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.
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.
[dropcap]F[/dropcap]or 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.
[dropcap]T[/dropcap]hose 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).
[dropcap]A[/dropcap]s 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.”
Dr. Winston-McPherson says she’s encouraged by how her colleagues are responding to attempts to address care gaps for transgender patients. But even as care improves, she says, “There are still some really big institutional challenges that make it hard at an individual level.”
It’s one thing to develop reference intervals for a healthy adult transgender population who are on gender-affirming hormone therapy. But putting those intervals into the system is a different matter. As Dr. Winston-McPherson notes: “One big limitation involves the options we have available in our electronic medical records and our laboratory information systems.”
It’s reasonable, she says, for providers to be aware of the patient’s sex assigned at birth, gender identity, preferred name, pronouns, and relevant organs. All of which, she says, should be available across the health care system to facilitate positive interactions and guide appropriate testing and screening. “But that information is not always collected uniformly, so that’s another area where we need to make progress.”
“The informatics piece is hard,” Dr. Krasowski agrees. Although he reports seeing improvements in EHRs as major vendors have started to incorporate fields that allow patients to include their gender identity and related information, there are “so many choices in how people can identify themselves. It becomes extremely complicated to sift that out,” he says.
This touches on the fact that there’s tremendous diversity within the transgender community, Dr. Winston-McPherson says. “Not everyone who’s transgender is on hormone therapy or has had surgical treatment. There are different ways that folks need to have their gender affirmed.”
For those who are on hormone therapy, Dr. Krasowski adds, “there’s not a very direct sort of marker that says, This patient’s taking hormones.” Moreover, some may start and stop or otherwise adjust their dose. “If you’re looking for some change in pathology or laboratory testing related to hormone therapy, it’s not so easy to link that up in the electronic medical record.”
“If you were to at least identify a group of patients,” he muses, “do you put a comment on lab tests? Do you somehow, for some things, make evident an informative comment related to reference ranges? That’s sort of what the capability is now.”
There are other logistical problems related to EHRs, Dr. Krasowski says. Some systems allow patients to select preferred name, gender identity, and sex assigned at birth in their patient portal, but depending on state laws, legal documentation can be required to officially change legal sex in the medical record. That can present problems in phlebotomy, where patients may be called by a legal name, and not a preferred name, or are misgendered using legal sex. Or, in cases where patients can identify as transgender or nonbinary, some may choose not to disclose or to mark “other” or “unknown” for a variety of reasons, including fear of discrimination.
All of which makes it complicated for labs. “If you wanted to have rules that try to assign test ranges based on those categories, I don’t think you have enough information,” Dr. Krasowski says.
And in cases where a patient has changed their legal sex, and provided no other information, “you would have no idea about their sex assigned at birth. That can present problems with certain tests, like Pap tests or PSA—some of those have no reference range in the opposite gender. Because it’s usually not ordered.”
He speaks admiringly of providers who see a large number of transgender patients in their practice. “Their clinical notes are very templated. They’re so easy to read because they include all the pertinent information.” It can be harder when patients access other parts of the health care system where physicians are less familiar with transgender care, although things have gotten better as those who practice in LGBTQ clinics do grand rounds and continuing education in other departments, he says.
[dropcap]I[/dropcap]t’s a field in flux, medically as well as politically. As the medical community learns more, many are taking stock of how transgender patients receive ordinary care in a less-than-ordinary social context.
The two aren’t separate, says Dr. Winston-McPherson, who notes her own longstanding interests in health disparities. She started down the path of laboratory medicine, and clinical chemistry in particular, and then Dr. Greene became a mentor, drawing her attention to inequities related to the transgender population. It quickly became clear to Dr. Winston-McPherson that labs were critical to creating change. “It’s a space in medicine, particularly laboratory medicine and clinical chemistry, where there’s a lot we can provide.”
Dr. Greene says her research is inextricably bound with social issues. With cardiac medicine, she says, treatment is complicated by how feminine or masculine a patient appears, regardless of whether the patient is cisgender or transgender. “It influences the type of care you receive and what tests are ordered.” She was scheduled to present at this year’s AACC annual meeting (along with Amy Saenger, PhD), in a session titled “At the Heart of Sex and Gender.”
The biggest change she’s seen in recent years, Dr. Greene says, “is the heated political nature around providing gender-affirming care.” When she first began working in the field of transgender health care, Dr. Greene recalls being excited (“Although the work still excites me,” she says), perceiving that her work and that of other specialists was bringing more awareness to normalize gender and diversity. “And it did—for a minute. And then it didn’t,” she says ruefully.
