Research Considerations in Digestive and Liver Disease in Transgender and Gender-Diverse Populations

Increasing numbers of people openly identify as transgender and gender diverse (TGD). TGD individuals are people whose gender identity and/or expression do not correspond to the social and cultural expectations commonly associated with their birth sex. Transgender people may adopt visual and behavioral indicators associated with their affirmed gender and sometimes use medical and surgical interventions to induce anatomic and physiologic changes. In contrast, gender-diverse people may reject the constraints of culturally defined social roles associated with their birth sex, or they may reject the concept of gender in its entirety. Gender-diverse people often self-label or are identified as nonbinary, genderqueer, agender, or gender-nonconforming. Additional terms exist (Table 1),1Ashley F. ‘Trans’ is my gender modality: a modest terminological proposal.in: Erickson-Schroth L. Trans bodies, trans selves: a resource by and for transgender communities. 2nd ed. Oxford University Press, New York, NY2022: 704Google Scholar,2Streed Jr., C.G. Beach L.B. Caceres B.A. et al.Assessing and addressing cardiovascular health in people who are transgender and gender diverse: a scientific statement from the American Heart Association.Circulation. 2021; 144: e136-e148Crossref PubMed Scopus (79) Google Scholar and the acceptability of specific terminology can vary over time.Table 1Glossary of TermsCisgenderA term for people whose gender identity aligns with the gender that is socially expected based on their sex assigned at birth.Gender diverseA term for people with gender identities that are not constrained by binary concepts of gender (ie, man/woman).Gender expressionWays in which people communicate femininity, masculinity, androgyny, or other aspects of gender, often through speech, behavior, grooming, or clothing. All people make choices that express their gender.Gender identityA person’s internal sense of being a girl/woman, a boy/man, a combination of girl/woman and boy/man, or something else (including a sense of having no gender). All people have a gender identity.Gender minorityA broad term for the diverse group of people who experience incongruence between their gender identity and what is socially expected of them based on sex assigned at birth. This includes transgender and gender diverse people.Gender nonbinaryA term some people use to identify as a gender outside of the binary concept of gender. A person may identify as a combination of girl/woman and boy/man, as something else, or as having no gender. It is related to the term gender nonconforming.Gender nonconformingA term some people use to identify as a gender outside of the binary concept of gender or to describe gender expression that is incongruent with what is socially expected based on their sex assigned at birth or gender identity. It is related to the term gender nonbinary.QueerHistorically a derogatory term, queer has been embraced and reclaimed by LGBTQ communities. Queer can be used as an umbrella term for all sexual and gender minority people or more narrowly to represent individuals who identify outside of other categories or labels of sexual and gender identity.Sex assigned at birthUsually male or female, based on a medical provider’s assessment of an infant’s phenotypic presentation (ie, genitals). It is distinct from gender identity.SexA categorization of male, female, or intersex based on biological sex characteristics (chromosomes, gonads, sex hormones, and/or genitals). Often used synonymously with sex assigned at birth.Transgender manA person who identifies as male but whose sex assigned at birth was female.Transgender womanA person who identifies as female but whose sex assigned at birth was male.LGBTQ, lesbian, gay, bisexual, transgender, and queer.Adapted from Streed et al.2Streed Jr., C.G. Beach L.B. Caceres B.A. et al.Assessing and addressing cardiovascular health in people who are transgender and gender diverse: a scientific statement from the American Heart Association.Circulation. 2021; 144: e136-e148Crossref PubMed Scopus (79) Google Scholar Open table in a new tab LGBTQ, lesbian, gay, bisexual, transgender, and queer. Adapted from Streed et al.2Streed Jr., C.G. Beach L.B. Caceres B.A. et al.Assessing and addressing cardiovascular health in people who are transgender and gender diverse: a scientific statement from the American Heart Association.Circulation. 