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Barriers in Transgender Research

Author: Keila Turino Miranda, BSc Honours in Pharmacology, University of Alberta, Twitter: @keila_turino

The transgender community is a growing and underserved population estimated to reach over one million in the USA alone.[1] In comparison to their cis-counterparts, where sex (biological attributes) and gender (socially constructed roles, behaviours, expressions and identities) align, transgender individuals experience gender dysphoria. Gender dysphoria is defined as a persistent feeling that an individual’s biological sex does not match their gender identity.[6] As a result, transgender individuals experience severe distress, which significantly impairs their ability to function in society. This condition occurs on a spectrum, where transgender individuals are at the extreme end. This clinical diagnosis results in gender-affirming hormone therapy initiation, where feminization or masculinization goals are initiated. For transgender women, gender-affirming hormone therapy consists of the use of exogenous synthetic estrogens often in conjunction with anti-androgens to promote feminization (breast growth, decreased facial and body hair, genital atrophy, etc.) and minimize the effects of endogenous androgens like testosterone (deepening of the voice, differential distribution of body fat and muscle).[6]  

Protocols for Transgender Care

Estrogen gender-affirming hormone therapy formulation, dose, administration route, and co-administration with anti-androgens vary on individual goals for transitioning. Higher doses may be used for a more pronounced transitioning, while lower doses may be used if the individual is predisposed to other health complications.[10] Additionally, the administration route may vary based on personal preference or recommendation by the health care practitioner. An example of this is seen in the preference for non-oral (transdermal patch, intravenous injection, etc.) estrogen gender-affirming hormone therapy over oral routes. This preference is a direct result of experimental data in cis-women showing that oral estrogen therapy, whether for contraceptive or postmenopausal use, is associated with an increased cardiovascular risk compared to non-oral estrogen.[10] As a result, transgender women over the age of 45 or with a predisposition to cardiovascular disease are prescribed non-oral forms of estrogen to minimize risk.[12] However, no current research suggests that this finding is also consistent or applicable to transgender women. Therefore, protocols for the care of transgender women have been modelled after research done in cis-women populations. However, this can become problematic as these two populations differ by biological attributes, societal pressures and other factors. Whether or not this is appropriate can only be determined through further research into gender-affirming hormone therapy routes of administration.

Current Research in the Transgender Field

Transgender women face healthcare disparities and have higher rates of substance use disorders, depression, anxiety and suicidality.[2] Moreover, transgender women receiving gender-affirming hormone therapy are disproportionally affected by cardiovascular disease.[3,4] Despite the growing number of the transgender population and the increased prevalence of gender-affirming hormone therapy use, research outside of HIV prevalence is limited. A newly published study on HIV prevention reported the positive impact greater social support in discussing HIV-related issues has on HIV prevention knowledge.[7] These results point to the growing body of thought regarding minority stress. Stigmatized minority groups, such as the transgender population, show chronically elevated levels of stress.[8] In addition to the limited research seen in transgender health, there is a lack of acknowledgement of minority stress and its implications on disease progression.[9]

Barriers in Transgender Research 

As an up-and-coming field, transgender research is limited by its heterogeneity in terminology and study quality. Researchers in this field must often consider the variability and advancement of the use of transgender terminology in active avoidance of transphobia. For example, outdated terms such as she-male, cross-sex and trans-sexual are often seen in previous literature, and Alberta Health Services contraindicates its use.[11] Additionally, systematic reviewers in the field must consider these terms to capture relevant transgender research adequately. 

As previously discussed, there is great variability in gender-affirming hormone therapy dose, formulation and administration route. As a result, there is significant heterogeneity in available studies, which is a barrier for appropriate quantification of their effects on transgender health and disease progression. Route of gender-affirming hormone therapy administration is postulated as partly responsible for this as the pharmacokinetics (drug absorption, distribution, metabolism and excretion) and pharmacodynamics (drug action and mechanism) vary. Pharmacokinetics is an important consideration as oral and non-oral therapies are subjected to differential levels of metabolism, total systemic dose, excretion rates, and other variables, which affect their drug actions and mechanism (pharmacodynamics). These are vital considerations as drug interactions affect disease progression, and in long term cases, morbidity and mortality. 

In addition to experimental group variability, there are also inappropriate control groups, thus serving as an additional barrier. The psychological benefits provided by gender-affirming hormone therapy renders the use of placebo groups unethical.[11] Researchers are limited to recruiting transgender individuals who have not initiated gender-affirming hormone therapy in search of an appropriate control. Although it would be unlikely to recruit these individuals and abstain from therapy initiation throughout the study, this would provide an appropriate control group as these individuals would share the same gender-identity. Additionally, researchers may opt to use cis-men as a sex (biological attributes) control. With this, studies looking to compare morbidity and mortality of diseases would be better equipped to assess transgender health as it pertains to gender-affirming hormone therapy use.

