200 mg every 2 wk), with or without finasteride, hip and lumbar spine bone mineral densities increased by 3% and 10%, respectively, despite dose reduction for polycythemia in 25% of all men (39). In summary, the effect of exogenous androgenic enhancement on skeletal bone content in healthy older men appears to depend on the androgen dose used and the degree of baseline T deficiency. The safety margin for T use appears particularly narrow for injectable T, but may be wider with more steady state preparations provided sufficient T can be delivered.


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  		TABLE 4. Randomized placebo-controlled studies of the effects of androgenic supplementation on bone mineral density (BMD) and markers of bone turnover in older men

 
Outcomes of physiological importance are emerging from randomized placebo-controlled studies, which will help to guide the choice of androgen for future studies in the elderly male. In a randomized, placebo-controlled study of 12-month duration in middle-aged, glucocorticoid-treated men, both minimally aromatizable (nandrolone) and aromatizable (T) androgens administered in equal doses augmented muscle strength equivalently, but only T increased lumbar spine bone mineral density (40). Aromatizability (conversion of androgen to estrogen, resulting in diversification of androgen’s effect), therefore, appears to be crucial for bone effects (41). Similar studies in older men are not available. However, short-term, randomized, placebo-controlled studies have dissected the relative contributions of androgenic vs. estrogenic action to alterations in blood markers of bone turnover in older men (12, 16, 38, 39, 42, 43, 44) (Table 4Go). These studies confirm the importance of aromatizability in mediating up to 70% of short-term androgenic effects (43). Data correlating increased bone formation after sc recombinant human chorionic gonadotropin administration with increased serum estradiol concentrations support the relevance of this sex steroid (44). In contrast, amplification of T to DHT by 5{alpha}-reductase does not appear to be critical (39).


   Prostatic disease, cardiovascular disease, and obstructive sleep apnea
Top
 Abstract
 Introduction
 Muscle, fat, and bone
 Prostatic disease,...
Current recommendations and...
 References
 
Despite the equivocal benefits of androgen supplementation on muscular strength, physical function, and insulin sensitivity as well as fracture efficacy and bone mass, T prescription and use are increasing almost exclusively in the U.S. (45). Importantly, there is an increased prevalence of prostatic disease, cardiovascular disease, and obstructive sleep apnea with age. The likelihood that such male-predominant/exclusive diseases are androgen sensitive implies that even small detrimental effects of androgen on these end points in a large population at potential risk could negate any other modest benefits. Prostate disease, particularly prostate cancer, and cardiovascular disease are the preeminent safety concerns. Although prostate risk has been emphasized, cardiovascular disease is the leading cause of mortality in industrialized countries, and therefore, androgen effects on cardiovascular outcome, even if minor or transient, could trump all other androgen actions (46).

The effect of androgen supplementation on long-term prostate cancer incidence is not known. One analysis estimated that 6000 elderly men treated with T for 6 yr would be required to detect a 30% increase in prostate cancer risk at a cost of $100 million (47). Such a study was deemed premature by the U.S. National Institute of Medicine, particularly because even short-term efficacy of androgen supplementation in aging is not established. However, fundamental and essential knowledge concerning the management of prostate cancer is emerging. Such insights are crucial in guiding the design of the next generation of androgen supplementation studies. Radical prostatectomy for locally advanced cancer decreases prostate-specific mortality by 7%, and distant metastases by 14% (48). The utility of radical prostatectomy for impalpable prostate neoplasm and the efficacy of prostate-specific antigen (PSA) screening will be known by the end of this decade (49, 50). The Prostate Cancer Prevention Trial, which randomized 18,882 older men to receive 5 mg finasteride or placebo daily for 7 yr, recently reported a 25% reduction in prostate cancer incidence with a benefit restricted mostly to the smaller and less aggressive cancers (51). This finding has major implications in assessing the safety of androgen therapy in older men and highlights the potential therapeutic relevance of novel, synthetic androgen analogs with potential tissue-selective effects. These so-called selective androgen receptor modulators are under active research development (52), although they are not yet available. Other prototype designer androgens (e.g. 7{alpha}-methyl-19-nortestosterone) have been evaluated (53). Such androgens, if not 5{alpha}-reducible, may lack androgen amplification in the prostate. Whether the use of these androgens diminishes the long-term risk of adverse prostatic events or causes symptomatically troublesome reduced ejaculate volume remains to be determined. Given this uncertainty and the strong androgen dependence of the prostate, it remains prudent to defer androgen administration in older men with moderate to severe obstructive or neoplastic prostate disease requiring surgical or medical treatment. As future clinical trials are likely to exclude these men based on existing standard medical practice, future clinical studies will always leave open the question of safety of T supplementation in such men.

