Gender-affirming hormone therapy and cardiovascular health in transgender adults.

A growing number of people identify as transgender and gender non-binary in the USA and worldwide. Concomitantly, an increasing number of patients are receiving gender-affirming hormone therapy (GAHT) to achieve gender congruence. GAHT has far-ranging effects on clinical and subclinical markers of cardiovascular risk. Transgender patients also appear to be at higher risk for cardiovascular diseases compared to their cisgender peers and the impact of gender-affirming therapy on cardiovascular health is unclear. Studies on the effect of GAHT on cardiovascular outcomes are confounded by differences in GAHT regimens and methodological challenges in a diverse and historically hard-to-reach population. Current cardiovascular guidelines do not incorporate gender identity and hormone status into risk stratification and clinical decision-making. In this review, we provide an overview on the cardiometabolic impact and clinical considerations of GAHT for cardiovascular risk in transgender patients.

Breaking the Binary: The Approach to Chest Masculinizing Gender-Affirming Surgery in Trangender Men.

BACKGROUND: The purpose of mastectomy for the transgender patient is to produce a masculine appearance of the chest. A number of algorithms have been proposed for selecting the surgical technique. A holistic and surgical approach to transgender men includes our experience-based classification system for selecting the correct surgical technique. OBJECTIVES: To present and discuss the Transgender Standard of Care and our personal experience. METHODS: Data were collected from the files of female-to-male transgender persons who underwent surgery during 2003-2019. Pictures of the patients were also analyzed. RESULTS: Until May 2021, 342 mastectomies were performed by the senior author on 171 patients. The 220 mastectomies performed on 110 patients until November 2019 were included in our cohort. Patient age was 13.5 to 50 years (mean 22.5 ± 6.1). The excision averaged 443 grams per breast (range 85-2550). A periareolar approach was performed in 14 (12.7%), omega-shaped resection (nipple-areola complex on scar) in 2 (1.8%), spindle-shaped mastectomy with a dermal nipple-areola complex flap approach in 38 (34.5%), and a complete mastectomy with a free nipple-areola complex graft in 56 (50.9%). Complications included two hypertrophic scars, six hematomas requiring revision surgery, three wound dehiscences, and three cases of partial nipple necrosis. CONCLUSIONS: A holistic approach to transgender healthcare is presented based on the World Professional Association for Transgender Health standard of care. Analysis of the data led to Wolf's classification for female-to-male transgender mastectomy based on skin excess and the distance between the original and the planned position of the nipple-areola complex.

Testosterone Therapy With Subcutaneous Injections: A Safe, Practical, and Reasonable Option.

CONTEXT: Injections with intramuscular (IM) testosterone esters have been available for almost 8 decades and not only result in predictable serum testosterone levels but are also the most inexpensive modality. However, they are difficult to self-administer and associated with some discomfort. Recently, subcutaneous (SC) administration of testosterone esters has gained popularity, as self-administration is easier with this route. Available data, though limited, support the feasibility of this route. Here we review the pharmacokinetics and safety of SC testosterone therapy with both long- and ultralong-acting testosterone esters. In addition, we provide guidance for clinicians on how to counsel and manage their patients who opt for the SC route. EVIDENCE ACQUISITION: Systematic review of available literature on SC testosterone administration including clinical trials, case series, and case reports. We also review the pharmacology of testosterone absorption after SC administration. EVIDENCE SYNTHESIS: Available evidence, though limited, suggests that SC testosterone therapy in doses similar to those given via IM route results in comparable pharmacokinetics and mean serum testosterone levels. With appropriate training, patients should be able to safely self-administer testosterone esters SC with relative ease and less discomfort compared with the IM route. CONCLUSION: Although studies directly comparing the safety of SC vs IM administration of testosterone esters are desirable, clinicians should consider discussing the SC route with their patients because it is easier to self-administer and has the potential to improve patient adherence.

Risk of Venous Thromboembolism in Transgender People Undergoing Hormone Feminizing Therapy: A Prevalence Meta-Analysis and Meta-Regression Study.

