Effect of testosterone therapy on breast tissue composition and mammographic breast density in trans masculine individuals.

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(ß) = 0.97, 95% CI 0.95,0.98, adj p = 0.005) and fibrous stroma (exp(ß) = 0.99, 95% CI 0.98,1.00, adj p = 0.05), but not fat (exp(ß) = 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(ß) = 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(ß) = 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.

The Use of Injectable Estradiol in Transgender and Gender Diverse Adults: A Scoping Review of Dose and Serum Estradiol Levels.

OBJECTIVE: Feminizing gender-affirming hormone therapy is the mainstay of treatment for many transgender and gender diverse people. Injectable estradiol preparations are recommended by the World Professional Association for Transgender Health Standards of Care 8 and the Endocrine Society guidelines. Many patients prefer this route of administration, but few studies have rigorously assessed optimal dosing or route. METHODS: We performed a scoping review of the available data on estradiol levels achieved with various dosages of estradiol injections in transgender and gender diverse adults on feminizing gender-affirming hormone therapy. We also report on testosterone suppression, route (ie, subcutaneous vs intramuscular), and type of injectable estradiol ester as well as timing of blood draw relative to the most recent dose, where available. RESULTS: The data we reviewed suggest that the current guidelines, which recommend starting doses 2 to 10 mg weekly or 5 to 30 mg every 2 weeks of estradiol cypionate or valerate, are too high and likely lead to patients having supraphysiologic levels across much of their injection cycle. CONCLUSIONS: The optimal starting dose for injectable estradiol remains unclear and whether it should differ for cypionate and valerate. Based on the data available, we suggest that clinicians start injectable estradiol cypionate or valerate via subcutaneous or intramuscular injections at a dose ≤5 mg weekly and then titrate accordingly to keep levels within guideline-recommended range. Future studies should assess timing of injections and subsequent levels more precisely across the injection cycle and between esters.

Effect of testosterone therapy on breast tissue composition and mammographic breast density in trans masculine individuals.

Objective: Determine the association between TT and breast tissue composition and breast tissue density in trans masculine individuals (TMIs). Design: This is a cross-sectional study. Setting: TMIs (n=444) underwent chest-contouring surgeries to treat their gender dysphoria between 2013 and 2019 at an urban medical center. Participants: Of the 444 TMIs, 425 had pathology images analyzed by our deep-learning algorithm to extract breast tissue composition. A subset of 42/444 TMIs had mammography prior to surgery; mammography files were available for 25/42 TMIs and analyzed using a breast density software, LIBRA. Main Outcomes and Measures: The first outcome was the association of duration of TT and breast tissue composition assessed by pathologists (categories of lobular atrophy and stromal composition) or by our algorithm (% epithelium, % fibrous stroma, and % fat). The second outcome is the association of TT and breast density as assessed by a radiologist (categorical variable) or by LIBRA (percent density, absolute dense area, and absolute non-dense area). Results: Length of TT was associated with increasing degrees of lobular atrophy ( p <0.001) but not fibrous content ( p =0.821) when assessed by the pathologists. Every six months of TT was associated with decreased amounts of both epithelium (exp(ß)=0.97, 95% CI 0.95-0.98, adj p =0.005) and stroma (exp(ß)=0.99, 95% CI 0.98-1.00, adj p =0.051), but not fat (exp(ß)=1.01, 95%CI 0.98-1.05, p =0.394) in fully adjusted models. There was no association between TT and radiologist's breast density assessment ( p =0.575) or LIBRA measurements ( p >0.05). Conclusions: TT decreases breast epithelium and fibrous stroma, thus potentially reducing the breast cancer risk of TMIs. Further studies are warranted to elucidate the effect of TT on breast density and breast cancer risk. Summary Box: Very little is known about the effect of gender-affirming testosterone therapy on cancer risks, such as breast cancer.Epidemiological studies had different conclusions about the association between testosterone and breast cancer in cisgender women (positive association) and trans masculine individuals (inverse association).More laboratory-based research are needed to understand the effect of testosterone on breast cancer risk in the understudied trans masculine population.Our study provides quantitative histological evidence to support prior epidemiological reports that testosterone may reduce breast cancer risk in trans masculine individuals.

Invasive Ductal Carcinoma of the Breast in a Transgender Man: A Case Report.

