Hormone therapy is associated with an increased thrombotic risk. The objective of this systematic review is to assess the incidence of venous thromboembolism in the transgender population undergoing gender-affirming hormone therapy and compare it with that in cisgender individuals of the same sex assigned at birth.

A literature search was conducted in databases including PubMed, Cochrane Library, Scopus, and EMBASE, encompassing all studies that report data related to the incidence of venous thromboembolism in transgender individuals on hormone therapy.

Twenty-one studies were included. Five studies assessed the incidence of thromboembolic events in both populations. The occurrence of thrombosis was higher in transgender women than cisgender men (OR: 2.23; 95%CI: 1.93-2.57; P<.001). No differences between transgender men and cisgender women (OR: 0.96; 95%CI: 0.87-2.31; P=.60) were found.

Our systematic review suggests that hormone therapy in transgender women may increase the risk of venous thromboembolism.

The transgender population has been steadily increasing, with more individuals seeking gender-affirming care to align their physical characteristics with their gender identity. Despite advances in healthcare, transgender individuals face significant barriers to accessing culturally competent care, resulting in heightened cardiovascular risks and disparities. Cardiovascular disease prevalence among transgender individuals is influenced by a combination of physiological, psychological, and social factors, including the impacts of gender-affirming hormone therapy, surgical interventions, and minority stress. This review examines the cardiovascular risks associated with estrogen therapy in transfeminine individuals and testosterone therapy in transmasculine individuals, highlighting their effects on lipid profiles, thromboembolic risks, and metabolic parameters. Furthermore, it explores the implications of gender-affirming surgeries and the role of psychosocial stress in cardiovascular outcomes. Current evidence underscores the need for tailored risk assessment, proactive management strategies, and lifestyle interventions to optimize cardiovascular health in this population. Significant research gaps remain regarding the long-term cardiovascular effects of gender-affirming care. Large-scale, prospective studies and the development of transgender-specific cardiovascular care guidelines are crucial to address these gaps. This review advocates for a multidisciplinary, patient-centered approach to mitigate cardiovascular risks and improve outcomes for transgender individuals.

Increasing numbers of transgender and gender-diverse individuals are seeking initiation of gender-affirming hormone therapy. This aligns an individual's physical characteristics with their gender identity and improves psychological outcomes. Physical changes, including changes to muscle mass and body fat redistribution, can alter sex-specific laboratory reference ranges.

We review the impact of gender-affirming hormone therapy on laboratory parameters with sex-specific reference ranges, with a focus on hemoglobin/hematocrit, renal function, cardiac biomarkers, and prostate-specific antigen.

Gender-affirming hormone therapy results in changes in laboratory parameters with sex-specific reference ranges. For individuals established on gender-affirming hormone therapy, reference ranges that align with an individual's gender identity should be used for hemoglobin/hematocrit, serum creatinine, and high-sensitivity cardiac troponin and N-terminal brain natriuretic peptide. Clinicians should interpret these biomarkers according to the reference range that aligns with one's affirmed gender.

Approximately, 11% of trans men experience erythrocytosis diagnosis due to testosterone administration during the first year of the gender-affirming hormone treatment (GAHT).

To identify and compare the effect of different testosterone formulations on hematocrit (Hct) and diagnose erythrocytosis in trans men.

This systematic review was based on PRISMA guidelines. We performed an electronic search of PubMed, Embase, and Web of Science in January 2024. The Newcastle-Ottawa scale was used to evaluate the quality of evidence in the observational studies.

Of the 152 records retrieved, 18 met the eligibility criteria. Studies observed an increase of up to 5% in Hct in trans men using injectable testosterone undecanoate (TU), and up to 6.9% in trans men using intermediate injectable testosterone esters (TE). Trans men using TE experience a larger increase in serum Hct levels compared to those receiving TU. Erythrocytosis prevalence varies according to the cutoff used (50%, 52%, and 54%). Erythrocytosis was also associated with tobacco use, age at initiation of hormone therapy, body mass index (BMI), and pulmonary conditions. Studies that evaluated the effect of testosterone formulation on erythrocytosis diagnosis present conflicting result. Trans men have a hazard ratio of 7.4 (95% CI: 4.1, 13.4) of developing erythrocytosis compared to cisgender men, using a 52% hematocrit cutoff.

All testosterone formulations result in an increase in Hct, irrespective of dose, formulation, and administration method. Smoking, higher age at initiation of the testosterone therapy, higher BMI, and a predisposing medical history are associated with this increase in Hct. The difference in effect of TE and TU on Hct is conflicting, although it is important to point out that these data come from observational studies, retrospective, and with a small-sample size.

The prevalence of female-to-male (FtM) transgender individuals has risen recently, yet the effects of cross-sex hormone therapy on volumetric differences in the hippocampal subfields remain poorly understood. This study aimed to evaluate the differences of gray matter (GM) volume, especially focusing on the hippocampal subfields, in FtM transgender individuals and premenopausal cisgender women.

Seventeen FtM transgender individuals who had undergone hysterectomies and were receiving testosterone therapy before participating in this study, along with 20 premenopausal women, underwent a single session of T1-weighted magnetic resonance imaging (MRI).

FtM transgender group had significantly higher free-testosterone (free-T) levels and lower estradiol levels compared with premenopausal women group (p < 0.001). In voxel-wise analysis, FtM transgender individuals showed significantly larger GM volumes in the caudate nucleus, hypothalamus, and thalamus compared with premenopausal women (p < 0.01, FWE-corrected). More specifically, the right hippocampal subiculum volume was larger in FtM transgender individuals (p < 0.05, Bonferroni-corrected), and these volumes were positively correlated with the free-T levels (r = 0.34, p = 0.04). This study revealed the specific hippocampal subfield volume differences in the testosterone-treated FtM transgender group when compared to cisgender premenopausal women group.

These findings might help elucidate the morphological variation of the specific cerebral regions associated with testosterone therapy in FtM transgender individuals and contribute to our understanding of the effects of gender-affirming hormone treatments as well.

To assess the effects of testosterone (T)-based gender affirming hormone therapy (GAHT) on liver blood tests (LBTs) in assigned female at birth adults, using a meta-analytic approach.

