01 Apr 2017-JAMA Internal Medicine (American Medical Association)-Vol. 177, Iss: 4, pp 471-479
TL;DR: Testosterone treatment for 1 year of older men with low testosterone significantly increased volumetric BMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip.
Abstract: Importance As men age, they experience decreased serum testosterone concentrations, decreased bone mineral density (BMD), and increased risk of fracture. Objective To determine whether testosterone treatment of older men with low testosterone increases volumetric BMD (vBMD) and estimated bone strength. Design, Setting, and Participants Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization. Interventions Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year. Main Outcomes and Measures Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months. Results There were 211 participants (mean [SD] age, 72.3 [5.9] years; 86% white; mean [SD] body mass index, 31.2 [3.4]). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, −1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%;P Conclusions and Relevance Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk. Trial Registration clinicaltrials.gov Identifier: NCT00799617
TL;DR: It is suggested that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost.
Abstract: Objective To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010. Participants The participants include an Endocrine Society-appointed task force of 10 medical content experts and a clinical practice guideline methodologist. Evidence This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus process One group meeting, several conference calls, and e-mail communications facilitated consensus development. Endocrine Society committees and members and the cosponsoring organization were invited to review and comment on preliminary drafts of the guideline. Conclusions We recommend making a diagnosis of hypogonadism only in men with symptoms and signs consistent with testosterone (T) deficiency and unequivocally and consistently low serum T concentrations. We recommend measuring fasting morning total T concentrations using an accurate and reliable assay as the initial diagnostic test. We recommend confirming the diagnosis by repeating the measurement of morning fasting total T concentrations. In men whose total T is near the lower limit of normal or who have a condition that alters sex hormone-binding globulin, we recommend obtaining a free T concentration using either equilibrium dialysis or estimating it using an accurate formula. In men determined to have androgen deficiency, we recommend additional diagnostic evaluation to ascertain the cause of androgen deficiency. We recommend T therapy for men with symptomatic T deficiency to induce and maintain secondary sex characteristics and correct symptoms of hypogonadism after discussing the potential benefits and risks of therapy and of monitoring therapy and involving the patient in decision making. We recommend against starting T therapy in patients who are planning fertility in the near term or have any of the following conditions: breast or prostate cancer, a palpable prostate nodule or induration, prostate-specific antigen level > 4 ng/mL, prostate-specific antigen > 3 ng/mL in men at increased risk of prostate cancer (e.g., African Americans and men with a first-degree relative with diagnosed prostate cancer) without further urological evaluation, elevated hematocrit, untreated severe obstructive sleep apnea, severe lower urinary tract symptoms, uncontrolled heart failure, myocardial infarction or stroke within the last 6 months, or thrombophilia. We suggest that when clinicians institute T therapy, they aim at achieving T concentrations in the mid-normal range during treatment with any of the approved formulations, taking into consideration patient preference, pharmacokinetics, formulation-specific adverse effects, treatment burden, and cost. Clinicians should monitor men receiving T therapy using a standardized plan that includes: evaluating symptoms, adverse effects, and compliance; measuring serum T and hematocrit concentrations; and evaluating prostate cancer risk during the first year after initiating T therapy.
TL;DR: This critical review of existing theories explaining the evolutionary origins of obesity and novel biological and sociocultural agents of evolutionary change to help explain the modern‐day distribution of obesity‐predisposing variants are appraised.
Abstract: Genetic predisposition to obesity presents a paradox: how do genetic variants with a detrimental impact on human health persist through evolutionary time? Numerous hypotheses, such as the thrifty genotype hypothesis, attempt to explain this phenomenon yet fail to provide a justification for the modern obesity epidemic. In this critical review, we appraise existing theories explaining the evolutionary origins of obesity and explore novel biological and sociocultural agents of evolutionary change to help explain the modern-day distribution of obesity-predisposing variants. Genetic drift, acting as a form of 'blind justice,' may randomly affect allele frequencies across generations while gene pleiotropy and adaptations to diverse environments may explain the rise and subsequent selection of obesity risk alleles. As an adaptive response, epigenetic regulation of gene expression may impact the manifestation of genetic predisposition to obesity. Finally, exposure to malnutrition and disease epidemics in the wake of oppressive social systems, culturally mediated notions of attractiveness and desirability, and diverse mating systems may play a role in shaping the human genome. As an important first step towards the identification of important drivers of obesity gene evolution, this review may inform empirical research focused on testing evolutionary theories by way of population genetics and mathematical modelling.
148 citations
Cites background from "Effect of Testosterone Treatment on..."
...diate this relationship: testosterone therapy among aging (142) and hypogonadal males (140) has been linked to in-...
TL;DR: Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or Prostate risk.
