Shalender Bhasin

• Harvard Medical School

Background A spinal cord injury (SCI) is a devastating, life-changing event that has profoundly deleterious effects on an individual’s health and well-being. Dysregulation of neuromuscular, cardiometabolic, and endocrine organ systems following an SCI contribute to excess morbidity, mortality and a poor quality of life. As no effective treatments c...

Sarcopenia and frailty represent two burdensome conditions, contributing to a broad spectrum of adverse outcomes. The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force met virtually in September 2021 to discuss the challenges in the development of drugs for sarcopenia and frailty. Lifestyle interventions are the current...

In male mammals, changes at all levels of the hypothalamic-pituitary-testicular axis, including alterations in the GnRH pulse generator, gonadotropin secretion, and testicular steroidogenesis, in addition to alterations of feed-forward and feed-back relationships contribute to the age-related decline in circulating testosterone concentrations. The...

Testosterone treatment increases muscle mass, strength, and leg power in menopausal women, hypogonadal men, older men with mobility limitation, COPD and ESRD. Testosterone's effects on muscle mass and strength are augmented by exercise training and growth hormone. Testosterone treatment improves some measures of physical performance, such as stair...

Objective This narrative review offers a guideline-based approach to optimizing the diagnostic evaluation and treatment decision-making in men being evaluated for testosterone deficiency. Methods A narrative review Results Testosterone deficiency is a clinical syndrome that results from the inability of the testes to produce normal amounts of tes...

Background Cut-points to define slow walking speed have largely been derived from expert opinion. Methods Study participants (13,589 men and 5,043 women aged ≥65years) had walking speed (m/s) measured over 4-6 meters (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as self-reported any difficulty wi...

Background: Growth and differentiation factor (GDF)-11 controls embryonic development and has been proposed as an anti-aging factor. GDF-8 (myostatin) inhibits skeletal muscle growth. Difficulties in accurately measuring circulating GDF-11 and GDF-8 have generated controversy. Methods: We developed a liquid chromatography-tandem mass spectrometry...

Background: Androgen deficiency is common among prostate cancer survivors, but many guidelines consider history of prostate cancer a contraindication for testosterone replacement. We determined the safety and efficacy of a selective androgen receptor modulator (OPK-88004) in symptomatic, testosterone-deficient men who had undergone radical prostat...

The substantial increase in life expectancy of men has focused growing attention on quality-of-life issues associated with reproductive aging. Serum total and free testosterone levels in men, after reaching a peak in the second and third decade of life, decline gradually with advancing age. The trajectory of age-related decline is affected by comor...

Background It remains controversial whether high protein diets improve cardiometabolic profile. We investigated whether increasing protein intake to 1.3-g/kg/day in functionally-limited older adults with usual protein intake ≤RDA (0.8-g/kg/day) improves visceral fat accumulation and serum cardiovascular risk markers more than the RDA. Methods The...

Physical performance measures, including cardiopulmonary exercise testing (CPXT), are widely used in geriatric practice and aging research. Theoretically, research participants and study personnel could get infected in the closed environment of the exercise laboratory by contact with respiratory droplets from an infected person, by breathing virus-...

Background/objectives: Accurate estimates of clinically important difference (CID) are required for interpreting the clinical importance of treatments to improve physical function, but CID estimates vary in different disease populations. We determined the CID for two common measures of walking ability in mobility-limited older men. Design: Longi...

Context Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase. Objective To analyse associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men. Design, setting and partic...

Background/objectives: In the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study, a multifactorial intervention was associated with a nonsignificant 8% reduction in time to first serious fall injury but a significant 10% reduction in time to first self-reported fall injury relative to enhanced usual care. The effect of t...

Background: 90-day mortality and rehospitalizations are important hospital quality metrics. Biomarkers that predict these outcomes among malnourished hospitalized patients could identify those at risk and help direct care plans. Objectives: To identify biomarkers that predict 90-day (primary) and 30-day (secondary) mortality or nonelective rehos...

Objective: Serum testosterone concentrations are affected by factors unrelated to hypothalamo-pituitary-testicular axis pathology. We evaluated the impact of sociodemographic, lifestyle and medical factors, on serum testosterone and sex hormone-binding globulin (SHBG) in men aged 40-69 years. Design: Cross-sectional analysis of 208,677 community...

