Testosterone Treatment In Older Men Research Articles

Association of testosterone therapy with disease progression in older males with COVID-19.

ImportanceLow testosterone levels in males have been linked with increase in proinflammatory cytokines—a primary culprit in COVID‐19 disease progression—and with adverse COVID‐19 outcomes. To date, however, no published studies have assessed the effect of testosterone therapy on COVID‐19 outcomes in older men.ObjectiveTo examine whether testosterone therapy reduced disease progression in older men diagnosed with COVID‐19.Design, setting, and participantsNested within a national cohort of older (aged ≥50 years) male patients diagnosed with COVID‐19 between January 1, 2020 and July 1, 2021 from the Optum electronic health record COVID‐19 database, two matched case–control studies of COVID‐19 outcomes were conducted. Cases—defined, respectively, as persons who (a) were hospitalized ≤30 days after COVID‐19 diagnosis (n = 33,380), and (b) were admitted to the intensive care unit or received mechanical ventilation during their COVID‐19 hospitalization (n = 10,273)—were matched 1:1 with controls based on demographic and clinical factors.ExposuresTestosterone therapy was defined based on receipt of prescription at ≤60, ≤90, or ≤120 days before COVID‐19 diagnosis.Main outcomes and measuresAdjusted odds ratios (ORs) for the risk of hospitalization within 30 days of COVID‐19 diagnosis and intensive care unit admission/mechanical ventilation during COVID‐19 hospitalization.ResultsThe use of testosterone therapy was not associated with decreased odds of hospitalization (≤60 days: OR = 0.92, 95% confidence interval [CI] = 0.70–1.20; ≤90 days: OR = 0.87, 95% CI = 0.68–1.13; ≤120 days: OR = 0.97, 95% CI = 0.72–1.32) or intensive care unit admission/mechanical ventilation (≤60 days: OR = 0.67, 95% CI = 0.37–1.23; ≤90 days: OR = 0.63, 95% CI = 0.36–0.11; ≤120 days: OR = 0.58, 95% CI = 0.29–1.19).Conclusions and relevanceThis study showed that testosterone therapy was not associated with decreased risks of COVID‐19 adverse outcomes. These findings may provide clinically relevant information regarding testosterone treatment in older men with COVID‐19 and other respiratory viral infections with similar pathogenesis.

Relation of Testosterone, Dihydrotestosterone, and Estradiol With Changes in Outcomes Measures in the Testosterone Trials.

Many effects of testosterone are mediated through dihydrotestosterone (DHT) and estradiol. To determine the relative contributions of each hormone to the observed effects of testosterone treatment in older men with hypogonadism. Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and DHT levels over 12 months of testosterone treatment with hemoglobin, high-density lipoprotein (HDL) cholesterol, volumetric bone mineral density (vBMD) of lumbar spine, sexual desire, and prostate-specific antigen (PSA). We used random forests to model the associations of predicted mean changes in outcomes with change in each hormone at low, mean, or high change in the other 2 hormones. Stepwise regression models were run to confirm the findings of random forests. Predicted increases in hemoglobin and sexual desire were greater with larger increases in estradiol and were larger with high change in DHT compared with low change in DHT. Greater increases in estradiol were associated with larger decreases in HDL cholesterol; this association did not vary according to changes in DHT or testosterone. Change in vBMD was most robustly associated with change in estradiol and was greater with high change in testosterone and DHT. There was no consistent relation between change in PSA and change in any hormone. Change in estradiol level was the best predictor not only of the change in vBMD and sexual desire but also of the changes in hemoglobin and HDL cholesterol. Consideration of testosterone, estradiol, and DHT together offers a superior prediction of treatment response in older hypogonadal men than testosterone alone.

Testosterone Therapy for Men With Age-Related Low Testosterone: Tempest in a Teacup

Serum testosterone concentrations decrease in men with age, but benefits and risks of raising testosterone levels in older men remain controversial. In the T-Trials, a total of 790 men, age 65 and older, with a serum testosterone concentration of < 275 ng/dL and symptoms of sexual dysfunction, fatigue or physical dysfunction were randomized to either testosterone gel or placebo gel for 1 year. Treatment in the testosterone arm increased serum testosterone levels to the mid-normal range for young men. Testosterone replacement was associated with a significant increase in sexual activity (p < 0.001), libido and erectile function. In contrast, there was no improvement in vitality or physical function. Adverse findings included increases in non-calcified plaque formation and a higher rate of prostate events. In sum, testosterone treatment in older men was associated with modest benefits, while the risk on prostate and cardiovascular health remain unclear.

