New advances in the treatment of hypogonadism in the aging male

The signs and symptoms of low testosterone in the aging male include erectile dysfunction, decreased libido, mood disturbances such as depression, loss of muscle mass, osteoporosis, and increase in body fat. Many of these signs and symptoms were previously believed to be part of the normal aging process, and only recently has treatment of low testosterone in the aging male been shown to provide long-term physical and mental improvement. In the past, oral and injectable testosterone delivery methods had disadvantages that limited their use, but the introduction of transdermal testosterone patches has allowed testosterone to be delivered into the circulation in a consistent fashion. Long-term use of these patches over the last 3 to 10 years has been effective in maintaining sexual function and bone and muscle mass, and from short-term studies it does not appear that testosterone treatment puts men at risk for the development of prostate cancer. A new topical gel formation (Testim) has been designed to provide consistent transdermal absorption of testosterone over 24 hours after a single dose.     

Déficit androgénique lié à l’âge. Que faut-il attendre de l’androgénothérapie?

With the exception of disease or drug-induced changes in Leydig cell function, aging is accompanied by specific changes of androgen status in healthy men. The level of testosterone production decreases in contrast with the rise in plasma protein testosterone binding capacity. Free testosterone, considered to be the biologically active fraction, decreases, leading to tissue androgen deficiency. The resulting clinical picture mimics hypogonadism, including physical and psychological asthenia, decreased libido and sexual behaviour, increased fat mass and decreased lean mass, gynaecomastia, osteoporosis and pro-atherogenic metabolic changes. The cut-off value for plasma testosterone below which androgen deficiency can be considered to be responsible for clinical signs is a key point which determines the therapeutic approach. In the absence of clearly validated data in healthy aging males, this cut-off value has been consensually defined as the mean plasma testosterone levels of men between 30 and 50 years of age minus two standard deviations, corresponding to the zone of hypogonadism in adult males. The association of clinical signs compatible with hypogonadism and reduced total (or preferably bioavailable) plasma testosterone level justifies initiation of hormone replacement therapy after excluding any contraindications (especially prostatic). The aim of this treatment is to reverse the consequences of age-related hypogonadism. Some benefits of this treatment have been clearly demonstrated, such as a decrease of fat mass, and an increase of lean mass and muscle strength. Similarly, bone mineral density increases, particularly in men with the lowest pretreatment plasma testosterone levels. It must be stressed that these changes are observed in truly hypogonadal aging men, but not in aging men with normal plasma testosterone levels. Testosterone replacement therapy can promote the development of gynaecomastia, while dihydrotestosterone tends to reduce gynaecomastia. Finally, androgen replacement therapy appears to improve a hypogonadism-related decrease in libido or sexual behaviour, provided other associated non-endocrine factors have been previously treated. Androgen replacement therapy improves well-being, and physical and psychological asthenia in hypogonadal men. However, this treatment has not been demonstrated to be effective in healthy aging men. Although androgen replacement therapy does not have a negative impact on lipid parameters, its possible cardiovascular protective effects have not yet been demonstrated. In conclusion, androgen replacement therapy, respecting the contraindications, is beneficial in patients of all ages with clearly demonstrated hypogonadism, but has no efficacy on symptoms in other cases.     

Androgen levels and components of aggressive behavior in men

Serum concentrations of testosterone (Tser), 5 alpha-dihydrotestosterone (DHT), and free testosterone (Tsal) in saliva were determined in 117 healthy young men between the ages of 20 and 30. A battery of standardized tests and projective techniques were administered simultaneously in order to measure various components of aggression, including sexual aggressiveness. All three androgens show reliable positive correlations with self-ratings of spontaneous aggression. Dominance exhibits a positive, statistically significant correlation to Tser and to DHT. In addition, DHT is negatively related to the scale restraint of aggression. These results support previous findings about Tser and point to the importance of other androgens--especially DHT--for this aspect of endocrine-affect relationships. Interest in sexual aggression yielded no significant results for Tser and DHT (Tsal shows a low positive correlation). The ratio DHT/Tser, however, correlates significantly with this component of aggression.     

Fundamental aspects of hypogonadism in the aging male

With aging in men, serum testosterone levels decline progressively and the prevalence of hypogonadism increases; these changes are associated with alterations in androgen-regulated physiological functions. In young hypogonadal men, similar alterations improve with testosterone replacement. In older men, short-term testosterone treatment trials suggest benefits (eg, on body composition and bone mineral density), without significant adverse effects. Therefore, androgen deficiency may contribute to physiological decline with aging, and testosterone therapy is reasonable for older men with clinical manifestations of androgen deficiency and low testosterone levels. However, the long-term benefits and potential risks (eg, for prostate disease) of testosterone treatment in older men are unknown.     