Prospective and retrospective studies were selected that reported the prevalence of biochemical liver damage (BLD) and LBTs changes during T therapy. Data collected included pre-and-during therapy alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), gamma-glutamyl-transferase (GGT), and alkaline phosphatase (ALP) mean concentration values.

The prevalence of BLD in 14 studies on 1698 subjects was 1% (95% CI 0.00-3.00; I2 = 14.1%; p = 0.82). In 17 studies on 2758 subjects, GAHT was associated with a statistically (but not clinically) significant increase in AST, GGT and ALP at 12 months and ALT at 3-7 (MD: 1.19 IU/l; 95% CI 0.31, 2.08; I2: 0%), at 12 (MD: 2.31 IU/l; 95% CI 1.41, 3.21; I2: 29%), but with no more significant increase at 24 months (MD: 1.71 IU/l; 95% CI -0.02, 3.44; I2: 0%).

Analysis of aggregate estimates confirms a low risk of BLD and abnormalities in LBTs, transient in most cases, during T-based GAHT, thus suggesting a limited need for careful liver monitoring in AFAB people.

The long-term effect of gender-affirming hormone therapy (GAHT) on glucose metabolism is an area of priority in transgender health research.

To evaluate the relation between GAHT and changes in fasting blood glucose (FG) and glycosylated hemoglobin (HbA1c) in transmasculine (TM) and transfeminine (TF) persons relative to the corresponding temporal changes in presumably cisgender persons (ie, without any evidence of gender diversity).

Retrospective cohort study.

Three large integrated health systems.

A total of 2148 TF and 1679 TM persons compared with 28 036 cisgender males and 32 548 cisgender females enrolled in the same health plans.

Temporal changes in FG and HbA1c levels examined using linear mixed models with main results expressed as ratios-of-ratios.

The pre- vs post-GAHT ratios-of-ratio (95% CI) estimates adjusted for age, race/ethnicity, study site, and body mass index in the model comparing TF and cisgender males groups were 1.05 (1.01-1.09) for FG and 1.03 (0.99-1.06) for HbA1c. By contrast, the corresponding results in the models contrasting TM and cisgender cohort members were in the 0.99 to 1.00 range. The ratio-of-ratios comparing post-GAHT changes among transgender and cisgender persons were close to the null and without a discernable pattern.

Though the within-transgender cohort data suggest an increase in the levels of FG and HbA1c following feminizing GAHT initiation, these changes were no longer evident when compared with the corresponding changes in cisgender referents. Based on these results, clinically important effects of GAHT on routine laboratory markers of glucose metabolism appear unlikely.

There is a paucity of data on the safety and efficacy of long-term testosterone (T)-based gender-affirming hormone therapy (GAHT) on anthropometric parameters, body composition, and glycolipid metabolism in assigned female at birth (AFAB) persons. The purpose of this study was to provide an updated meta-analysis on this topic.

We searched PubMed, Scopus, and Cochrane Library for relevant studies. Pre-/post-therapy changes in body mass index (BMI), waist-to-hip ratio (WHR), body composition, lipid glycemic/insulinemic profiles were combined as mean differences (MD) with 95% confidence interval (CI), using random-effect models.

Thirty-nine studies (N=1949) were analyzed. At pooled estimates, GAHT was associated with significant decrease in fat mass (MD: -1.29 kg; 95% CI: -2.52 to -0.05; p=0.04) and increase in lean mass (4.12 kg; 95% CI: 3.07-5.16; p<0.00001), BMI (0.78 kg/m2; 95% CI: 0.50-1.07; p<0.00001), and WHR (0.02; 95%CI: 0.01-0.03; p=0.003) in the absence of heterogeneity (I 2=0%). T therapy was also accompanied by unfavorable effects on lipid profile, including increases in total cholesterol (4.95 mg/dL; 95% CI: 1.53-8.37; p=0.005), LDL (11.15 mg/dL; 95% CI: 7.57-14.74; p<0.00001), and triglycerides (9.49 mg/dL; 95% CI: 4.39-14.58; p=0.0003) and decrease in HDL concentration (-7.52 mg/dL; 95% CI: -9.38 to -5.67; p<0.00001). Finally, T therapy resulted in a significant decrease in blood glucose concentration (-2.06 mg/dL; 95% CI: -3.37 to -0.74; p=0.002), with no significant effects on homeostatic model assessment index of insulin resistance.

T-based GAHT in AFAB people is associated with androgenic changes in body composition and body fat distribution, accompanied by the acquisition of a more unfavorable cardiovascular lipid profile.

Testosterone therapy is the main hormonal treatment offered in transmen to alleviate somatic gender dysphoria. Testosterone can be administered via topical or injectable preparations to achieve physical changes resulting in masculinisation and improve quality of life for the treated individuals. The aim of our paper is to outline methods for testosterone replacement, their impact on main body systems of transmen, potential associated health risks and long term follow up. Androgen use in transgender medicine is safe with appropriate endocrine guidance and monitoring. Studies with longer follow-up period, including those who may prefer low dose testosterone, interested in pregnancy or older people may further improve the management of female-to-male transgender persons.

The aim of this study was to conduct a systematic review and meta-analysis of changes in low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol, and triglycerides following initiation of feminizing or masculinizing gender affirming hormone therapy (GAHT).

A search of Ovid MEDLINE, Embase, Web of Science, SCOPUS, and CINAHL databases identified potentially relevant articles published from 1990 through 2024. Both observational and randomized trials of adults receiving feminizing or masculinizing GAHT with baseline and follow-up measures were included. Articles were reviewed for eligibility using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines. The risk of bias in each study was quantified using the NHLBI Study Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group. Random effects models were used to compute the before-and-after meta-differences in mean values for each parameter along with the I2 statistic to assess heterogeneity of results.

Thirty-five studies met the criteria for inclusion in the meta-analysis. Masculinizing GAHT was associated with significant changes in serum lipids from baseline up through the 60-month timepoint with meta-difference of means (95% CI) estimates of 26.2mg/dL (23.3,29.0) for LDL-C, 26.1mg/dL (22.8,29.4) for total cholesterol, 30.7mg/dL (6.9,54.6) for triglycerides and -9.4mg/dL (-12.1, -6.7) for HDL-C. Studies evaluating the effects of feminizing GAHT on balance demonstrated no notable changes in HDL-C or triglycerides while the results for LDL-C and total cholesterol were inconsistent. Heterogeneity of results ranged from minimal (I2 = 0%) to substantial (I2 = 90%).

