Introduction

Testosterone is the primary male sex hormone or androgen present in the circulation. It is secreted by the testes in response to luteinizing hormone (LH) produced by the pituitary gland, which in turn is regulated by hypothalamic secretion of gonadotropin-releasing hormone.¹ Testosterone circulates bound with high affinity to sex hormone-binding globulin (SHBG) or with lower affinity to albumin, with a small fraction unbound or free. Non-SHBG-bound testosterone has also been referred to as bioavailable testosterone (consisting albumin-bound and free testosterone). Androgens acting through the androgen receptor have a function in prenatal sexual differentiation, pubertal change, development of male secondary sexual characteristics and subsequently body composition in adult men. Testosterone can be converted by the enzyme 5-reductase into dihydrotestosterone (DHT), which has greater binding affinity for the androgen receptor, or by the enzyme aromatase into estradiol, which interacts with the estrogen receptor.^{1, 2} Nonclassical pathways of androgen action also have been identified that do not involve nuclear androgen receptor-mediated transcriptional activation of target genes.³ However, the central role of androgens acting through the androgen receptor in the regulation of male physiology is elegantly illustrated by androgen insensitivity syndrome where 46XY males possessing a mutated androgen receptor unresponsive to androgen have the outward appearance of normal females.⁴

Testosterone levels decline as men grow older

In men, circulating levels of testosterone increase at the time of puberty and peak in early adulthood. This is followed by a steady decline in testosterone levels with increasing age. In cross-sectional and longitudinal studies of men aged 30 or 40 years and above, total, bioavailable and free testosterone concentrations fall with increasing age with a steeper decline in bioavailable and free compared with total testosterone concentrations.^{5, 6, 7, 8, 9, 10, 11, 12} It is noteworthy that the falls in total and bioavailable or free testosterone levels are consistently greater in longitudinal studies than in cross-sectional analyses.^{11, 12} Thus, in the Massachusetts Male Aging Study of 1709 men aged 40–70 years at baseline, total testosterone declined cross-sectionally by 0.8% per year of age compared with a 2% decline in free and bioavailable testosterone, whereas the longitudinal declines within participating men were 1.6 and 2–3% per year of age, respectively.¹¹ In older men above the age of 65 or 70 years, the changes in total testosterone are overshadowed by more significant declines in free testosterone levels.^{13, 14} The observation that in a cross-sectional analysis of 3638 men aged 70 years and above total testosterone levels were stable whereas free testosterone levels declined with increasing age¹⁴ is supported by a study describing comparable total testosterone levels in groups of men aged 18.9 vs 75.4 years.¹⁵ At constant total testosterone, increased SHBG by providing more binding sites for testosterone would be expected to reduce the fraction of free testosterone and SHBG levels rise with increasing age.^{16, 17, 18} Thus, even though total testosterone and SHBG remain correlated in older men, the age-related increase in SHBG could modulate levels of free testosterone in a setting where total testosterone is relatively preserved.^{13, 14} However, multiple mechanisms are likely to influence the decline in testosterone levels in aging men.¹⁹ Lower testosterone levels may result from reduced testicular responses to LH with aging coupled with incomplete hypothalamo–pituitary compensation for the fall in total and free testosterone levels.^{16, 20} The critical issue is whether these changes in circulating androgens and SHBG reflect the physiology of normal aging, or whether reduced androgen availability is a potentially remediable cause of ill-health in older men.

