Testosterone supplementation increases red blood cell susceptibility to oxidative stress, decreases membrane deformability, and decreases survival after cold storage and transfusion.

BACKGROUND: Blood collection from donors on testosterone therapy (TT) is restricted to red blood cell (RBC) concentrates to avoid patient exposure to supraphysiological testosterone (T). The objective of this study was to identify TT-related changes in RBC characteristics relevant to transfusion effectiveness in patients. STUDY DESIGN: This was a two-part study with cohorts of patients and blood donors on TT. In part 1, we conducted longitudinal evaluation of RBCs collected before and at three time points after initiation of T. RBC assays included storage and oxidative hemolysis, membrane deformability (elongation index), and oximetry. In part 2, we evaluated the fate of transfused RBCs from TT donors in immunodeficient mice and by retrospective analyses of NIH's vein-to-vein databases. RESULTS: TT increased oxidative hemolysis (1.45-fold change) and decreased RBC membrane deformability. Plasma free testosterone was positively correlated with oxidative hemolysis (r = .552) and negatively correlated with the elongation index (r = -.472). Stored and gamma-irradiated RBCs from TT donors had lower posttransfusion recovery in mice compared to controls (41.6 ± 12 vs. 55.3 ± 20.5%). Recipients of RBCs from male donors taking T had 25% lower hemoglobin increments compared to recipients of RBCs from non-TT male donors, and had increased incidence (OR, 1.80) of requiring additional RBC transfusions within 48 h of the index transfusion event. CONCLUSIONS: TT is associated with altered RBC characteristics and transfusion effectiveness. These results suggest that clinical utilization of TT RBCs may be less effective in recipients who benefit from longer RBC survival, such as chronically transfused patients.

Associations of Serum Testosterone and Sex Hormone-Binding Globulin With Incident Cardiovascular Events in Middle-Aged to Older Men.

BACKGROUND: The influence of testosterone on risk for cardiovascular events in men is uncertain. Previous observational studies of sex hormones and incident cardiovascular disease in men have reported inconsistent findings, limited by cohort sizes and different selection criteria. OBJECTIVE: To analyze associations of serum total testosterone and sex hormone-binding globulin (SHBG) with incident cardiovascular events in men. DESIGN: Cohort study. SETTING: UK Biobank prospective cohort. PARTICIPANTS: Community-dwelling men aged 40 to 69 years. MEASUREMENTS: Testosterone and SHBG were assayed, and free testosterone was calculated. Cox proportional hazards regression was done, with outcomes of incident myocardial infarction (MI), hemorrhagic stroke (HS), ischemic stroke (IS), heart failure (HF), and major adverse cardiovascular events (MACE), adjusted for sociodemographic, lifestyle, and medical factors. RESULTS: Of 210 700 men followed for 9 years, 8790 (4.2%) had an incident cardiovascular event. After adjustment for key variables, lower total testosterone concentrations (quintile 1 vs. quintile 5) were not associated with incident MI (fully adjusted hazard ratio [HR], 0.89 [95% CI, 0.80 to 1.00]), HS (HR, 0.94 [CI, 0.70 to 1.26]), IS (HR, 0.95 [CI, 0.82 to 1.10]), HF (HR, 1.15 [CI, 0.91 to 1.45]), or MACE (HR, 0.92 [CI, 0.84 to 1.00]). Men with lower calculated free testosterone values had a lower incidence of MACE (HR, 0.90 [CI, 0.84 to 0.97]). Lower SHBG concentrations were associated with higher incidence of MI (HR, 1.23 [CI, 1.09 to 1.38]) and lower incidence of IS (HR, 0.79 [CI, 0.67 to 0.94]) and HF (HR, 0.69 [CI, 0.54 to 0.89]), but not with HS (HR, 0.81 [CI, 0.57 to 1.14]) or MACE (HR, 1.01 [CI, 0.92 to 1.11]). LIMITATION: Observational study; single baseline measurement of testosterone and SHBG. CONCLUSION: Men with lower total testosterone concentrations were not at increased risk for MI, stroke, HF, or MACE. Calculated free testosterone may be associated with risk for MACE. Men with lower SHBG concentrations have higher risk for MI but lower risk for IS and HF, with causality to be determined. PRIMARY FUNDING SOURCE: Western Australian Health Translation Network, Medical Research Future Fund, and Lawley Pharmaceuticals.