While the results for transfeminine individuals on GAHT appear somewhat reassuring, transmasculine patients receiving testosterone may benefit from closer monitoring of lipid profiles.

Hormone replacement therapy is associated with an increased thromboembolic risk. The effects of testosterone (T) on coagulation markers in people assigned female at birth (AFAB) under gender affirming hormone therapy (GAHT) are not well described.

Systematic review and meta-analysis on English-language articles retrieved from PubMed, Scopus and Cochrane Library up to April 2023 investigating T therapy in AFAB people. Coagulation parameters included international normalized ratio (INR), fibrinogen, activated partial thromboplastin clotting time (aPTT), plasminogen activator inhibitor-1 (PAI-1); hematological variables included hemoglobin (Hb) and hematocrit (HCT). We also reported the rate of thromboembolic events. Data were combined as mean differences (MD) with a 95 % confidence interval (CI) of pre- vs post-follow-up values, using random-effects models.

We included 7 studies (6 prospective and 1 retrospective) providing information on 312 subjects (mean age: 23 to 30 years) who underwent GAHT with variable T preparation. T therapy was associated with a significant increase in INR values [MD: 0.02, 95 % confidence interval (CI): 0.01-0.03; p = 0.0001], with negligible heterogeneity (I2 = 4 %). T therapy was associated with increased Hb (MD: 1.48 g/dL, 95%CI: 1.17 to 1.78; I2 = 9 %) and HCT (4.39 %, 95%CI: 3.52 to 5.26; I2 = 23 %) values. No effect on fibrinogen, aPTT and PAI-1 was found. None of the study reported thromboembolic events during the follow-up.

Therapy with T increased blood viscosity in AFAB men. A slight increase in INR values was also found, but the clinical relevance and mechanism(s) of this finding needs to be clarified.

To investigate the erythropoietic activity and safety aspects of testosterone undecanoate (TU) injections in transgender men, assigned female at birth.

Twenty-three men (13 hypogonadal cisgender men and 10 transgender men) who initiated TU at the study start (naïve) and 15 men (10 hypogonadal cisgender men and 5 transgender men) on steady-state treatment with TU (non-naïve) were included in this prospective 1-year observational study. A control group of 32 eugonadal cisgender men was investigated once at baseline. Complete blood count, testosterone in serum and saliva, and plasma lipids, and liver enzymes were assessed.

For naïve transgender men, a significant increase in hemoglobin concentration was noted (mean (SD)), 141 (8) g/L to 151 (13) g/L, while no increase was seen in naïve hypogonadal cisgender men. At the end of the study, naïve transgender men exhibited comparable levels of hemoglobin, hematocrit, and testosterone levels in serum and saliva to hypogonadal cisgender men, as well as to the eugonadal cisgender men. During the study, HDL-cholesterol decreased significantly in naïve transgender men, 1.4 (0.4) mmol/L to 1.2 (0.4) mmol/L, P = 0.03, whereas no significant change was noted in naïve hypogonadal cisgender men. Liver enzymes remained unchanged in all groups.

After 12 months of treatment with TU in naïve transgender men, hemoglobin and hematocrit increased to levels within the cisgender male reference range. A slight decrease in HDL-cholesterol was seen in naïve transgender men but liver enzymes remained unchanged.

Hormone therapy in transgender people might be associated with an increased risk of cardiovascular disease (CVD). We aimed to investigate whether the risk of CVD is increased in transgender people compared with people of the same birth sex.

PubMed, Cochrane, Embase, and Google Scholar were searched until July 2022. Studies evaluating cardiovascular events in transgender women or men were included. Primary outcomes were stroke, myocardial infarction (MI), and venous thromboembolism (VTE). The risk for transgender women versus cisgender men and for transgender men versus cisgender women was analysed through random-effects meta-analysis.

Twenty-two studies involving 19 893 transgender women, 14 840 transgender men, 371 547 cisgender men, and 434 700 cisgender women were included. The meta-analysis included 10 studies (79% of transgender women and 76% of transgender men). In transgender women, incidence of stroke was 1.8%, which is 1.3 (95% confidence interval [CI], 1.0-1.8) times higher than in cisgender men. Incidence of MI was 1.2%, with a pooled relative risk of 1.0 (95% CI, 0.8-1.2). Venous thromboembolism incidence was 1.6%, which is 2.2 (95% CI, 1.1-4.5) times higher. Stroke occurred in 0.8% of transgender men, which is 1.3 (95% CI, 1.0-1.6) times higher compared with cisgender women. Incidence of MI was 0.6%, with a pooled relative risk of 1.7 (95% CI, 0.8-3.6). For VTE, this was 0.7%, being 1.4 (95% CI, 1.0-2.0) times higher.

Transgender people have a 40% higher risk of CVD compared with cisgender people of the same birth sex. This emphasizes the importance of cardiovascular risk management. Future studies should assess the potential influence of socio-economic and lifestyle factors.

Many transgender (trans) individuals utilize gender-affirming hormone therapy (GAHT) to promote changes in secondary sex characteristics to affirm their gender. Participation rates of trans people in sport are exceedingly low, yet given high rates of depression and increased cardiovascular risk, the potential benefits of sports participation are great. In this review, we provide an overview of the evidence surrounding the effects of GAHT on multiple performance-related phenotypes, as well as current limitations. Whilst data is clear that there are differences between males and females, there is a lack of quality evidence assessing the impact of GAHT on athletic performance. Twelve months of GAHT leads to testosterone concentrations that align with reference ranges of the affirmed gender. Feminizing GAHT in trans women increases fat mass and decreases lean mass, with opposite effects observed in trans men with masculinizing GAHT. In trans men, an increase in muscle strength and athletic performance is observed. In trans women, muscle strength is shown to decrease or not change following 12 months of GAHT. Haemoglobin, a measure of oxygen transport, changes to that of the affirmed gender within 6 months of GAHT, with very limited data to suggest possible reductions in maximal oxygen uptake as a result of feminizing GAHT. Current limitations of this field include a lack of long-term studies, adequate group comparisons and adjustment for confounding factors (e.g. height and lean body mass), and small sample sizes. There also remains limited data on endurance, cardiac or respiratory function, with further longitudinal studies on GAHT needed to address current limitations and provide more robust data to inform inclusive and fair sporting programmes, policies and guidelines.