2021; 144: e136-e148Crossref PubMed Scopus (79) Google Scholar TGD people comprise 0.6% of the US adult population3Baker K.E. Findings from the behavioral risk factor surveillance system on health-related quality of life among US transgender adults, 2014-2017.JAMA Intern Med. 2019; 179: 1141-1144Crossref PubMed Scopus (45) Google Scholar and nearly 2% of the US high school–age population.4Johns M.M. Lowry R. Andrzejewski J. et al.Transgender identity and experiences of violence victimization, substance use, suicide risk, and sexual risk behaviors among high school students - 19 states and large urban school districts, 2017.MMWR Morb Mortal Wkly Rep. 2019; 68: 67-71Crossref PubMed Google Scholar Given their increasing prevalence, all health care professionals, including gastroenterologists and hepatologists, will care for TGD people. To provide optimal care, it is important to understand how the unique combination of psychosocial, biomedical, and legal experiences of TGD people can lead to different gastrointestinal (GI) health needs and outcomes for non-TGD people. Obtaining the knowledge to inform best practices will require funding, performance, and dissemination of high-quality, reproducible, and ethical research. State laws restricting gender-affirming care and the legal recognition of TGD people and unconscious bias by medical providers impact TGD people and may increase hesitancy to participate in digestive health research. Integrating TGD persons and advocacy groups as partners in the planning and performance of research will be necessary to create sustainable future endeavors. In this report, we (1) identify areas in which research is needed to fill knowledge gaps relating to TGD people with or being investigated for GI disease and key GI areas requiring research; (2) describe a set of best practices for thoughtful, sensitive inclusion and involvement of TGD people as study participants and in the role of research partners; and (3) provide actionable initial steps the GI research community can take to close these knowledge gaps. TGD individuals have a 7-year–shorter life expectancy; reduced health care access; higher prevalence of human immunodeficiency virus, cardiovascular disease, diabetes, and mental and behavioral health conditions; and higher rates of self-harm, substance use disorders, and suicide than non-TGD individuals.5Hughes L.D. King W.M. Gamarel K.E. et al.Differences in all-cause mortality among transgender and non-transgender people enrolled in private insurance.Demography. 2022; 59: 1023-1043Crossref PubMed Scopus (12) Google Scholar TGD people are more likely to experience interpersonal violence and be victims of homicide than are cis-gender people, with Black and Latina TGD people at higher risk than white TGD people.6Dinno A. Homicide rates of transgender individuals in the United States: 2010-2014.Am J Public Health. 2017; 107: 1441-1447Crossref PubMed Scopus (70) Google Scholar Because of discrimination, 23% of transgender adults reported avoiding or delaying health care in the past year.7Kcomt L. Gorey K.M. Barrett B.J. et al.Healthcare avoidance due to anticipated discrimination among transgender people: a call to create trans-affirmative environments.SSM Popul Health. 2020; 11100608PubMed Google Scholar TGD people are less likely to have sustained health care provider relationships, undergo recommended disease screening, be insured, or have stable housing than cisgender people. As of June 1, 2023, 20 US state legislatures have passed laws limiting access of TGD people to gender-affirming care. The impact of the unique combination of social, political, and economic determinants on the health of TGD individuals can be best understood through the framework of the minority stress model. The model8Testa R.J. Habarth J. Peta J. et al.Development of the gender minority stress and resilience measure (vol 2, pg 65, 2015).Psychol Sex Orientat. 2022; 9: 286Google Scholar (Figure 1) posits that a combination of distal and proximal factors from systematic discrimination of minority populations, conscious and unconscious biases against members of those populations, and ignorance and disinterest in the needs of these population, ultimately lead to socioeconomic displacement and worse health-related outcomes. Chronic perceived stress is a major driver of GI symptomatology, especially GI-related pain and other noxious symptoms, and their impact on social functioning, quality of life, and the physiologic function of the GI tract. Stress impacts the hypothalamic–adrenal axis, which has been implicated in the immunologic dysregulation implicated in the pathogenesis of inflammatory bowel diseases (IBD) and the activities of the enteric nervous system, which coordinate the physiologic function of the gut. Because TGD persons are more likely to experience chronic stress, it stands to reason that this may influence the development and course of GI disease both directly and through individual behaviors. For instance, TGD people who experience more discrimination are more likely to use tobacco and alcohol,9Gamarel K.E. Mereish E.H. Manning D. et al.Minority stress, smoking patterns, and cessation attempts: findings from a community-sample of transgender women in the San Francisco Bay area.Nicotine Tob Res. 2016; 18: 306-313Crossref PubMed Scopus (56) Google Scholar which are known risk factors for multiple