Background: Although venous thromboembolism (VTE) is a recognized side effect of some formulations of estrogen therapy, its impact in transgender people remains uncertain. The aim of this study was to define pooled prevalence estimate and correlates of VTE in Assigned Males at Birth (AMAB) trans people undergoing gender affirming hormone therapy. Methods: A thorough search of MEDLINE, COCHRANE LIBRARY, SCOPUS and WEB OF SCIENCE databases was carried out to identify suitable studies. Quality of the articles was scored using the Assessment Tool for Prevalence Studies. Data were combined using random effects models and the between-study heterogeneity was assessed by the Cochrane's Q and I2. Results: The eighteen studies included gave information about 11,542 AMAB undergoing gender affirming hormone therapy. The pooled prevalence of VTE was 2% (95%CI:1-3%), with a large heterogeneity (I2 = 89.18%, P<0.0001). Trim-and-fill adjustment for publication bias produced a negligible effect on the pooled estimate. At the meta-regression analysis, a higher prevalence of VTE was significantly associated with an older age (S=0.0063; 95%CI:0.0022,0.0104, P=0.0027) and a longer length of estrogen therapy (S=0.0011; 95%CI:0.0006,0.0016, P<0.0001). When, according to the meta-regression results, the analysis was restricted to series with a mean age ≥37.5 years, the prevalence estimate for VTE increased up to 3% (95%CI:0-5%), but with persistence of a large heterogeneity (I2 = 88,2%, P<0.0001); studies on younger participants (<37.5 years) collectively produced a pooled VTE prevalence estimate of 0% (95%CI:0-2%) with no heterogeneity (I2 = 0%, P=0.97). Prevalence estimate for VTE in series with a mean length of estrogen therapy ≥53 months was 1% (95%CI:0-3%), with persistent significant heterogeneity (I2 = 84,8%, P=0.0006); studies on participants subjected to a shorter length of estrogen therapy (<53 months), collectively produced a pooled VTE prevalence estimate of 0% (95%CI:0-3%) with no heterogeneity (I2 = 0%, P=0.76). Conclusions: The overall rate of VTE in AMAB trans people undergoing gender affirming hormone therapy was 2%. In AMAB population with <37.5 years undergoing estrogen therapy for less than 53 months, the risk of VTE appears to be negligible. Further studies are warranted to assess whether different types and administration routes of estrogen therapy could decrease the VTE risk in AMAB trans people over 37.5 years subjected to long-term therapy. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021229916].

Ovarian, breast, and metabolic changes induced by androgen treatment in transgender men.

Gender-affirming hormone therapy (GAHT) is often provided to transgender people. In this review of the literature, the current knowledge of ovarian, breast, and metabolic changes (body composition, insulin resistance, bone density, cardiovascular risk factors such as lipids, blood pressure, and hematocrit) observed following GAHT in adult transgender men is discussed. A body of literature concurs to describe that long-term androgen therapy in transgender men exerts atrophic effects on the breast. There is currently no evidence of an increased risk of breast cancer. Long-term testosterone treatment induces ovarian effects that become visible after 6 months of therapy. These changes consist of both macroscopic and microscopic alterations of ovarian morphology that mimic the typical ovarian aspect encountered in women with polycystic ovary syndrome but without an effect on antral follicle count. Metabolic effects of long-term androgen treatment in transgender men put them at par with cisgender men in terms of lipid profile, insulin resistance, and overall mortality. Body composition changes as desired after testosterone administration in most transgender men, and insulin resistance decreases with virilization. There are no detrimental effects on bone mineral density. Cardiometabolic risk and morbidity data are currently reassuring, even if certain studies show conflicting results. An increase in blood pressure and a decrease in high-density lipoprotein cholesterol have been reported as risk factors, whereas polycythemia is rare and treatable. Most available data are observational and based on biochemical markers instead of the more direct measures of cardiovascular damage. An explanation for these observed changes is mostly lacking. Psychological stress and lifestyle factors are often forgotten in a much needed integrated approach.

The uterus in transgender men.

Transgender men experience a disharmony between their birth sex and their intimate sense of gender belonging. Gender-affirming hormone therapy and gender-affirming surgery (GAS) are often inherently part of the gender-affirming process. In this context, we should ask whether it is better to keep or remove the uterus. Keeping the uterus and ovaries avoids a surgical procedure and a pubic scar. Furthermore, it preserves fertility and the possibility of carrying a baby. On the other hand, keeping the uterus is often psychologically unbearable for transgender men and the long-term effects of androgens on the uterus and ovaries remain uncertain. Conversely, hysterectomy and oophorectomy are part of the GAS process. New mini-invasive surgery procedures for hysterectomies decrease the risks and limit the likelihood of scars to a minimum. In practice, the data suggest that very few transgender men carry a pregnancy and/or use their oocytes after gender-reaffirming treatment. Clinicians should counsel their transgender men patients about the definitive infertility consequences of hysterectomy and oophorectomy and discuss all fertility preservation options before undertaking GAS. Individualized approaches must be preferred to systematic procedures regarding the personal decision to keep or not keep the uterus and ovaries.

