Abstract
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.
摘要
在美国和全球范围内, 越来越多的人自我认同为跨性别者和性别非二元者。与此同时, 越来越多的患者接受性别肯定激素治疗(GAHT)以实现性别一致性。GAHT对心血管风险的临床和亚临床标志物产生了广泛影响。与顺性别患者相比, 跨性别患者似乎也有更高的心血管疾病风险, 性别肯定治疗对心血管健康的影响尚不清楚。关于GAHT对心血管结局影响的研究因GAHT治疗方案的差异以及在不同和历史上难以接近的人群中的方法学挑战而受到混淆。目前的心血管指南并没有将性别认同和激素状态纳入危险分层和临床决策。本文就GAHT对跨性别患者心血管风险的心血管代谢影响及临床考虑进行综述。
Introduction
The importance of incorporating sexual orientation and gender identity into all aspects of health care – from representation in research to risk stratification and treatment – has received increasing recognition in recent years. The transgender population is a diverse group of people whose affirmed gender identity – that is, one’s innate sense of gender – differs from their sex assigned at birth, which is usually based on external genitalia. In the USA, 2% of all adults overall identify as transgender and the population appears to be growing, in part due to greater societal acceptance and visibility. The latest Pew survey in 2022 showed that 5% of adults younger than 30 years old identify as transgender or gender non-binary.
The number of transgender people seeking gender-affirming hormone therapy (GAHT) is increasing in parallel [Citation1,Citation2]. While a transgender identity does not necessarily mean that a person will alter their physical appearance through surgical or hormonal interventions, according to the National Transgender Discrimination Survey Report on Health and Health Care, at least 80% of transgender people report having used or planning to use GAHT [Citation3].
Nonetheless, while binary sex – that is, male or female – has long been understood to influence the pathophysiology of cardiovascular diseases (CVDs) such as coronary artery disease, heart failure, stroke, venous thromboembolism and arrhythmias, the burden of CVD within the transgender community has received limited attention relative to other health issues such as mental health, substance use and HIV/AIDS. Recent data from the Behavioral Risk Factor Surveillance Survey from 2014 to 2019 showed that people recorded with female sex at birth and currently identifying as transgender had 2.66 times higher odds of CVD (95% confidence interval 1.60–4.41) compared to those identifying as cisgender. However, the odds of CVD appeared similar between people with male sex recorded at birth regardless of gender status [Citation4].
Factors related to GAHT such as hormone regimen, administration route and duration of treatment can potentially elevate or improve cardiovascular risk. However, the effects of transgender status on major adverse cardiovascular events have been inconsistent, in part due to methodological and ethical challenges such as younger patient age, small sample size and challenges in randomization of hormonal treatment. In this review, we discuss specific cardiovascular risks within the transgender population, and evaluate the current landscape of cardiovascular research in transgender persons as well as the impact of gender-affirming care on cardiac health.
Transgender identity
Transgender identity encompasses a wide spectrum of gender identities and expressions. Historical exclusions of these gender identities from population-based surveys and research data along with societal bias and lack of health provider familiarity contribute to current gaps in knowledge regarding the cardiovascular health of the transgender population. For example, the US Census Bureau included transgender identity in the national census for the first time in 2021. As the language used by transgender and gender non-binary people to describe their gender identity is continuing to evolve, it is important to use the terms most affirming to the specific individual. A person who was assigned male at birth (AMAB) but who identifies as female gendered is often referred to as transfeminine, a transwoman or male-to-female, and a person assigned female at birth but who identifies as male gendered can be referred to as transmasculine, a transman or female-to-male.
Gender-affirming therapy
Gender dysphoria refers to the condition where a person’s gender identity does not align with their sex assigned at birth and may cause significant distress. Many transgender patients who experience gender dysphoria will undergo medical and surgical interventions to realize their gender identity, including interventions such as hormone blockers and cross-sex hormone therapy as well as bilateral oophorectomy or bilateral orchiectomy. The goal of hormone therapy for gender transition is to suppress the secondary sex characteristics of the sex assigned at birth and achieve secondary sex characteristics of the affirmed gender. Professional societies recommend the use of estradiol, androgen blockers and testosterone based on published clinical experience from international centers for transgender care [Citation5,Citation6]. The use of progesterone and selective estrogen receptor modulators is more controversial. presents a summary of select scientific statements and guidelines for the care of transgender and gender diverse patients by specialty.