Context Testosterone treatment of hypogonadal men improves their hemoglobin, but the mechanism is not understood. Objective To investigate possible mechanisms by which testosterone stimulates erythropoiesis in hypogonadal older men with unexplained or iron-deficiency anemia. Design The Anemia Trial of The Testosterone Trials, a placebo-controlled...

ContextIn preclinical studies, high androgen levels during pregnancy are associated with low birth weight and rapid postnatal weight gain in the offspring. However, human data linking prenatal androgens with birth weight and early life weight gain in the offspring are scarce.DesignWe evaluated 516 mother–child pairs enrolled in the New England birt...

Testosterone stimulates iron‐dependent erythropoiesis and suppresses hepcidin. To clarify the role of iron in mediating testosterone's effects on erythropoiesis, we induced iron deficiency in mice by feeding low iron diet. Iron‐replete and iron‐deficient mice were treated weekly with testosterone propionate or vehicle for 3 weeks. Testosterone trea...

Background Injuries from falls are major contributors to complications and death in older adults. Despite evidence from efficacy trials that many falls can be prevented, rates of falls resulting in injury have not declined. Methods We conducted a pragmatic, cluster-randomized trial to evaluate the effectiveness of a multifactorial intervention tha...

BACKGROUND The Sarcopenia Definitions and Outcomes Consortium (SDOC) is a collaborative initiative seeking to develop and evaluate cut‐points for low muscle strength and lean mass that predict an increased risk for slowness (usual walking speed <.8 m/s) among older adults. OBJECTIVES The goal of the present study was to provide clinicians and rese...

BACKGROUND The Sarcopenia Definitions and Outcomes Consortium (SDOC) sought to identify cut points for muscle strength and body composition measures derived from dual‐energy x‐ray absorptiometry (DXA) that discriminate older adults with slow walking speed. This article presents the core analyses used to guide the SDOC position statements. DESIGN C...

Background/objectives: The extent to which the prevalence of muscle weakness in the US population varies by different putative grip strength constructs developed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) has not been described. Design: Cross-sectional analysis. Setting: Two nationally representative cohorts-2010 and 2012 wav...

OBJECTIVES Analyses performed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) identified cut‐points in several metrics of grip strength for consideration in a definition of sarcopenia. We describe the associations between the SDOC‐identified metrics of low grip strength (absolute or standardized to body size/composition); low dual‐ener...

Background Testosterone treatment increases erythrocytes in men, but its effects on leukocyte and platelet counts are unknown and could affect its safety. Objective To determine if testosterone affects circulating leukocytes and platelets in men. Methods Secondary analyses of two randomized testosterone trials were performed: the 5α‐Reductase (5a...

This letter comments on the letter by Ayse Merve Ata.

Introduction This study aims to clarify the role(s) of endogenous sex hormones to influence health outcomes in men, specifically to define the associations of plasma testosterone with incidence of cardiovascular events, cancer, dementia and mortality risk, and to identify factors predicting testosterone concentrations. Data will be accrued from at...

Background Persons with HIV may experience greater mobility limitations than uninfected populations. Accurate tools are needed to identify persons at greatest risk of decline. We evaluated the performance of novel muscle weakness metrics (grip, grip/body mass index [BMI], grip/weight, grip/total body fat, grip/arm lean mass) and association with sl...

Background Sarcopenia is often conceptualized as a precursor to loss of mobility, but its effect on recovery of mobility after a hip fracture is unknown. We determined the prevalence of low muscle strength (weakness) after hip fracture using putative sarcopenia metrics (absolute grip strength, and grip strength normalized to body mass index, total...

Objectives: To develop an evidence-based definition of sarcopenia that can facilitate identification of older adults at risk for clinically relevant outcomes (eg, self-reported mobility limitation, falls, fractures, and mortality), the Sarcopenia Definition and Outcomes Consortium (SDOC) crafted a set of position statements informed by a literatur...