Gender-affirming care is a key clinical area that can benefit from implementation of patient-reported outcome measures (PROMs). Identifying barriers to and enablers of PROM implementation is needed to develop an evidence-based implementation strategy.

To identify (1) PROMs previously implemented for gender-affirming care and constructs measured, (2) how patients completed PROMs and how results were reported and used, and (3) barriers to and enablers of PROM implementation.

In this systematic review, PubMed, Embase, MEDLINE, PsycINFO, CINAHL, and Web of Science were searched from inception to October 25, 2021, and updated on December 16, 2022. Gray literature was searched through gray literature database, online search engine, and targeted website searching. Inclusion criteria were (1) original articles of (2) a formally developed PROM or ad hoc instrument administered for gender-affirming care to (3) patients accessing gender-affirming care. The Critical Appraisal Skills Programme tool was used to evaluate quality of included studies. This review was registered on PROSPERO (CRD42021233080).

In total, 286 studies were included, representing 85 395 transgender and nonbinary patients from more than 30 countries. A total of 205 different PROMs were used in gender-affirming care. No studies described using an implementation science theory, model, or framework to support PROM deployment. Key barriers to PROM implementation included issues with evidence strength and quality of the PROM, engaging participants, and PROM complexity. Key enablers of PROM implementation included using PROMs validated for gender-affirming care, implementing PROMs able to be deployed online or in person, implementing PROMs that are shorter and reduce patient burden, engaging key stakeholders and participants as part of developing an implementation plan, and organizational climate.

In this systematic review of barriers to and enablers of PROM implementation in gender-affirming care, PROM implementation was inconsistent and did not follow evidence-based approaches in implementation science. There was also a lack of patient input in creating implementation strategies, suggesting a need for patient-centered approaches to PROM implementation. Frameworks created from these results can be used to develop evidence-based PROM implementation initiatives for gender-affirming care and have potential generalizability for other clinical areas interested in implementing PROMs.

Gender-affirming hormone therapy (GAHT) is one of the most important therapeutic interventions sought by people with gender dysphoria (GD). In the present study, we aimed to examine the effects of GAHT on body satisfaction, self-esteem, quality of life, and psychopathology in people with female-to-male (FtM) GD.

Thirty-seven FtM GD participants who did not receive any gender-affirming therapy, 35 FtM GD participants who received GAHT for over 6 months, and 38 cisgender women were included in the study. The Body Cathexis Scale (BCS), Rosenberg Self Esteem Scale (RSES), World Health Organization's Quality of Life Questionnaire Brief Form (WHOQOL-BREF), and Symptom Checklist-90-Revised (SCL-90-R) were completed by all participants.

The BCS scores of the untreated group were significantly lower than both the GAHT group and the female controls (p<0.001); while the WHOQOL-BREF-psychological health scores of the untreated group were significantly lower than those of the female controls (p=0.003). The psychoticism subscale scores on the SCL-90-R of the untreated group were higher than those of the GAHT group (p=0.04) as well as the female controls (p=0.003). With regard to the RSES, there were no significant differences between the groups.

Our findings suggest that people with FtM GD who receive GAHT are more satisfied with their bodies and have less psychopathological problems compared to those who do not receive GAHT, but their quality of life and self-esteem do not change as a result of GAHT.

Gender-affirming hormone therapy (GAHT) is prescribed to produce secondary sex characteristics aligning external anatomy with gender identity to mitigate gender dysphoria. Transgender women are generally treated with oestrogens and anti-androgens, whereas transgender men are treated with testosterone. The objective of this narrative review was to characterise the influence of GAHT on body composition and bone health in the transgender population to help address weight concerns and chronic disease risk.

Studies were extracted from PubMed and Scopus and limited to only those utilising imaging technologies for precise adipose tissue, lean mass, and bone mineral density (BMD) quantification.

Although methodologies differed across the 20 investigations that qualified for inclusion, clear relationships emerged. Specifically, among transgender women, most studies supported associations between oestrogen therapy and decreases in lean mass and increases in both, fat mass and body mass index (BMI). Within transgender men, all studies reported associations between testosterone therapy and increases in lean mass, and although not as consistent, increases in BMI and decreases in fat mass. No consistent changes in BMD noted for either group.

Additional research is needed to appropriately assess and evaluate the implications of these body composition changes over time (beyond 1 year) in larger, more diverse groups across all BMI categories. Future studies should also seek to evaluate nutrient intake, energy expenditure and other important lifestyle habits to diminish health disparities within this vulnerable population. Policies are needed to help integrate registered dietitians into the routine care of transgender individuals.

Background: Transgender healthcare is a rapidly evolving interdisciplinary field. In the last decade, there has been an unprecedented increase in the number and visibility of transgender and gender diverse (TGD) people seeking support and gender-affirming medical treatment in parallel with a significant rise in the scientific literature in this area. The World Professional Association for Transgender Health (WPATH) is an international, multidisciplinary, professional association whose mission is to promote evidence-based care, education, research, public policy, and respect in transgender health. One of the main functions of WPATH is to promote the highest standards of health care for TGD people through the Standards of Care (SOC). The SOC was initially developed in 1979 and the last version (SOC-7) was published in 2012. In view of the increasing scientific evidence, WPATH commissioned a new version of the Standards of Care, the SOC-8. Aim: The overall goal of SOC-8 is to provide health care professionals (HCPs) with clinical guidance to assist TGD people in accessing safe and effective pathways to achieving lasting personal comfort with their gendered selves with the aim of optimizing their overall physical health, psychological well-being, and self-fulfillment. Methods: The SOC-8 is based on the best available science and expert professional consensus in transgender health. International professionals and stakeholders were selected to serve on the SOC-8 committee. Recommendation statements were developed based on data derived from independent systematic literature reviews, where available, background reviews and expert opinions. Grading of recommendations was based on the available evidence supporting interventions, a discussion of risks and harms, as well as the feasibility and acceptability within different contexts and country settings. Results: A total of 18 chapters were developed as part of the SOC-8. They contain recommendations for health care professionals who provide care and treatment for TGD people. Each of the recommendations is followed by explanatory text with relevant references. General areas related to transgender health are covered in the chapters Terminology, Global Applicability, Population Estimates, and Education. The chapters developed for the diverse population of TGD people include Assessment of Adults, Adolescents, Children, Nonbinary, Eunuchs, and Intersex Individuals, and people living in Institutional Environments. Finally, the chapters related to gender-affirming treatment are Hormone Therapy, Surgery and Postoperative Care, Voice and Communication, Primary Care, Reproductive Health, Sexual Health, and Mental Health. Conclusions: The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person.