Testosterone and cognitive function in older men

Cognitive decline is a characteristic of advancing age and several studies have reported associations between lower testosterone levels and poorer performance in tests of cognitive function in men. A higher ratio of total testosterone to SHBG was associated with better scores on visual and verbal memory, visuospatial functioning and visuomotor scanning, and a reduced rate of longitudinal decline in visual memory in men aged 50–91 years²¹ (Table 1). In studies of men ranging from 35 to 90 years of age, higher bioavailable and free testosterone concentrations have each been associated with better performance in specific aspects of memory and cognitive function, with optimal processing capacity found within the third and fourth quintiles of total and bioavailable testosterone.^{22, 23, 24, 25} In men aged 70–89 years, after adjustment for potential confounders including age, educational attainment and cardiovascular morbidity, higher serum-free testosterone was associated with better cognitive function assessed using a simple clinically utilized test, the Standardised Mini-Mental State Examination, whereas total testosterone was not.²⁶ Men with Alzheimer's disease had a lower ratio of total testosterone to SHBG compared with age-matched controls,²⁷ and a higher ratio of total testosterone to SHBG predicted reduced incidence of Alzheimer's disease in a longitudinal study of men aged 32–87 years at baseline.²⁸ However, one cross-sectional study did not show a relationship between total or free testosterone and measures of working memory, speed/attention or spatial relations in men aged from 48 to 80 years.²⁹ Contradictory findings have also been reported from other cross-sectional analyses of similarly aged men, including associations between lower free testosterone levels and higher performance on spatial visualization tasks, and between higher free and total testosterone levels and poorer verbal memory and executive performance but faster processing speed.^{30, 31} A possible source of conflicting results in these studies may stem from interactions between testosterone levels and other risk factors for cognitive impairment such as apolipoprotein E 4 genotype.³² Furthermore, as systemic illness can result in lower testosterone levels,^{16, 44} reverse causation needs to be considered even in studies where statistical analyses have been adjusted for the presence of potential confounders such as age and medical comorbidity. Additional clarification of the relationship between lower testosterone levels and poorer cognitive function can be sought from studies involving dynamic changes in testosterone levels. In men undergoing hormonal therapy for prostate cancer, suppression of endogenous testosterone synthesis and blockade of the androgen receptor resulted in a beneficial effect on verbal memory but an adverse effect on spatial ability in one study,³³ and visuomotor slowing and slowed reaction times in several attentional domains in another.³⁴ Discontinuation of treatment resulted in improved memory but not visuospatial abilities.³⁵ Ultimately, randomized controlled trials of testosterone therapy are important to confirm the direction of causality and explore the potential beneficial impact of testosterone therapy. In this context, trials of testosterone therapy in men to evaluate its effects on measures of cognitive function have shown mixed results.^{36, 37} Short-term hormonal therapy can induce measurable changes in cognitive performance in young men.³⁸ In a randomized, placebo-controlled crossover trial of 15 elderly men with baseline total testosterone >8.3 nmol l^-1 (to convert to ng per 100 ml, divide value in nmol l^-1 by 0.0347), intramuscular testosterone therapy resulted in decreased verbal memory,³⁹ whereas in men with Alzheimer's disease testosterone treatment appeared to improve quality of life as assessed by caregivers without impacting on measures of cognition.⁴⁰ By contrast, transdermal testosterone or DHT treatment in men aged 34–70 years with a screening total testosterone level <10.4 nmol l^-1 improved verbal memory and spatial memory respectively,⁴¹ and intramuscular testosterone improved verbal and spatial memory and constructional abilities in non-hypogonadal men with mild cognitive impairment and Alzheimer's disease.⁴² In one study of healthy men aged 50–90 years, intramuscular testosterone alone or in combination with anastrozole improved spatial memory, whereas verbal memory only improved in testosterone-treated men in the absence of anastrozole, raising the possibility that part of the effect of exogenous testosterone is mediated by its aromatization to estradiol.⁴³ Therefore, although the evidence from observational studies is not uniform, lower free testosterone, or a lower ratio of total testosterone to SHBG, appears to be associated with poorer outcomes on measures of cognitive function particularly in older men. Considering the varying outcomes of interventional studies, it would be reasonable to conclude that testosterone therapy in hypogonadal men could result in improved cognitive performance, and that further evaluation of the role of testosterone supplementation in men with or at risk of cognitive impairment is justified.

Table 1 - Studies of testosterone and cognitive function in older men.