Stem cell activation in adults can reverse detrimental changes in body composition to reduce fat and increase lean mass in both sexes

Detrimental changes in body composition are often associated with declining levels of testosterone. Here, we evaluated the notion that multipotent mesenchymal stem cells, that give rise to both fat and muscle tissue, can play a significant role to alter existing body composition in the adult. Transgenic mice with targeted androgen receptor (AR) overexpression in stem cells were employed. Wild-type littermate and AR-transgenic male and female mice were gonadectomized and left untreated for 2 months. After the hypogonadal period, mice were then treated with 5α-dihydrotestosterone (DHT) for 6 weeks. After orchidectomy (ORX), wild-type males have reduced lean mass and increased fat mass compared to shams. DHT treatment was beneficial to partially restore body composition. In wild-type females, ovariectomy (OVX) produced a similar change but there was no improvement with DHT. In targeted AR transgenic mice, DHT treatment increased lean and reduced fat mass to sham levels. In contrast to wild-type females, DHT treatment in female transgenic mice significantly ameliorated the increased fat and decreased lean mass changes that result after OVX. Our results show that DHT administration reduces fat mass and increases lean mass in wild-type males but not females, indicating that wild-type females are not as sensitive to androgen treatment. Because both male and female transgenic mice are more responsive than wild-type, results suggest that body composition remains linked to stem cell fate in the adult and that targeted androgen signaling in stem cells can play a significant role to reverse detrimental changes in body composition in both sexes.     

Testosterone replacement in hypogonadal men alters the HDL proteome but not HDL cholesterol efflux capacity

The effects of androgens on cardiovascular disease (CVD) risk in men remain unclear. To better characterize the relationship between androgens and HDL, we investigated the effects of testosterone replacement on HDL protein composition and serum HDL-mediated cholesterol efflux in hypogonadal men. Twenty-three older hypogonadal men (ages 51-83, baseline testosterone < 280 ng/dl) were administered replacement testosterone therapy (1% transdermal gel) with or without the 5α-reductase inhibitor dutasteride. At baseline and after three months of treatment, we determined fasting lipid concentrations, HDL protein composition, and the cholesterol efflux capacity of serum HDL. Testosterone replacement did not affect HDL cholesterol (HDL-C) concentrations but conferred significant increases in HDL-associated paraoxonase 1 (PON1) and fibrinogen α chain (FGA) (P = 0.022 and P = 0.023, respectively) and a decrease in apolipoprotein A-IV (apoA-IV) (P = 0.016). Exogenous testosterone did not affect the cholesterol efflux capacity of serum HDL. No differences were observed between men who received testosterone alone and those who also received dutasteride. Testosterone replacement in older hypogonadal men alters the protein composition of HDL but does not significantly change serum HDL-mediated cholesterol efflux. These effects appear independent of testosterone conversion to dihydrotestosterone. Further research is needed to determine how changes in HDL protein content affect CVD risk in men.     

Rôle des androgènes dans la motivation sexuelle masculine: approche par la neuroanatomie cérébrale fonctionnelle

The central nervous system plays a crucial role in all of the successive stages of sexual behaviour, particularly for the processing of external stimuli. One important step consists of the evaluation of these stimuli and the assessment of their potential reward value, which will determine the development of the sexual response. These different stages involve complex cognitive processes interacting with emotional and physiological components. Androgens, and particularly testosterone, are closely related to the regulation of sexual behaviour. Many of the various effects of testosterone on sexual behaviour have been thought to result from its effects on the central nervous system. Several studies have demonstrated that a minimum concentration of plasma testosterone is necessary to maintain a normal level of sexual desire in human males. Consequently, in normal men, acute and profound androgen deficiency induced by an experimental pharmacological treatment results in decreased sexual desire and fantasies. This reduced sexual desire is also one of the major symptoms observed in male hypogonadism. Conversely, in hypogonadal men, androgen substitution therapy results in increased sexual interest and activity. Over recent years, the development of brain functional imaging techniques (Positron Emission Tomography, functional Magnetic Resonance Imaging) has demonstrated the brain regions participating in a neural network that controls and regulates sexual arousal. We have proposed a four component neurobehavioural model, comprising cognitive (e.g. orbitofrontal cortex), motivational (e.g. anterior cingulate gyrus), emotional (e.g. somatosensory cortex, insula) and physiological (e.g. hypothalamus) processes, to describe this cerebral control of sexual motivation in human males. This network comprises activating and inhibiting structures that interact with each other. As testosterone can modulate sexual desire via its action on cerebral function, we decided to perform a brain imaging study in hypogonadal patients (both when they were untreated and when they received hormone replacement therapy), to obtain e better understanding of the specificity of these brain regions in sexual arousal processes. This study could also help describe the brain regions via which testosterone acts to modulate sexual behaviour.     

