Update in Adult Transgender Medicine.

Transgender people often face barriers in health care due to lack of access to care, lack of knowledgeable healthcare professionals, discrimination, and gaps in medical and mental health research. Existing research on transgender health has focused heavily on mental health, HIV/AIDS, sexually transmitted diseases/infections, and substance abuse. Gender-affirming hormone therapy and/or surgery allows for some alignment of biology and gender identity. Gender-affirming care may offer quality-of-life benefits, which may outweigh modest concerns related to exogenous hormone therapy. The Endocrine Society treatment guidelines were revised in 2017, and this article reviews recent data that might inform a future guideline revision. Future longitudinal research is needed to close the gap in knowledge in the field of transgender medicine.

Evaluating the Risk of Venous Thromboembolism in Transfeminine and Gender Diverse People: A Retrospective Analysis.

OBJECTIVE: The risk of venous thromboembolism (VTE) with feminizing gender-affirming hormone therapy is an area of concern. This analysis aimed to assess whether gender-affirming hormone therapy and other potential risk factors are associated with VTE in transfeminine and gender diverse individuals. METHODS: We conducted a chart review of 2126 transfeminine and gender diverse adults receiving care within a large urban health system. The primary outcomes were the prevalence of VTE and odds ratios for the association of VTE with insurer, use of estrogen, and select comorbidities. RESULTS: A history of VTE was documented in 0.8% of the cohort. Those with a history of VTE were older (P < .001), more often self-identified as Hispanic or Black compared to White or Asian (P < .05) and were more likely to have Medicaid or Medicare (P < .01) when compared to those without a history of VTE. The prevalence of hyperlipidemia (P < .001), diabetes mellitus (P < .05), and hypercoagulable conditions (P < .001) were all greater in the positive VTE group. Hyperlipidemia (P < .001), diabetes mellitus (P < .05), and insurer (P < .05) were associated with increased odds of VTE in univariate analyses. None of the exposure variables analyzed were associated with VTE when controlling for age, race, and the number of comorbidities. CONCLUSIONS: The prevalence of VTE in our cohort was lower than previously observed. VTE was not associated with any one risk factor, including estrogen use, when controlling for age, race, and the number of comorbidities. Those of advanced age and those with multiple cardiometabolic comorbidities may benefit from increased surveillance and mitigation of modifiable risk factors.

Pubertal Status at the Time of Fertility Preservation in Transgender Girls.

BACKGROUND: Puberty blockade and gender-affirming hormone therapy can impair fertility. Counseling on fertility preservation is important before initiation of therapy. Our study aimed to assess Tanner staging and the presence of virilizing secondary sex characteristics at the time of sperm collection and correlate the viability of sperm with the Tanner staging and degree of virilization. METHODS: A retrospective chart review of 23 transgender girls referred to pediatric urology at our academic pediatric transgender clinic for fertility preservation counseling was performed. At the initial visit before treatment, pubertal staging along with the assessment of virilizing secondary characteristics was performed. The semen analyses were evaluated for volume, sperm concentration, total sperm count, motility, and total motile count. RESULTS: Of the first 23 transgender girls evaluated and counseled, 8 transgender females successfully produced a sperm sample for cryopreservation. The average testicular volume was 18.5 ml and ranged from 12 ml to 20 ml. The median semen parameters were at or above the 2021 World Health Organization threshold. The 8 transgender females who successfully underwent fertility preservation presented with at least 1 secondary sex characteristic. In 1 subject with Tanner stage 3 pubic hair development and a testicular volume of 12 ml, only voice change was reported. Facial hair and laryngeal prominence were not present on examination. CONCLUSION: More than a third of our patients who accepted a referral to pediatric urology agreed to produce a sperm sample for cryopreservation. All of these patients successfully preserved sperm. With counseling and early referral to pediatric urology, a high percentage of fertility preservation in transgender girls was achieved.

Examining the influence of the route of administration and dose of estradiol on serum estradiol and testosterone levels in feminizing gender-affirming hormone therapy.