Full table

Testosterone, general health and quality of life in aging men

In addition to cognitive decline, aging is accompanied by gradual deterioration in general measures of health and well-being, which may be related to suboptimal testosterone levels. Several authors have sought to relate lower testosterone levels in older men with associated adverse consequences including reduced general well-being and sexual satisfaction^{45, 46, 47} (Table 2). For example, in one study men older than 50 years with free testosterone levels <200 pmol l^-1 had poorer quality of life as assessed by the Short-Form SF-12 Health Survey questionnaire, particularly the physical health index.⁴⁸ However, another study of men 55 years or older did not find a correlation between bioavailable testosterone and various health outcomes including sexual and quality of life assessments.⁴⁹ In the setting of androgen deprivation therapy in men with prostate cancer, men receiving treatment that drastically reduced circulating total and free testosterone levels reported impotence, reduced vitality and reduced overall quality of life.^{50, 51, 52} Conversely, intermittent androgen suppression in men with prostate cancer resulted in improvements in health-related quality of life during the off-treatment period, in parallel with the recovery of testosterone levels.⁵³ In the absence of prostate cancer and androgen deprivation therapy, lower total or bioavailable testosterone levels are associated with sarcopenia, lower muscle strength, poorer physical performance and increased risk of falls in older men.^{54, 55, 56, 57, 58} In men aged 65 years, low total testosterone levels (<6.94 nmol l^-1) were associated with increased prevalence of osteoporosis defined as bone mineral density T-score of -2.5 at either hip or femoral neck and a higher incidence of rapid hip-bone loss.⁵⁹ Lower total testosterone levels are also associated with increased incidence of fracture, particularly hip and nonvertebral fractures in men older than 60 years.⁶⁰ Thus, lower circulating testosterone is related to vulnerability to falls and fractures that are highly relevant to the general health of older men. Lower testosterone levels are also predictive of anemia in older men, supporting its role as a marker of poorer overall health outcomes.^{61, 62} In keeping with these observations, over a third of men aged 45 years visiting primary care practices either for general health checks or with specific illnesses had serum total testosterone <10.4 nmol l^-1.⁶³

Table 2 - Studies of testosterone and general or sexual health in older men.

Full table

Overviews of randomized controlled trials of testosterone therapy in men without or with underlying chronic illness using a variety of testosterone formulations report improvements in body composition with increased lean body mass and reduced fat mass, but limited benefit in physical capabilities and equivocal improvements in quality of life measures, including general well-being and fatigue.^{64, 65, 66} However, the studies reported tend to be of limited size and duration, with a lack of large-scale trials with extended long-term follow-up. Thus, additional studies have been recommended incorporating vitality, well-being and/or quality of life as end points.⁶⁵ Testosterone therapy does result in a significant increase in bone mineral density, although this may be most apparent at the lumbar spine with intramuscular formulations of testosterone.^{16, 65, 66, 67, 68} More recently, a randomized controlled trial of oral testosterone undecanoate in 237 healthy men between the ages of 60 and 80 years with total testosterone <13.7 nmol l^-1 at entry confirmed that 6 months of therapy increased lean body mass and decreased fat mass without any accompanying increase in bone mineral density, functional mobility or muscle strength.⁶⁹ There were no differences between treatment and placebo groups for quality of life assessed using the Short-Form 36 Health Survey (SF-36), and only a single measure of quality of life showed an improvement with testosterone therapy, leaving the question whether lower testosterone levels are a remediable risk factor for poorer general health and quality of life open to ongoing debate. Other trials of testosterone therapy are underway, including an open-label observational study with projected recruitment of 1700–2400 men assessing the effects of transdermal testosterone therapy on symptoms of hypogonadism, quality of life and erectile dysfunction.⁷⁰