Andropause or Male Menopause? Rationale for Testosterone Replacement Therapy in Older Men with Low Testosterone Levels

ObjectiveTo provide rationale for testosterone replacement therapy (TRT) in older men with low testosterone levels and symptoms consistent with testosterone deficiency.MethodsThe relevant literature was reviewed using PubMedResultsCross-sectional and longitudinal population-based studies indicate that total and free testosterone levels fall with aging, and they may be accompanied by symptoms consistent with androgen deficiency. Testosterone treatment of younger men with very low testosterone levels and hypothalamic, pituitary, or testicular disease is associated with improvements in symptoms, body composition, bone density, and hematocrit/hemoglobin. Studies evaluating testosterone treatment of older men with low testosterone levels are limited, but they suggest some increase in fat free mass, some decrease in fat mass, and some increase in bone density of the lumbar spine and femoral neck.ConclusionThe Testosterone Trial should provide definitive information regarding the potential benefits of TRT in men ≥ years of age. If efficacy is confirmed, we will still need more information regarding the risks of TRT in older men. (Endocr Pract. 2013;19:847-852)     

Déficit androgénique: effet de la substitution sur la composition corporelle

Male hypogonadism is responsible for an increase in fat body mass and a decrease in lean body mass. Similar changes are observed in aging men. Aging is also frequently associated with a decrease in testicular function. Androgen replacement therapy in adult men with hypogonadism has been shown to reverse these changes in body composition. Androgens stimulate protein synthesis, especially in muscles, leading to a gain of muscle mass and muscle strength. In contrast, androgen therapy inhibits tissue utilization of lipids, predominantly in visceral fat and consecutively induces a decrease in fat body mass. As the same changes in body composition are observed in aging and in hypogonadal adult men, the value of androgen replacement therapy was evaluated in aging men with an age-related decrease in androgen production. About ten studies have included human males over the age of 65. The results obtained indicate the benefit of such therapy in terms of improvement in body composition in aging men due to a rise in plasma testosterone levels up to the normal range of young adult men.     

Androgen Treatment of Abdominally Obese Men

Middle-aged men with abdominal obesity were treated in a double-blind study with moderate doses of transdermal preparations of testosterone (T), dihydrotestosterone (DHT), or placebo. This resulted in moderately elevated T concentrations and marked decreases in follicle stimulating and luteinizing hormones in the group treated with T, while the DHT group showed elevated DHT, markedly lower T values, and less diminution of gonadotropin concentrations. In the group treated with T visceral fat mass decreased (measured by computerized tomography) without significant changes in other depot fat regions. Lean body mass did not change. In the group treated with T, glucose disposal rate, measured with the euglycemic hyperinsulinemic clamp method, was markedly augmented. Plasma triglycerides, cholesterol, and fasting blood glucose concentrations as well as diastolic blood pressure decreased. There were no such changes in the DHT or placebo treatment groups. The men treated with T reported increased well-being and energy. In none of the groups did prostate volume, specific prostate antigen concentration, genitourinary history, or urinary flow measurement change. It is suggested that supplementation of abdominal obese men with moderate doses of T might have several beneficial effects. (OBESITY RESEARCH 1993;1:245–251)     

Inverse relationship between serum levels of interleukin-1beta and testosterone in men with stable coronary artery disease.