INTRODUCTION: Individuals may seek gender-affirming hormone therapy (GAHT) to align their physical appearance with their gender identity. Feminizing GAHT typically involves the use of estrogen. This study investigates the effect of route of administration (ROA) and dose of estradiol on estradiol (E2) and testosterone (T) levels in transfeminine individuals. METHODS: We conducted a chart review of 573 patients with an active prescription for estradiol for feminizing GAHT and serum hormone levels available. Multiple linear regression and ANOVA were used to analyze the effect of dose and ROA of estradiol on serum E2 and T. RESULTS: Oral estradiol was the only ROA demonstrating a linear dose-response, with each 1 mg/day increase associated with a reduction in T of 19.03 ng/dL (p=0.005). Lower T levels were seen with higher doses of transdermal estradiol but a significant dose-response was not demonstrated. Intramuscular estradiol was associated with lower T and higher E2 compared to oral and transdermal ROAs (p<0.001), with many achieving target hormone levels even at low doses. With higher oral estradiol doses, ANOVA detected dose dependent decreases in mean serum LH and FSH (p<.05). CONCLUSION: Oral estradiol can be titrated to achieve a stepwise decrease in serum T. The intramuscular ROA appears to be the most potent delivery of estradiol with impact on serum hormone levels with doses on the low end of guideline-suggested ranges. Serum T may be a more reliable biomarker than E2 for managing feminizing GAHT. Serum LH and FSH may also help with the management of feminizing GAHT.

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.

Gender-Affirming Surgery: Perioperative Medical Care.

OBJECTIVE: Gender-affirming surgeries are becoming increasingly common in the United States. For many transgender and gender-diverse patients, gender-affirming surgery is a critical aspect of their overall health and wellness and has a significant impact on their social functioning. Although often the role of the primary care provider, endocrinology specialists may also need to counsel their patients and collaborate with surgical teams. METHODS: This narrative review provides an overview of the preoperative assessment and perioperative management for the most common gender-affirming surgeries. RESULTS: Preoperative assessment prior to gender-affirming surgeries can resemble assessment for other surgeries. CONCLUSION: In the absence of data specific to gender-affirming surgeries, risk stratification and amelioration must use surrogate data from other populations.

Development and Validation of Urological and Appearance Domains of the Post-Affirming Surgery Form and Function Individual Reporting Measure (AFFIRM) for Transwomen following Genital Surgery.

PURPOSE: As feminizing gender-affirming surgery becomes increasingly accessible, functional outcomes are increasingly relevant. We aimed to develop and validate the first patient-reported outcome questionnaire focusing on postoperative symptomatology and quality of life. MATERIAL AND METHODS: Questions were developed from interviews with postoperative transwomen followed by face validation from a multispecialty clinician group. The measure was co-administered with established relevant questionnaires for concurrent validity testing. Participants were asked to complete the questionnaire at baseline and at a 2-week retest interval. RESULTS: The AFFIRM questionnaire is a 33-item patient-reported outcome measure comprising Appearance, Urological and Gynecologic domains, each scored to create a composite AFFIRM score. A total of 102 women participated, with 60% completing the test-retest. The overall Cronbach's α for AFFIRM was 0.79, and domain α for AFFIRM-A, AFFIRM-U and AFFIRM-G was 0.85, 0.87 and 0.42, respectively. Test-retest demonstrated score reliability (z values -1.862 to -0.005, p >0.05) with intraclass coefficients demonstrating moderate to good absolute correlation (0.54 to 0.88). The AFFIRM-A and AFFIRM-U correlated well with the Genital Appearance Satisfaction Measure and Urinary Distress Inventory-6, respectively (ρ 0.556 and 0.618, p <0.001); 89% of participants confirmed congruence between their external genitalia and gender identity, 87.8% reported clitoral sensation and 75.6% expressed satisfaction with vaginal caliber. Reported symptoms included a misdirected urinary stream (68.9%), nocturia (51.3%), urinary frequency (29.7%) and vaginal pain (46.7%). CONCLUSIONS: Transwomen have diverse symptoms not captured by unstructured questions or cisgender questionnaires. The AFFIRM questionnaire is the first tool available to reliably evaluate outcomes following feminizing gender-affirming surgery.

