Article in press - uncorrected proof Horm Mol Biol Clin Invest 2010;4(1):529–538
2010 by Walter de Gruyter • Berlin • New York. DOI 10.1515/HMBCI.2010.060

The relationship between testosterone deficiency and frailty in elderly men

Farid Saad1,2,* 1

Bayer-Schering Pharma, Scientific Affairs, Men’s Health Care, Berlin, Germany 2 Gulf Medical University, School of Medicine, Ajman, United Arab Emirates

Abstract The vulnerable health status usually preceding the onset of overt disability is often referred to as frailty. A stringent definition is elusive but it can be viewed as a physiological syndrome, characterized by decreased reserve and diminished resistance to stressors, resulting from a cumulative decline across multiple physiological systems and causing vulnerability to adverse outcomes. Elements of frailty are related to the neurological system, metabolism, joints, bones, and muscles. Sarcopenia seems to be the major determinant of frailty. Several components of the frailty syndrome are related to loss of physiological actions of testosterone (T). T and/or its aromatized metabolite, estradiol, are necessary for maintenance of bone mineral density. Furthermore, T stimulates erythrocyte formation. T has a profound effect on body composition. Androgens promote differentiation of mesenchymal pluripotent cells into the myogenic lineage and inhibit differentiation into the adipogenic lineage. Skeletal muscles of older men are as responsive to the anabolic effects of T as of younger men. Thus, although frailty is obviously a complex syndrome, some elements are androgen-associated and these can improve in men with subnormal T levels when treated with T. Evidence suggests that T treatment in frail elderly men with low T improves body composition, quality of life, and physical function, including increased axial bone mineral density and body composition. The data available to date strongly suggest a relationship between T-deficiency and frailty and warrant further basic and clinical investigations to extend these observations to the management of elderly men with frailty. Keywords: bone mineral density; frailty; sarcopenia; sarcopenic obesity; testosterone; testosterone deficiency.

weight loss of more than 10 lbs in the preceding year, selfreported exhaustion (CES-D Depression scale), low physical activity (-270 kcal/week, based on the Minnesota Leisure Time Physical Activity Questionnaire), slow walk time (for a 15-ft walk, cut-off times for height F173 and )173 cm were G7 and G6 s, respectively), and low handgrip strength wthreshold for body mass index (BMI) F24 was F29 kg, for BMI 24.1–28 F30 kg, for BMI )28 F32 kg, respectivelyx (1). In the study by Fried et al. (1) comparing the death rate in three subgroups based on the presence of three or more criteria in the frail group and one or two criteria in the intermediate frail group and no frailty criteria in the nonfrail group, it was shown that death rate among frail individuals was 35% (130 deaths out of 368) which is far greater than 19% in the intermediate frail (474 deaths out of 2480) and the 10.5% in non-frail individuals (260 deaths out of 2469) over a 3-year period with unadjusted data. It was further demonstrated that frailty overlaps significantly in individuals with disability or with co-morbidities such as myocardial infarction, angina, congestive heart failure, claudication, arthritis, cancer, diabetes, hypertension, and chronic obstructive pulmonary disease (1). Pel-Littel et al. (2) discussed the various instruments that are used for characterization of frailty and the potential pathological pathways contributing to frailty. The authors suggested that diminished bone mineral density (BMD), and increased sarcopenia concomitant with aging of the organ systems all contribute to frailty. These changes are associated with reduced nutrition, reduced mobility, instability, and reduced reserve capacity with marked disability. This leads to increased dependence on others, reduced quality of life, and increased morbidity, mortality, and institutionalization. The goal of this mini-review is to discuss the relationship between low testosterone (T) in elderly men and frailty and to evaluate the data which show that treatment of frail men with T improves physical functioning and quality of life.