There is limited literature about breast cancer in the transgender population. Very little is known about how gender-affirming hormone therapy affects their breast cancer risk. On the other end, for those diagnosed with breast cancer, there are no clinical guidelines to manage their breast cancer, specifically, how to manage their gender-affirming hormone therapy during breast cancer treatment. Here, we report a 52-year-old transman diagnosed with a grade 2 invasive ductal carcinoma (ER+/PR+/HER2-), and ductal carcinoma in situ (DCIS) of intermediate grade. We discussed his risk factors as well as treatment options.

Beliefs and counseling practices among dermatologists regarding sexual and other adverse effects of finasteride.

Finasteride may cause low libido and erectile dysfunction and the product label of finasteride also includes post-marketing reactions of sexual dysfunction that continued after discontinuation of treatment, as well as male infertility and depression. The aim of this study was to evaluate the beliefs and counseling practices among dermatologists regarding adverse effects of finasteride. Anonymous paper surveys were personally distributed to 122 attendees at two annual major dermatology meetings. The participation rate was 82% with 47% women and 77% residents of the United States. 51% of respondents believed that finasteride could cause sexual side effects and 18% believed that it could cause persistent sexual side effects. Fewer than a quarter believed that finasteride could cause depression or lower sperm counts. When initiating finasteride, 69% of respondents counseled at least half of their patients about potential sexual side effects with 52% for persistent sexual side effects and 30% for depression. This study identifies the need for greater awareness of the potential adverse effects of finasteride and identifies opportunities for improvement in counseling practices that reflect finasteride's product labeling.

Hypertension in transgender individuals.

Although there has been a dramatic increase in visibility and recognition of transgender and gender-diverse populations, remarkably little has been published on prevalence rates of hypertension within these populations. In addition to summarizing the limited data on prevalence rates, this review compares the prevalence rates with those of cisgender populations and explores whether gender-affirming hormone therapy affects blood pressure and hypertension rates. The studies show that hypertension affects a significant proportion of transgender and gender-diverse people and support the practice of routinely monitoring blood pressure in transgender and gender-diverse people, especially after the initiation of gender-affirming hormone therapy. The two largest studies both found that estrogen plus an antiandrogen was associated with a decrease in systolic blood pressure and that testosterone was associated with an increase in systolic blood pressure.

Lipid profiles and hypertriglyceridemia among transgender and gender diverse adults on gender-affirming hormone therapy.

BACKGROUND: The effects of gender-affirming hormone therapy on lipid profiles among transgender adults have been inconsistent and incompletely characterized. OBJECTIVE: To longitudinally assess changes to lipid profiles following hormone therapy and to establish prevalence rates of hyperlipidemia/low HDL-cholesterol. METHODS: This longitudinal study followed lipid profiles of 366 transgender and gender-diverse adult patients (170 transfeminine and 196 transmasculine; mean age, 28 years) in Washington DC USA. Lipid profiles were measured at baseline and at multiple follow-up clinical visits up to 57 months after the initiation of hormone therapy. RESULTS: Within 2-10 months of starting gender-affirming hormone therapy, mean levels of HDL-cholesterol decreased by 16% in transmasculine individuals and increased by 11% in transfeminine individuals. Over the study, mean triglyceride levels increased by 26-37% in the transmasculine group. Over the study, the prevalence of moderate hypertriglyceridemia (175-499 mg/dL) ranged from 11 to 32% in the transfeminine group and 6-19% in the transmasculine group. Severe hypertriglyceridemia (≥500 mg/dL) was only observed in one individual. On hormone therapy, 24-30% of the transfeminine group had a HDL-cholesterol < 50 mg/dL and 16-24% of the transmasculine group had a HDL-cholesterol < 40 mg/dL. LDL-cholesterol levels ≥160 mg/dL were rare among both groups. CONCLUSIONS: In a gender-diverse population on hormone therapy, low HDL-cholesterol and moderate hypertriglyceridemia were relatively common. HDL-cholesterol decreased with testosterone therapy and increased with a combination of oral estrogen and spironolactone. Testosterone use was associated with an increase in triglycerides. Our data support the recommendation to routinely monitor lipid profiles in gender-diverse patients on GAHT.

Diagnostic criteria for enduring sexual dysfunction after treatment with antidepressants, finasteride and isotretinoin.