Minimizing Venous Thromboembolism in Feminizing Hormone Therapy: Applying Lessons From Cisgender Women and Previous Data.

OBJECTIVE: To review he impact of estrogen-containing feminizing hormone regimens on transgender individuals' risk for VTE. METHODS: We evaluated VTE risk by screening 1170 relevant studies published from 1994 to 2020, focusing on meta-analysis data. RESULTS: The type of oral estrogen, route of administration, patient demographics, and comorbidities may affect the risk of VTE. Venous thrombosis is the most common vascular complication associated with HT. CONCLUSION: Conjugated equine estrogens and 17-ß estradiol appear to be safer than oral ethinyl estradiol. Transdermal estrogen formulations appear to be the least thrombogenic estrogens. Estrogens used concomitantly with progestins increase the risk of VTE compared to estrogens alone. To date, there are no data to demonstrate the benefit of holding HT prior to vaginoplasty or other gender affirming surgeries. For most young, healthy transgender women, there is little risk of VTE with HT, while older patients with risk factors should be discussed case by case.

CARDIOVASCULAR HEALTH MAINTENANCE IN AGING INDIVIDUALS: THE IMPLICATIONS FOR TRANSGENDER MEN AND WOMEN ON HORMONE THERAPY.

OBJECTIVE: To review screening guidelines for cardiometabolic disease in aging patients and review literature describing the effect of hormone therapy (HT) on several key cardiometabolic processes to inform providers caring for older transgender individuals. METHODS: A traditional literature review was performed using PubMed and Google Scholar databases. RESULTS: The risk of cardiovascular disease increases with age. Exogenous sex hormones may interact with hormone-dependent metabolic pathways and affect some biochemical assays, but they do not necessarily impact clinical outcomes. While long-term HT is associated with an increased risk of some adverse cardiovascular outcomes, modern treatment regimens minimize this risk. CONCLUSION: Screening for cardiometabolic derangements and risk reduction are important for all aging individuals. Currently, there is insufficient evidence to propose separate screening recommendations for transgender individuals on long-term HT. Aging transgender men and women should be monitored for cardiovascular disease in much the same way as their cisgender counterparts.

Caring for the Transgender Patient: Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

The term transgender refers to persons whose gender identity is different from that recorded at birth. Similar to other marginalized populations, transgender patients commonly experience discrimination in the health care setting, and they may not have access to medical professionals who can provide competent care. In addition to primary medical and preventive health care, transgender patients need access to gender-affirming interventions, including hormone therapy and surgeries. In 2017, the Endocrine Society updated its clinical practice guideline for the care of transgender persons on the basis of the best available evidence from systematic reviews and individual studies. Among its general requirements for adolescents and recommendations for adults were the following: Involvement of a mental health professional who is knowledgeable about the diagnostic criteria for gender dysphoria and criteria for gender-affirming treatment, has training and experience in assessing psychopathology, and is willing to participate in ongoing care. Hormone therapy should be offered to transgender adult patients, with levels maintained within the normal range for gender identity and treatment appropriately monitored. Clinicians involved in the care of transgender adult patients should be knowledgeable about diagnostic criteria for gender dysphoria/gender incongruence, the use of medical and surgical gender-affirming interventions, and appropriate monitoring for reproductive organ cancer risk. Here, 2 clinicians with expertise in this area debate whether psychological evaluation is warranted in a transgender patient requesting gender-affirming hormones or surgery, the potential risks and benefits of estrogen therapy, and the role of the primary care practitioner in the care of transgender persons.

HIGH BODY MASS INDEX IS A SIGNIFICANT BARRIER TO GENDER-CONFIRMATION SURGERY FOR TRANSGENDER AND GENDER-NONBINARY INDIVIDUALS.

