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Background: The effect of gender-affirming testosterone therapy (TT) on breast cancer risk is unclear. This study investigated the association between TT and breast tissue composition and breast tissue density in trans masculine individuals (TMIs)., Methods: Of the 444 TMIs who underwent chest-contouring surgeries between 2013 and 2019, breast tissue composition was assessed in 425 TMIs by the pathologists (categories of lobular atrophy and stromal composition) and using our automated deep-learning algorithm (% epithelium, % fibrous stroma, and % fat). Forty-two out of 444 TMIs had mammography prior to surgery and their breast tissue density was read by a radiologist. Mammography digital files, available for 25/42 TMIs, were analyzed using the LIBRA software to obtain percent density, absolute dense area, and absolute non-dense area. Linear regression was used to describe the associations between duration of TT use and breast tissue composition or breast tissue density measures, while adjusting for potential confounders. Analyses stratified by body mass index were also conducted., Results: Longer duration of TT use was associated with increasing degrees of lobular atrophy (p < 0.001) but not fibrous content (p = 0.82). Every 6 months of TT was associated with decreasing amounts of epithelium (exp(β) = 0.97, 95% CI 0.95,0.98, adj p = 0.005) and fibrous stroma (exp(β) = 0.99, 95% CI 0.98,1.00, adj p = 0.05), but not fat (exp(β) = 1.01, 95%CI 0.98,1.05, adj p = 0.39). The effect of TT on breast epithelium was attenuated in overweight/obese TMIs (exp(β) = 0.98, 95% CI 0.95,1.01, adj p = 0.14). When comparing TT users versus non-users, TT users had 28% less epithelium (exp(β) = 0.72, 95% CI 0.58,0.90, adj p = 0.003). There was no association between TT and radiologist's breast density assessment (p = 0.58) or LIBRA measurements (p > 0.05)., Conclusions: TT decreases breast epithelium, but this effect is attenuated in overweight/obese TMIs. TT has the potential to affect the breast cancer risk of TMIs. Further studies are warranted to elucidate the effect of TT on breast density and breast cancer risk., (© 2024. The Author(s).)

Male hypogonadism is defined as an abnormally low serum testosterone concentration or sperm count. As men age, often in the context of obesity and other comorbid conditions, serum testosterone levels may decrease. Normalizing serum testosterone levels in male adults with hypogonadism may improve symptoms related to androgen deficiency, but controversies exist regarding the long-term benefits and risks of hormone supplementation in this setting. In 2020, the American College of Physicians published a clinical guideline for the use of testosterone supplementation in adult men based on a systematic review of available evidence. Among their recommendations were that clinicians discuss whether to initiate testosterone treatment in men with age-related low testosterone with sexual dysfunction who want to improve sexual function and not initiate testosterone treatment in men with age-related low testosterone to improve energy, vitality, physical function, or cognition. Here, two clinicians with expertise in this area, one a generalist and the other an endocrinologist, debate the management of a patient with sexual symptoms and a low serum testosterone level. They discuss the diagnosis of male hypogonadism, the indications for testosterone therapy, its potential benefits and risks, how it should be monitored, and how long it should be continued.

[Figure: see text].

Objective: The decrease in testosterone levels that occurs with aging has become an important clinical issue both due to the growth of the geriatric population and patient interest in testosterone therapy. The decision to assess for testosterone deficiency and the ability to determine whether the benefits exceed the risks require a comprehensive evaluation of the aging patient. This article is part of a series of papers focused on the endocrinology of aging. This review addresses common issues needed for clinical decision making, including how to interpret test results, differential diagnosis, potential impact of testosterone treatment on insulin resistance and cardiovascular disease, and options for therapy., Methods: Papers reviewed were identified through literature searches conducted on PubMed., Results: Assessment of testosterone levels in the geriatric male requires an understanding of the limitations of the assay that is used, the symptoms associated with low testosterone, the impact of comorbid conditions on levels, and risks of therapy. Successful treatment requires setting realistic expectations of the benefits of replacement therapy., Conclusion: While the prevalence of low testosterone concentrations is increased with aging, the common comorbidities such as obesity and diabetes may contribute to changes in testosterone levels. Clinical trial evidence shows modest benefit for treatment of low testosterone in the presence of symptoms. Assessment of the geriatric male should include evaluation of their testosterone level in the context of their functional status and comorbidities., Abbreviations: CDC = Centers for Disease Control and Prevention; CI = confidence interval; CVD = cardiovascular disease; DXA = dual-energy X-ray absorptiometry; EMAS = European Male Aging Study; FDA = U.S. Food and Drug Administration; FHS = Framingham Heart Study; HDL = high-density lipoprotein; HOMA-IR = homeostasis model assessment of insulin resistance; LH = luteinizing hormone; OR = odds ratio; PSA = prostate-specific antigen; SHBG = sex hormone-binding globulin; T2DM = type 2 diabetes mellitus; vBMD = volumetric bone mineral density.