Table 1. Transgender and gender diverse medical guidelines and select statements by specialty.
A large body of work has supported the finding that GAHT for gender dysphoria can reduce symptoms of anxiety and depression and can improve a patient’s quality of life, particularly when used along with psychosocial support for individuals to attain gender congruence, which is a state where a person’s inner gender identity aligns with their outward appearance [Citation7,Citation8]. But despite these known benefits, there is a lack of strong quality data on the effects of these therapies on cardiac health.
Feminizing regimens
The bioidentical 17β-estradiol, approved by the US Food and Drug Administration (FDA) for use in cisgender women, is the standard of care for people AMAB who are seeking a feminine transition. Synthetic estrogens (e.g. ethinyl estradiol) and conjugated equine estrogens are no longer recommended because the former are associated with increased risk of thromboembolic events and cardiovascular death and both are not detected in commercial estradiol assays [Citation9,Citation10]. There are several different formulations of bioidentical estradiol available in standard pharmacies: pill, intramuscular depot oil suspension (cypionate and valerate), transdermal patch and transdermal gel. Transdermal estradiol is associated with less risk of venous thromboembolism, stroke and myocardial infarction than oral estradiol, as seen in observational studies [Citation11–13]. Oral estrogen also increases triglycerides and reactive oxygen species [Citation14,Citation15]. The World Professional Association for Transgender Health (WPATH) recommends titrating the estradiol dose to achieve a serum level in the premenopausal cisgender female range but below supraphysiologic levels, and the Endocrine Society recommends that the serum estradiol level does not exceed 200 pg/ml [Citation5,Citation6].
Androgen blockers are usually needed in addition to estradiol to suppress testosterone to levels within the cisgender female reference range (<50–75 ng/dl) [Citation16,Citation17]. The first-line androgen blocker in the USA is spironolactone, whereas cyproterone acetate (CPA), a steroid with antiandrogenic and progestin-like activity, is often used in Europe. Second-line agents include 5α-reductase inhibitors (e.g. finasteride, dutasteride) and non-steroidal anti-androgens (e.g. flutamide and bicalutamide). In addition, gonadotropin-releasing hormone (GnRH) agonists (e.g. leuprolide, goserelin) provide the greatest suppression of androgen production by downregulating luteinizing hormone and follicular stimulating hormone (FSH), which in turn decreases testicular testosterone secretion. However, they are often cost-prohibitive and require monthly injection by a health-care provider.
Some providers use progesterone as a part of transfeminine care because of theoretical benefits including enhanced breast growth and structure, an increase in bone mineral density and androgen antagonism [Citation18–20]. However, there have been no randomized controlled trials evaluating these effects in transgender people AMAB. In terms of potential risks, the Women’s Health Initiative (WHI) studies showed that when used together in postmenopausal cisgender women, synthetic progestins and estrogens are associated with an increased risk of coronary artery disease and invasive breast cancer which were not observed in estrogen-only (specifically conjugated equine estrogen) regimens [Citation21]. However, more recent studies have shown that bioidentical progesterone is associated with higher high-density lipoprotein (HDL) and less risk of breast cancer and venous thromboembolism than synthetic progestins [Citation22,Citation23].
Masculinizing regimens
Testosterone is used for the transmasculine transition and the Endocrine Society recommends aiming for serum testosterone levels in the physiologic cisgender male range [Citation24]. Testosterone formulations FDA-approved for use in cisgender men include transdermal gel, intramuscular depot (cypionate or enanthate), nasal spray, subcutaneous testosterone enanthate and oral testosterone. Trained clinicians can also insert testosterone pellets (the brand Testopel is FDA-approved) into the subdermal fat.
Gender non-binary regimens
For gender non-binary people, the University of California, San Francisco (UCSF) and the WPATH recommend that hormone therapy should be individualized to achieve the physical characteristics desired [Citation25]. This may entail lower doses of testosterone for people assigned female at birth. If menses are a source of dysphoria, oral or intramuscular progestogens may be used. Intrauterine devices or surgical hysterectomy are also options for decreasing or eliminating menses, respectively. Gender non-binary people AMAB may choose to use estradiol patches or take lower doses of estradiol. They may also take an androgen blocker without estradiol for a limited amount of time. Another option for transgender people AMAB who do not wish for breast growth is a selective estrogen receptor modulator such as raloxifene, which has an antagonistic effect on breast tissue and agonistic effect on vertebral bones, skin and gynoid fat distribution [Citation26]. Raloxifene is not yet widely used for this purpose.