GI conditions. Receiving gender-affirming care is associated with health improvements, including decreased rates of depression, suicidality, and substance use.10Tordoff D.M. Wanta J.W. Collin A. et al.Mental health outcomes in transgender and nonbinary youths receiving gender-affirming care.JAMA Netw Open. 2022; 5e220978Crossref PubMed Scopus (102) Google Scholar The use of gender-affirming medical and surgical therapies conceivably can impact GI wellness or affect the course of GI disease. Sex hormones alter the function and development of the GI tract, including the incidence and course of several GI diseases. Gender-affirming hormone treatment (GAHT), minority stress, and altered hypothalamic–adrenal axis function could impact the course of most GI diseases. Prospective work should validate patient-reported outcome measure use in TGD communities receiving GAHT. Objective laboratory, imaging, and motility testing should be collected prospectively to better understand GI tract function in people receiving GAHT. The liver is sensitive to sex hormones, genetics, and environmental exposures. Sex-based differences exist in nonalcoholic fatty liver disease risk profiles, and estrogen is implicated in metabolic states and adenomas. It is unknown if GAHT replicates these endogenous hepatic sensitivities. When prospective research is designed to collect biobank specimens in patients before and during GAHT treatment, ideally, liver chemistry and noninvasive markers of fibrosis should be collected to address the potential impact of GAHT on liver disease. Data on the management of GAHT in the setting of liver transplantation also are important, especially regarding thromboembolism risk in the immediate postoperative period. Because cessation of GAHT can be catastrophic, this risk must be clarified. Finally, there is also a need for pharmacologic research to consider the role of GAHT on GI medication pharmacokinetics and outcomes. Given the known association between these comorbidities and GI and liver health outcomes ranging from disorders of gut–brain interaction (DGBI) to colorectal cancer, there are hypothetically benefits of gender-affirming care for GI conditions that should be evaluated further. Research assessing the risks and benefits of GAHT for digestive diseases should also weigh these against the risks of withholding and benefits of providing GAHT on mental health and wellbeing. Increased minority stress may increase psychological distress and behaviors such as greater alcohol and tobacco use, decreased physical activity, and poor nutrition. However, it is unknown whether this equates to increased rates of alcohol-related liver disease, nonalcoholic fatty liver disease, viral hepatitis, and cirrhosis among TGD populations. The incidence of liver transplantation also is unknown in this population and whether TGD individuals face barriers to liver transplantation. This is important because social support and psychiatric comorbidities are key factors in transplantation but vary in TGD populations.11Ramadan O.I. Naji A. Levine M.H. et al.Kidney transplantation and donation in the transgender population: a single-institution case series.Am J Transplant. 2020; 20: 2899-2904Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar In addition, efforts to improve sex disparities in liver transplant have resulted in an updated Model for End-Stage Liver Disease calculator, version 3.0, which now includes female sex as a variable.12Kim W.R. Mannalithara A. Heimbach J.K. et al.MELD 3.0: the model for end-stage liver disease updated for the modern era.Gastroenterology. 2021; 161: 1887-1895 e4Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar The implications of this for TGD patients are unknown. TGD people may be less likely to receive treatment for pancreatic cancer.13Jackson S.S. Han X. Mao Z. et al.Cancer stage, treatment, and survival among transgender patients in the United States.J Natl Cancer Inst. 2021; 113: 1221-1227Crossref PubMed Scopus (43) Google Scholar There is a need for further research to determine the barriers to care. Case reports of pancreatitis in TGD women on GAHT suggest an association between GAHT and pancreatitis.14Freier E. Kassel L. Rand J. et al.Estrogen-induced gallstone pancreatitis in a transgender female.Am J Health Syst Pharm. 2021; 78: 1674-1680Crossref PubMed Scopus (2) Google Scholar There is a need for cohort studies with appropriate control groups, including non-TGD populations on exogenous hormones, to determine if this is a valid association and whether it is attributable to GAHT or other factors. TGD individuals are less likely to receive recommended cancer screenings, including colorectal cancer screening, and future research must understand these barriers.15Kiran T. Davie S. Singh D. et al.Cancer screening rates among transgender adults: cross-sectional analysis of primary care data.Can Fam Physician. 