The effect of androgen supplementation on cardiovascular risk is not known, because outcome-based data in men of any age are not available. However, short-term (<3-month), randomized, placebo-controlled studies in middle-aged men with coronary artery disease report some improvement in chest pain and in objective responses to cardiac stress testing (46). Similarly, surrogate cardiovascular end points, such as flow-mediated arterial dilatation, lipid profiles, inflammatory markers (such as C-reactive protein), and thrombotic markers (such as fibrinogen), may be improved or unaffected by short-term androgen supplementation in older men. Limited data indicate that responses are modulated by dose and mode of T delivery (46, 54). Furthermore, epidemiological associations relate low, rather than high, T concentrations to cardiovascular morbidity (54). Hence, cardiovascular safety is less clear than ever, because the newly recognized benefits must be weighed against the long-presumed, but undemonstrated, concerns that androgens may accelerate cardiovascular disease. A major unanswered question is whether androgen supplementation improves or worsens cardiovascular outcome, and if so, how this is modulated. Because cardiovascular mortality is paramount, these answers will fundamentally alter the risk-benefit profile of androgen use.

The idiosyncratic adverse effects of T must also be considered. In relation to sleep-disordered breathing, two randomized, placebo-controlled studies in older men are available and document that high dose im T administration worsens sleep and breathing (55), although lower dose, steady state T delivery may be less likely to do so (15). Androgen supplementation at higher doses also exacerbates polycythemia (56), which may necessitate dose reduction (39), particularly with im androgen ester administration. Whether physiological quasi-depot steady state T delivery is therefore preferable is possible, but not proven, by these studies. Furthermore, the dose dependency of these adverse effects suggests that dose escalation to increase muscle, bone, or other efficacy will require careful evaluation. Long-term surveillance will be required to properly assess the incidence of these idiosyncratic and uncommon adverse effects of T supplementation in older men. Although uncommon, these idiosyncratic effects of androgens are unequivocally detrimental, in contrast with androgenic effects on cardiovascular and prostatic disease, which remain ambiguous or potentially beneficial at this stage, and therefore highlight that overall safety needs to be carefully assessed.


   Current recommendations and future research
Top
 Abstract
 Introduction
 Muscle, fat, and bone
 Prostatic disease,...
 Current recommendations and...
References
 
A key lesson from the Heart and Estrogen/Progestin Replacement and Women’s Health Initiative studies is that conventional medical practice should not precede substantiation with reliable clinical evidence of safety and efficacy. Androgen replacement in older men is the male counterpart of hormone replacement therapy in postmenopausal women, but differs crucially in that a clear syndrome of androgen deficiency is lacking, and conventional medical practice is still evolving. The increasing use of T in healthy older men in the absence of proven efficacy and in the presence of considerable safety concerns has prompted national consensus or best-practice guidelines. The intent has been to guide appropriate and curb unnecessary androgen prescription in older men. These guidelines will continue to evolve as new information becomes available. In contrast to investigational trials in healthy older men, organic (disease-related) androgen deficiency is a clinical diagnosis at any age, which must be confirmed by hormone assays and investigated for pathophysiological cause in an age-appropriate manner. Clinical features of androgen deficiency are nonspecific, but necessary for diagnosis. Common markers are symptoms, such as lethargy, fatigability, diminished libido, depressive mood, and tiredness, and signs, such as reduced muscle and bone mass, increased visceral fat, impotence, and mild cognitive impairment. The Endocrine Society of Australia and the U.S. Endocrine Society have independently formulated similar recommendations for the biochemical confirmation of androgen deficiency in older men (57, 58) (Fig. 1Go). Total T concentrations of less than 200 ng/dl in men in the U.S. (8 nmol/liter in Australia) and 200–400 ng/dl (9–15 nmol/liter) indicate overt and possible androgen deficiency, respectively. Concentrations greater than 400 ng/dl (15 nmol/liter) exclude androgen deficiency. Proper evaluation before commencing treatment requires a second confirmatory blood T concentration. Determination of blood LH, FSH, and SHBG concentrations as well as bioavailable and free T should also be considered. Bioavailable or free T may help clarify the clinical picture in men with symptoms or signs suggestive of androgen deficiency and borderline total T concentrations of 200–400 ng/dl, particularly in older men, because SHBG increases with age. Nevertheless, how androgen deficiency is best confirmed by which T measure remains unresolved, because empirical validation of these measures against independent biological markers of androgen action is lacking (46).