Relationships between endogenous and exogenous testosterone and cardiovascular disease in men.

In this narrative review, we discuss the evidence about the controversy about the cardiovascular effects of endogenous and exogenous testosterone in men. Prospective cohort studies with follow-up of ~5-15 years generally indicate no association or a possible inverse relationship between serum endogenous testosterone concentrations and composite major cardiovascular events, cardiovascular deaths and overall mortality. Pharmacoepidemiological studies of large databases generally show no association between testosterone therapy and incident major cardiovascular events, and some pharmacoepidemiological studies demonstrate an association with decreased overall mortality. Randomized, placebo-controlled trials indicate that there is no increased incidence of overall major cardiovascular events with 1-3 years of testosterone therapy. These placebo-controlled trials have major limitations including small numbers of participants, short duration of testosterone therapy and follow-up, and lack of systematic adjudication of cardiovascular events. Overall, the evidence indicates that endogenous testosterone concentrations and testosterone therapy at physiological dosages confer no or minimal effects on the incidence of cardiovascular outcomes. There is insufficient evidence to make conclusions about testosterone therapy for patients at high risk of cardiovascular events (e.g., men with recent myocardial infarctions or stroke and men with recurrent idiopathic deep venous thromboses). In general, clinicians should avoid prescribing supraphysiological testosterone therapy to hypogonadal men or men with slightly low to low-normal serum testosterone concentrations and no identified disorder of the hypothalamus-pituitary-testicular axis because of the uncertain cardiovascular risks and the lack of proven health benefits. For most men with bona fide hypogonadism, benefits of testosterone therapy exceed the potential risk of adverse cardiovascular effects.

Aging and androgens: Physiology and clinical implications.

In men > ~35 years, aging is associated with perturbations in the hypothalamus-pituitary-testicular axis and declining serum testosterone concentrations. The major changes are decreased gonadotropin-releasing hormone (GnRH) outflow and decreased Leydig cell responsivity to stimulation by luteinizing hormone (LH). These physiologic changes increase the prevalence of biochemical secondary hypogonadism-a low serum testosterone concentration without an elevated serum LH concentration. Obesity, medications such as opioids or corticosteroids, and systemic disease further reduce GnRH and LH secretion and might result in biochemical or clinical secondary hypogonadism. Biochemical secondary hypogonadism related to aging often remits with weight reduction and avoidance or treatment of other factors that suppress GnRH and LH secretion. Starting at age ~65-70, progressive Leydig cell dysfunction increases the prevalence of biochemical primary hypogonadism-a low serum testosterone concentration with an elevated serum LH concentration. Unlike biochemical secondary hypogonadism in older men, biochemical primary hypogonadism is generally irreversible. The evaluation of low serum testosterone concentrations in older men requires a careful assessment for symptoms, signs and causes of male hypogonadism. In older men with a body mass index (BMI) ≥ 30, biochemical secondary hypogonadism and without an identifiable cause of hypothalamus or pituitary pathology, weight reduction and improvement of overall health might reverse biochemical hypogonadism. For older men with biochemical primary hypogonadism, testosterone replacement therapy might be beneficial. Because aging is associated with decreased metabolism of testosterone and increased tissue-specific androgen sensitivity, lower dosages of testosterone replacement therapy are often effective and safer in older men.

Toxic masculinity in red blood cell units? Testosterone therapy in blood donors revisited.