BACKGROUND: A set of enduring conditions have been reported in the literature involving persistent sexual dysfunction after discontinuation of serotonin reuptake inhibiting antidepressants, 5 alpha-reductase inhibitors and isotretinoin. OBJECTIVE: To develop diagnostic criteria for post-SSRI sexual dysfunction (PSSD), persistent genital arousal disorder (PGAD) following serotonin reuptake inhibitors, post-finasteride syndrome (PFS) and post-retinoid sexual dysfunction (PRSD). METHODS: The original draft was designed using data from two published case series (Hogan et al., 2014 and Healy et al., 2018), which represent the largest public collections of data on these enduring conditions. It was further developed with the involvement of a multidisciplinary panel of experts. RESULTS: A set of criteria were agreed upon for each of the above conditions. Features of PSSD, PFS and PRSD commonly include decreased genital and orgasmic sensation, decreased sexual desire and erectile dysfunction. Ancillary non-sexual symptoms vary depending on the specific condition but can include emotional blunting and cognitive impairment. PGAD presents with an almost mirror image of unwanted sensations of genital arousal or irritability in the absence of sexual desire. A new term, post-SSRI asexuality, is introduced to describe a dampening of sexual interest and pleasure resulting from a pre-natal or pre-teen exposure to a serotonin reuptake inhibitor. CONCLUSIONS: These criteria will help in both clinical and research settings. As with all criteria, they will likely need modification in the light of developments.

How Would You Manage This Male Patient With Hypogonadism? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

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.

Blood Pressure Effects of Gender-Affirming Hormone Therapy in Transgender and Gender-Diverse Adults.

[Figure: see text].

Routine Screening for Transgender and Gender Diverse Adults Taking Gender-Affirming Hormone Therapy: a Narrative Review.

Despite the growing number of adult transgender and gender diverse (TGD) patients seeking health services, there are many unknowns regarding how routine screening recommendations should be applied to TGD persons receiving gender-affirming hormone therapy (GAHT). Patients taking GAHT may have disease risks that differ from what is expected based on their sex assigned at birth or affirmed gender identity. We discuss two patient cases, one transgender man and one transgender woman who present for routine medical care, to review several conditions that may be impacted by the hormones utilized in masculinizing and feminizing GAHT and for which screening recommendations are available for TGD adults: cardiovascular risk factors, osteoporosis, breast cancer, cervical cancer, and prostate cancer. We reviewed the TGD-specific screening recommendations from several major medical organizations and programs and found them to be largely based upon expert opinion due to a lack of evidence. The goal of this narrative review is to assist healthcare professionals in counseling and screening their TGD patients when and where appropriate. Not all TGD adults have the ability or need to receive routine medical care from a specialized TGD health clinic; therefore, it is essential for all healthcare professionals involved in routine and gender-affirming care to have knowledge about these conditions and screenings.

Is there a role for 5α-reductase inhibitors in transgender individuals?

This commentary will explore the important clinical question regarding whether the antiandrogen class of 5α-reductase inhibitors should be considered as an effective and safe treatment option for transfeminine and/or transmasculine individuals. The use of finasteride in transfeminine individuals is based upon the theory that the goal of medical treatment is to reduce the concentrations of androgens, including dihydrotestosterone. Nonetheless, it is unclear that finasteride will have any additive clinical benefit once testosterone levels have already been lowered with standard treatment regimens (i.e. estrogen with spironolactone or cyproterone acetate). For transmasculine individuals, 5α-reductase inhibitors may be a potential treatment option for a subset with androgenetic alopecia but may come at the expense of impairing virilization driven by dihydrotestosterone. In the absence of efficacy and safety data on 5α-reductase inhibitors in gender diverse populations, clinicians should discuss this issue with patients who request or are contemplating their use.

The Association Between Race, Obesity, and Sperm Quality Among Men Attending a University Physician Practice in Washington, DC.