Androgen therapy is the mainstay of treatment in female to male (FtM) transgender persons to increase testosterone levels, suppress oestrogens and treat gender dysphoria. Testosterone is widely used for male hypogonadism, but is comparatively under-investigated in FtM transgender persons. The aim of our study was to identify treatment and safety outcomes associated with testosterone use in transgender medicine. Androgens in FtM transgender persons are effective to lower voice frequency, increase facial hair-growth, and increase hematocrit and hemoglobin levels to adult male reference ranges. A 1.2-fold-3.7-fold higher rate of myocardial infarction has been reported retrospectively, compared to cisgender women. Blood pressure, glycaemic control and body mass index remained unchanged in FtM transgender persons. Androgens in FtM transgender persons have important cardio-metabolic implications. Randomised control trials, longer follow-up periods and studies involving older persons may further improve the management of FtM transgender persons.

In line with increasing numbers of transgender (trans) and gender nonbinary people requesting hormone treatment, the body of available research is expanding. More clinical research groups are presenting data, and the numbers of participants in these studies are rising. Many previous review papers have focused on all available data, as these were scarce, but a more recent literature review is timely. Hormonal regimens have changed over time, and older data may be less relevant for today's practice. In recent literature, we have found that even though mental health problems are more prevalent in trans people compared to cisgender people, less psychological difficulties occur, and life satisfaction increases with gender-affirming hormone treatment (GAHT) for those who feel this is a necessity. With GAHT, body composition and contours change towards the affirmed sex. Studies in bone health are reassuring, but special attention is needed for adolescent and adult trans women, aiming at adequate dosage of hormonal supplementation and stimulating therapy compliance. Existing epidemiological data suggest that the use of (certain) estrogens in trans women induces an increased risk of myocardial infarction and stroke, the reason that lifestyle management can be an integral part of trans health care. The observed cancer risk in trans people does not exceed the known cancer-risk differences between men and women. Now it is time to integrate the mostly reassuring data, to leave the overly cautious approach behind, to not copy the same research questions repeatedly, and to focus on longer follow-up data with larger cohorts.

Embraced with apolipoproteins (Apo) B and Apo E, triglyceride-enriched very-low-density lipoprotein (VLDL) is secreted by the liver into circulation, mainly during post-meal hours. Here, we present a brief review of the physiological role of VLDL and a systemic review of the emerging evidence supporting its pathological roles. VLDL promotes atherosclerosis in metabolic syndrome (MetS). VLDL isolated from subjects with MetS exhibits cytotoxicity to atrial myocytes, induces atrial myopathy, and promotes vulnerability to atrial fibrillation. VLDL levels are affected by a number of endocrinological disorders and can be increased by therapeutic supplementation with cortisol, growth hormone, progesterone, and estrogen. VLDL promotes aldosterone secretion, which contributes to hypertension. VLDL induces neuroinflammation, leading to cognitive dysfunction. VLDL levels are also correlated with chronic kidney disease, autoimmune disorders, and some dermatological diseases. The extra-hepatic secretion of VLDL derived from intestinal dysbiosis is suggested to be harmful. Emerging evidence suggests disturbed VLDL metabolism in sleep disorders and in cancer development and progression. In addition to VLDL, the VLDL receptor (VLDLR) may affect both VLDL metabolism and carcinogenesis. Overall, emerging evidence supports the pathological roles of VLDL in multi-organ diseases. To better understand the fundamental mechanisms of how VLDL promotes disease development, elucidation of the quality control of VLDL and of the regulation and signaling of VLDLR should be indispensable. With this, successful VLDL-targeted therapies can be discovered in the future.

Risk of type 2 diabetes mellitus (T2DM) in transgender and gender diverse (TGD) persons, especially those receiving gender-affirming hormone therapy (GAHT) is an area of clinical and research importance.

We used data from an electronic health record-based cohort study of persons 18 years and older enrolled in 3 integrated health care systems. The cohort included 2869 transfeminine members matched to 28 300 cisgender women and 28 258 cisgender men on age, race/ethnicity, calendar year, and site, and 2133 transmasculine members similarly matched to 20 997 cisgender women and 20 964 cisgender men. Cohort ascertainment spanned 9 years from 2006 through 2014 and follow-up extended through 2016. Data on T2DM incidence and prevalence were analyzed using Cox proportional hazards and logistic regression models, respectively. All analyses controlled for body mass index.

Both prevalent and incident T2DM was more common in the transfeminine cohort relative to cisgender female referents with odds ratio and hazard ratio (95% CI) estimates of 1.3 (1.1-1.5) and 1.4 (1.1-1.8), respectively. No significant differences in prevalence or incidence of T2DM were observed across the remaining comparison groups, both overall and in TGD persons with evidence of GAHT receipt.

Although transfeminine people may be at higher risk for T2DM compared with cisgender females, the corresponding difference relative to cisgender males is not discernable. Moreover, there is little evidence that T2DM occurrence in either transfeminine or transmasculine persons is attributable to GAHT use.

Gender Incongruence (GI) is a marked and persistent incongruence between an individual's experienced and the assigned gender at birth. In the recent years, there has been a considerable evolution and change in attitude as regards to gender nonconforming people.

According to the Italian Society of Gender, Identity and Health (SIGIS), the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE) rules, a team of experts on the topic has been nominated by a SIGIS-SIAMS-SIE Guideline Board on the basis of their recognized clinical and research expertise in the field, and coordinated by a senior author, has prepared this Position statement. Later on, the present manuscript has been submitted to the Journal of Endocrinological Investigation for the normal process of international peer reviewing after a first internal revision process made by the SIGIS-SIAMS-SIE Guideline Board.