Testosterone and sexual health in aging men

Although sexual health is relevant to broader quality of life assessments, the role of androgens to regulate sexual desire and erectile function in men warrants specific discussion. Diminished sexual desire or loss of libido is a recognized symptom of hypogonadal men, and is included in screening questionnaires to define symptomatic androgen deficiency in men with low testosterone levels.^{71, 72, 73} Although screening questionnaires such as the Androgen Deficiency in Aging Male (ADAM) and the Aging Male Survey (AMS) are sensitive (97 and 83%, respectively) they possess low specificity (30 and 39%) for the detection of hypogonadism defined as bioavailable testosterone <2.4 nmol l^-1.⁷⁴ In a community-based survey of men aged 40 years and older, total testosterone and libido were significantly associated.⁷³ In men aged 40 years and above attending andrological outpatient clinics, low total testosterone was associated with reduced motivation and reduced sexual desire.⁷⁵ However, loss of libido can be reported by men with total testosterone levels in the normal range.⁷⁶ Erectile dysfunction signifies the lack of ability to achieve and sustain penile erection sufficient for satisfactory intercourse and its prevalence increases markedly with age.^{77, 78, 79, 80, 81, 82} Given the temporal association of aging, erectile dysfunction and declining testosterone levels in men the question whether lower testosterone levels contribute to erectile dysfunction has been subject of much attention. In a study of men aged 31–78 years, after controlling for age, serum free testosterone was significantly correlated with erectile and orgasmic function domains of the International Index of Erectile Function (IIEF) questionnaire.⁸³ Free testosterone levels were also lower in men aged 21–76 years with sexual dysfunction as determined by the IIEF questionnaire compared with men without sexual dysfunction.⁸⁴ In this study, dehydroepiandrosterone-sulfate (DHEAS) levels were also lower in men with sexual dysfunction. Thus, this adrenal androgen that circulates at mol concentrations might also be involved in the symptoms of aging men.⁸⁴ However, total and bioavailable testosterone were not independently associated with self-reported erectile dysfunction in a large population-based sample of middle-aged and older men.⁸⁵ Therefore, the association between lower testosterone levels and erectile dysfunction is not uniform across studies. Furthermore, cross-sectional analyses cannot accurately identify the direction of causation, thus it is possible that both erectile dysfunction and low testosterone levels are related to a third factor such as underlying ill-health.

In middle-aged men with lower total testosterone levels treatment with testosterone improves libido or increases sexual desire.^{86, 87, 88} Overviews of randomized controlled clinical trials indicate some benefit of testosterone therapy on sexual health-related outcomes, however further investigation in this area is warranted particularly in older men who are not clearly hypogonadal.^{65, 88, 89, 90} In men with erectile dysfunction, low free testosterone levels correlate with impaired relaxation of cavernous endothelial and corporeal smooth muscle cells to a vasoactive challenge.⁹¹ A direct effect of testosterone is feasible as testosterone modulates expression of endothelial nitric oxide synthase and phosphodiesterase type 5 (PDE5) within penile tissues.^{92, 93, 94} Testosterone therapy can improve IIEF scores in men who do not respond to PDE5 inhibitors by improving sexual desire and orgasmic function and increasing penile arterial inflow during sexual stimulation.⁹³ Thresholds of serum total testosterone of 10–13 nmol l^-1 and free testosterone of 200–250 pmol l^-1 have been proposed as levels below which erectile function may be impaired.⁹⁴ Testosterone supplementation may improve therapeutic efficacy of PDE5 inhibitors, and the combination of testosterone and PDE5 inhibitors may improve erectile function in older men with low testosterone levels who fail first-line oral therapy.^{93, 94, 95} However, the role of testosterone supplementation in men with erectile dysfunction who are not androgen deficient remains to be clarified. Further investigation is needed to determine whether testosterone therapy will improve erectile function in older men with testosterone levels in the low-normal range and to weigh the risk–benefit ratio for testosterone therapy in this setting.⁶⁵