Gender-affirming hormone therapy and cardiometabolic outcomes
Differences in the vascular distribution and density of sex hormone receptors along with sex-specific modulation of the autonomic nervous system contribute to observed differences in cardiovascular risk among cisgender men and women [Citation27,Citation28]. The cardiovascular risk attributable to changes in sex hormone and sympathetic–parasympathetic regulation across time further compounds with aging, resulting in elevated CVD risk in older men and postmenopausal women [Citation29]. Differences in CVD risk in transgender men and women, however, are less well understood as long-term, high-quality data on the cardiovascular effects of GAHT are scarce, making it difficult to ascertain long-term risk and determine appropriate cardiovascular prevention therapies in a largely young patient cohort. Understanding the impact of GAHT on cardiometabolic outcomes in transgender patients is challenging due to inter-individual variations in hormone regimens, doses and duration of therapy as well as methodological challenges with randomization and follow-up times.
Lipid profile and blood pressure
A few prospective and retrospective studies showed that testosterone is associated with a small increase in blood pressure [Citation30–33], a decrease in HDL and an increase in triglyceride levels [Citation34,Citation35]. Results overall suggest that testosterone is associated with increased dyslipidemia and elevated blood pressure. One recent study showed a low-density lipoprotein (LDL) median increased by 12 mg/dl and a decrease in HDL by 10 mg/dl in transgender men initiating testosterone [Citation36]. The longer-term trajectory of changes in lipid profile and the consequent impact on CVD outcomes remain to be seen. A retrospective longitudinal study conducted in 2021 re-demonstrated the changes in LDL and HDL, and suggested that the decrease in HDL may stabilize after 24 months of therapy [Citation37]. A mean increase in systolic blood pressure of 2.9 mmHg was observed in transgender men within 11–21 months of initiating testosterone, resulting in higher percentage of Stage 1 hypertension [Citation38].
There is considerable heterogeneity in the reported effects of feminizing hormones on lipid metabolism and blood pressure. The associations of estrogen with blood pressure in those AMAB were inconsistent among several studies [Citation10,Citation31,Citation33,Citation39]. In terms of lipids, although estrogen is associated with increases in triglycerides in some studies, this relationship is not found in all studies [Citation35,Citation39,Citation40]. These results in transgender women may have been affected by progesterone use, which was variably reported. CPA compared to leuprolide acetate in the suppression of gonadotrophins (luteinizing hormone and FSH) and testosterone has differential effects on lipids: leuprolide was associated with an increase in total cholesterol and HDL, and CPA with a reduction in total cholesterol and HDL over 1 year of treatment [Citation41].
In a large observational study, most transgender women who began feminizing hormones experienced a decrease in mean systolic blood pressure of 6 mmHg [Citation38]. However, a quarter of the transgender women had a ≥5 mmHg increase in either systolic or diastolic blood pressure in the opposite direction of the overall trend after GAHT initiation. Changes in diastolic blood pressure have been found to be more variable across these studies. The variable effects of estrogen on blood pressure may be related to the type and mode of delivery, for example with oral estradiol valerate compared to transdermal estrogen or with co-administration of androgen antagonists. In studies in which CPA was used as the androgen blocker and the estrogen regimen consisted of ethinyl estradiol or transdermal estradiol, both systolic and diastolic blood pressure increased significantly from baseline to 1 or 2 years after starting therapy [Citation33,Citation42].
Central adiposity and obesity
Body fat percentage tends to increase after starting feminizing hormones and decrease after starting testosterone. One study of 55 transfeminine patients showed that the mean body mass index (BMI) increased by 2% after 12 months on hormones and the mean body fat percentage increased by 32% [Citation43]. In the same study, among 35 transmasculine patients, mean BMI increased by 4% but there was a decrease of 15% in mean body fat percentage. Another more recent study of 470 patients showed that weight increased within 2–4 months of testosterone initiation in transmasculine people and after 21 months in transfeminine people [Citation44]. The prevalence of obesity was higher in the transmasculine group at baseline (39%) compared to the transfeminine group (25%) and a greater proportion gained 5 kg or more after initiation of hormones.