Functional hypogonadism in middle-aged and older men: testosterone treatment or not?

Clinicians commonly encounter middle-aged and older men who present with functional hypogonadism, that is, with clinical features compatible with androgen deficiency and lowered serum testosterone, but without evidence of organic hypothalamic-pituitary-testicular axis pathology. Whether, and when, testosterone therapy should be offered to such men remains uncertain and controversial, in part due to the lack of definitive evidence regarding long-term patient-important health outcomes with testosterone treatment. In this debate, we address this controversy and provide two opposing points of view on the role of testosterone treatment in older men with functional hypogonadism.

Role of testosterone in cognition and mobility of aging men.

Cognitive decline and impairment of physical performance and mobility are age-related clinical problems with major negative impact on quality of life of elderly men. In how far the decline of testosterone production contributes to these problems in older men and whether testosterone therapy can contribute to slow down, prevent, or reverse their development remains subjects of debate. This narrative review presents the current knowledge on association of sex steroid status with cognitive decline and impairment of physical function and mobility in elderly men and on the effects of testosterone therapy on cognition and on physical performance and mobility in elderly men. The review is based on electronic database searches with primary focus on evidence from larger prospective observational studies and from controlled randomized trials, respectively. In most observational studies, testosterone levels do not predict cognitive decline or development of Alzheimer's disease. In randomized trials, testosterone therapy did not significantly affect cognition in men with low or low-to-normal serum testosterone, regardless of whether they have preexisting cognitive impairment. Overall, observational data indicate that the usually moderate decline of androgen exposure in older men cannot fully account for the parallel decline of physical performance and mobility. Trials of testosterone therapy in older men with low or low-normal serum testosterone, whether they were generally healthy or suffered from physical function impairments, either did not show any effect on mobility and physical performance or showed limited effects of uncertain clinical relevancy. The whole of the evidence tends to downplay the role of sex steroid status in the decline of cognitive function and impairment of physical function and mobility in older men. Based on the available evidence, prevention or treatment of cognitive decline or of impairment of mobility and physical function are not valid indications for testosterone treatment in older men with low or low-to-normal serum testosterone levels.

Testosterone deficiency in men with Type 2 diabetes: pathophysiology and treatment.

Epidemiological studies consistently demonstrate that lowered serum testosterone is not only common in men with established Type 2 diabetes, but also predicts future diabetic risks and increased mortality. Preclinical studies report plausible mechanisms by which low testosterone could mediate dysglycaemia. Exogenous testosterone treatment consistently reduces fat mass, increases muscle mass and improves insulin resistance in some studies, but the majority of currently available randomized controlled trials (RCTs) do not report a consistent glycaemic benefit. In men with diabetes, testosterone treatment effects on androgen deficiency-like clinical features are inconsistent, and effects on sexual dysfunction may be attenuated compared with men without diabetes. The long-term risks of testosterone treatment in older men without medical disease of the hypothalamic-pituitary-testicular axis are not known. Current RCTs are not definitive, owing to their small size, short duration and enrolment of men with mostly relatively good baseline glycaemic control not specifically selected for the presence of androgen deficiency symptoms. Although large, well-designed clinical trials are needed, given the benefit-risk ratio of testosterone treatment is not well understood, routine serum testosterone testing or testosterone treatment of asymptomatic men with Type 2 diabetes is currently not recommended. Carefully selected, symptomatic men with low testosterone who are informed of the lack of high-level evidence regarding the long-term benefits and risks of this approach may be offered a trial of testosterone treatment in combination with lifestyle measures, weight loss and optimization of comorbidities.

Testosterone and Physical Function

The purpose of this review is to provide an overview of recent data on the relationship of testosterone with physical function. The safety of testosterone treatment in older men who do not have hypogonadism has increasingly been questioned. In recent years, multiple studies have been performed to better understand the relationship between testosterone and physical function. Overall, the relationship between testosterone and physical function is unclear. Endogenous and exogenous testosterones are associated with favorable changes in body composition and, to a lesser extent, muscle strength. However, the relationship between testosterone and physical function is less clear in healthy older men. Exogenous testosterone is associated with favorable changes in body composition and strength, but further data are needed to understand if treatment is associated with functional improvements and ultimately decreased disability and morbidity.

