CLN - Feature
Gender-affirming hormone therapy changes the body in ways that matter in a clinical laboratory. Testosterone prescribed to transgender men and estradiol with or without anti-androgens given to transgender women shift some of the biological markers that labs routinely measure. Yet until now, laboratory medicine has had no dedicated guidance for interpreting those results.
To fill this gap, the Association for Diagnostics & Laboratory Medicine (ADLM) convened a group of pathologists, clinical chemists, endocrinologists, and clinicians who directly care for transgender patients. Together, the team devised the first comprehensive, U.S.-based laboratory medicine and pathology recommendations for the gender diverse population.
Before this point, guidance in this area primarily came from World Professional Association for Transgender Health guidelines and the Endocrine Society. These guidelines had some sections specific to laboratory medicine, said Gabrielle Winston-McPherson, PhD, DABCC, co-first author of the guidance document and director of clinical chemistry at the University of Wisconsin, Madison. But there hasn’t been a place where she could go to get all of that information, she said.
The guidance document addresses key focus areas, including reference intervals and lab test interpretation; transfusion medicine; autopsy and medicolegal death investigation; surgical pathology and histology; and informatics.
“This is a way to expand people’s understanding of gender, sex, and also the clinical laboratory’s responsibility for providing inclusive results and reference intervals for the populations that they serve,” said Dina Greene, PhD, co-chair of the guidance document and one of its co-corresponding authors, as well as clinical professor at the University of Washington in Seattle.
Defining the transgender population itself is difficult because of the sheer diversity it comprises. The document focuses primarily on adults who have been on gender-affirming hormone therapy for at least 6 months, since this is where the strongest data currently exists. The authors acknowledge that this excludes important groups, including adolescents, those early in transition, and nonbinary individuals who may not use hormones, but explain that this scoping reflects the current state of the literature rather than a judgement about those populations’ needs.
Some of the most impactful recommendations can be found in the guidance on reference intervals. Reassuringly, the list of tests significantly affected by hormone therapy is relatively short. But room for improvement remains. “Laboratory values among transgender people on hormone therapy do not always correspond to their cisgender counterparts, and there is a great deal of variation between using the typical cisgender male and cisgender female ranges,” said Zil Goldstein, FNP-BC, associate medical director at Callen-Lorde Community Health Center in New York City and a co-author of the guidance document.
Goldstein, who works in primary care, said she sees this confusion among clinicians trying to interpret laboratory results play out in her day-to-day work. “When we get reports back from the lab, we have highlights in red that show abnormal values, but these are often erroneous because the wrong normal range is being applied,” she said. These inaccuracies can be confusing to providers who rely on the lab to report the most relevant reference ranges for the patient, she said. When reporting results, labs now can use the newly proposed reference intervals in the guidance document, which in turn will help time-pressed clinicians interpret results correctly and faster, said Goldstein.
For Greene, the most significant finding in the document was related to deciphering concentrations of estradiol, which is used for its feminizing effects and to suppress endogenous testosterone. The current guidance recommends that estradiol should be maintained in a range of 100−200 pg/mL. However, this new guidance document argues that there is insufficient evidence to support this range, and most evidence to date supports a broader range, said Greene. “Really, it needs to be looked at holistically as a combination of what the brain is saying, what testosterone is doing, and how your patient is feeling.”
Beyond laboratory testing, the section on autopsy and medicolegal death investigations addresses a problem that is both clinical and ethical. Medicolegal death investigations currently do not abide by standardized guidance on documenting gender identity, which often results in inaccurate or absent reporting of gender identity in the official records. Over half of transgender decedents had the incorrect gender on their death certificates, according to one study that the guidance cites.
The guidance recommends that autopsy reports document both legal sex and affirmed gender identity, use the decedent’s chosen name and correct pronouns, describe anatomical findings in gender-neutral terms, and note evidence of gender-affirming care without speculation.
“Part of the goal in medicine is dignity in life, as well as dignity in death, and language matters. So as much as we can use neutral language, I think that that’s the way that we can make sure that we honor people while they’re here, and afterwards as well,” said Tiffany Thomas, PhD, co-first author of the guidance document and an assistant professor in the department of pathology and cell biology at Columbia University in New York.
For Goldstein, some of the most notable recommendations are found in the section dedicated to informatics. The document describes the cascading effects that occur when a transgender patient changes their legal sex in an electronic health record. That single alteration changes which reference intervals the lab applies, which billing codes are used, and which clinical decision-support logic is used. For instance, a transgender man who has changed his legal sex to male may no longer receive prompts for cervical cancer screening or be prioritised for Rh-negative blood products in an emergency, both of which remain clinically relevant.
When it comes to informatics, the capabilities of different electronic health record systems vary widely. “What I really like in terms of our approach in the guidance document is how it looks at different ways that you can tackle some of these informatics issues and provides advantages, disadvantages, and risks for doing something one way versus another,” Winston-McPherson said. For people reading this document, one of the first things that they might want to do is take a deep dive to understand the capabilities of their electronic health record systems. How do you pull in sex fields? Where does that come from? What options do you have? What are the tools that you have at your disposal to append a reference interval or ways in which you can trigger a particular comment? “I think that could help a lot of folks when they’re trying to improve how they approach care for this population — just knowing what they can and can't do,” she said.
The guidance document recommends the inclusion of an organ inventory within a patient’s electronic health record, which would take the form of a table or checklist that documents the presence or absence of specific organs and dates of surgical procedures. “An organ inventory allows for more precise interpretation of all laboratory results and guides preventive screening decisions like whether or not a patient needs a mammogram,” Goldstein said.
Going forward, the document’s authors are realistic that implementation will not be uniform. Some recommendations, particularly around informatics, will require institutional investment that not all laboratories are in the position to make immediately. Other recommendations touch on areas where the evidence base remains limited and clinicians may be uncertain. In the future, Winston-McPherson would like to see some kind of focused guide for implementation that laboratory professionals can have at hand, specific to whatever system they’re working with.
There are also other challenges that plague the field in general that this guidance document only begins to tackle. There are two ways to read this document, Goldstein said: as a reference for working with transgender patients, or “as a recipe for systemic change in the laboratory to undo some of the transphobia baked into our medical system,” she said. “These guidelines point out the ways in which our systems betray transgender people and prevent us from pursuing optimal health because our medical providers don’t know how to interpret labs.”
This guidance, Greene said, stands to help all patients, regardless of whether they are cisgender or transgender. “We all have sex hormone differences, and the guidance document is looking at how sex hormone differences play into human physiology,” she said. The questions the guidance raises about how biological sex and hormone status interact with laboratory values have implications far beyond the gender diverse population.
Still, the guidance document strives to begin to plug a major gap for a minority population. “This is an underserved, understudied population, and these recommendations are based on currently available studies. So we hope that there’ll be more studies and that these recommendations can further evolve and become more refined,” Thomas said.
Grace Browne is a freelance journalist who lives in London. +Email: [email protected]