BACKGROUND: FDA guidelines limit the use of blood from donors taking testosterone replacement therapy (TRT) to red blood cell (RBC) concentrates, whereas plasma and platelets are discarded. The purpose of this study is to bring awareness to above-average free testosterone concentrations in RBC units from TRT donors. STUDY DESIGN: We quantified the concentrations of free (bioavailable; pg/ml) and total (protein bound and free; ng/dl) testosterone in plasma (frozen within 24 h) and supernatants from 42-day stored leukocyte-reduced RBC units from 17 TRT male donors and 17 matched controls (no TRT). Total testosterone concentrations were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Free testosterone concentrations were quantified in the same samples using equilibrium dialysis/LC-MS/MS. RESULTS: Plasma free and total testosterone concentrations in TRT donors were 2.9 and 1.8 times higher than that of controls. Total testosterone concentrations in RBC supernatants were about 30% of that of plasma. In contrast, free testosterone concentrations in RBC supernatants were 80%-100% of that of plasma and were significantly (p = .005) higher in TRT compared with controls (252.3 ± 245.3 vs. 103.4 ± 88.2 pg/ml). Supraphysiological free testosterone concentrations (>244 pg/ml) in RBC supernatants were observed in five TRT donors and two control donors. CONCLUSIONS: RBC units from TRT donors may contain supraphysiological concentrations of free testosterone. This may be resolved by avoiding blood collections soon after testosterone dosing and by enhanced screening of TRT donors. These data establish a rationale for new studies and reexamination of the current guidelines concerning the utilization of blood components from TRT donors.

Clinical practice patterns in the assessment and management of low testosterone in men: an international survey of endocrinologists.

OBJECTIVE: To document current practices in the approach to low testosterone in older men. Given that recommendations are based on low-level evidence, we hypothesized that there would be a wide variability in clinical practice patterns. DESIGN: Members of all major endocrine and andrological societies were invited to participate in a Web-based survey of the diagnostic work-up and management of a hypothetical index case of a 61-year old overweight man presenting with symptoms suggestive of androgen deficiency, without evidence of hypothalamic-pituitary-gonadal (HPT) axis disease. RESULTS: Nine hundred and forty-three respondents (91·2% adult endocrinologists) from Northern America (63·7%), Europe (12·7%), Oceania (8·2%), Latin America and Caribbean (7·6%), and the Middle East, Asia, or Africa (7·8%) completed the survey. Response rates among participating societies ranged from 4·1-20·0%. There was a wide variability in clinical practice patterns, especially regarding biochemical diagnosis of androgen deficiency, exclusion of HPT axis pathology, and monitoring for prostate cancer. In a man with suggestive symptoms, 42·4% of participants would offer testosterone treatment below a serum total testosterone of 10·4 nmol/l (300 ng/dl). A total of 46·0% of participants were, over the last five years, 'less inclined' to prescribe testosterone to men with nonspecific symptoms and borderline testosterone levels, compared to 'no change' (29·3%) or 'more inclined' (24·7%), P < 0·001. CONCLUSIONS: This large-scale international survey shows a wide variability in the management of lowered testosterone in older men, with deviations from current clinical practice guidelines, and a temporal trend towards increasing reluctance to prescribe testosterone to men without classical hypogonadism. These findings highlight the need for better evidence to guide clinicians regarding testosterone therapy.

The association of obesity with sex hormone-binding globulin is stronger than the association with ageing--implications for the interpretation of total testosterone measurements.

OBJECTIVE: Total testosterone concentrations are influenced by sex hormone-binding globulin (SHBG) concentrations, which are decreased by obesity and increased with ageing. Therefore, we sought to understand and compare the associations of ageing and obesity with SHBG. DESIGN: We performed a retrospective, cross-sectional analysis of the associations of obesity and age on SHBG and testosterone measurements in men being evaluated for hypogonadism. PATIENTS, MEASUREMENTS AND ANALYSIS: A total of 3671 men who underwent laboratory testing for testosterone deficiency from the Veterans Administration Puget Sound Health Care System from 1997 through 2007 was included. Univariate and multivariate linear regression modelling of the associations between age and body mass index (BMI) and SHBG was performed. RESULTS: Obesity was associated with a significantly lower SHBG [ß = -1·26 (95% CI -1·14, -1·38) nmol/l] per unit increase in BMI. In contrast, ageing was associated with a significantly increased SHBG [ß = 0·46 (95% CI 0·39, 0·53) nmol/l per year] (P < 0·001 for both effects). The association of obesity with lower SHBG was two to three times larger than the association of ageing with increased SHBG in both univariate and multivariate modelling. On average, obese men (BMI >30 kg/m(2)) had significantly lower SHBG and total testosterone concentrations than nonobese men [(mean ± SD) SHBG: 36 ± 22 vs 50 ± 27 nmol/l and total testosterone: 10·5 ± 5·4 nmol/l vs 14·1 ± 7·4 nmol/l; (P < 0·001 for both comparisons)], but calculated free testosterone concentrations did not differ between obese and nonobese men. CONCLUSIONS: We found that the association between obesity and lowered SHBG is greater than the association of ageing with increased SHBG. These competing effects may impact total testosterone measurements for the diagnosis of low testosterone, particularly in obese men.