Testosterone treatment in older men still controversial after new findings

Testosterone treatment in older men still controversial after new findings

Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment

Most cognitive functions decline with age. Prior studies suggest that testosterone treatment may improve these functions. To determine if testosterone treatment compared with placebo is associated with improved verbal memory and other cognitive functions in older men with low testosterone and age-associated memory impairment (AAMI). The Testosterone Trials (TTrials) were 7 trials to assess the efficacy of testosterone treatment in older men with low testosterone levels. The Cognitive Function Trial evaluated cognitive function in all TTrials participants. In 12 US academic medical centers, 788 men who were 65 years or older with a serum testosterone level less than 275 ng/mL and impaired sexual function, physical function, or vitality were allocated to testosterone treatment (n = 394) or placebo (n = 394). A subgroup of 493 men met criteria for AAMI based on baseline subjective memory complaints and objective memory performance. Enrollment in the TTrials began June 24, 2010; the final participant completed treatment and assessment in June 2014. Testosterone gel (adjusted to maintain the testosterone level within the normal range for young men) or placebo gel for 1 year. The primary outcome was the mean change from baseline to 6 months and 12 months for delayed paragraph recall (score range, 0 to 50) among men with AAMI. Secondary outcomes were mean changes in visual memory (Benton Visual Retention Test; score range, 0 to -26), executive function (Trail-Making Test B minus A; range, -290 to 290), and spatial ability (Card Rotation Test; score range, -80 to 80) among men with AAMI. Tests were administered at baseline, 6 months, and 12 months. Among the 493 men with AAMI (mean age, 72.3 years [SD, 5.8]; mean baseline testosterone, 234 ng/dL [SD, 65.1]), 247 were assigned to receive testosterone and 246 to receive placebo. Of these groups, 247 men in the testosterone group and 245 men in the placebo completed the memory study. There was no significant mean change from baseline to 6 and 12 months in delayed paragraph recall score among men with AAMI in the testosterone and placebo groups (adjusted estimated difference, -0.07 [95% CI, -0.92 to 0.79]; P = .88). Mean scores for delayed paragraph recall were 14.0 at baseline, 16.0 at 6 months, and 16.2 at 12 months in the testosterone group and 14.4 at baseline, 16.0 at 6 months, and 16.5 at 12 months in the placebo group. Testosterone was also not associated with significant differences in visual memory (-0.28 [95% CI, -0.76 to 0.19]; P = .24), executive function (-5.51 [95% CI, -12.91 to 1.88]; P = .14), or spatial ability (-0.12 [95% CI, -1.89 to 1.65]; P = .89). Among older men with low testosterone and age-associated memory impairment, treatment with testosterone for 1 year compared with placebo was not associated with improved memory or other cognitive functions. clinicaltrials.gov Identifier: NCT00799617.

Testosterone treatment in older men: glass half empty or half full?

In a series of randomized controlled trials published in JAMA and JAMA Intern Med, US researchers have examined the effect of testosterone treatment in older men with testosterone levels <275 ng dl−1 on coronary artery plaque volume,1 cognitive function,2 anemia,3 and volumetric bone density.4 While the trials have shown positive results with respect to improvement in anemia and bone density, longer-term studies are required to delineate the long-term risks and benefits in this population.

Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy.