Context Endogenous sex hormones may be involved in the pathogenesis of cardiovascular disease (CVD) in women. Carotid plaque characteristics, such as echogenicity, an ultrasound measure that reflects plaque composition, may identify unstable plaques that are more likely to rupture, precipitating a CVD event. However, few studies have considered sex...

For clinical studies of sarcopenia and frailty, clinically meaningful outcome measures are needed to monitor disease progression, evaluate efficacy of interventions, and plan clinical trials. Physical performance measures including measures of gait speed and other aspects of mobility and strength have been used in many studies, although a definitio...

Biomarkers of frailty and sarcopenia are essential to advance the understanding of these conditions of aging and develop new diagnostic tools and effective treatments. The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force - a group of academic and industry scientists from around the world -- met in February 2019 to disc...

Importance: Androgen deficiency is common among male opioid users, and opioid use has emerged as a common antecedent of testosterone treatment. The long-term health outcomes associated with testosterone therapy remain unknown, however. Objective: To compare health outcomes between long-term opioid users with testosterone deficiency who filled te...

Objective: Recent results from the Cardiovascular (CV) Trial of the Testosterone(T) Trials showed that T treatment of older men with low T was associated with greater progression of non-calcified plaque (NCP). We evaluated the effect of anthropometric measures and cardiovascular biomarkers on plaque progression in individuals in the T Trial. Meth...

Objective The task force of the International Conference of Frailty and Sarcopenia Research (ICFSR) developed these clinical practice guidelines to overview the current evidence-base and to provide recommendations for the identification and management of frailty in older adults. Methods These recommendations were formed using the GRADE approach, w...

People aging with HIV infection (PAWH) experience greater impairments in physical and cognitive function, in addition to higher rates of peripheral comorbid conditions (e.g. renal failure, diabetes, bone fracture, hypertension, cardiovascular disease, polypharmacy and multimorbidity). While multifactorial drivers including HIV infection itself, ant...

Objective: The aim of this study was to determine the effect of testosterone administration on trunk and pelvic floor muscle area in women with low testosterone levels. Methods: Participants were hysterectomized women with total testosterone<31 ng/dL and/or free testosterone<3.5 pg/mL; participating in the Testosterone Dose Response in Surgicall...

Context Prostate specific antigen (PSA) changes during testosterone treatment of older hypogonadal men have not been rigorously evaluated. The Endocrine Society Guidelines recommendation of urological referral for a confirmed increase in PSA >1.4 ng/mL is not based on PSA changes in testosterone-treated men. Design Double-blinded, placebo-controll...

Standardization of performance-based physical function measures that are reliable and responsive to intervention is necessary for efficacy trials of function promoting therapies (FPT). Herein, we describe a standardized method of measuring stair climbing power (SCP) and evaluate its ability to assess improvements in physical function in response to...

Background Biomarkers that predict response to anabolic therapies could expedite the development of function promoting anabolic drugs. This study aimed to identify serum biomarkers that are responsive to testosterone administration and associated with increases in fat-free mass (FFM). Methods Serum samples were obtained from the 5α-Reductase Trial...

Background We have shown that testosterone administration suppresses hepcidin, stimulates iron‐dependent erythropoiesis, and increases hemoglobin and hematocrit. Objective We investigated whether testosterone‐mediated suppression of hepcidin plays an essential role in mediating testosterone's stimulatory effects on erythropoiesis. Methods We util...

Context Powerful demographic transitions towards aging of human populations, older age at first childbirth, and lower birth-rates will profoundly influence the health, vitality, and economies of human societies, and deserve greater attention in health policy and research. Evidence Acquisition Information on birth-rates, fertility rates, and outcom...

In Vitro fertilization (IVF) is a widely accepted method for attaining pregnancy in sub-fertile couples. A primary step in IVF is controlled ovarian hyperstimulation (COHS) by reproductive hormones, including Follicle Stimulating Hormone (FSH), to stimulate the production of eggs that can be harvested for IVF. However, there is substantial variatio...

Background Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut-points for lean mass and/or muscle strength that identify people at increased risk of mobility disa...

Background The relation between endogenous testosterone concentrations and myocardial mass and function remains incompletely understood. Objectives To determine the cross‐sectional association between endogenous hormone levels with cardiac magnetic resonance measures of myocardial mass, structure, and function in community‐dwelling men across a wi...