Effects of testosterone therapy on body composition, muscle mass, physical strength, and frailty

Introduction Frailty in aging men is characterized by several changes in body composition and function including unintentional *Corresponding author: Farid Saad, Bayer-Schering Pharma, Scientific Affairs, Men’s Health Care, Berlin, Germany Phone: q49-30-46815057, Fax: q49-30-46895057, E-mail: [email protected] Received October 22, 2010; accepted October 22, 2010; previously published online January 21, 2011

T is an important regulator of body composition. Svartberg et al. (3) have demonstrated that T therapy for 1 year improved body composition in elderly men and noted a marked increase in fat-free mass and a significant reduction in fat mass in response to T therapy. Similar findings were reported by Page et al. (4) in elderly men treated with T alone or T and finasteride for a 3-year period. Ferrando et al. (5) also reported increased muscle mass after 6 months of treatment with T in men over 60 years with concomitant

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muscle function, and similar findings were noted in increased leg strength 90 days after treatment with T gel (6). Minnemann et al. (7) demonstrated improvement in grip strength 30 weeks after treatment with T in hypogonadal men, using two different formulations of T. These findings were corroborated by Page et al. (4) who demonstrated changes in the grip strength in elderly men 36 months after T therapy. Indeed, these findings support the data that T and exercise together are superior to either treatment alone (8, 9). The effect of T on lean body mass in elderly men was reported recently by O’Connell et al. (10). As shown in Table 1, there is a consistent effect of T on lean body mass and some evidence of increased physical strength, although this was not observed in all studies. Clearly, androgens influence muscle mass in elderly men, with some effects on muscle strength and physical function. However, it should be noted that frailty is a composite syndrome and not all aspects of frailty will be ameliorated by T treatment. Jockenho¨vel et al. (31, 32) demonstrated that treatment of hypogonadal men with T for 30 weeks consistently reduced fatigue in these

androgen-deficient men, irrespective of the T formulation used. Furthermore, T stimulates erythropoiesis in hypogonadal men and improvement in hematocrit in response to T treatment was observed in men with metabolic syndrome treated with androgens (33).

Is low T associated with frailty in elderly men? Considerable evidence exists that T is an anabolic hormone and is involved in regulating protein, carbohydrate, and lipid metabolism. Furthermore, T is believed to regulate pluripotent cell differentiation to enhance myogenesis and inhibit adipogenesis (34). Thus, it is of interest to determine if a relationship exists between T levels and reduced muscle mass in elderly frail men and if this can be ameliorated by T treatment. Travison et al. (35) investigated the relationship between total T and frailty in the Massachusetts Male Aging Study and stratified these values by the polymorphism of the androgen receptor CAG repeats. The findings of this study

Table 1 Effects of interventional studies with testosterone on physical strength and function in elderly men. Study (Ref.)

Number of patients

Method

LBM

Strength

Emmelot-Vonk et al. (11) Ferrando et al. (5)

113 7

DXA DXA

≠ ≠

Page et al. (4)

24

DXA

≠

Snyder et al. (12)

96

DXA

≠

Kenny et al. (13) Wittert et al. (14)

24 39

DXA DXA

≠ ≠

Gruntmanis et al. (15)

23

DXA

l

Nair et al. (16)

27

DXA

≠

168 7

DXA DXA

≠ l

l (grip, leg strength) ≠ (leg extension, leg flexion, triceps extension, biceps, curl) ≠ (grip strength, l knee extension and flexion) l (grip strength, knee extension and flexion) ≠ (knee extension) l (grip strength, knee extension, plantar flexion) l (grip strength, knee extension and flexion) l (chest press, double leg press, knee extension) ≠ (arm/chest press, leg press) l (grip strength, knee extension and flexion) l (grip strength) ≠ (knee flexion, l knee extension, shoulder flexion and extension) l (total body strength) ≠ (grip strength) l (knee extension and flexion, shoulder extension and flexion) ≠ (grip strength) l (knee extension and flexion) ≠ (knee extension and flexion) ≠ (knee extension, l knee flexion, grip strength) ≠ (composite strength in high dose) ≠ (chest press, ns38; leg press, ns49)

Wang et al. (17) Clague et al. (18) Tenover (19) Ly and Handelsman (20), Ly et al. (21)

13 17

Hydrostatic weighing DXA

≠ ≠

Blackman et al. (22) Sih et al. (23) Liu et al. (24)

21 17 20

DXA

≠ NA ≠

Morley et al. (25) Brill et al. (26) Urban et al. (27) Srinivas-Shankar et al. (28)

BIA/anthropometry

8 10 6 130

DXA

NA l NA ≠

Sattler et al. (29)

40

DXA

≠

Basaria et al. (30)

106

Hydrostatic weighing

NA

Adapted from O’Connell et al. (10). DXA, dual energy X-ray absorptiometry; LBM, lean body mass; NA, not avaialble.