This article, Part 1 of the Endocrine Society of Australia's position statement on male hypogonadism, focuses on assessment of male hypogonadism, including the indications for testosterone therapy. (Part 2 will deal with treatment and therapeutic considerations.) Key points and recommendations are:Pathological hypogonadism arises due to diseases of the hypothalamus or pituitary gland (hypogonadotropic hypogonadism) or testes (hypergonadotropic hypogonadism). It is a clinical diagnosis with a pathological basis, confirmed by hormone assays.Hormonal assessment is based on measurement of circulating testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations. Measurement of sex hormone-binding globulin levels can be informative, but use of calculated free testosterone is not recommended for clinical decision making.Testosterone replacement therapy is warranted in men with pathological hypogonadism, regardless of age.Currently, there are limited data from high-quality randomised controlled trials with clinically meaningful outcomes to justify testosterone treatment in older men, usually with chronic disease, who have low circulating testosterone levels but without hypothalamic, pituitary or testicular disease.Obesity, metabolic syndrome and type 2 diabetes are associated with lowering of circulating testosterone level, but without elevation of LH and FSH levels. Whether these are non-specific consequences of non-reproductive disorders or a correctable deficiency state is unknown, but clear evidence for efficacy and safety of testosterone therapy in this setting is lacking.Glucocorticoid and opioid use is associated with possibly reversible reductions in circulating testosterone level, without elevation of LH and FSH levels. Where continuation of glucocorticoid or opioid therapy is necessary, review by an endocrinologist may be warranted.Changes in management as result of the position statement: Men with pathological hypogonadism should be identified and considered for testosterone therapy, while further research is needed to clarify whether there is a role for testosterone in these other settings.

Re: Effects of Testosterone Treatment in Older Men

Re: Effects of Testosterone Treatment in Older Men

Testosterone gel improved sexual function, but not walk distance or fatigue, in older men with low testosterone

ACP Journal Club17 May 2016Testosterone gel improved sexual function, but not walk distance or fatigue, in older men with low testosteroneOksana Hamidi, DO, Victor M. Montori, MD, MScOksana Hamidi, DOMayo Clinic, Rochester, Minnesota, USA (O.H., V.M.M.)Search for more papers by this author, Victor M. Montori, MD, MScMayo Clinic, Rochester, Minnesota, USA (O.H., V.M.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2016-164-10-056 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationSnyder PJ, Bhasin S, Cunningham GR, et al; Testosterone Trials Investigators. Effects of testosterone treatment in older men. N Engl J Med. 2016;374:611-624. https://pubmed.ncbi.nlm.nih.gov/26886521Clinical Impact RatingsGIM/FP/GP: Endocrinology: Geriatrics: References1 Boloña ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007;82:20-8. [PMID: 17285782] Google Scholar2 Bhasin S, Cunningham GR, Hayes FJ, et al; Task Force Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-59. [PMID: 20525905] Google Scholar Author, Article, and Disclosure InformationAffiliations: Mayo Clinic, Rochester, Minnesota, USA (O.H., V.M.M.)This article was published at Annals.org on 3 May 2016. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 17 May 2016Volume 164, Issue 10Page: JC56KeywordsAgingFatigueHypogonadismPhysical functioningProstate cancerQuality of lifeSafetyStrokeTestosteroneWalking ePublished: 17 May 2016 Issue Published: 17 May 2016 Copyright & PermissionsCopyright © 2016 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...

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Effects of Testosterone Treatment in Older Men

BackgroundSerum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established.MethodsWe assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials — the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants.ResultsTestosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy–Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups.ConclusionsIn symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.)

Testosterone Treatment and Mortality in Men with Low Testosterone Levels

Low testosterone levels in men have been associated with increased mortality. However, the influence of testosterone treatment on mortality in men with low testosterone levels is not known. The objective of the study was to examine the association between testosterone treatment and mortality in men with low testosterone levels. This was an observational study of mortality in testosterone-treated compared with untreated men, assessed with time-varying, adjusted Cox proportional hazards regression models. Effect modification by age, diabetes, and coronary heart disease was tested a priori. The study was conducted with a clinical database that included seven Northwest Veterans Affairs medical centers. Patients included a cohort of 1031 male veterans, aged older than 40 yr, with low total testosterone [≤250 ng/dl (8.7 nmol/liter)] and no history of prostate cancer, assessed between January 2001 and December 2002 and followed up through the end of 2005. Total mortality in testosterone-treated compared with untreated men was measured. Testosterone treatment was initiated in 398 men (39%) during routine clinical care. The mortality in testosterone-treated men was 10.3% compared with 20.7% in untreated men (P<0.0001) with a mortality rate of 3.4 deaths per 100 person-years for testosterone-treated men and 5.7 deaths per 100 person-years in men not treated with testosterone. After multivariable adjustment including age, body mass index, testosterone level, medical morbidity, diabetes, and coronary heart disease, testosterone treatment was associated with decreased risk of death (hazard ratio 0.61; 95% confidence interval 0.42-0.88; P = 0.008). No significant effect modification was found by age, diabetes, or coronary heart disease. In an observational cohort of men with low testosterone levels, testosterone treatment was associated with decreased mortality compared with no testosterone treatment. These results should be interpreted cautiously because residual confounding may still be a source of bias. Large, randomized clinical trials are needed to better characterize the health effects of testosterone treatment in older men with low testosterone levels.

