TL;DR
- Almost every clinical post on this account includes a caveat about limited evidence — that is not accidental, it reflects a genuine and systemic research gap
- Trans people have historically been underrepresented in clinical research, with the limited literature disproportionately concentrated in a small number of therapeutic areas
- The randomised controlled trial — the gold standard of clinical evidence — faces genuine practical and ethical challenges in trans health research
- Guidelines rely heavily on observational studies, expert consensus, and extrapolation from cisgender populations rather than extensive direct trial data in trans women
- Better trans health research infrastructure is not an academic luxury. It is a clinical necessity.
If you have read the clinical posts on this account, you will have noticed a recurring phrase: the evidence is limited. It appears in the SHBG post, the progesterone post, the therapeutic range post, the testosterone suppression post. It is not a caveat inserted for caution. It is a genuine description of the state of the field.
Trans health research is sparse, often methodologically limited, and historically concentrated in a relatively narrow set of topics, including HIV/AIDS and mental health, while large areas of clinical practice remain poorly studied. Understanding why matters for understanding what the gaps in your own care might be.
The clinical trial exclusion problem
A 2024 analysis of clinical trials registered on ClinicalTrials.gov from 2007 to 2023 identified 97 drug and biologics trials that represented transgender people at all — a very small fraction of the trials registered over that period. Of those, the majority were trials in which trans participants were merely eligible to enrol, and most of those eligible trials were concentrated in a single therapeutic area: infectious disease, overwhelmingly HIV-related research. Eligibility has been improving — trans women and trans men are now eligible to participate in the large majority of these “inclusive” trials — but eligibility is not the same as representation across medicine. For many medications prescribed outside transgender care, the available efficacy and safety data are derived predominantly from populations that did not specifically study transgender women or examine how gender-affirming hormone therapy might influence treatment response or risk profiles.
Why RCTs are difficult in trans health
The randomised controlled trial — the design that carries the most evidentiary weight in medicine — faces genuine methodological challenges in trans health research. Blinding can be difficult because the physiological effects of hormone therapy often become apparent. Recruiting treatment-naive participants is increasingly difficult as access to care expands. And there is a genuine ethical tension in randomising someone to delayed or withheld gender-affirming care when that care is already supported by existing evidence and guideline recommendations — a problem of clinical equipoise that applies across medicine wherever treatment efficacy is already well-supported.
These are real challenges. They do not have easy solutions, and they mean that some important questions in transgender medicine are less amenable to traditional RCT designs than questions in many other areas of medicine.
What fills the gap
In the absence of robust trial data, trans healthcare guidelines rest on observational studies, retrospective cohort analyses, expert consensus, and extrapolation from cisgender populations. This is not nothing — observational data can be genuinely informative, and expert consensus from experienced clinicians has value. Indeed, many areas of medicine necessarily rely on high-quality observational evidence when randomised trials are impractical or unethical. But it is a weaker evidentiary foundation than exists in many other well-established areas of endocrinology.
A 2021 paper in the Journal of Clinical Investigation on research gaps in trans healthcare stated directly that dedicated research infrastructure and funding are needed to address the knowledge gap in the field, and that guidelines referencing cancer risk, cardiac risk, and bone health often rely on physiological models rather than conclusive clinical data.
The consequences
The consequences of poor evidence are not abstract. They are one reason why commonly cited estradiol targets are based largely on physiological reasoning and observational experience rather than direct outcome trials. They are the reason the evidence for progesterone in trans women remains inconclusive. They are the reason long-term cardiovascular risk data for trans women on HRT are limited. They are the reason monitoring standards vary between guidelines and between clinicians.
Gaps in the evidence base inevitably limit the certainty with which clinicians can make recommendations. Better research is not an academic priority disconnected from clinical reality. It is the mechanism through which clinical reality improves.
Existing research infrastructure and funding have been widely described as insufficient relative to the unanswered clinical questions facing transgender medicine.
⚠️ Note: The research gaps described here are documented in peer-reviewed literature and acknowledged within WPATH SOC-8 and Endocrine Society guidelines themselves. The absence of robust evidence is not a reason to withhold established care — it is a reason to invest in the research that would improve it.
Sources
- Schonrock C, et al. Transgender people in clinical trials of drugs and biologics: An analysis of ClinicalTrials.gov from 2007 to 2023. Br J Clin Pharmacol. 2024.
- Safer JD. Research gaps in medical treatment of transgender/nonbinary people. J Clin Invest. 2021;131(4):e142029.
- Coleman E, Radix AE, Bouman WP, et al. Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. International Journal of Transgender Health. 2022;23(S1):S1–S259.
- Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017;102(11):3869–3903.
