Abstract

Transgender or trans individuals have a gender identity or gender expression that differs from the sex they were assigned at birth.  Many trans people elect to undergo cross-sex hormone therapy (CSHT) to encourage the development of desired secondary sex characteristics for their emotional and physical wellbeing and personal safety. While the medical community is beginning to address health disparities experienced by trans people and more literature is being published on the health outcomes for this population, the independent effect of CSHT on patients’ physical health has not been studied extensively. This review will examine the impact of CSHT on trans patients’ cardiovascular, metabolic, and bone health.

Introduction

There are about 1.4 million transgender adults in the United States, and this estimate grows slightly each year as more people feel comfortable identifying themselves as such (Flores, 2016). Although trans people are better represented in popular culture today than in the past, many feel unsafe in their daily life due to discrimination they face because of their gender identity. This discrimination is also present in the medical field: 33% of trans individuals surveyed in the US Transgender Survey report that they have had one or more “negative experiences”[1] in clinical settings and 23% have forgone medical care out of fear that they will be mistreated due to their gender identity (James, 2016 p. 97). Healthcare providers’ individual attitudes towards the community are changing and transgender health is becoming a more prevalent focus in research. Current guidelines are more comprehensive and sensitive to the needs of trans patients, but many physicians still feel unprepared to treat their trans patients. In fact, 24% of trans individuals report having to teach their physicians how to care for them, which can create a hostile environment for the patient (James, 2016). In some cases, physicians cannot predict exactly how a medical intervention would interact with gender-affirming treatments the patient has undergone. A lack of training as well as a lack of nuanced research on long-term health outcomes for this population are two factors that contribute to this discomfort among providers. While the relationship between hormone therapy (HT) on the prognosis of HIV, prostate cancer, and breast cancer in the trans community is well studied, the relationship between gender-affirming treatments and other aspects of trans patients’ health is unclear (Deutsch, 2016; IOM, 2011).

There is a general consensus that hormone therapy and other gender-affirming treatments do not induce any diseases, but patients with pre-existing conditions who undergo treatment might need to go through a process of trial and error to determine which interventions or dosages are safe for them. To address this problem, this review will summarize the latest research on health outcomes for trans patients, specifically for trans men and women who are undergoing cross-sex hormone therapy (CSHT).  It will analyze the effect of CSHT on the general cardiovascular, metabolic, and bone health of trans patients. This will be done by comparing the morbidity rates and prevalence of risk factors for common cardiovascular, metabolic, and bone conditions between trans populations undergoing CSHT and cis populations. Outcomes for these broad categories of health are not well documented - this review will both outline what is known and highlight gaps in the literature that should be prioritized. 

This review will focus on outcomes for men and women who undergo hormone therapy indefinitely to suppress undesirable secondary sex characteristics and promote the development of the characteristics of the desired gender. While non-binary populations are important to study, their hormone regimens vary depending on individuals’ original hormone levels and the physical changes they wish to induce. As a result, it is easier to make generalizations using individual hormone levels than it is to characterize nonbinary patients as a group.[2]

Impact of CSHT on Cardiovascular Health

Undergoing CSHT is associated with worsening risk factors for cardiovascular disease (CVD) in both trans men and trans women, but the treatment does not significantly affect morbidity or mortality due to CVD (Deutsch, 2016; Streed, 2017). The risk factors in question are hypercholesterolemia, hypertriglyceridemia, diabetes mellitus, hypertension, and depression. Depression and hypertension are exacerbated by minority stress and lifestyle factors such as smoking, which is more common in TW than in TM, cis men, or cis women (Asscheman, 2011). Many existing studies do not control for these external factors, so it is unclear whether CSHT alone significantly increases the risk of CVD. CSHT is not associated with higher morbidity or mortality rates for any other cardiovascular conditions in TM, but TW experience higher incidence rates of venous thromboembolism (VTE) (Fernandez, 2016; Quinn, 2017; Streed, 2017).