OBJECTIVES: To examine the relationship between serum levels of inflammatory cytokines and testosterone in men with stable coronary artery disease (CAD). Evidence supports a beneficial effect of testosterone upon objective measures of myocardial ischaemia in men with CAD, and in animal models of atherosclerosis. Inflammatory cytokines are involved in many stages of the atherosclerotic process, however, the effect of testosterone upon inflammatory cytokines within the cardiovascular system is largely unknown. METHODS: Serum was collected from 69 men (59+/-1 years) having >75% occlusion of 1, 2, or 3 coronary arteries. Levels of total testosterone (TT), bioavailable testosterone (BT), tumour necrosis factor-alpha (TNFalpha), interleukin (IL)-1-beta (IL-1beta), IL-6 and IL-10 were measured and analysis made between men with 1, 2, or 3 vessel CAD, and between men with hypogonadal, borderline hypogonadal and eugonadal serum levels of testosterone. RESULTS: In patients with 1, 2, or 3 vessel CAD, significant stepwise increases were observed in levels of IL-1beta: 0.16+/-0.03, 0.22+/-0.06, and 0.41+/-0.08 pg/ml (p=0.035), and IL-10: 0.93+/-0.11, 1.17+/-0.14, and 2.94+/-0.65 pg/ml (p=0.008). A significant stepwise increase in levels of IL-1beta was also observed in eugonadal, borderline hypogonadal, and hypogonadal men: 0.19+/-0.05, 0.29+/-0.05, and 0.46+/-0.13 pg/ml (p=0.047). CONCLUSION: Consequently this data implicates IL-1beta and IL-10 in the pathogenesis of CAD and suggests that testosterone may regulate IL-1beta activity in men with CAD.     

Testosterone and Regional Fat Distribution

The effects of testosterone treatment of abdominally obese men have been assessed by evaluating the following parameters: The metabolic activity of different adipose tissue regions in vivo (using lipid label as a tracer) and in vitro (measuring lipoprotein lipase(LPL) activity), the total and visceral adipose tissue mass, insulin sensitivity, fasting blood glucose, blood lipids, and blood pressure as well as prostate volume. Middle-aged men with abdominal obesity were treated with transdermal administration of testosterone (T), dihydrotestosterone (DHT) or placebo (P) during 9 months. The study was double-blind. Treatment with T was followed by an inhibited uptake of lipid label in adipose tissue triglycerides, a decreased LPL-activity and an increased turn-over rate of lipid label in the abdominal adipose tissue region in comparisons with the DHT and P groups. These effects on adipose tissue metabolism were not detected in the femoral adipose tissue region in any of the groups. T treatment was also followed by a specific decrease of visceral fat mass (measured by CT-scan), by increased insulin sensitivity (measured with the euglycemic glucose clamp), by a decrease in fasting blood glucose, plasma cholesterol and triglycerides as well as a decrease in diastolic blood pressure. In the DHT group an increased visceral mass was detected. No other changes in these variables were found in the DHT and P groups. There were no detectable changes in prostate volume (measured by ultra-sound), prostate specific antigen concentration, genito-urinary history or urinary flow measurements in any of the groups. It is suggested that T substitution to a selected group of men results in general metabolic and circulatory improvements. The prostate area needs further careful attention.     

Invalidation of a commercially available human 5α-dihydrotestosterone immunoassay

Enzyme immunoassays (EIA) are commonly utilized for the evaluation of androgens in biological fluids; however, careful consideration must be given to cross-reactivity with other endogenous sex-steroid hormones. Our purpose was to determine the validity of a commonly-utilized commercially-available dihydrotestosterone (DHT) EIA. Serum samples obtained from older hypogonadal men who participated in a 12-month randomized controlled trial evaluating the effects of testosterone-enanthate (125 mg/week) or vehicle in combination with finasteride (5 mg/day) or placebo were assayed for DHT via EIA and using a validated gold-standard LC–MS/MS approach. Additionally, commercially-available (DHT-free) buffer containing graded testosterone doses was evaluated by DHT immunoassay. DHT concentrations measured via EIA were 79% to >1000% higher than values obtained by LC–MS/MS (p < 0.05), with the largest differences (415–1128%) occuring in groups receiving finasteride. Both LC–MS/MS and EIA indicated that testosterone-enanthate increased serum DHT to a similar magnitude. In contrast, finasteride-induced reductions in DHT were detected by LC–MS/MS, but not EIA (p < 0.05). No significant associations were present for DHT concentrations between measurement techniques. Cross-reactivity of testosterone with the immunoassay ranged from 18% to 99% and DHT concentrations measured by EIA were highly associated with the spiked testosterone concentrations in DHT-free buffer (r = 0.885, p < 0.001). In conclusion, we provide evidence invalidating a commonly-utilized commercially-available DHT immunoassay because significant cross-reactivity exists between testosterone and the EIA and because the changes in DHT observed via EIA were not associated with a validated gold-standard measurement technique. The cross-reactivity of testosterone is particularly concerning because testsoterone is present in 100-fold greater concentrations than is DHT within the circulation.     