Testosterone therapy in older men: clinical implications of recent landmark trials.

Testosterone therapy for men with hypogonadism due to identifiable hypothalamic-pituitary-testicular (HPT) pathology is uncontroversial. However, the risks and benefits of testosterone for men with clinical features of hypogonadism in the absence of identifiable HPT axis pathology have been uncertain. Recent landmark placebo-controlled trials assessed the benefits and risks of testosterone therapy (≤ 3 years) for middle aged and older men with symptoms and possible signs of hypogonadism or end-organ androgen deficiency, low or low-normal serum testosterone concentrations, but no HPT pathology: testosterone therapy 1) had modest-but clinically significant-benefits on average self-reported energy and mood, sexual function and satisfaction; 2) in conjunction with a lifestyle program, reversed or reduced incident diabetes mellitus type 2 (T2D) in men at high risk of or newly diagnosed with T2D; 3) modestly improved objectively assessed muscle strength and timed walking distance; 4) increased bone density and strength, but did not reduce falls or typical osteoporotic fractures and surprisingly increased the risk of fractures typically attributable to trauma; and 5) did not significantly increase the risk of myocardial infarction, stroke or prostate cancer. These landmark trials help to inform clinical decision-making about testosterone therapy for men.

Approach to the Patient: The Evaluation and Management of Men ≥50 Years With Low Serum Testosterone Concentration.

Although testosterone replacement in men with classic hypogonadism due to an identified pathology of the hypothalamic-pituitary-testicular axis is uncontroversial, the role of testosterone treatment for men with age-related declines in circulating testosterone is unclear. This is due to the lack of large, long-term testosterone therapy trials assessing definitive clinical endpoints. However, men ≥50 years of age, particularly those who have a body mass index >25 kg/m2 and multiple comorbidities, commonly present with clinical features of androgen deficiency and low serum testosterone concentrations. Clinicians are faced with the question whether to initiate testosterone therapy, a difficult dilemma that entails a benefit-risk analysis with limited evidence from clinical trials. Using a case scenario, we present a practical approach to the clinical assessment and management of such men.

Design of an international male contraceptive efficacy trial using a self-administered daily transdermal gel containing testosterone and segesterone acetate (Nestorone).

Injectable male hormonal contraceptives are effective for preventing pregnancy in clinical trials; however, users may prefer to avoid medical appointments and injections. A self-administered transdermal contraceptive gel may be more acceptable for long-term contraception. Transdermal testosterone gels are widely used to treat hypogonadism and transdermal administration may have utility for male contraception; however, no efficacy data from transdermal male hormonal contraceptive gel are available. We designed and are currently conducting an international, multicenter, open-label study of self-administration of a daily combined testosterone and segesterone acetate (Nestorone) gel for male contraception. The transdermal approach to male contraception raises novel considerations regarding adherence with the daily gel, as well as concern about the potential transfer of the gel and the contraceptive hormones to the female partner. Enrolled couples are in committed relationships. Male partners have baseline normal spermatogenesis and are in good health; female partners are regularly menstruating and at risk for unintended pregnancy. The study's primary outcome is the rate of pregnancy in couples during the study's 52-week efficacy phase. Secondary endpoints include the proportion of male participants suppressing sperm production and entering the efficacy phase, side effects, hormone concentrations in male participants and their female partners, sexual function, and regimen acceptability. Enrollment concluded on November 1, 2022, with 462 couples and enrollment is now closed. This report outlines the strategy and design of the first study to examine the contraceptive efficacy of a self-administered male hormonal contraceptive gel. The results will be presented in future reports. IMPLICATIONS: The development of a safe, effective, reversible male contraceptive would improve contraceptive options and may decrease rates of unintended pregnancy. This manuscript outlines the study design and analysis plan for an ongoing large international trial of a novel transdermal hormone gel for male contraception. Successful completion of this and future studies of this formulation may lead to the approval of a male contraceptive.

