Beyond the Binary

Beyond the Binary

Researchers are expanding the understanding of the body beyond “male” and “female.”
By Isobel Whitcomb

Male or female: For decades, this was the choice that patients and research participants had to make, whether they were checking in at their primary care provider’s office or enrolling in a clinical trial. And for decades, this choice left out an entire group of people: the trans community.

People who identify as transgender and gender non-conforming—umbrella terms referring to people whose gender identity doesn’t match the sex they were assigned at birth—tend to have very different health outcomes from their cisgender peers (people whose gender identity does match the sex they were assigned at birth).

Transgender people experience higher rates of cardiovascular disease, mental illness, chronic illness and some cancers compared to the cisgender population. They’re also less likely to have access to medical care, due to factors such as denied insurance coverage, fear of coming out to medical providers and discrimination in doctor’s offices, according to the 2015 U.S. Transgender Survey from the National Center for Transgender Equality.

Until recently, the little research that did shed light on this population did so with a narrow lens, focusing on mental health or HIV/AIDS, according to a review published in the February 21, 2021, issue of The Journal of Clinical Investigation. That’s changing, but slowly. In 2017, APS published the first animal model for gender-affirming hormone therapy in the American Journal of Physiology–Endocrinology and Metabolism. In 2022, the National Institutes of Health announced it would increase funding for research on gender-affirming care.

A small, growing group of researchers is working to fill the gaps in the understanding of trans bodies and the best ways to care for them—from the potential cardiovascular risks inherent to being trans to the effects of gender-affirming hormone therapy. However, there are still more questions than answers. For physiologists, it’s vital to get up to date on what is known and unknown—and how to approach these gaps in research, from both a research and clinical standpoint.

A Diversity of Experiences

The term “transgender” encompasses a wide swath of experiences. Every trans person has a different understanding of their gender and different goals for their body. For example, not all trans people experience gender dysphoria, which is distress around a perceived misalignment between one’s body and gender.

And to be trans doesn’t necessarily involve medical transition, which is the process of aligning the body with one’s understanding of their gender, usually through gender-affirming hormone therapy or surgery. Many trans people don’t have access to gender-affirming health care; others may not seek it out in the first place, according to a June 2019 report published in Translational Andrology and Urology. For example, around three-quarters of respondents to the 2015 U.S. Transgender Survey reported wanting gender-affirming hormone therapy. A much smaller percentage—19% of trans men (men assigned female at birth) and around half of trans women (women assigned male at birth)—reported wanting gender-affirming genital surgery (labiaplasty or phalloplasty).

It’s also important to understand that for those who do seek out gender-affirming care, these therapies and procedures are lifesaving. According to the Cleveland Clinic, trans people experience higher rates of mood, personality and anxiety disorders than the general population. As many as 82% of transgender people have considered suicide, and 40% have made a suicide attempt, according to the 2015 U.S. Transgender Survey. These issues are substantially lower in people who have received gender-affirming care. An observational cohort study published in February 2022 in JAMA Network Open found that among 104 trans youth, those who received gender-affirming care experienced a 73% decrease in suicidality and 60% decreased risk of depression compared to those who didn’t. Cornell University has compiled over 50 studies that report similar trends.

The data on the benefits of gender-affirming care are unambiguous, says Jesse Moreira-Bouchard, PhD, a cardiovascular physiologist at Boston University. “All our anecdotal evidence suggests that gender-affirming care is good and that it’s working,” they say. But beyond the tenet that gender-affirming care saves lives, the understanding of trans health gets murkier.

The term “transgender” encompasses a wide swath of experiences. Every trans person has a different understanding of their gender and different goals for their body.

Missing the Forest for the Trees

Take cardiovascular health. Moreira-Bouchard got their start as a cardiovascular physiologist focusing on blood pressure. It was during their postdoctoral research that they became interested in the impacts of stress on the cardiovascular health of minoritized populations, particularly trans people. More research, such as a December 2022 report in Circulation: Cardiovascular Quality and Outcomes, was pointing to the fact that sexual minorities (gay, lesbian or bisexual, for example) were more likely to experience hypertension than their heterosexual peers. Some initial research pointed to a similar trend in trans people. In the U.S., trans men are four times more likely to experience a heart attack compared to cisgender women and are two times more likely compared to cisgender men, according to an April 2019 report published in Circulation: Cardiovascular Quality and Outcomes. But there was an important discrepancy between these two lines of inquiry. While research into the cardiovascular health of sexual minorities focused on environmental stress and experiences of discrimination and stigma, research into trans people was laser-focused on one thing: gender-affirming hormone therapy.

There is some early evidence pointing to an association between gender-affirming hormone therapy and cardiovascular risk markers. Researchers followed 470 transgender adults for up to 57 months after starting hormone therapy. Their results, published in the June 2021 issue of Hypertension, found that within two to four months, average systolic blood pressure was higher in the transmasculine group by 2.6 mm Hg and lower in the transfeminine group by 4.0 mm Hg.

In a retrospective cohort study, Danish researchers compared 2,671 trans participants to cisgender controls. Their results, published in the September 2022 issue of the European Journal of Endocrinology, found that both transfeminine and transmasculine people had a higher risk of any cardiovascular diagnosis compared to cisgender people of either sex. The most notable difference was between trans men and cis men; trans men were more than twice as likely to receive a cardiovascular diagnosis. The study found that gender-affirming hormone therapy accounted for some of this difference.