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showed that the probability of frailty increased with reduced total T irrespective of the CAG repeat length. Krasnoff et al. (36) have suggested that men with low free T had 57% higher odds of reporting incident mobility limitation (ps 0.03) and 68% higher odds of worsening of mobility limitation (ps0.007). The authors concluded that lower levels of free T are associated with a greater risk of incident or worsening mobility limitation in community-dwelling older men. These findings raise the question of whether low T could be a predictor of incidence and progression of frailty. In a prospective cohort study by Hyde et al. (37), frailty was investigated in 3616 community-dwelling men aged 70–88 years by assessing fatigue, difficulty climbing a flight of stairs, difficulty walking more than 100 m, presence of more than five illnesses, or weight loss )5%. The data from this study showed that lower free T levels are associated with an increased risk of becoming frail. These data suggest that T therapy can potentially ameliorate or prevent the development of frailty. Furthermore, the study showed that there is an association between frailty and all-cause mortality, suggesting that T amelioration or prevention of frailty can also reduce mortality.

Effects of testosterone on bone mineral density and the relationship between osteoporosis and risk of frailty Low T levels are thought to be associated with an increased risk of falls and an increased risk of bone fracture (38–40). Several studies have shown that low T serum levels in men are associated with hip fractures (41) and that T therapy improves BMD in elderly men and increased total hip BMD based on DEXA (3), and changes in hip and spine BMD during 36 months of T gel treatment were noted (17). To highlight the scale and scope of this issue, an article by Gruntmanis (15) suggested that male osteoporosis is deadly, but yet ignored. The author suggested that although approximately 500,000 fractures occur in US men every year as compared to approximately 200,000 men diagnosed annually with prostate cancer, bone fracture receives less attention. Mortality rate during the first year of hip fracture is )30%, and approximately 50% of patients do not regain their previous mobility and independence (15). A significant increase in risk of falls was observed with reduced bioavailable T levels in a cohort of 2578 relatively healthy men (aged 65–99 years) in the MrOS Study (42). In light of the observation that low T is associated with an increased risk of falls leading to fracture and increased frailty and morbidity (38), it is paramount that the relationship between T and bone be given serious attention. In a large clinical study by Emmelot-Vonk et al. (11), total body lean body mass increased significantly in the T group relative to the placebo group. Furthermore, insulin sensitivity increased and insulin resistance decreased significantly in the T treated group compared to the placebo group, despite no measurable changes in total or free T levels among the two study groups. The latter was probably due to use of a T

preparation (oral T undecanoate) which can increase serum T only transiently so that at the time of measurement there might not have been any measureable increases in T levels compared to those at baseline. In a recent study in which 99 frail elderly men were treated for 12 months with T, BMD increased 1.4% at the femoral neck and 3.2% at the lumbar spine and decreased 1.3% at the mid-radius in the T treated group (13). The authors also reported increased lean mass and decreased fat mass in the T group but no differences in strength or physical performance. These findings suggest that frail men treated with T experienced positive changes in body composition, and limited changes in axial BMD but little substantial changes in physical function. Because muscle tissue response to T is dose-dependent, a favorable effect might have been missed due to inadequate increases in T levels. It should be noted that this study had very low adherence to treatment and this could have contributed to the inconsistent results.

Testosterone therapy in frail elderly men: a balancing act Recently, the changes in isometric and isokinetic extension and flexion of the knee (lower limb muscle strength parameters) were investigated in 262 frail men after 6 months of treatment with T gel or a matched placebo gel (28). The T dose was adjusted according to serum T levels at day 10 and 3 months. This adjustment in treatment was undertaken only if T levels remained outside the target range (18–30 nmol/L); the placebo group therefore received the maximum ‘‘dose’’ and double blinding was preserved. The study demonstrated that T treatment improved lean body mass and reduced fat mass in elderly frail men (28). T increased peak torque of isometric leg extension, isometric leg flexion, and isokinetic peak torque in frail elderly men. There was a significant improvement in quality of life as assessed by the aging male total score (AMS) and the somatic and sexual subscales. The aggregate locomotor function test and physical performance test indicated the beneficial effects of T treatment in these frail men. Although the physical performance test was only tendentially improved in the total cohort, improvement reached statistical significance in the subgroup of men 75 years of age and older as well as in those men with two or more frailty criteria. In the latter subgroup, the aggregate locomotor function test also reached statistical significance. In addition to the noted improvement in the somatic, psychological, and sexual domain in the T treated group, compared with placebo, the AMS somatic subscale score indicated greater improvement in men with at least two frailty criteria and older men subgroups (Figures 1, 2 and 3). Furthermore, there was a significant improvement in the 6-min walk test in men treated with T as compared to men treated with placebo (28). Six months after discontinuation of the medication, all parameters in the T treated men returned to baseline and significant differences between groups were lost indicating that continuous treatment is required in this specific patient pop-

