The benefits and risks of testosterone replacement therapy: a review
TL;DR: Although controversy remains regarding indications for testosterone supplementation in aging men due to lack of large-scale, long-term studies assessing the benefits and risks of testosterone-replacement therapy in men, reports indicate that TRT may produce a wide range of benefits for men with hypogonadism that include improvement in libido and sexual function.
Abstract: Increased longevity and population aging will increase the number of men with late onset hypogonadism. It is a common condition, but often underdiagnosed and undertreated. The indication of testosterone-replacement therapy (TRT) treatment requires the presence of low testosterone level, and symptoms and signs of hypogonadism. Although controversy remains regarding indications for testosterone supplementation in aging men due to lack of large-scale, long-term studies assessing the benefits and risks of testosterone-replacement therapy in men, reports indicate that TRT may produce a wide range of benefits for men with hypogonadism that include improvement in libido and sexual function, bone density, muscle mass, body composition, mood, erythropoiesis, cognition, quality of life and cardiovascular disease. Perhaps the most controversial area is the issue of risk, especially possible stimulation of prostate cancer by testosterone, even though no evidence to support this risk exists. Other possible risks include worsening symptoms of benign prostatic hypertrophy, liver toxicity, hyperviscosity, erythrocytosis, worsening untreated sleep apnea or severe heart failure. Despite this controversy, testosterone supplementation in the United States has increased substantially over the past several years. The physician should discuss with the patient the potential benefits and risks of TRT. The purpose of this review is to discuss what is known and not known regarding the benefits and risks of TRT.
Citations
More filters
TL;DR: Current teaching recommends the use of protein supplementation and exercise, however, this fails to address many other factors which contribute to muscle loss in this setting.
Abstract: SummaryBackground
Sarcopenia (loss of muscle mass) is common in cirrhosis and is associated with poor outcomes. Current teaching recommends the use of protein supplementation and exercise, however, this fails to address many other factors which contribute to muscle loss in this setting.
Aims
To summarise existing knowledge regarding the aetiology of sarcopenia in cirrhosis, diagnostic modalities and the clinical significance of this condition. In addition to discuss recent research findings that may allow the development of more effective treatments.
Methods
We conducted a Medline and PubMed search using the search terms ‘sarcopenia’, ‘muscle’, ‘body composition’, ‘cirrhosis’, ‘liver’ and ‘malnutrition’ from inception to October 2015.
Results
Cirrhotic patients with sarcopenia have reduced survival, experience increased rates of infection and have worse outcomes following liver transplantation. The aetiology of this condition is more complex than simple protein and calorie malnutrition. Cirrhosis also results in depleted glycogen stores and metabolic alterations that cause excessive protein catabolism, increased activation of the ubiquitin–proteasome pathway and inappropriate muscle autophagy. Satellite cell differentiation and proliferation is also reduced due to a combination of elevated myostatin levels, reduced IGF-1 and hypogonadism. Although there is some evidence supporting the use of late evening snacks, branched chain amino acid supplementation and high protein/high calorie diets, well designed clinical trials addressing the effects of treatment on body composition in cirrhosis are lacking.
Conclusion
Sarcopenia in cirrhosis has a complex pathogenesis and simple dietary interventions are insufficient. Improved understanding of the multiple mechanisms involved should allow the development of more effective therapies, which target the specific underlying metabolic derangements.
245 citations
Cites background from "The benefits and risks of testoster..."
...It is interesting to note that some studies, particularly in the elderly, show that it is possible to stimulate an increase in muscle mass without necessarily demonstrating an increase in strength or physical activity.(50) Hand grip strength has been shown in a large population study of >140 000...
[...]
TL;DR: A large number of men aged 40 to 69 in the United States suffer from hypogonadism, and the number of these men is likely to increase as they age.
Abstract: Recent data from the Massachusetts Male Aging Study (MMAS) have revealed an increasing incidence of hypogonadism within the aging US population. The Massachusetts Male Aging Study estimates indicate that ≈2.4 million men aged 40 to 69 suffer from hypogonadism in the United States.[1][1] The
186 citations
TL;DR: Suggestions for future research on the DBS and psychopathology are provided, including investigations of the potential usefulness of DBS in differentiating specific disorder outcomes, the need for more sophisticated biological research, and the value of longitudinal dynamical research.