Performance of total testosterone measurement to predict free testosterone for the biochemical evaluation of male hypogonadism.

PURPOSE: Guidelines recommend serum total testosterone measurement as the initial test to evaluate male hypogonadism, reserving free testosterone assessment for men with suspected sex hormone-binding globulin abnormalities or total testosterone near the lower limit of normal. We determined the performance of total testosterone measurement as a test to identify men with normal vs low free testosterone. MATERIALS AND METHODS: We examined the electronic medical records of all 3,672 men evaluated for hypogonadism by a serum testosterone panel, including total testosterone, sex hormone-binding globulin, albumin and calculated free testosterone, from January 1, 1997 through December 31, 2007 in a network that serves veterans in Washington. RESULTS: The sensitivity and specificity of low total testosterone (less than 280 ng/dl) to rule out and predict low calculated free testosterone was 91.0% and 73.7%, respectively. At thresholds of less than 350 and less than 400 ng/dl the sensitivity of total testosterone for low calculated free testosterone increased to 96.8% and 98.2%, and at thresholds of less than 150 and less than 200 ng/dl specificity increased to 98.9% and 92.6%, respectively. CONCLUSIONS: Total testosterone between 280 and 350 ng/dl is not sensitive enough to reliably exclude hypogonadism. Total testosterone must exceed 350 to 400 ng/dl to reliably predict normal free testosterone. Except when levels are less than 150 ng/dl total testosterone measurement has low specificity for the biochemical diagnosis of hypogonadism.

Epidemiology of Male Hypogonadism.

The epidemiology of male hypogonadism has been understudied. Of the known causes of endogenous androgen deficiency, only Klinefelter syndrome is common with a likely population prevalence of greater than 5:10,000 men (possibly as high as 10-25:10,000). Mild traumatic injury might also be a common cause of androgen deficiency (prevalence 5-10:10,000 men), but large, long-term studies must be completed to confirm this prevalence estimation that might be too high. The classic causes of male androgen deficiency-hyperprolactinemia, pituitary macroadenoma, endogenous Cushing syndrome, and iron overload syndrome-are rare (prevalence < 10,000 men).

Androgenic Steroids Use and Abuse: Past, Present, and Future.

Androgenic steroids have been abused by elite athletes for decades. Their performance-enhancing properties for sports that involve strength and power have been confirmed, and this class has been banned from most elite athletic competitions since the mid-1970s. There is a risk of a withdrawal syndrome that includes severe depression, and there seems to be an increased risk of cardiovascular disease associated with chronic abuse. In contrast to high-dosage androgen abuse, androgen therapy at near-physiological dosages is generally safe and effective for male hypogonadism and potential use in sarcopenia and male hormonal contraception.

Acceptability of the oral hormonal male contraceptive prototype, 11ß-methyl-19-nortestosterone dodecylcarbonate (11ß-MNTDC), in a 28-day placebo-controlled trial.