The effects of GAHT on central adiposity and obesity are confounded by higher rates of food insecurity, poverty and psychosocial distress among transgender people compared to the cisgender population [Citation45]. Studies have also found that transgender men and women are less likely to meet aerobic and muscle-strengthening activity recommendations compared to cisgender peers, particularly when beginning their gender transition [Citation46]. Transgender patients cite both internal barriers such as body dissatisfaction as well as external or environmental barriers such as lack of appropriate changing facilities and sport clothing as chief barriers to physical activities.
Glucose metabolism and insulin resistance
A cross-sectional study showed that there was no difference in insulin resistance as measured by Homeostatic Model Assessment of Insulin Resistance (HOMA2-IR) between transmen who have been on GAHT for at least 12 months and age-matched cisgender women [Citation47]. Furthermore, many studies have shown that testosterone use is not associated with changes in glucose metabolism [Citation9,Citation48,Citation49] in those assigned female at birth. In fact, some studies showed that insulin resistance decreased after testosterone administration in transgender men [Citation43,Citation50], although this effect did not reach statistical significance in the study by Shadid et al. [Citation43].
Transgender women tended to become more insulin resistant after at least 6 months on a feminizing regimen, as seen in multiple studies in which different formulations of estrogens and anti-androgens were used [Citation43,Citation49,Citation51–53]. In addition, one study of 41 transwomen on a feminizing regimen for at least 12 months showed that they had higher insulin resistance than 30 age-matched cisgender men [Citation47]. Despite these observed differences in insulin sensitivity after starting feminizing hormones, a recent study from Amsterdam showed that the incidence of diabetes (as inferred by the first dispensing of a glucose-lowering agent) is not different in transgender individuals (on either a feminizing or masculinizing regimen) compared to people of the same birth-assigned sex in the general population [Citation54]. When transgender male and female youths on GnRH agonists for at least 11 months were matched to cisgender youths on birth-assigned sex, age and BMI, transgender youths assigned any sex at birth were found to have lower insulin sensitivity and higher HbA1c than their cisgender counterparts [Citation55].
In contrast, results of the Study of Transition Outcomes and Gender (STRONG), a retrospective–prospective American cohort study conducted in California and Georgia which assessed transgender adults both on and off GAHT, appeared to confirm the laboratory findings. There was no significant difference in the prevalence of type 2 diabetes in transgender men compared to cisgender men or women. However, type 2 diabetes was more prevalent in transgender women compared to cisgender women but not when compared with cisgender men, suggesting inherent risk related to male sex assigned at birth [Citation56].
Vascular aging and inflammation
Vascular aging is characterized by arterial stiffening and endothelial dysfunction – a state of reduced nitric oxide-mediated vasodilation, increased vascular smooth muscle tone, elastin degradation and collagen deposition. Endothelial dysfunction which precedes clinically detectable atherosclerotic plaque may be an important marker for cardiovascular risk stratification in transgender adults given the overall younger age of the population. There is also increasing recognition that chronic inflammation adversely affects the progression of a range of CVDs including atherosclerosis, atrial fibrillation and heart failure [Citation57].
Testosterone and estradiol have been implicated in vascular aging through endothelial-dependent vasodilation, inflammation and oxidative stress [Citation58,Citation59]. Estrogen has immunomodulatory and vasodilatory effects and has been shown to effect positive vascular remodeling following injury [Citation60]. Conversely, in vivo studies have shown that testosterone can impair endothelial function, although there is also research showing that testosterone deficiency may accelerate vascular aging in men and women and testosterone replacement may improve vascular stiffness in cisgender men with androgen insufficiency.
In a small study of transgender men and cisgender women with no history of CVD, vasodilatory testing showed diminished endothelial function in transgender men on testosterone therapy [Citation58]. Similar studies suggests changes in subclinical markers of CVD such as carotid intima media thickness [Citation61] and brachial–ankle pulse wave velocity [Citation32] as well as increases in proinflammatory cytokines such as IL-6 and TNF-α and adhesion molecules [Citation62]. Broadly, estrogen when used in feminizing therapies for transgender women has not been shown to have significant adverse effects on these markers of vascular aging in the short to medium term [Citation61,Citation63]. Early significant increases in proinflammatory cytokines such as IL-1 and coagulation factors were observed with oral estrogen but were not seen with transdermal estrogen [Citation46]. However, these changes appeared to return to baseline after 6 months of either oral or transdermal administration.