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Figure 1 Changes in functional parameters in the subgroup of men G75 years after 6 months of treatment with T gel. Aggregate locomotor function test (ALF); physical performance test (PPT) (28).

ulation (43). As part of the same trial, Atkinson et al. (44) investigated the effects of T in 30 men (65–89 years) on skeletal muscle architecture. The study showed a significant effect of T on muscle thickness after 6 months. Muscle thickness as assessed by ultrasound technique, increased by 2.6% in the T group and decreased by 5.4% in the placebo group. These findings demonstrate that T treatment for 6 months preserved muscle thickness compared to that of men treated with placebo. Caminiti et al. (45) investigated cardiorespiratory and muscular strength before and after 3 months of T treatment in 64 frail elderly men with chronic heart failure. The authors noted that T treatment resulted in improvement in isokinetic power torque, isometric maximal voluntary contractions peak work load, and peak VO2 suggesting improvement in overall strength and metabolic function. A recent study (30) investigated the changes in muscle performance and physical function from baseline to the endof-study in 209 frail, elderly men (mean age: 74 years) receiving T therapy. The authors noted increased leg strength, increased chest press strength, and increased stair climbing power with a load (Figure 4). These findings are congruent with the recent findings of Srinivas-Shankar et al. (28), which demonstrated significant improvement in physical

function in elderly frail men treated with T. However, the study by Basaria et al. (30) was terminated because of cardiovascular adverse effects reported in these research subjects. Several concerns were raised regarding the findings of this latter study. These concerns stem from the fact that the patients enrolled in this study were poorly randomized with more patients with hypertension and more patients with lipid reducing agents in the T treatment group, compared to the placebo group. Also, the exclusion criteria were disputable, because class I and class II cardiac heart failure patients were also included in this study in addition to patients with creatinine values exceeding 3.5. These observations suggest that a large number of patients exhibited subclinical cardiovascular disease and a high prevalence of hypertension, diabetes, dyslipidemia, and obesity. Furthermore, the selection of subjects was based mainly on plasma T levels alone and not on a combination with clinical symptoms, as recommended by the recently published Endocrine Society Guidelines (46). Also, the study was performed in a dose-seeking procedure and the T doses administered to some patients exceeded those recommended in the recent Endocrine Society Guidelines (46). It should also be pointed out that monitoring of the adverse events was not the primary endpoint and report-

Figure 2 Changes in the 6-min walk test in subgroup of men G75 years after 6 months of treatment with T gel (28). 6 MWT, 6-minute walk test.

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Figure 3 Changes in functional parameters in the subgroup of men with G2 frailty criteria after 6 months of treatment with T gel (28).

ing of these adverse events was not carried out directly by the physician but by telephone interviews of subjects or reviewing external medical records, post-factum. Thus, as pointed out by Zitzmann (47) subjective feelings of tachycardia, syncopes of unknown origins, arterial hypertension, and myocardial infarctions were all used as cardiovascular adverse events, which might have contributed to the conclusion depicted. The findings of this study are contrary to the conclusion made in a recent meta-analysis which concluded that ‘‘the adverse effects of T therapy include an increase in hemoglobin and hematocrit and a small decrease in highdensity lipoprotein cholesterol but pointed to no cardiovascular events’’ (48). No reports of cardiovascular events were made in the study by Srinivas-Shankar et al. (28) or in the meta-analyses (48). This casts doubts on relevance and significance of the findings by Basaria et al. (30) with regard to the cardiovascular side effects of T treatment. Several other unexplainable observations cast more doubt on the conclusions of this study including the observation that diabetes and smoking reduced the risk of a cardiac event, and treatment with high T doubled the risk, and normal to high hematocrit increased risk four- to five-fold wsee Appen-

dix in Ref. (30)x. Despite these unexplained anomalies, the authors drew broad conclusions on the adverse effect of T replacement therapy on cardiovascular health in frail and immobile men, with subclinical heart disease. Indeed, the authors stated that ‘‘the lack of a consistent pattern in these events and the small number of overall events suggest the possibility that the differences detected between the two trial groups may have been due to chance alone’’.