Purpose: The purpose of this study was to prospectively examine changes in gender-related voice domain of pitch measured by fundamental frequency, function-related domains of vocal quality, range, and habitual pitch level and the self-perceptions of transmasculine people during their first year of testosterone treatment., Method: Seven trans men received 2 voice assessments at baseline and 1 assessment at 3, 6, 9, and 12 months after starting treatment., Results: Vocal quality measures varied between and within participants but were generally within normal limits throughout the year. Mean fundamental frequency (MF0) during reading decreased, although to variable extents and rates. Phonation frequency range shifted down the scale, although it increased in some participants and decreased in others. Considering MF0 and phonation frequency range together in a measure of habitual pitch level revealed that the majority of participants spoke using an MF0 that was low within their range compared with cisgender norms. Although the trans men generally self-reported voice masculinization, it was not correlated with MF0, frequency range, or habitual pitch level at any time point or with MF0 note change from baseline to 1 year of testosterone treatment, but correlations should be interpreted with caution due to the heterogeneous responses of the 7 participants., Conclusion: In trans men, consideration of voice deepening in the context of objective and subjective measures of voice can reveal unique profiles and inform patient care.

Testosterone therapy is a cornerstone of medical treatment for transgender men who choose to undergo it. The goal of testosterone therapy is usually to achieve serum testosterone concentrations in the male reference range. Testosterone has several desired effects as well as undesired and unknown effects. The desired effects include increased facial and body hair, increased lean mass and strength, decreased fat mass, deepening of the voice, increased sexual desire, cessation of menstruation, clitoral enlargement, and reductions in gender dysphoria, perceived stress, anxiety, and depression. Achievement of these goals comes with potential undesired effects and risks including acne, alopecia, reduced HDL cholesterol, increased triglycerides, and a possible increase in systolic blood pressure. An additional benefit of testosterone therapy (with or without mastectomy) is a reduced risk of breast cancer. Most of the effects of testosterone start to develop within several months of starting therapy, although facial hair and alopecia continue to develop after 1 year. A major limitation in the study of testosterone therapy for transgender men is a paucity of high-quality data due to a shortage of randomised controlled trials (partly because of ethical issues), few prospective and long-term studies, the use of suboptimum control groups, loss to follow-up, and difficulties in recruitment of representative samples of transgender populations., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

There is sparse prospective data on the effects of testosterone therapy on the voices of transgender men (also referred to as trans men or female-to-male transsexuals). Our aim was to investigate the timing and degree of voice deepening over 12 months among an ethnically diverse sample of transgender men. This was a prospective 12-month study at an academic outpatient endocrinology clinic and speech and voice center. The participants were seven transgender men naïve to testosterone therapy. All patients received two voice assessments at baseline and one assessment at 3, 6, 9, and 12 months while on intramuscular testosterone esters. Serum testosterone and estradiol concentrations were measured at baseline and every 3 months. All seven transgender men reached a cisgender male mean fundamental frequency (MF0) within 6 months of testosterone therapy and four continued to experience a decrease after 6 months. The mean decrease in MF0 after 12 months of testosterone therapy was 6.4 semitones (49 Hz). Several patterns emerged regarding the extent and timing. For example, some participants showed no decrease in MF0 within the first 3 months of testosterone therapy, whereas others showed their greatest decrease in MF0. We concluded that transgender men who start testosterone therapy display different patterns of voice lowering. Clinicians should counsel transgender men that they may or may not experience voice lowering within the first 3 months of testosterone therapy and that the majority of voice deepening will occur within 6-9 months., (© 2016 American Society of Andrology and European Academy of Andrology.)