Abstract: The dominance behavioral system (DBS) can be conceptualized as a biologically based system that guides dominance motivation, dominant and subordinate behavior, and responsivity to perceptions of power and subordination. A growing body of research suggests that problems with the DBS are evident across a broad range of psychopathologies. We begin by describing psychological, social, and biological correlates of the DBS. Extensive research suggests that externalizing disorders, mania proneness, and narcissistic traits are related to heightened dominance motivation and behaviors. Mania and narcissistic traits also appear related to inflated self-perceptions of power. Anxiety and depression are related to subordination and submissiveness, as well as a desire to avoid subordination. Models of the DBS have received support from research with humans and animals; from self-report, observational, and biological methods; and use of naturalistic and experimental paradigms. Limitations of available research include the relative lack of longitudinal studies using multiple measures of the DBS and the absence of relevant studies using diagnosed samples to study narcissistic personality disorder and bipolar disorder. We provide suggestions for future research on the DBS and psychopathology, including investigations of the potential usefulness of DBS in differentiating specific disorder outcomes, the need for more sophisticated biological research, and the value of longitudinal dynamical research. Implications of using the DBS as a tool in clinical assessment and treatment are discussed.
179 citations
TL;DR: It is suggested that conditions such as germ cell apoptosis and DNA damage are common features in hypoxia and varicocele and testicular torsion and oxidative damage seems to be present in these conditions during the initiation stages of germ cell damage and apoptosis.
Abstract: Mammalian spermatogenesis is a complex biological process occurring in the seminiferous tubules in the testis. This process represents a delicate balance between cell proliferation, differentiation, and apoptosis. In most mammals, the testicles are kept in the scrotum 2 to 7°C below body core temperature, and the spermatogenic process proceeds with a blood and oxygen supply that is fairly independent of changes in other vascular beds in the body. Despite this apparently well-controlled local environment, pathologies such as varicocele or testicular torsion and environmental exposure to low oxygen (hypoxia) can result in changes in blood flow, nutrients, and oxygen supply along with an increased local temperature that may induce adverse effects on Leydig cell function and spermatogenesis. These conditions may lead to male subfertility or infertility. Our literature analyses and our own results suggest that conditions such as germ cell apoptosis and DNA damage are common features in hypoxia and varicocele and testicular torsion. Furthermore, oxidative damage seems to be present in these conditions during the initiation stages of germ cell damage and apoptosis. Other mechanisms like membrane-bound metalloproteinases and phospholipase A2 activation could also be part of the pathophysiological consequences of testicular hypoxia.
163 citations
Cites background from "The benefits and risks of testoster..."
...Thus, testosterone administration has been shown to stimulate the production of red blood cells in males, especially elderly males, and it is associated with the increment of hemoglobin that occurs during puberty in young men [80, 81]....
[...]
TL;DR: Because T plays an important role in all life stages for both sexes, future efforts should focus on better defining these relationships and their broader impacts.
Abstract: Context: There is evidence of declining trends in T levels among men in recent decades, as well as trends in related conditions at multiple life stages and in both sexes. There is also animal and limited human evidence that exposure to phthalates, chemicals found in plastics and personal care products, is associated with reduced androgen levels and associated disorders. Objective: To explore relationships between urinary concentrations of 13 phthalate metabolites and serum total T levels among men, women, and children when adjusting for important confounders and stratifying by sex and age (6–12, 12–20, 20–40, 40–60, and 60–80 y). Design: A cross-sectional study. Setting: US National Health and Nutrition Examination Survey, 2011–2012. Patients or Other Participants: US general population. Interventions: None Main Outcome Measures: Serum total T measured by isotope dilution-liquid chromatography-tandem mass spectrometry. Results: Multiple phthalates were associated with significantly reduced T in both sexes...
160 citations
Cites background from "The benefits and risks of testoster..."
...These results among men in this age group may have important public health implications because declined T levels in aging men can have adverse effects on muscle strength, energy, bone mass, leanness, intellectual capacity, and libido, and may be associated with increased risk of osteoporosis, obesity, type 2 diabetes, metabolic syndrome, cardiovascular disease, and erectile dysfunction (2, 37)....
[...]
References
More filters
TL;DR: The FT value, obtained by calculation from T and SHBG as determined by immunoassay, appears to be a rapid, simple, and reliable index of bioavailable T, comparable to AFTC and suitable for clinical routine, except in pregnancy.