2019; 65: e30-e37PubMed Google Scholar In TGD people status-post colonic neovagina creation, it is unknown if fecal-based colorectal cancer screening is appropriate. Along with men-who-have-sex-with-men, transgender women have excess human papilloma virus burden; large high-quality studies of human papilloma virus–related outcomes such as anal cancer among TGD people are lacking.16Meites E. Wilkin T.J. Markowitz L.E. Review of human papillomavirus (HPV) burden and HPV vaccination for gay, bisexual, and other men who have sex with men and transgender women in the United States.Hum Vaccin Immunother. 2022; 182016007Crossref PubMed Scopus (13) Google Scholar Risk factors for pelvic floor dysfunction in TGD individuals include gender-affirming pelvic surgeries and sexual violence; the incidence of pelvic floor disorders in TGD people is unknown. This is complicated by a lack of data on anorectal physiologic testing in TGD people. Anorectal function testing often relies on sex-based normal values.17Carrington E.V. Scott S.M. Bharucha A. et al.Expert consensus document: advances in the evaluation of anorectal function.Nat Rev Gastroenterol Hepatol. 2018; 15: 309-323Crossref PubMed Scopus (143) Google Scholar It is not known how to apply those to TGD individuals. Case reports and observational data have shown an association between GAHT and chronic abdominopelvic pain in transgender men,18Grimstad F.W. Boskey E. Grey M. New-onset abdominopelvic pain after initiation of testosterone therapy among trans-masculine persons: a community-based exploratory survey.LGBT Health. 2020; 7: 248-253Crossref PubMed Scopus (11) Google Scholar however, the effects of GAHT on other conditions is unknown. DGBIs can be prevalent in communities with a high biopsychosocial stress burden such as TGD ones19Vélez C. Casimiro I. Pitts R. et al.Digestive health in sexual and gender minority populations.Am J Gastroenterol. 2022; 117: 865-875Crossref PubMed Scopus (9) Google Scholar; it is not known if increased DGBI prevalence exists among TGD people. There has been limited systematic study of the interactions between TGD identity, gender-affirming care, and IBD.20Newman K.L. Chedid V.G. Boden E.K. A systematic review of inflammatory bowel disease epidemiology and health outcomes in sexual and gender minority individuals.Gastroenterology. 2023; 164: 866-871Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar TGD people with IBD may avoid medical care because of a fear of discrimination, experience possible medication–medication interactions, and have different osteopenia/osteoporosis and thromboembolism risk, but few data exist. Given advances in understanding the influence of the microbiome in IBD, efforts must be made to ensure TGD individuals are included in these efforts. Education interventions focusing on culturally humble and compassionate care of TGD individuals must be developed and evaluated to reduce the biases TGD people face in clinical care. Furthermore, implementation of evidence-based care to address barriers that exist in digestive disease care among TGD individuals will be critical to achieving equity and reducing the impact of adverse social determinants of health. Over the past decade, there has been increased focus, including by the National Institutes of Health,21Alvidrez J. Castille D. Laude-Sharp M. et al.The National Institute on Minority Health and Health Disparities Research Framework.Am J Public Health. 2019; 109: S16-S20Crossref PubMed Scopus (290) Google Scholar on the obligation of research and health care communities to address the needs of marginalized communities such as TGD people. Care must be taken to ensure that when research involves TGD people, it is performed with (1) cultural humility, (2) rigorous methods, and (3) early vetting for implicit biases (Supplementary Figure 1). GI and hepatology research only recently has begun to include TGD individuals. As such, there is foundational qualitative and descriptive research that has not yet been conducted. Qualitative work understanding TGD people’s perspectives on digestive disease is critical in generating hypotheses for which quantitative studies can provide robust data. In addition, there is a need to reconsider previous research in digestive and liver disease that conflates gender and sex to evaluate the potential impacts of sex hormones, gendered behaviors, and gender-specific exposures. This may have significant positive impacts for TGD and cisgender people. To this end, concerted efforts to recruit TGD individuals for biobanking should be mandated in work being funded by government, industry, and medical organizations. Researchers may need to revalidate study measures in TGD individuals. Because TGD people understandably may fear engagement with health care, best practices should be developed and studied for recruiting patients for research to emphasize ways in which study subjects are protected. Best practices might include the use of culturally