Introduction: Men referred for borderline testosterone levels represent an increasingly common clinical scenario, yet there is little literature on this population., Aim: We hypothesized that men referred for borderline testosterone levels would have higher rates of depression and depressive symptoms than the general population., Methods: Subjects included 200 adult men (mean age of 48 years old) referred for borderline total testosterone levels between 200 and 350 ng/dL (6.9-12 nmol/L). Collected data included demographic information, medical histories, medication use, signs and symptoms of hypogonadism, and assessments of depressive symptoms and/or a known diagnosis of depression or use of an antidepressant., Main Outcome Measures: The main outcome measure was a combination of known depression, current use of an antidepressant, and/or depressive symptoms according to the Patient Health Questionnaire 9 (PHQ-9) with scores ≥10 considered positive., Results: Depression and/or depressive symptoms were present in 56% of the subjects. This rate was significantly higher than rates of 6-23% (PHQ-9 scores ≥10) seen in general populations. Antidepressant use was 25%. The population was notable for high rates of overweight/obesity and physical inactivity. Common symptoms were erectile dysfunction, decreased libido, fewer AM erections, low energy, and sleep disturbances., Conclusions: While sexual and nonspecific symptoms (i.e., fatigue) likely prompted measurements of testosterone in this selected population, clinicians should recognize the high rates of depression and depressive symptoms in men referred for borderline testosterone levels. Clinicians should consider screening for depression/depressive symptoms and overweight and unhealthy lifestyle risk factors in men referred for tertiary care for potential hypogonadism., (© 2015 International Society for Sexual Medicine.)

Purpose of Review: To examine bone health in relation to testosterone and male hypogonadism., Recent Findings: An emerging area of research pertains to the newly described bone-testis axis. In particular, the peptide hormone osteocalcin, which is made by bone and fat, appears to play a role in testosterone production. Inconsistent weak associations have been noted between vitamin D deficiency or insufficiency and lower testosterone levels. Although a high prevalence of hypogonadism is associated with opioid use, HIV and transfusion-dependent thalassemia, the risk of fracture in these populations is unclear. In fact, one study found that the modest increase in fractures among opioid users was attributed to central nervous system adverse effects of the medications as opposed to chronic hypogonadism. In terms of therapy, many small studies have found that testosterone replacement therapy increases bone mineral density in hypogonadal men, including men with hypopituitarism., Summary: Further research is needed on the cross-talk that occurs in the bone-testis axis. When it comes to managing men with hypogonadism, the benefit of testosterone replacement therapy on prevention of incident fractures is uncertain. Large, long-term randomized controlled trials are needed with fracture as the primary outcome.

Purpose of Review: To examine the role of testosterone in skeletal health in men., Recent Findings: Evidence from recent studies shows that the contributing role of testosterone to osteoporosis is modest and likely trumped by other factors such as estradiol levels. A few studies have documented an association between low testosterone levels and lower bone mineral density (BMD), increased prevalence of osteoporosis of the hip and low bone mass-related fractures. Other studies, however, have found that testosterone levels are not independent predictors of bone resorption or formation markers, BMD at the hip or incident fractures. Curiously, hypogonadism does not account for the increased osteoporosis seen in men with Klinefelter Syndrome. Regardless of hypogonadism status, two recent clinical trials have found fewer new morphometric vertebral fractures in men treated with zoledronic acid and increased BMD in men treated with denosumab. Denosumab was also shown to modestly increase bone-metastasis-free survival in men with castration-resistant prostate cancer., Summary: Although male hypogonadism is associated with osteoporosis, estradiol is likely to be the more important hormone for bone health. Although a few large randomized controlled trials have been conducted in men with low bone density (a subset of whom have hypogonadism), more trials are needed, particularly with fractures as the main outcome.

Introduction: Exogenous androgens plus progestins can be used to suppress spermatogenesis, resulting in effective male hormonal contraception; however, induction of azoospermia can require 3-6 months, and these methods require injectable or implantable androgens. We hypothesized that testosterone (T) transdermal gel (T gel) could be combined with a depot formulation of the progestin, depomedroxyprogesterone acetate (DMPA), with or without the potent GnRH antagonist, acyline, to suppress spermatogenesis conveniently, rapidly, and reversibly., Objectives: The objectives of the study were: 1) to determine the rate of severe oligospermia (< or = 1 million sperm/ml) using T gel+DMPA; and 2) to determine whether the addition of acyline to T gel+DMPA during the first 12 wk of the regimen would accelerate and improve suppression of spermatogenesis., Methods: Forty-four healthy men, ages 18-55 yr, were randomized to T gel (100 mg daily)+DMPA (300 mg/3 months) or acyline (300 microg/kg.2 wk x 12 wk)+T gel+DMPA. Thirty-eight men completed the 24-wk treatment protocol., Results: All men had dramatic suppression of spermatogenesis; 90% of the subjects became severely oligospermic, a rate comparable to implantable and injectable T+progestin combinations. The addition of acyline did not significantly accelerate spermatogenic suppression or improve rates of severe oligospermia. There were no serious adverse events, and there were minimal changes in weight, serum lipids, and prostate-specific antigen., Conclusions: The combination of T gel+DMPA is a promising new regimen in male contraception. The addition of the GnRH antagonist acyline, as part of an induction phase in a male contraception regimen, has limited clinical utility. Additional studies using T gel for male contraception are warranted.