Testosterone, cardiovascular risk and mortality in aging men

Erectile dysfunction is a marker for impaired endothelial function and underlying vascular disease and its presence predicts increased incidence of subsequent cardiovascular disease events^{96, 97, 98} (Table 3). This association between erectile dysfunction and cardiovascular risk is complex as erectile dysfunction commonly coexists with conditions that are associated with increased risk of cardiovascular disease, namely obesity, metabolic syndrome and Type II diabetes, which are also associated with lower testosterone levels.^{80, 81, 97, 99} Thus, lower testosterone levels are associated with higher body mass index (BMI), and with increased prevalence and incidence of metabolic syndrome and Type II diabetes in middle-aged and older men.^{10, 11, 13, 14, 19, 100, 101, 102, 103, 104, 105, 106, 107} In addition, lower testosterone levels are associated with surrogate markers for cardiovascular disease, including less favorable carotid intima medial thickness,^{108, 109, 110} ankle/brachial index as a measure of peripheral arterial disease¹¹¹ and calcific aortic atheroma.¹¹² Thus, lower testosterone levels, erectile dysfunction and conditions associated with higher cardiovascular risk appear to be interrelated.^{113, 114} The direction of causation is debatable as marked obesity predisposes to type II diabetes and atherosclerosis, and may reduce LH pulse amplitude and testicular responses to LH.^{115, 116} However, testosterone therapy increases lean body mass and reduces fat mass, thus modulating insulin resistance and risk of metabolic syndrome.^{66, 117, 118} Testosterone may also exhibit antiatherogenic effects at the tissue level, whether mediated by classical or nonclassical pathways.^{119, 127, 128} The key question is whether testosterone therapy reduces the risk of cardiovascular disease distinct from any effects on erectile dysfunction. Trials of testosterone therapy generally have not been designed or adequately powered to detect effects on clinically significant cardiovascular events.^{16, 64, 65, 66, 119, 120} Although randomized controlled trial data are lacking, there are observational data which support a relationship between low testosterone and fatal cardiovascular events. Lower testosterone levels have been associated with increased overall and cardiovascular-related mortality in middle-aged and older men.^{121, 122, 123} However, other studies have not shown a clear relationship between lower testosterone and higher mortality.^{124, 125} In the Caerphilly study, a higher ratio of cortisol to testosterone was associated with ischemic heart disease but this was attenuated after adjustment for components of the insulin-resistance syndrome.¹²⁴ By contrast, in the Massachusetts Male Aging Study, higher free testosterone was significantly associated with ischemic heart disease mortality.¹²⁵ Finally, data are lacking as to whether higher testosterone levels predict reduced incidence of combined nonfatal and fatal major cardiovascular events.¹²⁶ Thus, although lower testosterone levels are associated with higher cardiovascular risk and to an extent with mortality in aging men, randomized controlled clinical trials of adequate size and duration are needed to determine whether testosterone therapy will reduce morbidity and mortality from cardiovascular disease in hypogonadal or eugonadal men.

Table 3 - Studies of testosterone and risk of cardiovascular disease in older men.

Full table

Can the age-related decline in testosterone levels be prevented?

Testosterone therapy is now available in a range of formulations and treatment can be individualized to achieve physiological testosterone levels.^{64, 65, 120, 129, 130} Topical testosterone formulations such as a patch or gel require daily applications, whereas testosterone supplementation using long-acting parenteral formulations provides stable circulating levels but require deep intramuscular injections or subcutaneous pellet implants. Furthermore, exogenous testosterone therapy is associated with known adverse effects including raised hematocrit.^{131, 132} Although endogenous testosterone concentrations are not associated with incidence of prostate cancer,¹³³ there is also some residual concern over the risk of developing or diagnosing prostate cancer following long-term treatment with testosterone, even though short-term therapy is probably safe in this regard.^{131, 132, 134} Testosterone therapy can be offered to hypogonadal men who meet accepted criteria for the diagnosis of androgen deficiency, with monitoring for efficacy and safety during treatment.^{120, 130, 135, 136, 137, 138, 139} Use of accurate, reliable and validated testosterone assays is important.^{138, 139} However, even with careful clinical and biochemical evaluation, symptomatic androgen deficiency may not be a stable physical state as up to half of men initially classified as such no longer met the criteria when reassessed after an interval of time.¹⁴⁰ Furthermore, if low testosterone levels are a causative factor contributing to poorer health in aging men, many men with testosterone levels in the low-normal range who do not meet diagnostic criteria might not qualify for treatment and may be at risk of ill-health. An attractive alternative to screening for and treating hypogonadal men would be to develop nonpharmacological interventions potentially applicable on a wide scale to ameliorate or prevent the age-related decline in testosterone levels.¹⁴¹ An added stimulus for these measures comes from recent reports of population-level falls in total testosterone levels superimposed on the age-related trend, which have occurred over two decades in US and Danish men.^{142, 143} These could be the result of accumulated adverse environmental or health and lifestyle factors that are difficult to quantitate in a systematic fashion and therefore not readily captured by statistical analyses.