specific TGD language in study materials, allowing patients to consent to varying amounts of data disclosure and follow-up evaluation, alternative consent procedures for TGD minors, and explicit discussion of how participants can refuse to participate or withdraw from the study. Given health care avoidance among TGD individuals, GI and hepatology researchers must recruit patients for studies beyond hospitals and clinics and consider other venues. In addition to long-term changes in research methods, there are actions GI and hepatology researchers can take today to support and improve TGD health research. These include advocacy for explicit legal protection of TGD people in the United States and internationally; engagement with TGD patients and communities to understand their research priorities in GI and hepatology; and clarity in ongoing research whether measuring sex, gender, or both is intended and necessary and adjusting recruitment, data collection, analysis, and interpretation accordingly.22Heidari S. Babor T.F. De Castro P. et al.Sex and gender equity in research: rationale for the SAGER guidelines and recommended use.Res Integr Peer Rev. 2016; 1: 2Crossref PubMed Google Scholar Equally important, researchers should avail themselves of existing educational initiatives to increase cultural humility around TGD people and their affirming inclusion in research (Supplementary Table 1). Here, we expand on each of these recommendations. First, it is critical for researchers to advocate for human subjects and political protections for TGD people. Without formal protections, TGD individuals are at risk of significant consequences in the event of data breaches and by openly participating in research.23Adams N. Pearce R. Veale J. et al.Guidance and ethical considerations for undertaking transgender health research and institutional review boards adjudicating this research.Transgend Health. 2017; 2: 165-175Crossref PubMed Scopus (116) Google Scholar Researchers must be explicit about the limits of confidentiality and the steps taken to protect participants’ identities and data. Sensitive data collection should be limited to the minimum necessary, data should be deidentified, and alternative informed consent processes should be considered for especially vulnerable groups, such as TGD minors. Second, researchers should engage with TGD patients and community members to understand their research priorities. This can be performed through outreach to existing community organizations or collaboration with gender-care clinics where available. Engaging TGD people of diverse racial, ethnic, cultural, socioeconomic, and other backgrounds is critical for providing a rich understanding of lived experiences, needs, and priorities (at all costs, avoiding tokenism). One helpful framework for this engagement is the trauma-informed approach. The guiding principles, as outlined by the US Substance Abuse and Mental Health Services Administration’s National Center for Trauma-Informed Care, are as follows: safety; trustworthiness and transparency; peer support; collaboration and mutuality; empowerment and choice; and cultural, historical, and gender issues.24Substance Abuse and Mental Health Service AdministrationSubstance Abuse and Mental Health Service concept of trauma and guidance for a trauma-informed approach. HHS publication (SMA) 14-4884. Substance Abuse and Mental Health Services Administration, Rockville, MD2014Google Scholar Third, research questions, even those not specifically focused on sex-related differences, should be explicit about whether gender identity, sex, or both are the outcome or a covariate of interest.25National Academies of Sciences, Engineering, and MedicineMeasuring sex, gender identity, and sexual orientation. The National Academies Press, Washington, DC2022Google Scholar Conflation of sex and gender identity and assuming that one can be used to infer the other is antithetical to collecting accurate demographic data on TGD people. Validated questions for collecting sex and gender identity data are publicly available. Lastly, research teams should use existing guidelines and resources to ensure patient and community engagement is culturally respectful (Supplementary Table 1). Although most toolkits have been developed for clinical contexts, they can be applied to many clinical and translational research settings and are important in the communication of findings related to TGD health. There is a need for high-quality research to clarify the GI needs in TGD people. Systematic, long-term changes in research approaches are needed. The benefit of a TGD lens on existing research questions includes the potential for generating novel hypotheses about the role of genetics, hormones, individual behaviors, and social context on GI and liver health that may benefit many members of society. Foundation, national society, and federal funding should be directed to such initiatives.