Cardiovascular mortality and myocardial infarction
A number of studies have described increased cardiovascular mortality and myocardial infarction in transgender patients [Citation9,Citation48]. In 2021, the largest observational study to date showed persistent elevated overall mortality and cardiovascular mortality over five decades in Dutch transgender men and women compared to cisgender peers [Citation64]. Transgender women were 2.6 times more likely to die from CVD compared with cisgender women and had 40% increased risk of cardiovascular death when compared to cisgender men (standardized mortality ratio 1.4, 95% confidence interval 1.0–1.8). Myocardial infarction was the most common cause of cardiovascular death (standardized mortality ratio 3.0, 95% confidence interval 1.7–4.5). Nota et al. found that both transgender men and transgender women experienced higher rates of myocardial infarction than reference cisgender women [Citation65].
Increased prevalence of cardiovascular morbidity and mortality in the transgender population, however, is not clearly linked to the safety of GAHT. In a large randomized controlled trial evaluating the safety of testosterone replacement in cisgender men with hypogonadism and pre-existing or high risk of CVD, treatment with transdermal 1.63% testosterone gel adjusted to maintain physiologic testosterone levels between 350 and 750 ng/dl was not associated with increased adverse cardiac events compared to placebo [Citation66]. Earlier reports of increased cardiovascular death and morbidity in transgender women may be attributable, in part, to the widespread use of ethynyl estradiol until about 2003. Nonetheless, elevated risks of CVD persist in transgender people in recent decades, even as bioidentical estradiol became the standard of care [Citation4,Citation67,Citation68]. Consequently, the observed increased CV death and myocardial infarction risk in transgender people may be associated with the cardiometabolic changes already described, such as changes in blood pressure, lipids, insulin resistance and body composition, when compared to cisgender people. Additionally, the burden of CVD attributable to GAHT in the transgender population is confounded by the elevated psychosocial risk that disproportionately impacts transgender people. Gender minority stress such as gender-based discrimination and bias-motivated aggression as well as structural stressors like anti-transgender laws can perpetuate unhealthy behavioral and coping mechanisms such as tobacco, alcohol and other substance use.
Physiologic changes in hormone levels will occur as transgender and cisgender patients age. However, there is a paucity of data on the effects of GAHT in older transgender people. Changes in lipid profile, insulin resistance and blood pressure observed with GAHT in the younger adult can be expected to persist or worsen with age. Additionally, transgender older adults have been shown to have poorer physical and mental health compared with their cisgender heterosexual, lesbian, gay or bisexual cohorts, which may contribute to elevated cardiovascular health risk [Citation69]. As the transgender population grows older, we may anticipate worse outcomes for CVD. There are no current guidelines on age-adjusted GAHT dosing; however, maintenance doses should be assessed and adjusted for changes in health conditions and aging to attain the desired feminizing or masculinizing effect. More research is needed to determine the ideal formulations of GAHT for optimal cardiovascular health in older transgender patients. presents an overview of current large ongoing trials to evaluate the effects of GAHT on cardiovascular health, to the best of our knowledge.
Table 2. Ongoing trials evaluating cardiovascular effects of gender-affirming hormone therapy.
Conclusions
Transgender people represent a diverse underserved population who face disproportionate cardiovascular risks. Treatment with GAHT to attain gender congruence provides important benefits to transgender patients who seek gender-affirming therapy. GAHT has been shown to have a variety of effects on cardiometabolic outcomes such as lipid profile, insulin sensitivity, body weight and blood pressure. Nonetheless, the impact of GAHT on cardiovascular health is confounded by substantial variation in treatment regimens with gender-affirming hormones, including the dose, type, mode of delivery and duration of use. Transgender patients face additional stressors related to their gender minority status that have been postulated to lead to higher rates of mental health issues such as anxiety, depression and chronic stress. These adverse psychosocial conditions have a significant impact on a wide variety of heart disease including stroke, heart failure, metabolic disease and myocardial infarction.
There is a lack of population-specific cardioprotective recommendations for transgender patients [Citation70]. Given the younger age of the transgender population, subclinical atherosclerotic markers which are currently not well provided for in cardiovascular prevention guidelines may offer added value in refining risk categories and guiding treatment decisions in this population. As detailed herein, there are ample opportunities for future research to better understand and care for this vulnerable population.
Disclosure statement
No potential conflict of interest was reported by the authors.
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