Headache in transgender and gender-diverse patients: A narrative review.

OBJECTIVE: To summarize the unique aspects of managing headache in gender minorities and current research in this area including the potential relationship between gender-affirming hormone therapy (GAHT) and headache. BACKGROUND: The study of headache in gender minorities is intrinsically important. Gender minorities are medically underserved, and their medical care to date has been limited by socioeconomic disadvantages including stigma and an unsupportive clinical environment. Despite the rising population of transgender and gender-diverse adults and youth, headache research has also been limited. Knowledge of hormonal effects on headache in cisgender patients raises the question of possible effects of GAHT on transgender patients. METHODS/RESULTS: The manuscript is a narrative review of current best practices in treating transgender patients, including the use of appropriate terminology and ways to create a supportive environment. It also contains current guidelines on GAHT and reviews drug-drug interactions and secondary headache related to hormone therapy. We also review transgender headache research and related research on hormonal effects on headache in cisgender individuals. CONCLUSION: Creating a supportive environment for transgender and gender-diverse patients and being knowledgeable about GAHT are key to providing quality headache care. This review identifies further research needs for this population including the epidemiology of headache disorders in sexual minorities and the potential effects of GAHT on headache disorders in transgender patients.

Transgender men: clinical care and implications in reproductive medicine: introduction.

Gender dysphoria, a discrepancy between gender identity and genetically determined sex, is encountered in approximately 0.5% of people uniformly across the world. In the case of transgender men, formerly called female-to-male transsexuals, the available gender-affirming measures, hormone therapy and possible surgical procedures, are multiple and discussed in detail in this series of articles.

Masculinizing gender-affirming surgery for trans men and non-binary individuals: what you should know.

Gender dysphoria, the discordance between one's gender identity and anatomy, affects nearly 25 million people worldwide, and the prevalence of transgender and non-binary identities is increasing because of greater acceptance and awareness. Because of the improved accessibility to gender-affirming surgery (GAS), many providers will care for patients during and after gender transition. For trans men (female-to-male), GAS represents a combination of procedures rather than a single surgery. The particular combination of masculinizing procedures is chosen on the basis of informed patient-provider discussions regarding the patient's goals and anatomy and implemented through a multidisciplinary team approach. In this review, we describe the common procedures comprising masculinizing GAS to improve delivery of specialized care for this patient population.

Toward a Lowest Effective Dose of Cyproterone Acetate in Trans Women: Results From the ENIGI Study.

CONTEXT: Cyproterone acetate (CPA) is a competitive inhibitor of the androgen receptor and exerts negative hypothalamic feedback. It is often used in combination with estrogens in trans women to achieve feminization. However, CPA has been associated with side effects such as changes in liver enzyme concentrations and increases in prolactin concentrations. The question is whether the testosterone-lowering effect, as well as these side effects, are dose dependent. OBJECTIVE: To assess the lowest effective dose of CPA in trans women to prevent side effects. METHODS: This longitudinal study, conducted at gender identity centers in Amsterdam, Ghent, and Florence, is part of the European Network for the Investigation of Gender Incongruence (ENIGI), a multicenter prospective cohort study. Participants were trans women (n = 882) using estrogens only or in combination with 10, 25, 50, or 100 mg CPA daily. The primary outcome measure was the concentration of testosterone at 3 and/or 12 months of hormone therapy. RESULTS: Using estrogens only (without CPA) led to testosterone concentrations of 5.5 nmol/L (standard error of the mean [SEM] 0.3). All doses of CPA resulted in testosterone concentrations below the predefined threshold of suppression of 2 nmol/L (10 mg, 0.9 nmol/L, SEM 0.7; 25 mg, 0.9 nmol/L, SEM 0.1; 50mg, 1.1 nmol/L, SEM 0.1; 100 mg, 0.9 nmol/L, SEM 0.7). Higher prolactin and lower high-density lipoprotein concentrations were observed with increasing doses of CPA. No differences in liver enzyme concentrations were found between the doses. CONCLUSION: Compared with higher doses of CPA, a daily dose of 10 mg is equally effective in lowering testosterone concentrations in trans women, while showing fewer side effects.

Reproductive functions and fertility preservation in transgender women: a French case series.

