Transgender care, in and beyond the lab

Karen Titus

July 2022—Gabrielle Winston-McPherson, PhD, could be talking about almost any aspect of laboratory medicine as she recounts how the Henry Ford Health chemistry division, in which she is associate director, has identified a patient care need.

She talks about the desire to improve health outcomes. Identifying problems in the preanalytical process. Appropriate test utilization. Putting together a team to develop training material. Assembling data and information prior to implementation. Informatics challenges. And, naturally, the perpetual financial concern of ensuring allocation of limited resources.

How else would she—or any other laboratory professional—talk about the lab’s role in transgender health care?

In fact, there are many other ways to discuss the topic. “It’s been in the news a lot these days, obviously,” says Matthew Krasowski, MD, PhD, clinical professor and vice chair, clinical pathology and laboratory services, University of Iowa Hospital and Clinics.

But Dr. Winston-McPherson is hard-pressed to think of a better way. It’s true that the topic has landed squarely in the middle of court cases, state laws, and policy debates in recent years, with words like “controversial,” “issue,” “politics,” “traditional family values,” and “beliefs” awkwardly mixed in with medical realities. But strip away the rhetoric, and labs continue to be charged with the same, enduring task: how to provide the best care to patients.

In that sense, there’s nothing particularly unusual about this population.

Dina Greene, PhD, provides one example. If a patient is transgender, nonbinary, or gender fluid, it’s important for physicians to know whether they’re on gender-affirming hormones. Whatever the patient’s status, she says, the transgender reference intervals can be appended to test results. “And it can say, Please note that these are transgender reference intervals specific to people on gender-affirming therapy. If the patient is not on gender-affirming therapy, please use sex assigned at birth to interpret these results.”

Laboratories should find nothing unusual about such notes. “We do stuff like this all the time,” says Dr. Greene, clinical associate professor, University of Washington, and associate laboratory director of LetsGetChecked, a direct-to-consumer and business-to-business testing company focused on home collection. “Not just with gender, but with anything. It’s common for us to use the comment section, because we’re always looking for a needle in the haystack. There’s always going to be somebody different,” she says, citing therapeutic ranges of tacrolimus for patients with liver versus kidney transplants—labs don’t always know the patient’s history and typically will append the therapeutic ranges for both. For complex medical situations, “It’s not unheard of for us to have results comments indicating, ‘There may be differences in this population,’” she says.

It’s entirely possible to make such notes boilerplate, when need be, she adds, drawing a comparison between hematology tests and those related to hormones. When looking at testosterone and estradiol levels, for example, it’s highly likely that the tests are being ordered in relation to gender: fertility, masculinizing or feminizing therapy, hormone replacement, surgical menopause, etc.

“But when we’re looking at hematology, we could be looking at that for any number of reasons,” she continues. It may not occur to providers to think about those test results as they relate to transgender individuals. “So for that, providing a result comment that says, for example: ‘For transgender individuals on hormone therapy, use adult cisgender male for transgender men or people on masculinizing therapy; use adult cisgender female for transgender women or people on feminizing therapy.’”

Such steps could fall into a flipped version of the mantra: If you see something, say something. For those who work in laboratories, Dr. Greene and others suggest, it’s incumbent to say something to help their patient-facing colleagues see a patient population that may not be easily visible or understood.

For Dr. Winston-McPherson, the say-something begins with phlebotomy and a simple question: What can the laboratory do to help improve care for the transgender population? In her own health care system (though she says Henry Ford is not alone in this), she’s seen instances in which interactions sometimes fall short. But in her observations, these were the result of frontline staff not having the right tools, she says, rather than purposefully disrespectful behavior.

This problem has been recognized beyond the laboratory, she says, noting that several studies have looked at how to educate health care providers about the gender-expansive community, particularly transgender patients, and why using preferred names and pronouns is crucial.

“But we haven’t found anything that focuses specifically on phlebotomists,” Dr. Winston-McPherson says. Thus her current efforts to help them understand their role in providing gender-affirming care, from patient interactions to specific technical aspects.

She and her team plan to create an educational intervention, then study whether it improves phlebotomists’ knowledge about appropriate, respectful interactions with transgender patients. “We don’t want to just put something out there,” she says. “We want a validated tool that can be shared with other labs.”

So far, she’s encountered very little pushback against the idea, she says. “Most folks I talk to recognize that this is important, a way in which the laboratory can improve care. As a laboratorian, I never want to hear about a situation where a patient doesn’t want to visit my lab because they’ve had a negative interaction. We own that. It’s our responsibility to get that right. And I think many other laboratorians feel the same way.”