Abstract: The free and nonspecifically bound plasma hormone levels generally reflect the clinical situation more accurately than total plasma hormone levels. Hence, it is important to have reliable indexes of these fractions. The apparent free testosterone (T) concentration obtained by equilibrium dialysis (AFTC) as well as the fraction of serum T not precipitated by 50% ammonium sulfate concentration (non-SHBG-T; SHBG, sex hormone-binding globulin), often referred to as bioavailable T, appear to represent reliable indexes of biologically readily available T, but are not well suited for clinical routine, being too time consuming. Several other parameters have been used without complete validation, however: direct immunoassay of free T with a labeled T analog (aFT), calculation of free T (FT) from total T and immunoassayed SHBG concentrations (iSHBG), and the free androgen index (FAI 5 the ratio 100T/iSHBG). In the view of substantial discrepancies in the literature concerning the free or bioavailable T levels, we compared AFTC, FT, aFT, FAI, and non-SHBG-T levels in a large number of sera with SHBG capacities varying from low, as in hirsute women, to extremely high as in hyperthyroidism. All these indexes of bioavailable T correlated significantly with the AFTC concentration; AFTC and FT values were almost identical under all conditions studied, except during pregnancy. Values for aFT, however, were only a fraction of either AFTC or FT, the fraction varying as a function of SHBG levels. Also, the FAI/AFTC ratio varied as a function of the SHBG levels, and hence, neither aFT nor FAI is a reliable index of bioavailable T. The FT value, obtained by calculation from T and SHBG as determined by immunoassay, appears to be a rapid, simple, and reliable index of bioavailable T, comparable to AFTC and suitable for clinical routine, except in pregnancy. During pregnancy, estradiol occupies a substantial part of SHBG-binding sites, so that SHBG as determined by immunoassay overestimates the actual binding capacity, which in pregnancy sera results in calculated FT values that are lower than AFTC. The nonspecifically bound T, calculated from FT, correlated highly significantly with and was almost identical to the values of non-SHBG-T obtained by ammonium sulfate precipitation, testifying to the clinical value of FT calculated from iSHBG. (J Clin Endocrinol Metab 84: 3666 ‐3672, 1999)
3,475 citations
"The benefits and risks of testoster..." refers background in this paper
...level below 65 pg/mL can provide supportive evidence for testosterone treatment.(53,54) The gold standard for bioavailable...
[...]
TL;DR: Observations of health factor independent, age-related longitudinal decreases in T and free T, resulting in a high frequency of hypogonadal values, suggest that further investigation of T replacement in aged men, perhaps targeted to those with the lowest serum T concentrations, are justified.
Abstract: Many studies have shown cross-sectional (and two small studies, longitudinal) declines in total and/or free testosterone (T) levels, with age, in men. The extent to which decline in T is the result of the aging process per se, as opposed to chronic illness, medication use, and other age-related factors, remains controversial. The frequency with which aging leads to T levels consistent with hypogonadism has also not been defined. These issues bear on the potential use of T replacement in aging men, because aging and hypogonadism have, in common, reduced bone and lean body mass and muscle strength and increased total and abdominal fat. We measured T and sex hormone-binding globulin (SHBG), by RIA, in stored samples from 890 men in the Baltimore Longitudinal Study on Aging. Using a mixed-effects model, we found independent effects of age and date of sampling to reduce T levels. After compensating for date effects, which investigation suggested was artifactual, we observed significant, independent, age-invariant, longitudinal effects of age on both T and free T index (free T index = T/SHBG), with an average change of -0.124 nmol/L.yr and -0.0049 nmol T/nmol SHBG.yr. T, but not free T index, also decreased with increasing body mass index. Use of beta-blocking drugs was associated with higher T and higher free T index levels. Using total T criteria, incidence of hypogonadal T levels increased to about 20% of men over 60, 30% over 70 and 50% over 80 yr of age, and even greater percentages when free T index criteria were employed. Our observations of health factor independent, age-related longitudinal decreases in T and free T, resulting in a high frequency of hypogonadal values, suggest that further investigation of T replacement in aged men, perhaps targeted to those with the lowest serum T concentrations, are justified.
2,446 citations
TL;DR: The paradoxical finding that longitudinal age trends were steeper than cross-sectional trends suggests that incident poor health may accelerate the age-related decline in androgen levels.