A decades-long decline in sperm counts in Western countries has coincided with an increase in obesity rates, prompting study into their association. Few of these studies have incorporated men of color, the sperm health of whom is relatively unknown. The present exploratory study evaluated the association between body mass index (BMI), race, ethnicity, and sperm parameters among a diverse sample of U.S. men attending a Washington, DC physician practice. Semen samples were collected and processed at a single laboratory and sperm concentration, motility, morphology, and count were evaluated according to World Health Organization (WHO) 5th edition criteria. Multivariate models accounted for covariates related to sperm health. The study population (n = 128) was largely obese (45.3%) or overweight (34.4%), and 36.0% were black or Hispanic. Black men had lower adjusted sperm concentration compared to white men (75.0 million/mL to 107.4 million/mL, p = .01) and were more likely to have oligozoospermia (p = .01), asthenozoospermia (p = .004), and low sperm count (p < .0001). Hispanic men had higher adjusted sperm concentration compared to non-Hispanic men (124.5 million/mL to 62.1 million/mL, p = .007) and were less likely to have teratozoospermia (p = .001). Obesity and BMI were associated with lower sperm motility and count in crude models only. Given the study's sample size its findings should be interpreted with caution but align with the limited epidemiological literature to date that has evaluated racial and ethnic differences in semen quality. Heightened clinical research attention is needed to ensure men of color are included in representative numbers in studies of urologic and andrologic health.

OFF-LABEL USE AND MISUSE OF TESTOSTERONE, GROWTH HORMONE, THYROID HORMONE, AND ADRENAL SUPPLEMENTS: RISKS AND COSTS OF A GROWING PROBLEM.

Over the past few decades, there has been an unprecedented rise in off-label use and misuse of testosterone, growth hormone, thyroid hormone, and adrenal supplements. Testosterone therapy is often promoted to men for the treatment of low energy, lower libido, erectile dysfunction, and other symptoms. Growth hormone is used in attempts to improve athletic performance in athletes and to attenuate aging in older adults. Thyroid hormone and/or thyroid supplements or boosters are taken to treat fatigue, obesity, depression, cognitive impairment, impaired physical performance, and infertility. Adrenal supplements are used to treat common nonspecific symptoms due to "adrenal fatigue," an entity that has not been recognized as a legitimate medical diagnosis. Several factors have contributed to the surge in off-label use and misuse of these hormones and supplements: direct-to-consumer advertising, websites claiming to provide legitimate medical information, and for-profit facilities promoting therapies for men's health and anti-aging. The off-label use and misuse of hormones and supplements in individuals without an established endocrine diagnosis carries known and unknown risks. For example, the risks of growth hormone abuse in athletes and older adults are unknown due to a paucity of studies and because those who abuse this hormone often take supraphysiologic doses in sporadic intervals. In addition to the health risks, off-label use of these hormones and supplements generates billions of dollars of unnecessary costs to patients and to the overall health-care system. It is important that patients honestly disclose to their providers off-label hormone use, as it may affect their health and treatment plan. General medical practitioners and adult endocrinologists should be able to begin a discussion with their patients regarding the unfavorable balance between the risks and benefits associated with off-label use of testosterone, growth hormone, thyroid hormone, and adrenal supplements. Abbreviations: DHEA = dehydroepiandrosterone; FDA = U.S. Food and Drug Administration; GH = growth hormone; IGF-1 = insulin-like growth factor 1; LT3 = L-triiodothyronine; LT4 = levothyroxine; T3 = total triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Finasteride and Suicide: A Postmarketing Case Series.

BACKGROUND: In 2011, depression was added to the product labeling of finasteride in the USA. The US Food and Drug Administration's Adverse Event Reporting System database contains at least 36 death cases for finasteride. The aim of this study is to characterize the clinical histories and symptoms reported by a series of 6 suicide victims who took finasteride for treatment of androgenic alopecia. METHODS: Medical records and autopsy reports were provided by family members of the cases. Relevant information was extracted according to guidelines for submitting adverse event reports. RESULTS: An important pattern of symptoms was common among all cases who committed suicide in the setting of finasteride use - insomnia and persistent sexual dysfunction after medication discontinuation. Insomnia and fatigue/tiredness were some of the most debilitating symptoms. Apart from 1 case who had hyperlipidemia, there was no documentation of concomitant medication use with finasteride or any baseline medical or psychiatric diagnoses prior to starting finasteride. The findings of this postmarketing series may not be generalizable to the population of men who committed suicide in the setting of finasteride use due to small sample size and bias. Associations between medication use and symptoms cannot prove causality. CONCLUSION: Men under the age of 40 who use finasteride for alopecia are at risk for suicide if they develop persistent sexual adverse effects and insomnia. Further research is needed to establish whether finasteride has a causal relationship to suicide.