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  		FIG. 1. Management algorithm.

 
Androgen treatment should be monitored age-appropriately. The diagnosis must be followed by specific appraisal and definition of the cause, which may involve the hypothalamus, pituitary gland, and/or testis (Fig. 1Go). Because undiagnosed prostate disease is more common in an older population and can be unmasked with androgen treatment, it is essential to confirm a normal digital prostatic examination and PSA concentration before and again 3 months after initiation of androgen therapy in men over the age of 50 yr. At these times, it may be useful to check the hemoglobin to exclude preexisting and induction of polycythemia. The initial dose of T may need to be reduced by one third to one half in older men with very low blood T concentrations to avoid unfamiliar and potentially bothersome fluid retention, facial oiliness, excessively heightened libido, and (less commonly) priapism, although all of these adverse effects are uncommon. Short-acting (daily oral or transdermal) or intermediate-acting (weekly or, at most, every 2 wk T ester injections) T delivery systems are preferred over longer-term depot androgens (available outside the U.S.). This strategy allows dose reduction and/or interruption in the event of significant adverse idiosyncratic effects or intercurrent illness, such as advanced prostate cancer.

Ongoing evaluation may include assessment of well-being, mood, sleep patterns, weight, sexual function, energy level, activity patterns, psychological status, prostatic obstructive symptoms or signs, and breast enlargement or tenderness. Focusing on the individual’s predominant androgen deficiency symptom(s) and any new symptoms is of major importance. Exhaustive laboratory tests are only required if new clinical features develop, otherwise only PSA needs to be monitored regularly in older men. During T administration, random blood T measurements are not useful. On occasion, when dose titration is clinically critical, peak (to monitor possible toxicity) and trough (for adequacy) concentrations are relevant. Serial monitoring of axial bone density at 1- to 2-yr intervals may aid in verifying long-term anabolic effects.

More research must be conducted to appropriately revise these guidelines. The Institute of Medicine has recommended that additional research should 1) focus on the population most likely to benefit (namely, men over the age of 65 yr with low T levels and with symptoms, signs, or disability that may be androgen responsive); 2) establish benefit by randomized placebo-controlled trials (before assessing long-term risks), which should be designed, where possible, so that data can be combined for analysis, thereby increasing overall power; 3) ensure safety of the research (particularly in relation to cardiovascular and prostate diseases); and 4) conduct research to elucidate how and why T availability declines with age to identify reversible factors that may prevent the age-related decline without the need for T supplementation (59). Corollary basic research should clarify the physiology of androgen action in particular tissues (whether mediated by aromatase or 5{alpha}-reductase) and the safety and utility of selective androgen receptor modulators. Such clinical and basic research may motivate additional research in middle-aged men, because the longer duration of androgen therapy and the differing background prevalence of comorbidities are likely to alter the efficacy and safety profile. The results of such investigations and the revision of these interim guidelines are anticipated.


   Footnotes
 
P.Y.L. was supported by fellowships from the National Health and Medical Research Council of Australia (Grant ID-262025) and the Royal Australasian College of Physicians.

Abbreviations: DHT, Dihydrotestosterone; PSA, prostate-specific antigen; T, testosterone.

Received April 29, 2004.

Accepted July 19, 2004.


   References
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 Abstract
 Introduction
 Muscle, fat, and bone
 Prostatic disease,...
 Current recommendations and...
 References
 

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