There are recognized risk factors for lower testosterone levels in aging men, which provide a starting point for designing putative lifestyle-based interventions. Higher BMI and waist circumference are associated with lower total, bioavailable or free testosterone and SHBG.^{6, 7, 144, 145, 146} The association between higher BMI and lower total testosterone appears more consistent that between BMI and free testosterone.^{146, 147} Smoking, lower alcohol intake and physical activity or vigorous exercise are factors associated with higher total testosterone and SHBG levels.^{6, 7, 147} However, other studies have not confirmed these associations.^{148, 149} It is important to note the severe damaging effects of smoking on cardiovascular and respiratory health far outweigh any possible benefit it may confer on testosterone levels. Therefore, one approach to preventing the age-related decline in testosterone levels in men would be to test a lifestyle intervention focused on specific lifestyle factors, primarily weight reduction or avoidance of overweight, also including limiting alcohol consumption and encouraging physical activity. The alternative would be to encourage greater engagement in healthy lifestyle behaviors in general. Support for the second approach comes from a recent study of overall lifestyle score as a predictor of subsequent testosterone levels.¹⁵⁰ In this observational study of 3453 men aged 65–83 years, lifestyle score was determined at baseline as the sum of eight behaviors comprising nonsmoking, moderate physical activity, avoiding excess alcohol, eating fish 3 times per week, eating meat <6 times per week, not adding salt to food, BMI<25 kg m^-2 and using reduced fat or skim milk. Higher lifestyle score reflecting greater engagement in healthy behaviors predicted higher subsequent total testosterone and SHBG levels measured after an interval of 5.7 years.¹⁵⁰ Possible advantages of this approach include better acceptability of a behavioral rather than a biomedical focus and allowing autonomy in selecting healthy habits to adopt. Randomized controlled clinical trials are now necessary to establish whether lifestyle interventions that focus on specific factors such as reducing BMI or that encourage greater uptake of healthy lifestyle behaviors overall will ameliorate or prevent the age-related decline in testosterone levels in middle-aged and older men, and if so which approach will be more successful.

Conclusions

Lower total and free testosterone levels are associated with poorer health outcomes in middle-aged and older men. These include cognitive function, measures of general and sexual health, and increased mortality. Older age, lower testosterone levels, erectile dysfunction and cardiovascular disease are interrelated. However, these observations largely derive from cross-sectional and longitudinal observational studies. Reverse causation needs to be considered in the context of whether lower testosterone levels are a cause or a marker of ill-health. Men who are clearly hypogonadal should be considered for testosterone therapy. However, there are relatively limited data from randomized placebo-controlled trials to support wider use of testosterone therapy to prevent cognitive decline, improve general health and modulate cardiovascular risk. Thus, further prospective studies and randomized controlled clinical trials are necessary to clarify the role of testosterone therapy to prevent adverse health outcomes in older men who are not clearly hypogonadal. Additional studies are needed to determine whether interventions that promote healthy lifestyle behaviors might ameliorate or prevent the age-related decline in testosterone levels in middle-aged and older men.

Notes

Disclosure/conflict of interest

The author has received a speaker's honorarium from Bayer Healthcare for presenting at an educational meeting.

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