Osteoporosis in male hypogonadism: responses to androgen substitution differ among men with primary and secondary hypogonadism

BACKGROUND: No randomized study exists comparing the effects of different modes of androgen substitution on bone mineral density (BMD). METHODS: We performed a prospective, randomized, trial assigning 53 hypogonadal men to the following treatment groups: mesterolone 100 mg p.o. daily, testosterone undecanoate 160 mg p.o. daily, testosterone enanthate 250 mg i.m. every 21 days, or a single subcutaneous implantation of 1,200 mg crystalline testosterone. The BMD was determined by peripheral quantitative computed tomography. RESULTS: At baseline, men with secondary hypogonadism (n = 33) had a lower BMD (-1.52 +/- 0.23 SDS; Z-scores) than men with primary hypogonadism (n = 20, -0.87 +/- 0.23 SDS, p < 0.01). In men with primary hypogonadism, the BMD increased dose dependently (crystalline testosterone +7.0 +/- 1.3%, testosterone enanthate +4.8 +/- 0.2%, testosterone undecanoate +3.4 +/- 2.5%, mesterolone +0.8 +/- 1.6%) after 6 months of therapy. Only secondary hypogonadal men treated with testosterone enanthate experienced an increase of the BMD. CONCLUSIONS: In primary hypogonadal men the BMD responds dose dependently to testosterone substitution, whereas in secondary hypogonadism only testosterone enanthate treatment significantly increased the BMD.     

Prostate cancer risk in testosterone-treated men

Men with classical androgen deficiency have reduced prostate volume and blood prostate-specific antigen (PSA) levels compared with their age peers. As it is plausible that androgen deficiency partially protects against prostate disease, and that restoring androgen exposure increases risk to that of eugonadal men of the same age, men using ART should have age-appropriate surveillance for prostate disease. This should comprise rectal examination and blood PSA measurement at regular intervals (determined by age and family history) according to the recommendations, permanently revisited, published by ISSAM, EAU, Endocrine Society….

Testosterone replacement therapy is now being prescribed more often for aging men, the same population in which prostate cancer incidence increases; it has been suggested that administration in men with unrecognised prostate cancer might promote the development of clinically significant disease. In hypogonadal men who were candidates for testosterone therapy, a 14% incidence of occult cancer was found. A percentage (15.2%) of prostate cancer has been found in the placebo group (with normal DRE and PSA) in the prostate cancer prevention study investigating the chemoprevention potential of finasteride.

The hypothesis that high levels of circulating androgens is a risk factor for prostate cancer is supported by the dramatic regression, after castration, of tumour symptoms in men with advanced prostate cancer. However these effects, seen at a very late stage of cancer development, may not be relevant to reflect the effects of variations within a physiological range at an earlier stage.

Data from all published prospective studies on circulating level of total and free testosterone do not support the hypothesis that high levels of circulating androgens are associated with an increased risk of prostate cancer. A study on a large prospective cohort of 10,049 men, contributes to the gathering evidence that the long standing “androgen hypothesis” of increasing risk with increasing androgen levels can be rejected, suggesting instead that high levels within the reference range of androgens, estrogens and adrenal androgens decrease aggressive prostate cancer risk. Indeed, high-grade prostate cancer has been associated with low plasma level of testosterone. Furthermore, pre-treatment total testosterone was an independent predictor of extraprostatic disease in patients with localized prostate cancer; as testosterone decreases, patients have an increased likelihood of non-organ confined disease and low serum testosterone levels are associated with positive surgical margins in radical retropubic prostatectomy.

A clinical implication of these results concerns androgen supplementation which has become easier to administer with the advent of transdermal preparations (patch or gel) that achieve physiological testosterone serum levels without supra physiological escape levels. During the clinical development of a new testosterone patch in more than 200 primary or secondary hypogonadal patients, no prostate cancer was diagnosed.     