Objective: Transgender and gender-nonbinary individuals (TGNB) are disproportionately impacted by obesity. In addition to the associated health impact, obesity represents a significant barrier to accessing gender-confirmation surgery (GCS). The purpose of this study was to determine the prevalence of obesity among TGNB surgical candidates at an urban academic medical center and evaluate the efficacy of self-monitored weight management. Methods: The study was conducted at the Center for Transgender Medicine and Surgery at Mount Sinai in New York City. Data abstraction from a quality improvement database was completed for patients with a documented body mass index (BMI) and a GCS consult from October 2015 through February 2019. A total of 1,457 TGNB patients with a documented BMI and a GCS consult in the historical period of review were included in analysis. Data were abstracted to determine the prevalence of obesity among GCS candidates and evaluate the current default pre-operative self-monitored weight management protocol. Results: Of 1,457 TGNB patients, 382 (26%) were obese (BMI ≥30 kg/m2) at initial surgical consult. In addition, 369 (27%) were obese at a subsequent follow-up, suggesting no statistically significant change in the rate of obesity among evaluated TGNB despite self-monitored weight management (P = .5272). Conclusion: Obesity is a significant barrier to gender affirming surgery for transgender individuals. Self-monitored weight management is an unsuccessful strategy for improvement even among individuals who would be predicted to be motivated. Abbreviations: BMI = body mass index; CTMS = Center for Transgender Medicine and Surgery (at Mount Sinai); GCS = gender confirmation surgery; TGNB = transgender and gender-nonbinary.

Care of the Transgender Patient.

Transgender persons are a diverse group whose gender identity differs from their sex recorded at birth. Some choose to undergo medical treatment to align their physical appearance with their gender identity. Barriers to accessing appropriate and culturally competent care contribute to health disparities in transgender persons, such as increased rates of certain types of cancer, substance abuse, mental health conditions, infections, and chronic diseases. Thus, it is important that clinicians understand the specific medical issues that are relevant to this population.

A REVIEW OF BREAST DEVELOPMENT IN CISGENDER WOMEN AND IMPLICATIONS FOR TRANSGENDER WOMEN.

Objective: The objective of this article is to describe the hormonal pathways required for breast development in cisgender women and to review the current available literature describing breast growth and breast cancer risk in transgender women. Methods: Literature review and discussion. Results: Early mammary tissue development occurs prenatally. This process is hormone-independent and occurs similarly in males and females. Breast tissue is quiescent until puberty, at which time surging estrogen levels in cisgender girls mediate breast development and growth. Adult breast tissue composition further evolves in cisgender women during pregnancy, lactation, and menopause, revealing the ever-changing interplay between breast structure and hormonal environment. Conclusion: Breast growth is a significant physical endpoint in the hormonal treatment of transgender women. Transgender hormone regimens, which typically pair an estrogen with an anti-androgen, can help achieve this goal.

Bone Densitometry in Transgender and Gender Non-Conforming (TGNC) Individuals: 2019 ISCD Official Position.

The indications for initial and follow-up bone mineral density (BMD) in transgender and gender nonconforming (TGNC) individuals are poorly defined, and the choice of which gender database to use to calculate Z-scores is unclear. Herein, the findings of the Task Force are presented after a detailed review of the literature. As long as a TGNC individual is on standard gender-affirming hormone treatment, BMD should remain stable to increasing, so there is no indication to monitor for bone loss or osteoporosis strictly on the basis of TGNC status. TGNC individuals who experience substantial periods of hypogonadism (>1 yr) might experience bone loss or failure of bone accrual during that time, and should be considered for baseline measurement of BMD. To the extent that this hypogonadism continues over time, follow-up measurements can be appropriate. TGNC individuals who have adequate levels of endogenous or exogenous sex steroids can, of course, suffer from other illnesses that can cause osteoporosis and bone loss, such as hyperparathyroidism and steroid use; they should have measurement of BMD as would be done in the cisgender population. There are no data that TGNC individuals have a fracture risk different from that of cisgender individuals, nor any data to suggest that BMD predicts their fracture risk less well than in the cisgender population. The Z-score in transgender individuals should be calculated using the reference data (mean and standard deviation) of the gender conforming with the individual's gender identity. In gender nonconforming individuals, the reference data for the sex recorded at birth should be used. If the referring provider or the individual requests, a set of "male" and "female" Z-scores can be provided, calculating the Z-score against male and female reference data, respectively.