Low testosterone and mortality in elderly men A host of epidemiological and clinical studies focused on men’s health suggested that a relationship exists between decreasing T levels and mortality in men. Low T levels are thought to be associated with increased type 2 diabetes (49), increased depression (50, 51), increased risk of cardiovascular disease (52), chronic obstructive pulmonary disease (53), chronic renal disease (54), and higher incidence of metabolic syndrome, thus increasing incidence of mortality (55, 56). However, the suppression of testicular function as a result of many of these illnesses and conditions (57, 58)

Figure 4 Changes in measures of muscle performance and physical function from baseline to the end-of-study assessment, among 209 frail, elderly men (mean age: 74 years) receiving T therapy (30).

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could suggest that low T levels are a marker of an underlying condition rather than an independent risk factor for mortality (59–62). Nonetheless, even after adjusting for several confounding clinical variables many studies have continued to show support for an inverse relationship between serum T levels and mortality (59). The discussion presented in this section summarizes the research efforts related to this topic, focusing on current issues regarding the potential link between low-level T and various causes of associated mortality. Decreasing levels of T in men could be a culprit for the discrepancy of cardiovascular disease noted among genders. Low serum T is associated with the risk of cardiovascular disease including hypertension, abdominal obesity, insulin resistance, thrombosis, and inflammatory markers (63). Conversely, T replacement therapy ameliorates some of these risk factors, producing reduction in waist circumference, cholesterol, proinflammatory cytokines, and improvement in insulin sensitivity (64). Furthermore, T has been shown to protect against myocardial ischemia, angina, and chronic heart failure (65, 66), while also impeding the progression of atherosclerosis in animal models (67, 68). Haring et al. (59) suggested that low serum T was associated with increased mortality, even after adjusting for medical morbidity and other clinical covariables, such as waist circumference, smoking habits, alcohol consumption, physical activity, renal insufficiency, and levels of dehydroepiandrosterone sulfate (DHEAS). A study by Khaw et al. (52) examined 2314 men between the ages of 42–78 years and noted that low T concentrations can be associated with increased cardiovascular risk factors, including high-density lipoprotein cholesterol, triglycerides, BMI, and diabetes prevalence. T-deficiency is associated with higher levels of total and low-density lipoprotein cholesterol (69–71). Nonetheless, the relationship with cardiovascular disease was unaltered after adjustment for these risk factors, suggesting that T is most likely responsible for mediating any protective effects (52). In a prospective, population-based study of men aged 50–91 years, those with T levels in the lowest quartile were 40% more likely to die than men with higher levels, independent of many risk factors including age, adiposity, metabolic syndrome, diabetes, and prevalent cardiovascular disease (70). In cause-specific analyses, low T predicted increased risk of cardiovascular and respiratory disease mortality but not cancer related deaths. Haring et al. (59) showed that men with low serum T had a significantly higher mortality from all causes than those with higher T levels in a population-based sample of men aged 20–79 years. In causespecific analyses, low serum T predicted increased risk of death from cardiovascular disease and cancer; however, it did not show an association with respiratory diseases or other causes.

Testosterone treatment in men with heart failure Free T and DHEA concentrations decrease in proportion to severity of heart failure in men (72–74). More importantly,