The 5 alpha-reductase activity of the subcortical white matter, the cerebral cortex, and the hypothalamus of the rat and of the mouse: possible sex differences and effect of castration

Previous studies have shown that the central nervous system is able to convert testosterone into 17-beta-hydroxy-5-alpha-androstan-3-one (DHT), by the action of the enzyme 5-alpha-reductase. The data here presented show that, in the brain of the rat and the mouse of both sexes, the 5-alpha-reductase activity is more concentrated in the subcortical white matter than in the hypothalamus and in the cerebral cortex. The enzymatic activity is apparently higher in the rat than in the mouse brain. The formation of DHT in the subcortical white matter, in the hypothalamus and in the cerebral cortex of both rats and mice does not show any sexual difference. Moreover, in the rat no effect of short- or long-term castration or neonatal castration or testosterone replacement could be observed on the formation of DHT in the three brain structures considered (even in the subcortical white matter, the cerebral tissue more active in converting testosterone into DHT). The present data support the view that the 5-alpha-reductase present in the brain is not under androgenic control.     

Effects of male hypogonadism on regional adipose tissue fatty acid storage and lipogenic proteins

Testosterone has long been known to affect body fat distribution, although the underlying mechanisms remain elusive. We investigated the effects of chronic hypogonadism in men on adipose tissue fatty acid (FA) storage and FA storage factors. Twelve men with chronic hypogonadism and 13 control men matched for age and body composition: 1) underwent measures of body composition with dual energy x-ray absorptiometry and an abdominal CT scan; 2) consumed an experimental meal containing [(3)H]triolein to determine the fate of meal FA (biopsy-measured adipose storage vs. oxidation); 3) received infusions of [U-(13)C]palmitate and [1-(14)C]palmitate to measure rates of direct free (F)FA storage (adipose biopsies). Adipose tissue lipoprotein lipase, acyl-CoA synthetase (ACS), and diacylglycerol acetyl-transferase (DGAT) activities, as well as, CD36 content were measured to understand the mechanism by which alterations in fat storage occur in response to testosterone deficiency. Results of the study showed that hypogonadal men stored a greater proportion of both dietary FA and FFA in lower body subcutaneous fat than did eugonadal men (both p<0.05). Femoral adipose tissue ACS activity was significantly greater in hypogonadal than eugonadal men, whereas CD36 and DGAT were not different between the two groups. The relationships between these proteins and FA storage varied somewhat between the two groups. We conclude that chronic effects of testosterone deficiency has effects on leg adipose tissue ACS activity which may relate to greater lower body FA storage. These results provide further insight into the role of androgens in body fat distribution and adipose tissue metabolism in humans.     

Bioavailability and LH-suppressing effect of different testosterone preparations in normal and hypogonadal men.

The therapeutic effectiveness of intramuscularly administered testosterone esters and free testosterone in suppositories was investigated by the measurement of plasma testosterone and LH levels after administration to normal and hypogonadal men. Testosterone levels were elevated above the lower physiological limit for 1 day after 25 mg testosterone one propionate, for 2 days after 50 mg testosterone propionate and for 14 days after 250 mg testosterone oenanthate. LH levels were suppressed for the corresponding periods. Elevated plasma testosterone and suppressed LH levels were maintained by testosterone suppositories (3 x 20 mg for 5 days).     

A randomized, double blind, cross-over, placebo-controlled clinical trial to assess the effects of Candesartan on the insulin sensitivity on non diabetic, non hypertense subjects with dysglyce mia and abdominal obesity. "ARAMIA"

In ageing men testosterone levels decline, while cognitive function, muscle and bone mass, sexual hair growth, libido and sexual activity decline and the risk of cardiovascular diseases increase. We set up a double-blind, randomized placebo-controlled trial to investigate the effects of testosterone supplementation on functional mobility, quality of life, body composition, cognitive function, vascular function and risk factors, and bone mineral density in older hypogonadal men. We recruited 237 men with serum testosterone levels below 13.7 nmol/L and ages 60–80 years. They were randomized to either four capsules of 40 mg testosterone undecanoate (TU) or placebo daily for 26 weeks. Primary endpoints are functional mobility and quality of life. Secondary endpoints are body composition, cognitive function, aortic stiffness and cardiovascular risk factors and bone mineral density. Effects on prostate, liver and hematological parameters will be studied with respect to safety. Measure of effect will be the difference in change from baseline visit to final visit between TU and placebo. We will study whether the effect of TU differs across subgroups of baseline waist girth (< 100 cm vs. ≥ 100 cm; testosterone level (<12 versus ≥ 12 nmol/L), age (< median versus ≥ median), and level of outcome under study (< median versus ≥ median). At baseline, mean age, BMI and testosterone levels were 67 years, 27 kg/m² and 10.72 nmol/L, respectively.