Gaps in transgender medical education among healthcare providers: A major barrier to care for transgender persons.

A lack of access to knowledgeable providers is the greatest reported barrier to care for transgender individuals. The purpose of this manuscript is to review the recent literature characterizing transgender medicine education for medical providers and to summarize effective interventions for improving education in transgender care. The PubMed database was searched for all literature that assessed transgender medical education among physicians or trainees and all papers that reported results of transgender-specific educational interventions. Literature that only evaluated general lesbian, gay, bisexual, and transgender (LGBT) educational interventions was excluded. The lack of education in transgender care continues among providers across all levels of medical education from medical students and physician trainees to primary care providers, endocrinologists and other specialists involved in transgender care. Several interventions have been shown to effectively improve transgender knowledge and cultural competency. Education among healthcare providers is deficient and is considered a major barrier to care for transgender individuals. Effective interventions should be applied to fundamental medical education. Additional focused education also should be taught with specialty-appropriate content to produce needed proficiency among providers of transgender care.

PROLACTIN LEVELS DO NOT RISE AMONG TRANSGENDER WOMEN TREATED WITH ESTRADIOL AND SPIRONOLACTONE.

OBJECTIVE: Existing transgender treatment guidelines suggest that there is a need to monitor prolactin levels in patients receiving transfeminine hormone treatment. Also, recent studies suggest that use of cyproterone acetate as an adjunctive anti-androgen during transgender hormone treatment may elevate serum prolactin. We sought to determine whether the reported relationship between transfeminine estradiol treatment and hyperprolactinemia would be evident when the regimen used spironolactone as the adjunctive anti-androgen. METHODS: Estradiol levels, testosterone levels, prolactin levels, body mass index (BMI), and prescribed spironolactone dosage were extracted from the electronic medical records of 98 de-identified transgender women treated with estrogen therapy at the Endocrinology Clinic at Boston Medical Center (BMC). Up to 6 years of data were available for some patients. RESULTS: We found no statistically significant relationship between prolactin and any of the other measures. No estrogen dose-associated elevations in prolactin were found. None of the patients were diagnosed with prolactinoma. CONCLUSION: Our data suggest that there may be no significant rise in prolactin when transgender women are treated with estrogen along with spironolactone as the adjunct anti-androgen. It may be unnecessary to monitor prolactin in patients on this treatment combination. ABBREVIATIONS: BMI = body mass index; BMC = Boston Medical Center; HT = hormone therapy.

TESTOSTERONE LEVELS ACHIEVED BY MEDICALLY TREATED TRANSGENDER WOMEN IN A UNITED STATES ENDOCRINOLOGY CLINIC COHORT.

OBJECTIVE: Most transgender women depend on medical treatment alone to lower testosterone levels in order to align physical appearance with gender identity. The medical regimen in the United States typically includes spironolactone and estrogens. The purpose of this cross-sectional study was to assess the testosterone suppression achieved among transgender women treated with spironolactone and estrogens. METHODS: Testosterone and estradiol levels were extracted from the electronic medical records of 98 anonymized transgender women treated with oral spironolactone and oral estrogen therapy at the Endocrinology Clinic at Boston Medical Center. RESULTS: Patients starting therapy required about 9 months to reach a steady-state testosterone, with significant heterogeneity of levels achieved among patients. Patients with normal body mass index (BMI) had higher testosterone levels, whereas patients with obese BMI had lower testosterone levels throughout treatment. Stratification of patients by age or spironolactone dosage revealed no significant difference in testosterone levels achieved. At steady state, patients in the highest suppressing quartile were able to achieve testosterone levels of 27 ng/dL, with a standard deviation of 21 ng/dL. Measured serum estradiol levels did not change over time and did not correlate with dosage of estradiol administered. CONCLUSION: Among a cohort of transgender women treated with spironolactone and estrogen, the highest suppressing quartile could reliably achieve testosterone levels in the female range at virtually all times. The second highest suppressing quartile could not achieve female levels but remained below the male range virtually all of the time. One quartile was unable to achieve any significant suppression. ABBREVIATIONS: BMC = Boston Medical Center BMI = body mass index CPY = cyproterone acetate LC-MS/MS = liquid chromatography-tandem mass spectrometry Q = quartile.