In male mammals, changes at all levels of the hypothalamic-pituitary-testicular axis, including alterations in the GnRH pulse generator, gonadotropin secretion, and testicular steroidogenesis, in addition to alterations of feed-forward and feedback relationships contribute to the age-related decline in circulating testosterone concentrations. The r...

The role of testosterone in the pathophysiology and treatment of depressive disorders in men has remained shrouded in controversy. We do not know whether depressive symptoms are a part of the syndrome of testosterone deficiency in men, and if so, whether testosterone replacement relieves such symptoms, whether low testosterone levels contribute to...

Background: The Physical Function Trial (PFT) was one of seven Testosterone Trials (TTrials), the aim of which was to assess the effect of testosterone on mobility, self-reported physical function, falls, and patient global impression-of-change (PGIC) in older men with low testosterone concentrations, self-reported mobility limitation, and walking...

Context The prevalence of body image disorders and anabolic-androgenic steroid (AAS) use is increasing, despite the evidence of their serious adverse health effects and despite the passage of laws regulating their sales. Here we review the evolution of the dual emerging epidemics of body image disorders and AAS use, adverse health effects of AAS, a...

Background Growing preclinical evidence suggests that hormonal programming by androgens in utero may contribute to cardiovascular disease risk in adult offspring. However, data linking prenatal androgens to cardiometabolic outcomes in the human population, especially their potential differential impact on male versus female offspring, has not been...

An important safety consideration in the use of antagonists of myostatin and activins is whether these drugs induce myocardial hypertrophy and impair cardiac function. The present study evaluated the effects of a soluble ActRIIB receptor Fc fusion protein (ActRIIB.Fc), a ligand trap for TGF-β/activin family members including myostatin, on myocardia...

Background We describe the recruitment of participants for Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE), a large pragmatic cluster randomized trial that is testing the effectiveness of a multifactorial intervention to prevent serious fall injuries. Eligible persons were 70 years or older, community-living, and at increase...

Background: Limited information is available on the performance characteristics of 2 questionnaires commonly used in clinical research, the Psychosexual Daily Questionnaire (PDQ) and the Derogatis Interview for Sexual Function (DISF)-II Assessment, especially in older men with low testosterone (T) and impaired sexual function. Aim: To determine...

Background We reported higher serum free testosterone (FT) and increased anal-HPV16/18 infection prevalence in MSM. Associations between serum-FT and -estradiol and anal-HPV16/18 infections and histological HSIL (hHSIL) are unclear. Methods Two cross-sectional analyses were performed. 340 HIV-infected/HIV-uninfected Multicenter AIDS Cohort MSM wer...

Context Testosterone increases skeletal muscle mass and strength, but long-term effects of testosterone supplementation on aerobic capacity (V˙O2peak) in healthy older men with low testosterone have not been evaluated. Objective To determine the effects of testosterone supplementation on V˙O2peak during incremental cycle ergometry. Design Testost...

Context Reproductive hormones are understood to be important to the pathophysiology of cardiovascular disease (CVD) in women. However, standard estradiol (E2) and testosterone (T) assays lack sensitivity at the levels of postmenopausal women. Objective Investigate relations of mass spectrometry-assessed estrone (E1), estradiol (E2), and testostero...

Vitamin D and calcium are key nutrients to support bone development in children and young adults and to maintain muscle strength and neuromuscular coordination throughout the life span. Vitamin D deficiency is a well-defined risk factor for falls and hip fractures among older adults. It is unclear if supplementation with these nutrients is effectiv...

Testosterone supplementation has been widely used in those infected with human immunodeficiency virus (HIV) for hypogonadism, and wasting. But with effective antiretroviral therapy and increasing recognition of atherosclerotic disease and adults infected with HIV, the risks of inappropriate testosterone use in HIV-infected patients are far better r...

Context The efficacy and safety of testosterone replacement therapy (TRT) in hypogonadal men remain incompletely understood. Objective To conduct a systematic review and meta-analysis of randomized clinical trials (RCT) to determine the effects of TRT on patient-important outcomes and adverse events in hypogonadal men. Data Sources We searched Ov...