In the present document by the SIGIS-SIAMS-SIE group, we propose experts opinions concerning the psychological functioning, gender affirming hormonal treatment, safety concerns, emerging issues in transgender healthcare (sexual health, fertility issues, elderly trans people), and an Italian law overview aimed to improve gender non-conforming people care.

In this Position statement, we propose experts opinions concerning the psychological functioning of transgender people, the gender-affirming hormonal treatment (full/partial masculinization in assigned female at birth trans people, full/partial feminization and de-masculinization in assigned male at birth trans people), the emerging issues in transgender health care aimed to improve patient care. We have also included an overview of Italian law about gender affirming surgery and registry rectification.

Data on body composition, bone mineral density (BMD) and microarchitecture between cis and trans men are scarce. Few studies have reported trabecular bone score (TBS) data for transgender men using testosterone.

We studied 19 transgender men and 19 cisgender men (mean age 23.6 ± 3.4 years, p = 0.539) paired by age and body mass index (BMI). They underwent clinical and hormonal evaluation, body composition measurement, and evaluation BMD, the TBS, grip strength, the level of physical activity (IPAQ) and physical performance (SPPB).

Median serum testosterone levels were similar between the cisgender and transgender groups (638 vs. 685 ng/dl; p = 0.863). Mean serum estradiol levels were slightly higher in the transgender men (51.95 ± 44.26 vs. 32.26 ± 8.40 pg/ml, p = 0.005), and the median testosterone use duration in the transgender group was 24 months. Total muscle mass (44.09 ± 6.27 vs. 55.71 ± 7.28 kg, p < 0.001), and hand grip strength (28.82 ± 5.42 vs. 40.34 ± 8.03 kg, p < 0.001) were considerably lower in the transgender men. Total body BMD (1.208 ± 0.132 vs. 1.271 ± 0.081 g/cm2, p = 0.008) and femoral neck BMD (1.019 ± 0.163 vs. 1.137 ± 0.166 g/cm2, p = 0.016) were lower in the transgender group. The TBS was similar between groups. Thus, our data demonstrated that despite similar serum testosterone levels, transgender men undergoing testosterone therapy had lower muscle strength, muscle mass, and total body and femoral neck BMD values than cisgender men.

Erythrocytosis is a known side effect of testosterone therapy that can increase the risk of thromboembolic events.

To study the prevalence and determinants in the development of erythrocytosis in trans men using testosterone.

A 20-year follow-up study in adult trans men who started testosterone therapy and had monitoring of hematocrit at our center (n = 1073).

Erythrocytosis occurred in 11% (hematocrit > 0.50 L/L), 3.7% (hematocrit > 0.52 L/L), and 0.5% (hematocrit > 0.54 L/L) of trans men. Tobacco use (odds ratio [OR] 2.2; 95% CI, 1.6-3.3), long-acting undecanoate injections (OR 2.9; 95% CI, 1.7-5.0), age at initiation of hormone therapy (OR 5.9; 95% CI, 2.8-12.3), body mass index (BMI) (OR 3.7; 95% CI, 2.2-6.2), and pulmonary conditions associated with erythrocytosis and polycythemia vera (OR 2.5; 95% CI, 1.4-4.4) were associated with hematocrit > 0.50 L/L. In the first year of testosterone therapy hematocrit increased most: 0.39 L/L at baseline to 0.45 L/L after 1 year. Although there was only a slight continuation of this increase in the following 20 years, the probability of developing erythrocytosis still increased (10% after 1 year, 38% after 10 years).

Erythrocytosis occurs in trans men using testosterone. The largest increase in hematocrit was seen in the first year, but also after the first years a substantial number of people present with hematocrit > 0.50 L/L. A reasonable first step in the care for trans men with erythrocytosis while on testosterone is to advise them to quit smoking, to switch to a transdermal administration route, and if BMI is high, to lose weight.

Transgender people are a vulnerable group with a higher incidence of mental health issues and, during the COVID-19 outbreak, they may have faced psychological, physical and social obstacles.

To evaluate the impact of the pandemic and the access to health care services during the COVID-19 pandemic on the mental health of the transgender people living in Italy.

An anonymous web-based survey was conducted among transgender people living in Italy.

The survey consisted of 41 questions (to address socio-demographic and COVID-19 related variables, general health problems and trans-related health issues) and three validated questionnaires (the Impact of Event Scale [IES], the Beck Depression Inventory [BDI-II] and the SF-12.

In total 108 respondents were included in the analysis, of these 73.1% were transmen and 26.9% transwomen. The mean age was 34.3 ± 11.7 years with 88.9% undergoing gender affirming hormonal treatment (GAHT). Of these respondents 55.6% were not working during the COVID-19 pandemic, mainly because they lost their jobs due to the lockdown (30.5%) or because they were otherwise unemployed (25.0%). Only four subjects were quarantined at home because of a positive COVID-19 swab. The mean total IES score was 21.1 ± 14.9 with 24.1% of subjects scoring over the cut-off score of 26 thereby suggesting a moderate-to-severe impact of the pandemic event. Mean BDI score was 8.6 ± 8.4. SF-12 total mean score was 96.1 ± 11.9 with a Mental Component Summary (MCS) score of 42.8 ± 9.1. Access to endocrinological consultations for hormonal prescription via telemedicine services was associated with better IES total scores (P = .01).

Our results highlight the impact of the pandemic on the mental health of this particular population and how telemedicine services may serve to mitigate negative psychological effects.

Internet-based surveys may select a group of people not necessary representative of the whole population. The self-reporting bias should also be considered. Those who responded to our survey were mainly from northern Italy were COVID-19 has had a greater impact.

Vulnerable groups such as the transgender population should receive more consideration also during pandemic events and their access to health services especially for endocrine and mental health care should be improved. A nationwide plan for the extended use of telemedicine should be established with targeted intervention to reduce psychological distress. Gava G, Fisher AD, Alvisi S, et al. Mental Health and Endocrine Telemedicine Consultations in Transgender Subjects During the COVID-19 Outbreak in Italy: A Cross-Sectional Web-Based Survey. J Sex Med 2021;18:900-907.