Cross-sectional studies aiming to obtain estimates of disease incidence and prevalence are limited by the inadequate collection of gender identity information in clinics and national surveys.[11] This further prevents accurate and up-to-date epidemiological analysis of transgender health and serves as a further barrier for researchers and clinicians looking to address this population's health adversities.

Future Directions 

Listed research barriers should be addressed through appropriate stratification of gender-affirming hormone therapy by dose, formation, administration route, and use of anti-androgens. Additionally, the implementation of appropriate control groups, cis-men and/or transgender women without therapy, is essential for adequate quantification of disease progression, morbidity and mortality. These modifications, accompanied by large cohort studies with sufficient follow-up4, will allow for the advancement of clinical understandings and protocols.  Lastly, practicing clinicians caring for transgender patients should appreciate gender-affirming hormone therapy's psychological benefits when considering the potential risks associated.[5]

Bibliography

1. Meerwijk, E. L., & Sevelius, J. M. (2017). Transgender Population Size in the United States: A Meta-Regression of Population-Based Probability Samples. American Journal of Public Health, 107(2). doi:10.2105/ajph.2016.303578

2. Reback, C. J., Clark, K., Holloway, I. W., & Fletcher, J. B. (2018). Health Disparities, Risk Behaviors and Healthcare Utilization Among Transgender Women in Los Angeles County: A Comparison from 1998–1999 to 2015–2016. AIDS and Behavior, 22(8), 2524-2533. doi:10.1007/s10461-018-2165-7

3. Alzahrani, T., Nguyen, T., Ryan, A., Dwairy, A., Mccaffrey, J., Yunus, R., . . . Reiner, J. (2019). Cardiovascular Disease Risk Factors and Myocardial Infarction in the Transgender Population. Circulation: Cardiovascular Quality and Outcomes, 12(4). doi:10.1161/circoutcomes.119.005597

4. Gosiker, B. J., Lesko, C. R., Rich, A. J., Crane, H. M., Kitahata, M. M., Reisner, S. L., . . . Poteat, T. C. (2020). Cardiovascular disease risk among transgender women living with HIV in the United States. Plos One, 15(7). doi:10.1371/journal.pone.0236177

5. White Hughto JM, Reisner SL. A systematic review of the effects of hormone therapy on psychological functioning and quality of life in transgender individuals. Transgend Health. 2016;1:21-31. [PMID: 27595141]

6. Brown, G., By, Brown, G., & Last full review/revision Aug 2019| Content last modified Aug 2019. (n.d.). Overview of Sexuality - Mental Health Disorders. Retrieved October 24, 2020, from https://www.merckmanuals.com/home/mental-health-disorders/sexuality-and-...

7. Lelutiu-Weinberger, C., Wilton, L., Koblin, B. A., Hoover, D. R., Hirshfield, S., Chiasson, M. A., Frye, V. (2020). The Role of Social Support in HIV Testing and PrEP Awareness among Young Black Men and Transgender Women Who Have Sex with Men or Transgender Women. Journal of Urban Health, 97(5), 715-727. doi:10.1007/s11524-019-00396-8

8. Meyer IH. Does an improved social environment for sexual and gender minorities have implications for a new minority stress re- search agenda? Psychol Sex Rev. 2016;7:81-90. [PMID: 27642514]

9. Streed, C. G., Harfouch, O., Marvel, F., Blumenthal, R. S., Martin, S. S., & Mukherjee, M. (2017). Cardiovascular Disease Among Transgender Adults Receiving Hormone Therapy. Annals of Internal Medicine, 167(4), 256. doi:10.7326/m17-0577

10.  Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, et al; Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hys- terectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701-12. [PMID: 15082697]

11. Terms and Phrases to Avoid* - Alberta Health Services. (n.d.). Retrieved October 24, 2020, from https://www.albertahealthservices.ca/assets/info/pf/div/if-pf-div-terms-...

12. Velzen, D. M., Paldino, A., Klaver, M., Nota, N. M., Defreyne, J., Hovingh, G. K., . . . Heijer, M. D. (2019). Cardiometabolic Effects of Testosterone in Transmen and Estrogen Plus Cyproterone Acetate in Transwomen. The Journal of Clinical Endocrinology & Metabolism, 104(6), 1937-1947. doi:10.1210/jc.2018-02138

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