RESEARCH QUESTION: The reproductive potential of transgender people may be impaired by gender-affirming hormone treatment (GAHT) and is obviously suppressed by gender-affirming surgery involving bilateral orchiectomy. The evolution of medical support for transgender people has made fertility preservation strategies possible. Fertility preservation in transgender women mainly relies on sperm cryopreservation. There are few studies on this subject, and the sample sizes are small, and so it difficult to know whether fertility preservation procedures are feasible and effective in trans women. DESIGN: This retrospective study reports the management of fertility preservation in transgender women referred to the study centre for sperm cryopreservation, and the semen parameters of trans women were compared with those of sperm donors. RESULTS: Ninety-six per cent of transgender women who had not started treatment benefitted from sperm cryopreservation, compared with 80% of those who attempted a therapeutic window and 50% of those receiving hormonal treatment at the time of sperm collection. No major impairment of semen parameters was observed in transgender women who had not started GAHT compared with sperm donors. However, even though the frequency of oligozoospermia was no different, two transgender women presented azoospermia. Some transgender women who had started GAHT could benefit from sperm freezing. None of them were treated with gonadotrophin-releasing hormone (GnRH) analogues. CONCLUSIONS: Parenthood strategies for transgender people have long been ignored, but this is an important issue to consider, especially because medical treatments and surgeries may be undertaken in adolescents or very young adults. Fertility preservation should ideally be offered prior to initiation of GAHT.

Gender-Affirming Surgeries in Transgender and Gender Diverse Adolescent and Young Adults: A Pediatric and Adolescent Gynecology Primer.

Transgender and gender diverse adolescent and young adults (AYA) may seek gender-affirming surgeries (GAS) as part of their gender affirmation. A number of GAS are related to reproductive and sexual health, and pediatric and adolescent gynecology (PAG) clinicians are well positioned as sexual and reproductive health experts to provide care in this area. PAG clinicians may encounter patients presenting for preoperative counseling (including discussions regarding fertility, family building, future sexual function, and choice of oophorectomy at time of hysterectomy), requesting referrals to GAS clinicians, or requiring GAS aftercare, or those seeking general sexual and reproductive health care who have a history of GAS. This article reviews presurgical considerations for AYA seeking GAS, types of GAS, their impact on pelvic, sexual, and reproductive health, and aftercare that may involve PAG providers, with the goal of helping PAG clinicians to better understand these procedures and to empower them to engage collaboratively with GAS teams. With this knowledge, reproductive health clinicians can have an integral role as skilled collaborators in the world of AYA GAS in partnership with GAS surgeons.

Low feasibility of in vitro matured oocytes originating from cumulus complexes found during ovarian tissue preparation at the moment of gender confirmation surgery and during testosterone treatment for fertility preservation in transgender men.

OBJECTIVE: To study the feasibility of in vitro maturation of ovarian tissue oocytes for fertility preservation in transgender men on testosterone treatment. DESIGN: Cross-sectional study SETTING: University hospital PATIENT(S): Eighty-three transgender men enrolled from November 2015 to January 2019 INTERVENTION(S): In vitro maturation of cumulus-oocyte complexes (COCs) harvested at the time of gender confirmation surgery, and fertilization through intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): In vitro maturation, fertilization, and blastulation rates; comparison of morphokinetics with vitrified-warmed oocytes; and analysis of the genetic profiles of embryos. SECONDARY OUTCOMES: association between serum hormone levels; COCs' morphologic characteristics, and vitrification rate. RESULT(S): All participants were on testosterone treatment for a median of 83 (64[Quartile 1]; 113.2[Quartile 2]) weeks. A total of 1,903 COCs (mean per participant, 23 ± 15.8) were collected. The in vitro maturation rate was 23.8%, vitrification rate was 21.5%, and survival rate after warming was 72.6% (n = 151). Intracytoplasmic sperm injection was performed in 139 oocytes. The rate of normal fertilized oocytes was 34.5%, and 25 (52.1%) embryos reached day 3. One blastocyst was achieved on day 5. Aberrant cleavage patterns and early embryo arrest were observed in 22 (45.8%) and 44 (91.7%) zygotes, respectively. Compared with vitrified-warmed donor oocytes, a delay was observed in pronuclei disappearance, t2 (time to reach 2 cell stage) timings, and CC1 (the duration of the 1st cell cycle) and SS3 (synchronization of cleavage pattern (calculated as t8-t5) time intervals. A normal genetic pattern was seen in 42% embryos. The proportion of vitrified oocytes was negatively associated with progesterone (odds ratio, 0.76) and positively associated with antimüllerian hormone serum levels (odds ratio, 1.23). The highest vitrification rate was achieved by the morphologic characteristic 344 at day 0 and by 433 at day 2. CONCLUSION(S): Ovarian tissue oocytes matured in vitro show low developmental capacity in transgender men, when collected under testosterone treatment.