Speaking more generally, she notes that a common problem among phlebotomy staff is misgendering a patient. “There are lots of subtleties there,” she says, including using the wrong pronoun or title—referring to a transgender man as “Mrs.,” for example. Phlebotomists might also mistakenly refer to a patient by their legal name rather than their preferred name (assuming the electronic health record accommodates both monikers). Phlebotomists would do well to steer clear of making any assumptions about a patient’s gender, she suggests, including presuming which restroom is appropriate for them to use.

“It’s a big deal,” she says. If someone seeking health care has multiple encounters with caregivers who suggest—regardless of intent—that the patient’s gender is not valid, “it can be incredibly toxic.”

It’s all rather simple, Dr. Winston-McPherson says. In her view, these steps are all preanalytical variables. “If there is something that prevents a collection of a sample—including a patient’s unwillingness to come to our lab because of how they have been treated in the past—that’s a problem in our process.” Phlebotomy is also one of the few ways that patients can register their satisfaction, or lack of it, with the care labs provide. From the patient perspective, the lab is less about having a test done and more about having their blood drawn.

Those who perform testing still have to figure out if, when, and how gender affects test results.

Looking at sex can provide some guidance, Dr. Greene says. “When sex influences lab results, we can assume that the use of gender-affirming hormones will influence test results as well.”

She pauses, then adds: “Some­times.”

At conferences, Dr. Krasowski says he’s often buttonholed by attendees who ask: This is complicated—can’t I just take the bottom of one reference range and the top of the other gender’s reference range, and just use one big reference range for transgender? He laughs. “That’s actually not a good idea.” But he welcomes such questions. “Because then I can work through why that would not be a good idea.”

For hemoglobin and hematocrit, for example, a broad reference range would regularly misclassify patients. In a transgender man taking testosterone, hemoglobin levels would be increased, and the appropriate range would be that of a cisgender man, he explains. But if that patient is still legally identified within the EHR as a woman, and the female reference range is used, the results might be reported in the “normal” range. And it would be normal—if the patient were not taking testosterone. But for a transgender man on hormones, the results would be abnormal; the patient would be anemic.

“That’s actually the easiest example I can think of,” says Dr. Krasowski. “Because anemia or high red cell count are two broad differentials that take you down different pathways.”

Creatinine also appears to be influenced by hormone therapy, he says, “although probably the changes there are a bit more subtle. But you could imagine a scenario where it delays recognition of renal failure, or early renal failure, versus all of a sudden it looks very abnormal.” This could happen if someone changed their legal sex in the EHR, for example, and the new sex is used in the calculation. “It changes your GFR significantly,” Dr. Krasowski says.

Cardiac markers are another area of burgeoning interest. Dr. Greene and colleagues anticipate publishing an article in JAMA Cardiology later this year (currently under review), looking at troponin and NT-proBNP in transgender patients and how the markers relate to gender.

“Use caution with troponin if you know the patient’s transgender, and trend serially,” Dr. Krasowski advises. “That’s probably the best advice we have right now.”

What’s missing in the field are outcomes studies, Dr. Krasowski says. The lipid profile of transgender men looks, in most cases, like that of cisgender men, and thus less favorable overall. But does that impact cardiovascular outcome? Lipid profiles in transgender women look more favorable, on the other hand, with higher HDL and lower LDL, but again, what does that mean in terms of outcomes?

Even in the general population those studies took a long time, he says with a laugh. Parsing through data in the transgender population will be a challenge. There may even be differences depending on how hormone therapy is delivered (patch, injection, sublingually), he says. “But we don’t have the data to split those apart right now.”

Another area he sees as likely worthy of further scrutiny is laboratory testing of growth hormones (including insulin-like growth factor) and puberty status. “The trouble is that we don’t really have reference ranges for adolescents.” Likewise, alkaline phosphatase varies quite a bit across growth stages.

Surgical pathologists who subspecialize are starting to look more closely at the transgender population as well, with researchers collecting data from retrospective studies to analyze gynecological, breast, and prostate specimens and the possible impact of gender-affirming treatments. “We need to understand what’s in the realm of normal or expected changes,” Dr. Krasowski says. He recommends two recent reviews published in Archives of Pathology & Laboratory Medicine (of which Dr. Greene is a coauthor) to help colleagues get a sense of how research is unfolding (Andrews AR, et al. Arch Pathol Lab Med. 2022;146​[2]:252–261; Andrews AR, et al. Arch Pathol Lab Med. 2022;146​[6]:766–779).

As they delve into reference intervals and other specifics of transgender care, laboratories are also taking stock of the outsized role the EHR plays in ordering tests and reporting results. “When we’re talking about care that’s required for this patient population, it’s largely the same care that everybody else needs,” Dr. Winston-McPherson says. “We need information to provide the highest-quality care.”