Abstract: We used longitudinal data from the Massachusetts Male Aging Study, a large population-based random-sample cohort of men aged 40-70 yr at baseline, to establish normative age trends for serum level of T and related hormones in middle-aged men and to test whether general health status affected the age trends. Of 1,709 men enrolled in 1987-1989, 1,156 were followed up 7-10 yr afterward. By repeated-measures statistical analysis, we estimated simultaneously the cross-sectional age trend of each hormone between subjects within the baseline data, the cross-sectional trend between subjects within the follow-up data, and the longitudinal trend within subjects between baseline and follow-up. Total T declined cross-sectionally at 0.8%/yr of age within the follow-up data, whereas both free and albumin-bound T declined at about 2%/yr, all significantly more steeply than within the baseline data. Sex hormone-binding globulin increased cross-sectionally at 1.6%/yr in the follow-up data, similarly to baseline. The longitudinal decline within subjects between baseline and follow-up was considerably steeper than the cross-sectional trend within measurement times for total T (1.6%/yr) and bioavailable T (2-3%/yr). Dehydroepiandrosterone, dehydroepiandrosterone sulfate, cortisol, and estrone showed significant longitudinal declines, whereas dihydrotestosterone, pituitary gonadotropins, and PRL rose longitudinally. Apparent good health, defined as absence of chronic illness, prescription medication, obesity, or excessive drinking, added 10-15% to the level of several androgens and attenuated the cross-sectional trends in T and LH but did not otherwise affect longitudinal or cross-sectional trends. The paradoxical finding that longitudinal age trends were steeper than cross-sectional trends suggests that incident poor health may accelerate the age-related decline in androgen levels.
1,632 citations
"The benefits and risks of testoster..." refers background in this paper
...No relationship between testosterone level and depressive symptoms was found in the Massachusetts Male Aging Study (MMAS).(14) This discrepancy in the results of the effects of testosterone replacement therapy on mood may be explained by the genetic polymorphism in the androgen receptor which defines a vulnerable group in whom depression is expressed when testosterone levels fall below a particular threshold....
[...]
...with increasing age with a steeper decline in bioavailable and free compared with total testosterone concentrations.(4,14,15) In...
[...]
TL;DR: It is suggested that a quantitative loss in muscle CSA is a major contributor to the decrease in muscle strength seen with advancing age and accounts for 90% of the variability in strength at T2.
Abstract: The present study examines age-related changes in skeletal muscle size and function after 12 yr. Twelve healthy sedentary men were studied in 1985–86 (T1) and nine (initial mean age 65.4 ± 4.2 yr) ...
1,378 citations
TL;DR: In this paper, a systematic review indicates that endogenous sex hormones may differentially modulate glycemic status and risk of type 2 diabetes in men and women, while the inverse association of SHBG with risk was stronger in women than in men.
Abstract: ContextInconsistent data suggest that endogenous sex hormones may have a role in sex-dependent etiologies of type 2 diabetes, such that hyperandrogenism may increase risk in women while decreasing risk in men.ObjectiveTo systematically assess studies evaluating the association of plasma levels of testosterone, sex hormone–binding globulin (SHBG), and estradiol with risk of type 2 diabetes.Data SourcesSystematic search of EMBASE and MEDLINE (1966-June 2005) for English-language articles using the keywords diabetes, testosterone, sex-hormone-binding-globulin, and estradiol; references of retrieved articles; and direct author contact.Study SelectionFrom 80 retrieved articles, 43 prospective and cross-sectional studies were identified, comprising 6974 women and 6427 men and presenting relative risks (RRs) or hormone levels for cases and controls.Data ExtractionInformation on study design, participant characteristics, hormone levels, and risk estimates were independently extracted by 2 investigators using a standardized protocol.Data SynthesisResults were pooled using random effects and meta-regressions. Cross-sectional studies indicated that testosterone level was significantly lower in men with type 2 diabetes (mean difference, −76.6 ng/dL; 95% confidence interval [CI], −99.4 to −53.6) and higher in women with type 2 diabetes compared with controls (mean difference, 6.1 ng/dL; 95% CI, 2.3 to 10.1) (P 60 vs ≤60 nmol/L) had an 80% lower risk of type 2 diabetes (RR, 0.20; 95% CI, 0.12 to 0.30), while men with higher SHBG levels (>28.3 vs ≤28.3 nmol/L) had a 52% lower risk (RR, 0.48; 95% CI, 0.33 to 0.69). Estradiol levels were elevated among men and postmenopausal women with diabetes compared with controls (P = .007).ConclusionsThis systematic review indicates that endogenous sex hormones may differentially modulate glycemic status and risk of type 2 diabetes in men and women. High testosterone levels are associated with higher risk of type 2 diabetes in women but with lower risk in men; the inverse association of SHBG with risk was stronger in women than in men.
1,197 citations