Sperm quality in transgender women before or after gender affirming hormone therapy-A prospective cohort study.

BACKGROUND: Due to recent changes in the legal framework, access to fertility preservation (FP) for transgender individuals has opened up in several countries. In Sweden and the Nordic countries, fertility preservation for medical reasons is fully reimbursed as part of the established tax-funded healthcare services. As this issue is relatively new, procedures for FP have seldom been reported in the transgender patient population. The very limited literature has indicated that transgender women may have poorer sperm quality than cisgender men when assessing samples aimed at semen banking. OBJECTIVES: To assess sperm quality parameters of semen samples provided for FP by transgender women before or after gender affirming hormone therapy (GAHT), and to compare sperm quality with a reference population of unscreened men defined by the World Health Organization (WHO). Additionally, we aimed to describe referral patterns over calendar time and estimate time from referral to semen cryopreservation. MATERIAL AND METHODS: Prospective cohort study of 212 transgender women referred for FP to the Reproductive Medicine Clinic of Karolinska University Hospital, Sweden, between 2013 and 2018. Among 177 individuals that provided semen samples for cryopreservation, 16 had previously received GAHT. RESULTS: Individuals with previous GAHT presented with significantly lower total sperm count than individuals without GAHT (p = 0.002). However, higher proportions of sperm abnormalities were also noted among individuals who had not undergone previous GAHT, compared to the WHO reference population (p < 0.001). Referrals of transgender women for FP increased over time. The median time from referral to semen cryopreservation was 27 days. CONCLUSIONS: A high occurrence of sperm abnormalities was found in transgender women, especially among individuals who had previously received GAHT. The results underline the importance of thoroughly discussing parenthood options and FP with patients early after diagnosis and referring the patients for semen banking preferably before starting GAHT.

Implications for management of ovarian cancer in a transgender man: Impact of androgens and androgen receptor status.

A 36-year-old transgender man (assigned female at birth) on exogenous testosterone therapy was found to have stage IIA ovarian endometrioid carcinoma, and underwent adjuvant chemotherapy. Diffuse androgen receptor expression in the tumor initiated a multidisciplinary discussion regarding the safety of continuing exogenous testosterone as gender-affirming hormone therapy.

Research gaps in medical treatment of transgender/nonbinary people.

With the growing number of transgender and gender-nonbinary individuals who are becoming visible, it is clear that there is a need to develop a rigorous evidence base to inform care practice. Transgender health research is often limited to HIV/AIDS or mental health research and is typically subsumed in larger studies with general LGBTQ focus. Although the number of knowledgeable health care providers remains modest, the model for the medical approach to transgender health is shifting owing to growing social awareness and an appreciation of a biological component. Gender-affirming medicine facilitates aligning the body of the transgender person with the gender identity; typical treatment regimens include hormone therapy and/or surgical interventions. While broadly safe, hormone treatments require some monitoring for safety. Exogenous estrogens are associated with a dose-dependent increase in venous thromboembolic risk, and androgens stimulate erythropoiesis. The degree to which progressing gender-affirming hormone treatment changes cancer risk, cardiac heart disease risk, and/or bone health remains unknown. Guidelines referencing the potential exacerbation of cancer, heart disease, or other disease risk often rely on physiology models, because conclusive clinical data do not exist. Dedicated research infrastructure and funding are needed to address the knowledge gap in the field.

Erythrocytosis in a Large Cohort of Trans Men Using Testosterone: A Long-Term Follow-Up Study on Prevalence, Determinants, and Exposure Years.

CONTEXT: Erythrocytosis is a known side effect of testosterone therapy that can increase the risk of thromboembolic events. OBJECTIVES: To study the prevalence and determinants in the development of erythrocytosis in trans men using testosterone. METHODS: A 20-year follow-up study in adult trans men who started testosterone therapy and had monitoring of hematocrit at our center (n = 1073). RESULTS: 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). CONCLUSION: 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.

Prescribing Isotretinoin for Transgender Patients: A Call to Action and Recommendations.

Case Scenerio: A 26-year-old patient presents to the dermatology clinic with severe nodulocystic scarring acne. The patient identifies as a transgender male and notes that he has been receiving hormone replacement therapy for the past 4 years with weekly intramuscular testosterone injections.