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...

Importance The Institute of Medicine set the recommended dietary allowance (RDA) for protein at 0.8 g/kg/d for the entire adult population. It remains controversial whether protein intake greater than the RDA is needed to maintain protein anabolism in older adults. Objective To investigate whether increasing protein intake to 1.3 g/kg/d in older a...

The Testosterone Trials (TTrials) were a coordinated set of seven, placebo-controlled, double blind trials in 788 men of mean age 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...

Background Serum testosterone levels and insulin sensitivity both decrease with age. Severe testosterone deficiency is associated with the development of insulin resistance. However, the effects of long-term testosterone administration on insulin sensitivity in older men with low or low-normal testosterone levels remain unknown. Methods The Testos...

Context Serum estradiol (E2) and estrone (E1) levels exhibit substantial heritability. No genome-wide association study (GWAS) of estrogen levels has been performed in men of European origin. Objective To investigate the genetic regulation of serum E2 and E1 in men. Design, setting and participants GWAS in 11,097 men of European origin from nine...

In a subset of men, sarcopenia and physical dysfunction occur due to destabilization of the neuromuscular junction (NMJ), which is manifested by elevated serum concentrations of C-terminal agrin fragment (CAF). Testosterone administration improves physical function in some studies; however, its effects on serum circulating CAF concentrations remain...

Testosterone dose-dependently increases appendicular muscle mass. However, the effects of testosterone administration on the core muscles of the trunk and the pelvis have not been evaluated. The present study evaluated the effects of testosterone administration on truncal and pelvic muscles in a dose–response trial. Participants were young healthy...

Context Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. Objective To determine the effect of testosterone treatment on cardiovascular (CV) biomarkers in older men with low testosterone. Design Double-blind, placebo-controlled trial Setting Twelve academic medical centers in the United States Participants...

Importance Recent reports have described the increasing use of nonsteroidal selective androgen receptor modulators, which have not been approved by the US Food and Drug Administration (FDA), to enhance appearance and performance. The composition and purity of such products is not known. Objective To determine the chemical identity and the amounts...

Objectives: Nutrition impacts the development of sarcopenia and protein intake is an important modulator of skeletal muscle mass loss in older people. The Optimizing Protein Intake in Older Men with Mobility Limitation (OPTIMEN) Trial was designed to assess the independent and combined effects of higher protein intake and a promyogenic agent, test...

Background Fall injuries are a major cause of morbidity and mortality among older adults. We describe the design of a pragmatic trial to compare the effectiveness of an evidence-based, patient-centered multifactorial fall injury prevention strategy to an enhanced usual care. Methods Strategies to Reduce Injuries and Develop Confidence in Elders (S...

The authors noticed mistake in values shown in the in the final publication of Figs. 3 and 1F. The following set should be used for the model in Figs. 1F and 3: Kd11 = 0.49 ± 0.12nM (ΔH = −4.4 ± 0.6 kCal/M), Kd1 = 128 ± 14nM (ΔH = −18.3k ± 3.9Cal/M), Kd1′ = 0.1nM ± 0.05nM, Kd-1′ = 0.21nM ± 0.08nM (ΔH = 2.9 ± 0.5 kCal/M), Kd2 = 4.82 ± 0.5nM (ΔH = 20...

There is substantial inter-individual variability in serum testosterone levels in hypogonadal men treated with testosterone gels. We aimed to elucidate participant-level factors that contribute to inter-individual variability in testosterone levels during testosterone therapy. An exploratory aim was to determine whether polymorphisms in genes encod...

Context Prescribing of testosterone increased substantially in the past decade. However, little is known about the context within which such prescriptions occur. Objective We evaluated provider- and site-level determinants of receipt of testosterone and of guideline-concordant testosterone prescribing. Design Cross-sectional. Setting Veterans He...

In circulation, testosterone and other sex hormones are bound to binding proteins which play an important role in regulating their transport, distribution, metabolism, and biologic activity. According to the free hormone hypothesis, which has been debated extensively, only the unbound or free fraction is biologically active in target tissues. Conse...