We sought to systematically review the effect of gender-affirming hormone therapy on psychological outcomes among transgender people. We searched PubMed, Embase, and PsycINFO through June 10, 2020 for studies evaluating quality of life (QOL), depression, anxiety, and death by suicide in the context of gender-affirming hormone therapy among transgender people of any age. We excluded case studies and studies reporting on less than 3 months of follow-up. We included 20 studies reported in 22 publications. Fifteen were trials or prospective cohorts, one was a retrospective cohort, and 4 were cross-sectional. Seven assessed QOL, 12 assessed depression, 8 assessed anxiety, and 1 assessed death by suicide. Three studies included trans-feminine people only; 7 included trans-masculine people only, and 10 included both. Three studies focused on adolescents. Hormone therapy was associated with increased QOL, decreased depression, and decreased anxiety. Associations were similar across gender identity and age. Certainty in this conclusion is limited by high risk of bias in study designs, small sample sizes, and confounding with other interventions. We could not draw any conclusions about death by suicide. Future studies should investigate the psychological benefits of hormone therapy among larger and more diverse groups of transgender people using study designs that more effectively isolate the effects of hormone treatment.

We sought to systematically review the effect of gender-affirming hormone therapy on psychological outcomes among transgender people. We searched PubMed, Embase, and PsycINFO through June 10, 2020 for studies evaluating quality of life (QOL), depression, anxiety, and death by suicide in the context of gender-affirming hormone therapy among transgender people of any age. We excluded case studies and studies reporting on less than 3 months of follow-up. We included 20 studies reported in 22 publications. Fifteen were trials or prospective cohorts, one was a retrospective cohort, and 4 were cross-sectional. Seven assessed QOL, 12 assessed depression, 8 assessed anxiety, and 1 assessed death by suicide. Three studies included trans-feminine people only; 7 included trans-masculine people only, and 10 included both. Three studies focused on adolescents. Hormone therapy was associated with increased QOL, decreased depression, and decreased anxiety. Associations were similar across gender identity and age. Certainty in this conclusion is limited by high risk of bias in study designs, small sample sizes, and confounding with other interventions. We could not draw any conclusions about death by suicide. Future studies should investigate the psychological benefits of hormone therapy among larger and more diverse groups of transgender people using study designs that more effectively isolate the effects of hormone treatment.

Gender-affirming hormone therapy (GHT) is utilized by people who are transgender to align their secondary sex characteristics with their gender identity. Data relating to cardiovascular outcomes in this population are limited. We aimed to review the impact of GHT on the blood pressure (BP) of transgender individuals.

We searched PubMed/MEDLINE, SCOPUS and Cochrane Library databases for articles published relating to the BP of transgender adults commencing GHT. Methodological quality was assessed via the 'Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group'.

Six hundred articles were screened, of which 14 studies were included in this systematic review encompassing 1309 individuals (∼50% transgender men and women) treated with GHT between 1989 and 2019. These articles were all pre-post observational studies without control groups. Mean ages ranged between 23.0-36.7 years (transgender men) and 25.2-34.8 years (transgender women). Interventions were diverse and included oral, transdermal and injectable hormonal preparations with 4 months to 5 years follow-up. Most studies in transgender men did not demonstrate a change in BP, whereas transgender women on GHT demonstrated both increases and decreases in SBP. These studies were heterogenous with significant methodological limitations and only two were determined to have a good quality rating.

There is currently insufficient data to advise the impact of GHT on BP in transgender individuals. Better quality research is essential to elucidate whether exogenous sex hormones modulate BP in transgender people and whether this putative alteration infers poorer cardiovascular outcomes.

While the effects of androgens on muscle are well described in hypogonadal men, literature is still scarce on muscular strength or size variations in transmen; in this population there are no data regarding the relative effect of testosterone (T) and its metabolite dihydrotestosterone on muscle.

Our primary objective was to compare the effects on muscle strength of 54-week administration of testosterone undecanoate (TU) combined with the 5α-reductase inhibitor dutasteride (DT) or placebo (PL). Secondary outcomes included evaluation of body composition, bone, cutaneous androgenic effects, and metabolic variations.

In this randomized, double-blind PL-controlled pilot trial, 16 ovariectomized transmen were randomized to receive TU 1,000 mg IM at week 0, 6, 18, 30, 42 plus a PL pill orally daily (TU + PL, n = 7) or plus DT 5 mg/d (TU + DT, n = 7).

At week 0 and 54 the following parameters were evaluated: isokinetic knee extension and flexion peak torque and handgrip strength, body composition, and bone mineral density, biochemical, hematological, and hormonal parameters.

Handgrip and lower limb strength increased significantly in both groups with no differences between the 2 groups. Fat mass decreased and lean mass increased significantly similarly in both groups. Metabolic parameters remained stable in the 2 groups except for high-density lipoprotein cholesterol that was reduced in both groups. Hepatic and renal function remained normal in both groups and no major adverse effects were registered in either group.

These results may be particularly relevant for transmen experiencing cutaneous androgenic adverse events such as acne and androgenetic alopecia and in light of the development of non-5α-reduced androgens.

The strength of this study was the randomized, double-blind PL-controlled design, while the small number of subjects was definitely the biggest limitation.

For the first time we demonstrated that the addition of DT does not impair the anabolic effects of T on muscles in transmen previously exposed to T, supporting the hypothesis that the conversion in dihydrotestosterone is not essential for this role. Gava G, Armillotta F, Pillastrini P, et al. A Randomized Double-Blind Placebo-Controlled Pilot Trial on the Effects of Testosterone Undecanoate Plus Dutasteride or Placebo on Muscle Strength, Body Composition, and Metabolic Profile in Transmen. J Sex Med 2021;18:646-655.

To examine the association of various gender-affirming hormone therapy regimens with blood sex hormone concentrations in transgender individuals.

This retrospective study included transgender people receiving gender-affirming hormone therapy between January 2000 and September 2018. Data on patient demographics, laboratory values, and hormone dose and frequency were collected. Nonparametric tests and linear regression analyses were used to identify factors associated with serum hormone concentrations.