ESTROGEN LEVELS DO NOT RISE WITH TESTOSTERONE TREATMENT FOR TRANSGENDER MEN.

OBJECTIVE: Existing transgender treatment guidelines suggest that for transmasculine treatment, there is a possible need for estrogen-lowering strategies adjunct to testosterone therapy. Further, guidelines advocate consideration of prophylactic female reproductive tissue surgeries for transgender men to avoid the possibility of estrogen-related health risks. Despite the paucity of objective data, some transgender men seek conversion inhibitors. We sought to determine estradiol levels in transgender men treated with testosterone therapy and the change in those levels with treatment, if any. METHODS: Estradiol levels were extracted from the electronic medical records of 34 anonymized transgender men treated with testosterone therapy at the Endocrinology Clinic at Boston Medical Center. Data were sufficient to observe 6 years of follow-up. RESULTS: With increased testosterone levels in trans-gender men, a significant decrease in estradiol levels was noted. There was a significant negative correlation between testosterone levels and body mass index, which may serve to explain part of the mechanism for the fall in estradiol levels. Even though the fall in estradiol levels was significant statistically, the actual levels remained within the normal male range, even with 6 years of follow-up. CONCLUSION: These data suggest that when exogenous testosterone is used to achieve normal serum male testosterone levels for transgender men, it is converted to normal male levels of estradiol, with some decline in those estradiol levels that might be attributable to a fall in fat mass. There appears to be no role for aromatase conversion inhibitors or other estrogen-reducing strategies in trans-gender men. Abbreviation: BMI = body mass index.

EXOGENOUS TESTOSTERONE DOES NOT INDUCE OR EXACERBATE THE METABOLIC FEATURES ASSOCIATED WITH PCOS AMONG TRANSGENDER MEN.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a complex condition which can include menstrual irregularity, metabolic derangement, and increased androgen levels. The mechanism of PCOS is unknown. Some suggest that excess production of androgens by the ovaries may cause or exacerbate the metabolic findings. The purpose of this study was to assess the role of increased testosterone on metabolic parameters for individuals presumed to be chromosomally female by examination of these parameters in hormone-treated transgender men. METHODS: In 2015 and 2016, we asked all transgender men who visited the Endocrinology Clinic at Boston Medical Center treated with testosterone for consent for a retrospective anonymous chart review. Of the 36 men, 34 agreed (94%). Serum metabolic factors and body mass index (BMI) levels for each patient were graphed over time, from initiation of therapy through 6 years of treatment. Bivariate analyses were conducted to analyze the impact of added testosterone. RESULTS: Regressions measuring the impact of testosterone demonstrated no significant changes in levels of glycated hemoglobin (HbA1c), triglycerides, or low-density-lipoprotein cholesterol. There was a statistically significant decrease in BMI with increasing testosterone. There was also a statistically significant decrease in high-density lipoprotein levels upon initiation of testosterone therapy. CONCLUSION: Testosterone therapy in transgender men across a wide range of doses and over many years did not result in the dyslipidemia or abnormalities in HbA1c seen with PCOS. Instead, treatment of transgender men with testosterone resulted only in a shift of metabolic biomarkers toward the average physiologic male body. ABBREVIATIONS: BMI = body mass index; HbA1c = glycated hemoglobin; HDL = high-density lipoprotein; LDL = low-density lipoprotein; PCOS = polycystic ovary syndrome.