Effects of testosterone supplementation on clinical and rehabilitative outcomes in older men undergoing on-pump CABG

Testosterone levels decrease with age. This decline is steeper during “critical illnesses”. Cardiac surgery is a particular representative model of major clinical condition producing stress responses similar to those observed during severe nonsurgical illness. Cardiac revascularization with extracorporeal circulation is characterized by marked postoperative complications such as insulin resistance, a pro-inflammatory state, acute anemia and renal dysfunction. These phenomena are more evident in older subjects, who are particularly vulnerable in the post-operative state, a condition that has been recently termed as “acute postoperative frailty”. We recently showed that in older men with low ejection fraction undergoing cardiac revascularization with extracorporeal circulation, there is a profound decline in anabolic hormones, including testosterone. After surgery testosterone concentration frequently declines to less than 200ng/dl, a situation suggestive of overt hypogonadism. Since men with low testosterone levels have a high probability of developing mobility limitations, we considered this a rationale for the perioperative use of testosterone treatment in older men undergoing cardiac revasularization surgery. We hypothesized that testosterone supplementation at this time might attenuate the impressive post-surgical catabolic hormonal milieu. The aim of this manuscript is to elucidate an ongoing randomized clinical trial in older men (70+ years old) undergoing elective cardiovascular revascularization with extracorporeal circulation. This randomized clinical trial will evaluate the effects of intramuscular testosterone administration on clinical and functional outcomes in this population. The study will also address potential mechanisms underlying the expected beneficial effects of testosterone supplementation including improvement of insulin sensitivity, markers of inflammatory status and improved hemoglobin levels.

Testosterone Treatment of Older Men—Why Are Controversies Created?

Cunningham and Toma have published an article entitled “Why Is Androgen Replacement in Males Controversial?” (1) in this issue of JCEM. This represents a new look at an old controversy. The article reviews the status of testosterone treatment in older men and serves as an extension to previously published guidelines on hypogonadism by Bhasin et al. (2) and recommendations published by Wang et al. (3) on late-onset hypogonadism. There are many causes for controversy in the practice of medicine, not the least of which is insufficiency of high-grade, evidence-based data. This is likely to occur when a medication was established in clinical use before the modern era of pharmaceutical regulation. This new review describes the insufficiency of evidence-based data to be certain that the benefit-to-risk ratio justifies testosterone treatment in older men, whereas taking the position that androgen replacement therapy in younger and middle-aged men is well established. The authors do acknowledge, as do the above guidelines (2), that relatively few large-scale, double-blind, placebo-controlled, multiple end point studies had been performed on testosterone treatment in men of any age. This position was also taken by the Institute of Medicine (4). Most of the data come from relatively small-size studies and meta-analyses of small- or medium-size databases (5,6,7,8).

Adverse Events Associated with Testosterone Administration

Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied. Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group. A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load. In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981.)

Androgens and the ageing male.

Serum testosterone levels peak in early adulthood in men and fall progressively with age. Since sex hormone binding globulin increases with age, the unbound forms of testosterone (free and bioavailable testosterone) fall more steeply than total testosterone levels. Serum testosterone levels below the normal range for young healthy adult males provide chemical evidence of androgen deficiency independent of the age of the patient. When accompanied by signs or symptoms that are compatible with androgen deficiency, treatment with testosterone should be considered in older men without evidence of prostate or breast cancer. While such therapy for younger hypogonadal men has shown benefit on libido, mood, muscle mass, muscle strength, bone mineral density and haematocrit, similar benefits in older men have not been as adequately assessed. While there is no convincing evidence that testosterone treatment in older men will increase the risk of cardiovascular or prostate cancer, long-term, well-controlled studies are lacking and needed. Treatment options for older men include injectable, transdermal and transbuccal testosterone preparations.