Overall, 196 subjects (134 transgender women and 62 transgender men), with a total of 941 clinical visits, were included in this study. Transgender men receiving transdermal testosterone had a significantly lower median concentration of serum total testosterone when compared with those receiving injectable preparations (326.0 ng/dL vs 524.5 ng/dL, respectively, P = .018). Serum total estradiol concentrations in the transgender women were higher in those receiving intramuscular estrogen compared with those receiving oral and transdermal estrogen (366.0 pg/mL vs 102.0 pg/mL vs 70.8 pg/mL, respectively, P < .001). A dose-dependent increase in the hormone levels was observed for oral estradiol (P < .001) and injectable testosterone (P = .018) but not for intramuscular and transdermal estradiol. Older age and a history of gonadectomy in both the transgender men and women were associated with significantly higher concentrations of serum gender-affirming sex hormones.

In the transgender men, all routes and formulations of testosterone appeared to be equally effective in achieving concentrations in the male range. The intramuscular injections of estradiol resulted in the highest serum concentrations of estradiol, whereas transdermal estradiol resulted in the lowest concentration. There was positive relationship between both oral estradiol and injectable testosterone dose and serum sex hormone concentrations in transgender people receiving GAHT.

Transgender individuals receiving gender-affirming hormone therapy (GAHT) are at increased risk of adverse cardiovascular outcomes. This may be related to effects on body composition and insulin resistance.

To examine relationships between body fat distribution and insulin resistance in transgender individuals on established GAHT.

Comparisons of body composition (dual energy X-ray absorptiometry) and insulin resistance [Homeostasis Model of Insulin Resistance (HOMA2-IR)] were made between transgender individuals (43 trans men and 41 trans women) on established GAHT (>12 months) and age-matched cisgender controls (30 males and 48 females). Multiple linear regressions were used to examine the relationship between HOMA2-IR and fat mass with gender, adjusting for age and total duration of GAHT and Pearson correlation coefficients are reported.

Compared with control cisgender women, trans men had mean difference of +7.8 kg (4.0, 11.5), p < 0.001 in lean mass and higher android:gynoid fat ratio [0.2 (0.1, 0.3), p < 0.001], but no difference in overall fat mass or insulin resistance. Compared with control cisgender men, trans women had median difference in lean mass of -6.9 kg (-10.6, -3.1), p < 0.001, fat mass of +9.8 kg (3.9, 14.5), p = 0.001, lower android:gynoid fat ratio -0.1 (-0.2,-0.0), p < 0.05), and higher insulin resistance 1.6 (1.3-1.9), p < 0.001). Higher HOMA2-IR correlated with higher android (r ² = 0.712, p < 0.001) and gynoid (r ² = 0.572, p < 0.001) fat mass in both trans men and trans women.

Android fat more strongly correlates with insulin resistance than gynoid fat in transgender individuals. Higher fat mass and insulin resistance in trans women may predispose to increased cardiovascular risk. Despite adverse fat distribution, insulin resistance was not higher in trans men.

The objective of this scoping review is to describe the extent, range, and nature of available literature examining nutrition-related intermediate and long-term health outcomes in individuals who are transgender. Specific sub-topics examined include 1) dietary intake, 2) nutrition-related health disparities, 3) validity and reliability of nutrition assessment methods, 4) the effects of nutrition interventions/exposures, and 5) hormone therapy.

A literature search was conducted using MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and other databases for peer-reviewed articles published from January 1999 until December 5, 2019 to identify studies addressing the research objective and meeting eligibility criteria. Conference abstracts and registered trials published or registered in the five years prior to the search were also included. Findings were reported in a study characteristics table, a bubble chart and heat maps.

The search of the databases identified 5403 studies, including full peer-reviewed studies, systematic reviews, conference abstracts and registered trials. Following title/abstract screening, 189 studies were included in the narrative analysis. Ten studies reported dietary intake in transgender individuals, 64 studies reported nutrition-related health disparities in transgender compared to cisgender individuals, one study examined validity and reliability of nutrition assessment methods, two studies reported nutrition interventions, and 127 studies reported on the intermediate and health effects of hormone therapy.

Individuals who are transgender have unique nutrition needs, which may vary according to the stage and type of gender-affirmative therapy that they are undergoing. There is scant research examining effective nutrition therapy methods for nutrition professionals working with transgender individuals. More research is needed in order to inform evidence-based clinical practice guidelines for nutrition practitioners working with transgender individuals.

Transgender individuals receiving masculinising or feminising gender-affirming hormone therapy with testosterone or estradiol respectively, are at increased risk of adverse cardiovascular outcomes, including myocardial infarction and stroke. This may be related to the effects of testosterone or estradiol therapy on body composition, fat distribution, and insulin resistance but the effect of gender-affirming hormone therapy on these cardiovascular risk factors has not been extensively examined.

To evaluate the impact of gender-affirming hormone therapy on body composition and insulin resistance in transgender individuals, to guide clinicians in minimising cardiovascular risk.

We performed a review of the literature based on PRISMA guidelines. MEDLINE, Embase and PsycINFO databases were searched for studies examining body composition, insulin resistance or body fat distribution in transgender individuals aged over 18 years on established gender-affirming hormone therapy. Studies were selected for full-text analysis if they investigated transgender individuals on any type of gender-affirming hormone therapy and reported effects on lean mass, fat mass or insulin resistance.

The search strategy identified 221 studies. After exclusion of studies that did not meet inclusion criteria, 26 were included (2 cross-sectional, 21 prospective-uncontrolled and 3 prospective-controlled). Evidence in transgender men suggests that testosterone therapy increases lean mass, decreases fat mass and has no impact on insulin resistance. Evidence in transgender women suggests that feminising hormone therapy (estradiol, with or without anti-androgen agents) decreases lean mass, increases fat mass, and may worsen insulin resistance. Changes to body composition were consistent across almost all studies: Transgender men on testosterone gained lean mass and lost fat mass, and transgender women on oestrogen experienced the reverse. No study directly contradicted these trends, though several small studies of short duration reported no changes. Results for insulin resistance are less consistent and uncertain. There is a paucity of prospective controlled research, and existing prospective evidence is limited by small sample sizes, short follow up periods, and young cohorts of participants.

Further research is required to further characterise the impact of gender-affirming hormone therapy on body composition and insulin resistance in the medium-long term. Until further evidence is available, clinicians should aim to minimise risk by monitoring cardiovascular risk markers regularly in their patients and encouraging healthy lifestyle modifications.