Abstract: The Testosterone Trials (TTrials) were a coordinated set of seven placebo-controlled, double-blind trials in 788 men with a mean age of 72 years to determine the efficacy of increasing the testosterone levels of older men with low testosterone. Testosterone treatment increased the median testosterone level from unequivocally low at baseline to midnormal for young men after 3 months and maintained that level until month 12. In the Sexual Function Trial, testosterone increased sexual activity, sexual desire, and erectile function. In the Physical Function Trial, testosterone did not increase the distance walked in 6 minutes in men whose walk speed was slow; however, in all TTrial participants, testosterone did increase the distance walked. In the Vitality Trial, testosterone did not increase energy but slightly improved mood and depressive symptoms. In the Cognitive Function Trial, testosterone did not improve cognitive function. In the Anemia Trial, testosterone increased hemoglobin in both men who had anemia of a known cause and in men with unexplained anemia. In the Bone Trial, testosterone increased volumetric bone mineral density and the estimated strength of the spine and hip. In the Cardiovascular Trial, testosterone increased the coronary artery noncalcified plaque volume as assessed using computed tomographic angiography. Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or prostate risk.
TL;DR: This Primer focuses on a reappraisal of the physiological role of testosterone, with emphasis on the critical interpretation of the hypog onadal conditions throughout the lifespan of the male individual, with the exception of hypogonadal states resulting from congenital disorders of sex development.
Abstract: The hypothalamic–pituitary–gonadal axis is of relevance in many processes related to the development, maturation and ageing of the male. Through this axis, a cascade of coordinated activities is carried out leading to sustained testicular endocrine function, with gonadal testosterone production, as well as exocrine function, with spermatogenesis. Conditions impairing the hypothalamic–pituitary–gonadal axis during paediatric or pubertal life may result in delayed puberty. Late-onset hypogonadism is a clinical condition in the ageing male combining low concentrations of circulating testosterone and specific symptoms associated with impaired hormone production. Testosterone therapy for congenital forms of hypogonadism must be lifelong, whereas testosterone treatment of late-onset hypogonadism remains a matter of debate because of unclear indications for replacement, uncertain efficacy and potential risks. This Primer focuses on a reappraisal of the physiological role of testosterone, with emphasis on the critical interpretation of the hypogonadal conditions throughout the lifespan of the male individual, with the exception of hypogonadal states resulting from congenital disorders of sex development. Male hypogonadism is a disorder associated with low testosterone levels and impaired spermatogenesis. The condition can arise from inherent defects in the testes or abnormalities in the regulation of testosterone secretion at the hypothalamic or pituitary level. This Primer summarizes the conditions that can lead to hypogonadism in boys and men.
TL;DR: Until the results of the TRAVERSE trial are available, clinicians should individualize testosterone treatment after having an informed discussion with their patients about the risks and benefits of testosterone replacement therapy.
Abstract: Testosterone is the main male sex hormone and is essential for the maintenance of male secondary sexual characteristics and fertility. Androgen deficiency in young men owing to organic disease of the hypothalamus, pituitary gland or testes has been treated with testosterone replacement for decades without reports of increased cardiovascular events. In the past decade, the number of testosterone prescriptions issued for middle-aged or older men with either age-related or obesity-related decline in serum testosterone levels has increased exponentially even though these conditions are not approved indications for testosterone therapy. Some retrospective studies and randomized trials have suggested that testosterone replacement therapy increases the risk of cardiovascular disease, which has led the FDA to release a warning statement about the potential cardiovascular risks of testosterone replacement therapy. However, no trials of testosterone replacement therapy published to date were designed or adequately powered to assess cardiovascular events; therefore, the cardiovascular safety of this therapy remains unclear. In this Review, we provide an overview of epidemiological data on the association between serum levels of endogenous testosterone and cardiovascular disease, prescription database studies on the risk of cardiovascular disease in men receiving testosterone therapy, randomized trials and meta-analyses evaluating testosterone replacement therapy and its association with cardiovascular events and mechanistic studies on the effects of testosterone on the cardiovascular system. Our aim is to help clinicians to make informed decisions when considering testosterone replacement therapy in their patients.
TL;DR: The results indicate that sexual dysfunction is an important public health concern, and emotional problems likely contribute to the experience of these problems.
Abstract: ContextWhile recent pharmacological advances have generated
increased public interest and demand for clinical services regarding
erectile dysfunction, epidemiologic data on sexual dysfunction are
relatively scant for both women and men.ObjectiveTo assess the prevalence and risk of experiencing sexual
dysfunction across various social groups and examine the determinants
and health consequences of these disorders.DesignAnalysis of data from the National Health and Social Life
Survey, a probability sample study of sexual behavior in a
demographically representative, 1992 cohort of US adults.ParticipantsA national probability sample of 1749 women and 1410
men aged 18 to 59 years at the time of the survey.Main Outcome MeasuresRisk of experiencing sexual dysfunction as
well as negative concomitant outcomes.ResultsSexual dysfunction is more prevalent for women (43%) than
men (31%) and is associated with various demographic characteristics,
including age and educational attainment. Women of different racial
groups demonstrate different patterns of sexual dysfunction.
Differences among men are not as marked but generally consistent with
women. Experience of sexual dysfunction is more likely among women and
men with poor physical and emotional health. Moreover, sexual
dysfunction is highly associated with negative experiences in sexual
relationships and overall well-being.ConclusionsThe results indicate that sexual dysfunction is an
important public health concern, and emotional problems likely
contribute to the experience of these problems.