low T and DHEA are thought to be independent predictors of death in men with heart failure (73). Low T could be a factor producing imbalance in the anabolic or catabolic effects in patients with advanced heart failure. Androgen receptors expressed in endothelial cells, vascular smooth muscle cells, and cardiomyocytes are thought to modulate T function, but T could exert its effect via genomic and nongenomic mechanisms (75). T facilitates vasodilatation of the vascular smooth muscle cells, probably via reducing intracellular Ca2q flux, secondary to interaction with voltageoperated calcium and potassium channels (75). However, it is suggested that T can induce hypertrophy due to increased protein synthesis in the cardiomyocytes (76). In a postmyocardial infarction model of heart failure, T induced physiological cardiac growth with no increment in hypertrophy markers or collagen accumulation (77). T exerted a protective effect on cardiomyocytes by activating ATP-sensitive K channels and upregulating cardiac a1-adrenoceptor in ischemia-reperfusion injury model in animals (78). Orchiectomy of male rats diminished expression of a number of genes including L-type Ca2q-channel, the Naq/Ca2q exchanger, a1-adrenoceptors, and myosin heavy chain subunits (79, 80). This reduction in gene expression is accompanied by attenuated cardiomyocyte contractile capacity. T-deficiency is noted in 24%–43% of patients with cardiac dysfunction and T treatment improved exercise capacity after 12 months (81). In a clinical study in which 76 men with moderately severe heart failure were randomized to receive T or placebo for 12 months (82). T improved exercise capacity as demonstrated by the significant increase in shuttle walk distance and enhanced handgrip strength. In total, 13 patients with moderate to severe heart failure received either T replacement treatment or placebo for 4 weeks. T treatment improved insulin resistance and increased total body mass and a decrease in body fat mass (83).

Testosterone therapy in elderly women The role of androgens in women’s overall health remains a topic of debate owing to many confounding factors. Nevertheless, several studies have suggested that androgens are important in women’s overall health. T levels are thought to be proportional to the severity of heart failure and can represent an independent predictor of death (84, 85). T replacement in women produced a beneficial metabolic affect on several metabolic parameters including insulin resistance and protein and carbohydrate metabolism. DHEA supplementation in 87 women for 6 months showed no significant changes in BMD or bone turnover markers (86), but produced gains in lower extremity strength and improved short physical performance battery scores. In healthy postmenopausal frail women receiving 100 mg DHEAS per day total body mass and lean body mass were increased (87), suggesting that DHEA improved lower extremity strength and function in older, frail women. In postmenopausal women, higher serum T levels were related to greater maximal aerobic capacity and reduced adiposity and androgens levels were

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correlated with greater insulin sensitivity (88), suggesting that androgens play a role in maintaining metabolic, morphometric, and functional parameters. Iellamo et al. (89) reported that treatment of women with T produced a significant 23% relative increase in 6-min walking time coupled with a parallel increase in peak oxygen consumption (VO2), similar to that observed in men treated with T. Decline in insulin resistance was observed in the T treated group, suggesting positive effects of T on metabolic function. The improvement in overall function with T therapy was attributed in part to increased hemoglobin concentration and improved oxygen-carrying capacity, thus enhancing physical activity and peak VO2. Furthermore, improvement in baroreceptor sensitivity in response to T treatment could represent another mechanism (45) for improvement in function. It is well accepted that T modulates anti-inflammatory factor production and immunosuppressive effects, thus it is probable that these biological processes contribute to the improvement in physical health (90). It should be noted that no major side effects were reported with 300 mg T patches applied twice weekly in this study. The aforementioned findings suggest that androgens play an important role in women’s metabolic function and reduced androgen levels could contribute to poor health.

Discussion Frailty is a physiological syndrome, characterized by decreased reserve and diminished resistance to stressors, resulting from a cumulative decline across multiple physiological systems and causing vulnerability to adverse outcomes. Many elements of frailty are related to changes in metabolism and this is accompanied by a drastic decline in muscle mass and strength and bone loss with aging. T and its metabolites have a profound effect on body composition and reduced T levels can contribute to sarcopenic obesity. One of the postulated mechanisms of androgen in regulating body composition is through differentiation of mesenchymal pluripotent cells into the myogenic lineage and inhibition of the adipogenic lineage. It is postulated that although frailty is a complex physiological syndrome, low T is associated with many criteria of frailty in men. Several studies using T in older men with different degrees of frailty showed encouraging outcomes. The body of evidence discussed in this review suggests that T treatment in frail elderly men with low T improved body composition, quality of life, and physical function, including increased axial BMD. T also lessened the level of fatigue and this could be attributed to the gain in the physical strength and BMD. Clinical studies are needed to determine those frail elderly men who are most likely to benefit from T therapy and those who might not and assess the benefit-risk ratio. In light of the findings that androgens also positively impact the health of postmenopausal and frail women, it necessitates further research on the effect of androgens in women’s health.

In summary, the data available to date suggest a strong relationship between T-deficiency and frailty and such findings warrant further basic and clinical investigations to extend these observations to the management and treatment of elderly men and women with frailty.

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Copyright of Hormone Molecular Biology & Clinical Investigation is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.