“Now we’re seeing kind of a backlash, where there’s deliberate targeting of transgender folks,” she says, referring to states that have passed or are considering laws restricting access to gender-affirming care for minors, with penalties, including fines and prison terms, for health care providers who prescribe or encourage guideline-supported treatment.
While this has not affected her work specifically—she notes the blue nature of Washington state—“It’s important to think about the implications for medicine in general,” she says. She compares it to state laws that limit access to abortion and related reproductive health care. “This is nonphysicians making medical decisions. That’s scary.” (See CAP statement on Dobbs v. Jackson Women’s Health ruling: https://capatholo.gy/3ajjqOz.)
Drawing out the comparison further, she notes that as some states limit abortion-related medical care, some labs have wondered about the implications of performing maternal serum screening tests. If abnormal results were used by a patient to justify an illegal abortion, would the lab be criminally liable?
In trying to normalize the conversation around transgender health care, Dr. Greene, like Dr. Winston-McPherson, also draws on the norms of science and medicine. Information is currency, she says. Gender and gender development are not widely understood—the more research, the more science, the better. In the meantime, she says, “What we do know is that when it develops, and when somebody has identified their gender, the best thing we can do for them, from a health care perspective, is affirm their gender.”
[dropcap]L[/dropcap]abs have long fought for a seat at the table, to be seen as providing services crucial to patient care. As discussions about inequities and disparities in health care have opened up more widely in recent years, do labs have a role in those discussions as well?
Certainly, says Dr. Winston-McPherson. “I have a lot to say about that. The existence of health care disparities and marginalization is the water that we drink. I think we get complacent and say to ourselves, Oh, there’s nothing that can be done about this, there’s nothing to be done about that. These problems just exist—without recognizing that the structures and the system we have in place contribute to the marginalization and the health disparities we see.
“Everybody has a role to play in addressing issues of inequity,” she continues. “It takes a radical type of thinking to say, This is not OK. We can do something. We can change this.” Closing one’s eyes and saying nothing can be done “is not the right approach,” she adds.
Laboratories can start by seeing the resources they already have. “We sit on a mountain of data,” she says. “We have a macro perspective on the utilization of laboratory testing.” If labs think about clinical testing as a resource that can be used and allocated, she says, “We are in a unique position to be able to investigate who has access to that resource and who does not.”
She sees no point in providers trying to extract themselves from the context in which they practice. “You really can’t,” she says. “There’s a reason there’s a term called ‘health policy.’ There’s a reason there’s a term, ‘social determinants of health.’ We know that social issues impact people’s health.”
While it’s not fully clear yet how labs can intervene, “We need to step back and engage in some radical thinking” to address health care inequities, she says. “We need to get away from this idea that health disparities just exist and nothing can be done about them. There is a role for us to play. We need to make a commitment to figuring out how we lend our services to this area.” (See “Tackling inequity in health care.”)
Like Dr. Winston-McPherson, Dr. Greene situates laboratory medicine within the social environment in which testing is performed. “That’s why I love doing this work,” she says. “It allows me to be at the interface of the social and the biological. We can’t separate those things.”
She ends on a blunt note. For all the medical research that’s needed, and for all that the EHR needs to be brought up to speed, social acceptance of the transgender patient population is “the number one thing that needs to happen.” Patients need to be able to access treatment; not having social acceptance is, in her view, “the biggest comorbidity” in this patient population.
Dr. Krasowski offers an equally sobering assessment.
“To me the patient population that’s really vulnerable right now is the adolescent transgender population, although the adult transgender population also faces significant challenges,” he says. “In many states Medicaid is not going to cover any gender-affirming treatment for minors, and there may even be restrictions on treatment of minors that extends to private insurers. For adults, Medicaid in some states may not cover some gender-affirming therapy, especially surgeries. This leads to disparity of transgender care between states and sometimes between Medicaid and private insurance in the same state,” he says. Labs cannot be aloof from these conversations. “We’re talking about a different standard of care.
“The issue of puberty blockers has gotten controversial, whereas that wouldn’t have been in the public eye before,” he continues. “I do think in the general public there’s a misconception that treatment in adolescents is far more common than it is.” If anything, he says, lack of parental support is more the norm. “And it’s a difficult journey even if you do have a supportive family.” Laws aimed at punishing those who provide and support treatment “don’t make it any easier.”
“My view is, whatever we can do in pathology to make it a little bit easier would be awesome,” he says.
Karen Titus is CAP TODAY contributing editor and co-managing editor.