Moreira-Bouchard says that with its heavy focus on gender-affirming hormone therapy, this research ignores the bigger picture of trans health. Researchers know that discrimination, housing insecurity and lifestyle factors such as smoking are all predictive of poor cardiovascular health. Researchers also know that trans people are more likely to check all of these boxes. But much of the research exploring a link between cardiovascular health and gender-affirming hormone therapy doesn’t adequately parse out these potential confounding factors. “There is this hypercritical lens on trans folks,” Moreira-Bouchard says.

Another key methodological flaw: Much of this research doesn’t include information on dose or participants’ hormone profiles. “You could be comparing apples to oranges,” Moreira-Bouchard says. Collecting this information is particularly crucial; research suggests that many trans people self-administer a different dose of hormone therapy than the one prescribed to them.

Moreira-Bouchard and other experts researching trans health agree that it’s important to establish the safety of gender-affirming care, but doing so will need to involve approaching research from a more comprehensive perspective. That means conducting longitudinal, rather than cross-sectional, research and collecting comprehensive information on demographics, lifestyle, environmental stressors and hormone dosing along the way, Moreira-Bouchard says.

Researchers know that discrimination, housing insecurity and lifestyle factors such as smoking are all predictive of poor cardiovascular health. Researchers also know that trans people are more likely to check all of these boxes.

The Right Models

Troy Roepke, PhD, who is genderqueer, sees a similar lack of attention to the effects of chronic environmental stress on the health of trans people. According to Roepke, who is an associate professor in the Department of Animal Sciences at Rutgers University in New Jersey, scientists know very little about what happens in the brain during gender-affirming hormone therapy. And any research that looks into these effects needs to take into account social stressors. “What’s the stress of being a trans, non-binary person in this society that is increasingly more transphobic and queer phobic? And what does that do to gender-affirming hormone therapy?” Roepke asks. “Gender-affirming hormone therapy can affect the response to stress; meanwhile, stress can affect how hormones are cleared from the body.”

One way to address these gaps in understanding is to develop better animal models, Roepke says. For the past six years that researchers have conducted these studies, they’ve done so in ways that don’t accurately replicate what hormone therapy looks like in trans people, Roepke adds. For example, modeling hormone therapy in a mouse often involves conducting a gonadectomy, then introducing hormones. “But that’s not what happens with trans people or non-binary people,” Roepke says. Much of the time, trans people receiving hormone therapy keep their gonads intact, then take some combination of hormones, androgen blockers or hormone enzyme blockers.

Roepke also sees issues with the route of administration in animal studies. Increasing evidence suggests that whether hormone therapy is given via injection, orally or topically alters the way the body metabolizes the drug. When hormones are only introduced to animals in the form of implanted pellets, another layer of inaccuracy is added. Finally, researchers can introduce chronic environmental stress into animal models to elucidate the role of this confounding factor, Roepke says.

Navigating the Known and Unknown

So how can researchers and clinicians approach their work with trans patients and participants, while keeping these uncertainties in mind?

First, it’s important to remember that there is strong evidence for the benefits of gender-affirming care and weak evidence for any potential risks, says Joshua Safer, MD, executive director of the Mount Sinai Center for Transgender Medicine and Surgery in New York. Research in cisgender populations further supports the safety of these therapies, he points out. A paper published in the June 2023 issue of the New England Journal of Medicine documented the safety of exogenous testosterone in older cisgender men with low levels of the hormone.

“What’s the stress of being a trans, non-binary person in this society that is increasingly more transphobic and queer phobic? And what does that do to gender-affirming hormone therapy?”

Troy Roepke, PhD

The Women’s Health Initiative demonstrated that older cisgender women who received hysterectomies and took pure estrogen (as opposed to estrogen-progesterone therapy) had lower risk of heart attack and breast cancer than those who did not. Although this research is not perfectly representative of the trans population, researchers should take these results into account when thinking about the safety of gender-affirming hormone therapy, experts say.

“Gender-affirming hormone therapy is very safe. Most of the so-called risks seem to be fears rather than true risks,” Safer says. “So, it might be more a matter of weighing unfounded fears versus harm of not treating.”

From there, clinicians can run potential risks on a patient-by-patient basis. Maybe a patient seeking gender-affirming hormone therapy has cardiovascular disease and chronic kidney disease; therefore, their doctor may consider that treatment might reduce their stress, which might benefit their heart health. Then, the clinician can monitor both heart and kidneys, Moreira-Bouchard says.

In response to interventions, trans people receiving gender-affirming care often see health markers improve beyond what is average for the population, perhaps because they are regularly engaging in health care, Safer says.

Nina Stachenfeld, PhD, FAPS, has noticed this trend in her own research on the effects of testosterone therapy on people assigned female at birth. Stachenfeld, a fellow at the John B. Pierce Laboratory and a senior research scientist in obstetrics, gynecology and reproductive sciences at Yale School of Medicine in New Haven, Connecticut, clearly remembers meeting a young trans man as part of one of her studies. When a preliminary test revealed that he had endothelial dysfunction and dyslipidemia (risk factors for cardiovascular disease), he asked what he could do. Stachenfeld suggested an exercise program might turn his health around. She didn’t meet with him again but heard through his health care provider that the young man had formed an all-trans exercise support group.

“If a doctor were to say, ‘I’m supportive of you, I want to help you get hormonal treatment, we’re going to work on this together, but to be safe, I’ll need you to start an exercise program, or get on a statin,’ many would be receptive of that,” Stachenfeld says. “This is a promising and exciting population to work with. They’re making a decision about their lives and how they want them to change.”

This article was originally published in the November 2023 issue of The Physiologist Magazine.