Incidence of Hematologic Disease

Ethinyl estradiol is a formulation known to significantly increase the risk of VTE. In the Amsterdam cohort, Asscheman and colleagues observed activated protein C (APC) resistance and decreased plasma protein S levels in TW taking ethinyl estradiol (Asscheman, 2011). As both proteins help trigger the anti-coagulation response in blood, it appears that ethinyl estradiol interferes with the body’s ability to resolve clots. Because of this risk, doctors are now advised to prescribe other formulations of estradiol. There is also a weak association between the use of non-pregane derived progestin in conjunction with oral (but not transdermal) estradiol and increased risk for VTE in post-menopausal women (Canonico, 2007). Other studies have found that TW have a higher risk of myocardial infarction (MI) and ischemic stroke (Iwamoto, 2019). As they did not control for lifestyle factors or clarify which formulations the TW in the study were taking, it is unclear whether ethinyl estradiol, the administration of exogenous estradiol in general, or external factors were the cause of these other cardiovascular problems. Under the current guidelines, TW who have clotting disorders or are in a hypercoagulable state are prescribed anticoagulants on the same basis as cis patients and can initiate CSHT after a discussion of associated risks (Deutsch, 2016). If a patient is diagnosed with a VTE, CSHT is halted for the duration of “acute treatment” and anticoagulants are prescribed based on guidelines used for cis patients (Deutsch, 2016 p. 41). As trans individuals have a higher incidence rate or myocardial infarctions and certain estrogen formulations place TW at higher risk for VTE, clinical trials on the effect of different testosterone and estrogen formulations and dosage levels on thrombogenicity would be beneficial (Meyer, 2017).

Impact of CSHT on Metabolic Health

Studies present conflicting findings on the effect of CSHT on metabolic markers depending on the geographical location where the study was conducted, the mean age of the participants, and the number of years participants had been undergoing HT (Iwamoto, 2019). In a small, retrospective study conducted by Fernandez and colleagues, initiation of CSHT did not have an adverse effect on patients’ metabolic health. The metabolic markers TW and TM changed minimally; the metabolic profiles of the TW improved by the end of the study period, and TM had significantly elevated creatinine, hemoglobin, and hematocrit levels and higher BMIs (Fernandez, 2016). A slightly larger study found increased insulin resistance in TW and TM compared to control groups of cis women and men, respectively (Gooren, 2014). While these findings indicate that CSHT did not significantly impact the risk factors for metabolic conditions, the patients in the Fernandez study were only observed for 18 months. Another prospective study found that TW had higher HDL and lower LDL levels than control groups of cis men or cis women (Elbers, 2003).  However, TW in this study also experienced more weight gain and increased blood pressure, so there is insufficient evidence to conclude that exogenous estrogen played a protective role or had any impact on the lipid profiles of the participants (Elbers, 2003). 

Longer cohort studies that tracked metabolic markers do not present any conclusive findings and are limited because the experimental populations are skewed by age, as TW have a greater mean age than TM. Because there is no compelling evidence that CSHT increases the morbidity for metabolic conditions like diabetes mellitus in otherwise healthy individuals, physicians currently screen trans patients the same way they would their cis counterparts (Deutsch, 2016). However, there are no studies on the management of diabetes or obesity in trans patients. While undergoing CSHT has appears to have a minimal effect on the metabolic markers of healthy trans individuals, the effect of HT on individuals that already have these two very common conditions is unknown (Fernandez, 2016). 

Impact of CSHT on Bone Health

CSHT does not pose a significant threat to the bone health of healthy adult patients. On average, TW have lower bone mineral density (BMD) than age-matched men before any gender-affirming treatments are administered, possibly due to lifestyle factors such as activity level or higher rates of Vitamin D deficiency (Rothman, 2019). Initiating CSHT improves the bone health of TW, as exogenous estrogen increases BMD (Singh-Ospina, 2017). There is no clear trend in BMD changes for TM taking testosterone. Rothman concluded that the BMD of TM does not differ significantly from the BMD of cis women before or after undergoing hormone therapy (Rothman, 2019). In contrast, an earlier study on the impact of long term CSHT (>10 years) on the bone health of TM found that test group had increased cortical bone mass compared to cis women, suggesting that testosterone helps maintain bone mass (Caenegem, 2012).  Hormone therapy, specifically GnRH agonist drugs, has a greater impact on trans youth than on trans adults. Net cortical bone thickness and overall bone size increases during early puberty, and cis boys and girls follow very different growth patterns (Rothman, 2019). Taking puberty blockers during this process is thought to disrupt the normal progress of bone development. However, it is unclear how much bone density and size will vary compared to the projected growth of the sex assigned at birth and whether any observed changes will lead to significantly weakened bones 50 or so years down the line. As GnRH agonists are associated with osteopenia and osteoporosis when they are used to treat prostate cancer, it is possible that the drug could have deleterious effects in this case as well (Bruder, 2002). The effects of GnRH agonists are largely reversible, but it is important to know how the drug modifies bone development during puberty so that guidelines for its use can be established. 