OBJECTIVE: To determine men's satisfaction with and the potential acceptability of 11ß-methyl-19-nortestosterone dodecylcarbonate (11ß-MNTDC) when used for 28 days as an experimental, once-daily, oral hormonal male contraceptive (HMC). STUDY DESIGN: We surveyed participants from a double-blind, randomized, placebo-controlled, phase 1 clinical trial, examining their experience with and willingness to use daily oral 11ß-MNTDC for male contraception. RESULTS: Of 42 trial participants, 40 (30 11ß-MNTDC, 10 placebo) completed baseline and end-of-treatment surveys. Based on a 28-day experience, few cited any baseline concerns about safety and drug adherence. Following treatment, nearly three-quarters (72.5%) of participants reported satisfaction with the study drug and nearly all (92.5%) would recommend the method to others. More than half of participants would be willing to pay for the study drug (62.5%) and indicated that the method exceeded initial expectations (53.9%). Nearly 90% reported that taking the pill was easy to remember and did not interfere with their daily routines. Approximately one-third of participants reported bothersome side effects (37% 11ß-MNTDC vs. 20% placebo, p = 0.45). Given the option, 42% of participants would prefer a daily HMC pill over injectable regimens or a daily topical gel. CONCLUSION: A majority of participants in this short-term trial of daily oral 11ß-MNTDC reported satisfaction with the regimen, would recommend it to others, and would pay to use the drug as HMC despite some bothersome side effects. IMPLICATIONS: Oral 11ß-MNTDC would be an acceptable and preferable method among men desiring reversible hormonal male contraception (HMC). These data support further trials of novel oral HMCs such as 11ß-MNTDC.

Serum Testosterone is Inversely and Sex Hormone-binding Globulin is Directly Associated with All-cause Mortality in Men.

CONTEXT: Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase. OBJECTIVE: To analyze 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 PARTICIPANTS: The UK Biobank prospective cohort study of community-dwelling men aged 40-69 years old, followed for 11 years. MAIN OUTCOME MEASURES: All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions, and other covariates. Models for testosterone included SHBG and vice versa. RESULTS: In a complete case analysis of 149 436 men with 10 053 deaths (1925 CVD and 4927 cancer-related), men with lower testosterone had a higher mortality rate from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 1.06-1.22, overall trend P < 0.001), and cancer (HR = 1.20, CI = 1.09-1.33, P < 0.001), with no association for CVD deaths. Similar results were seen for cFT. Men with lower SHBG had a lower mortality rate from any cause (Q1 vs Q5, HR = 0.68, CI = 0.63-0.73, P < 0.001), CVD (HR = 0.70, CI = 0.59-0.83, P < 0.001), and cancer (HR = 0.80, CI = 0.72-0.89, P < 0.001). A multiply imputed dataset (N = 208 425, 15 914 deaths, 3128 CVD-related and 7468 cancer-related) and analysis excluding deaths within the first 2 years (9261, 1734, and 4534 events) yielded similar results. CONCLUSIONS: Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related, and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials.

Acceptability of oral dimethandrolone undecanoate in a 28-day placebo-controlled trial of a hormonal male contraceptive prototype.

OBJECTIVE: To determine men's satisfaction with and acceptability of a once-daily, oral regimen of dimethandrolone undecanoate (DMAU) versus placebo when used for 28 days. STUDY DESIGN: After a Phase I double-blind, randomized, placebo-controlled, dose-escalating trial of oral DMAU for 28-days, 57 healthy male volunteers completed a survey assessing their experience and satisfaction with the regimen. In the trial, participants were randomized to receive up to 4 DMAU capsules daily versus placebo and instructed to ingest them within 30 min of consuming a high fat meal. Pharmacokinetic and pharmacodynamic profiles were performed, followed by a 6-week recovery phase. Participants were counseled that they could not rely on the drug for contraception. RESULTS: Fifty-seven participants were offered acceptability surveys (39 DMAU, 18 placebo). Most respondents, 80% (45/56), reported satisfaction with the method; 77% (44/57) would recommend it. 54% (31/57), reported that, if available, they would use the method as their primary contraceptive. More respondents reported satisfaction with active DMAU than placebo (87% vs. 67%; p = 0.05). Most respondents, 91% (52/57), reported no difficulty with having to take up to 4 pills within 30 min of ingesting a high-fat meal. CONCLUSION: Most participants reported that the study method, daily oral DMAU or placebo, was satisfactory and acceptable. Having to take the drug after a high-fat meal did not detract from acceptability. IMPLICATIONS: Most participants in a 4-week trial of daily DMAU capsules would recommend and use the method. High satisfaction among DMAU and placebo groups affirms acceptability of a daily male contraceptive pill, warranting further study of oral DMAU.