4,937 citations
"Effect of Testosterone Treatment on..." refers background in this paper
...Sexual desire, erection, and ejaculation decrease linearly from 20 to 70 years (16-18)....
TL;DR: The PANAS is a reliable and valid measure of the constructs it was intended to assess, although the hypothesis of complete independence between PA and NA must be rejected and the utility of this measure is enhanced by the provision of large-scale normative data.
Abstract: Objectives: To evaluate the reliability and validity of the PANAS (Watson, Clark, & Tellegen, 1988b) and provide normative data.
Design: Cross-sectional and correlational.
Method: The PANAS was administered to a non-clinical sample, broadly representative of the general adult UK population (N = 1,003). Competing models of the latent structure of the PANAS were evaluated using confirmatory factor analysis. Regression and correlational analysis were used to determine the influence of demographic variables on PANAS scores as well as the relationship between the PANAS with measures of depression and anxiety (the HADS and the DASS).
Results: The best-fitting model (robust comparative fit index = .94) of the latent structure of the PANAS consisted of two correlated factors corresponding to the PA and NA scales, and permitted correlated error between items drawn from the same mood subcategories (Zevon & Tellegen, 1982). Demographic variables had only very modest influences on PANAS scores and the PANAS exhibited measurement invariance across demographic subgroups. The reliability of the PANAS was high, and the pattern of relationships between the PANAS and the DASS and HADS were consistent with tripartite theory.
Conclusion: The PANAS is a reliable and valid measure of the constructs it was intended to assess, although the hypothesis of complete independence between PA and NA must be rejected. The utility of this measure is enhanced by the provision of large-scale normative data.
2,537 citations
"Effect of Testosterone Treatment on..." refers methods in this paper
...Testosterone treatment for one year, compared to placebo, of men in all trials will be associated with improved mood, as assessed by the Positive and Negative Affect Scales (PANAS) (41)....
[...]
...Primary Endpoint:
‚ Fatigue, as assessed by the 13-item FACIT-Fatigue Scale
Secondary Endpoints:
‚ Well-being, as assessed by the positive and negative scale (PANAS) ‚ Vitality scale of the SF-36 ‚ PHQ-9 depression score
Exploratory Endpoints:
‚ Patient global impression of change in fatigue/vitality...
[...]
...Mood, as assessed by the Positive and Negative Affect Scales (PANAS) 3....
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
"Effect of Testosterone Treatment on..." refers background in this paper
...Decrease in Testosterone as Men Age As men age, their serum testosterone concentration falls gradually from age 20 to over age 80, as demonstrated by both cross-sectional (1) and longitudinal studies (2-4)....
[...]
...By the eighth decade, approximately 30% of men have concentrations of total testosterone lower than normal for young men and 70% have free testosterone concentrations lower than normal for young men (3)....
TL;DR: Disruption of the estrogen receptor in humans need not be lethal and is important for bone maturation and mineralization in men as well as women.
Abstract: Background and Methods Mutations in the estrogen-receptor gene have been thought to be lethal. A 28-year-old man whose estrogen resistance was caused by a disruptive mutation in the estrogen-receptor gene underwent studies of pituitary-gonadal function and bone density and received transdermal estrogen for six months. Estrogen-receptor DNA, extracted from lymphocytes, was evaluated by analysis of single-strand-conformation polymorphisms and by direct sequencing. Results The patient was tall (204 cm [80.3 in.]) and had incomplete epiphyseal closure, with a history of continued linear growth into adulthood despite otherwise normal pubertal development. He was normally masculinized and had bilateral axillary acanthosis nigricans. Serum estradiol and estrone concentrations were elevated, and serum testosterone concentrations were normal. Serum follicle-stimulating hormone and luteinizing hormone concentrations were increased. Glucose tolerance was impaired, and hyperinsulinemia was present. The bone mineral d...
TL;DR: Biopsy-detected prostate cancer, including high-grade cancers, is not rare among men with PSA levels of 4.0 ng per milliliter or less--levels generally thought to be in the normal range.
Abstract: Background The optimal upper limit of the normal range for prostate-specific antigen (PSA) is unknown. We investigated the prevalence of prostate cancer among men in the Prostate Cancer Prevention Trial who had a PSA level of 4.0 ng per milliliter or less. Methods Of 18,882 men enrolled in the prevention trial, 9459 were randomly assigned to receive placebo and had an annual measurement of PSA and a digital rectal examination. Among these 9459 men, 2950 men never had a PSA level of more than 4.0 ng per milliliter or an abnormal digital rectal examination, had a final PSA determination, and underwent a prostate biopsy after being in the study for seven years. Results Among the 2950 men (age range, 62 to 91 years), prostate cancer was diagnosed in 449 (15.2 percent); 67 of these 449 cancers (14.9 percent) had a Gleason score of 7 or higher. The prevalence of prostate cancer was 6.6 percent among men with a PSA level of up to 0.5 ng per milliliter, 10.1 percent among those with values of 0.6 to 1.0 ng per mi...
2,425 citations
"Effect of Testosterone Treatment on..." refers background in this paper
...Many elderly men harbor occult prostate cancer (36)....