Conclusion

In summary, CSHT does not significantly increase morbidity or mortality for cardiovascular, metabolic, or bone pathology in otherwise healthy patients. However, the effect of CSHT on pre-existing cardiovascular or metabolic problems or on the bone health of trans youth is largely unknown. There is an urgent need for more research on the long-term health outcomes for trans patients to improve the quality of care that this population receives.

CSHT is invaluable to the process of socially transitioning; it impacts the psychosocial functioning and wellbeing of trans patients and has been defined as a medical necessity by the World Professional Association for Transgender Health for those who desire to medically transition (Coleman, 2012). The physical changes that the treatment induces can alleviate gender dysphoria, improve self-image, and make trans patients more compliant with treatments for other conditions (Coleman, 2012; Deutsch, 2016). Furthermore, CSHT can make it easier for a trans person to “pass” for a cisgender person, which shields them from discrimination or violence they might face otherwise (Coleman, 2012; Deutsch, 2016; James 2016). CSHT can be started at any age, and trans individuals often self-administer hormones even after undergoing gender-affirming surgeries. CSHT is by far the most common gender-affirming treatment. Thus, physicians need to be prepared to treat trans patients who are taking hormones and understand how HT interacts with patients’ risk factors for other conditions in order to serve the trans population properly.  

Recommendations for Future Research

A common concern among all reviews pertaining to trans health is the lack of randomized controlled trials that test the relationship among different formulations, administration routes, and dosages of CSHT and specific health conditions. Trans populations are difficult to reach for studies and to retain within clinics, so there is also a lack of research on long-term health outcomes for trans patients with any pre-existing conditions. The conclusions that can be drawn from small cohort studies that are not randomized and do not have controls are very limited. For example, though multiple reviews on cardiovascular health in trans populations state that undergoing CSHT is associated with worsening risk factors for cardiovascular disease for both TW and TM, they also note the low validity of the studies referenced (Asscheman, 2011; Feldman, 2016; Meyer, 2017). Because the studies they draw from have small sample sizes, do not control for lifestyle factors, and do not distinguish the formulations the trans patients take or how they administer them, researchers cannot determine whether CSHT is the causative agent. Some studies are limited by their design because they only use comparison groups consisting of cis individuals that share the interest group’s sex assigned at birth.[1] Reviewers may rely on more valid clinical trials that examine the effects of exogenous hormones on cis individuals or animal models to characterize the effect of CSHT on certain body systems, but these findings cannot always be extrapolated to draw conclusions about trans patients.

Since cohort studies have indicated that trans populations have a slightly higher incidence of cardiovascular disease than their cisgender counterparts, long-term studies need to be conducted to determine how exogenous hormones affect risk factors for cardiovascular and cardiometabolic conditions. In addition, research is needed to determine how CSHT and physiological changes associated with the treatment interact with pre-existing conditions like obesity and diabetes. Since trans youth are can be prescribed GnRH agonists at a young age, before their bones are fully developed, it is essential to conduct long-term studies to determine how GnRH modifies bone development, and whether exogenous sex hormones administered later on can fully reverse these changes. GnRH agonists are associated with osteoporosis in adults, so this research is needed to establish what constitutes normal bone density ranges for trans youth. When screening for bone diseases, physicians need to know whether bone health for trans youth should be evaluated based on norms for their sex assigned at birth or whether there is a different characteristic bone growth pattern. 

Developing an educational tool to provide additional training and summarize clinical guidelines for physicians who work with trans patients would also be useful. Existing CME modules for transgender care and LGBT competency trainings already cover the social context of this populations, common comorbidities, certain types of preventative care such as breast exams and pap tests for both TW and TM, and gender affirming treatments in detail. The addition of CME specializations pertaining to primary care for trans patients who have medically transitioned could support physicians and in turn improve trans patients’ experiences in clinical settings.

Ashrita Budharaju is a senior at the University of Florida, where they will graduate with a BS in Biology. Ashrita is passionate about social justice education and aims to incorporate this passion into their practice as a future physician to provide low-barrier care and bridge gaps in health outcomes.

Notes

[1] The most common negative experiences reported by individuals who have seen a provider in the past year were: having to educate their physician about their gender identity in order to receive “appropriate care” (24%), being asked invasive questions (15%), and being denied care related to their medical transition (8%) (James, 2016 p. 97).

[2] The sex hormone levels of men and women (cis or trans) also vary on an individual level but stay within a well-defined range in the larger population.Table 1. Key Terminology for Transgender Health.

[3] An example of this methodological limitation is found the study conducted by Caenegem and colleagues, which compared older TM to cis women and a small group of TM who had not undergone CSHT and did not use a control group of cis men (Caenegem, 2012).

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