Making it personal: transgender medicine

Karen Titus

August 2017—Talk about personalized medicine.

While the national discussion about transgender women and men often pivots on civil rights legislation (exhibit A: so-called bathroom bills), the medical community has quietly begun to ask questions about how to provide care for transgender patients. In the process, assumptions are being turned sideways. And as laboratory professionals are realizing, the impact can affect everything from start (patient identification, test ordering) to finish (test results, billing), seemingly one patient at a time.

Make no mistake: While the “T” in the LGBT moniker (now evolving to LGBTQ or LGBTQIA in many circles) stands for transgender, that word means something different—biologically, physically, emotionally—for nearly every patient. For laboratory professionals and other care providers, the implications are only starting to be felt. It’s not so much that everything they’ve thought up to now has been wrong. Rather, they’re now thinking about all the things they’ve simply never thought about before.

Bruce Levy, MD, associate chief medical informatics officer, Geisinger Health System, and professor of pathology, Geisinger Commonwealth School of Medicine, is finding this out each day at work, as the rural Pennsylvania health care system is in the midst of a major initiative to address the needs of these patients. “My one message is, the more you think about it, the more complex it gets.”

It seemed like a modest task at first. Spurred by leadership who wanted the system to become part of the Healthcare Equality Index—a benchmarking tool to help providers become LGBTQ-inclusive (www.hrc.org/hei)—Geisinger began by looking at its electronic health record, Epic. The vendor had already developed tools and additional fields to capture information about transgender (and other) patients. “So it would seem like this would be a simple issue. But it’s very complicated,” says Dr. Levy, who is also program director of the clinical informatics fellowship at Geisinger.

“If you change somebody’s gender in the EMR, that drives so many other things within the health system,” he continues. “In labs, it will drive control and normal values. In terms of best practice advisory reminders and decision support, it will drive testing.”

First of two parts

He speaks slowly and deliberately, with the cadence of someone narrating and playing a game of chess. He sees complications with every move—in this match, the board keeps expanding, the pieces grow more numerous. “Which fields do you change? Which need to remain the same? You also have the difficulty of some patients may identify differently but not have had any sort of either surgical or hormonal or medication changes that would effect a physical change in their body. How do you make sure they’re getting the right health care?”
Especially if you don’t know who “they” are. Or even if “they” might mean one patient. This is no longer a spirited debate only among grammarians.

Dr. Levy is firm about what this means for labs. Valuing patients and providing good care cannot be a tradeoff. “It’s a challenge. It’s not a balance,” he says.

Though the mandate at Geisinger came from on high, carrying it out meant convening a broad multidisciplinary group, says Dr. Levy, including those from informatics and the laboratory, as well as those who provide direct care to patients. “It’s not just, ‘Oh, what changes do we make in our EHR?’ We have to train our employees to ask the right questions and address patients properly. We also want to make sure they receive the absolute best care, based on who they are as well as their underlying biology.”

Dr. Levy reports reaching out to Geisinger employees who’ve expressed an interest in this topic, some of whom are LGBTQIA themselves. (The letters stand for lesbian, gay, bisexual, transgender, queer, intersex, and asexual.) He and colleagues have also tapped into departments with expertise in gender and race equality issues. They’ve also lawyered up. If, for example, a person has changed the gender on their driver’s license, what needs to change in the EHR to maintain consistency and meet legal standards? “It’s not just people in the lab saying, ‘We’ve got to do this’ and puzzling it through.”

As of mid-July, Geisinger had been making incremental changes in the records of a handful of patients. By the end of September, a systemwide rollout should be in place. “Sometimes it seems like we’re fairly far along,” says Dr. Levy, who then adds, a bit ruefully, “but when we go back to some of our earlier discussions to make sure we truly understand the implications of what we’re doing, and to make sure the data is flowing properly, well….” Even once it’s implemented, he predicts, the arrival might feel more like a pit stop than the end of the trip. “As thorough as we’re trying to be, I don’t think we’ve thought of everything this is going to impact.”

The biggest surprise, says Dr. Levy, “is that we didn’t fully realize how many places a person’s gender touches on different things in our system, and the implications of that,” including decision support tools, data warehousing, and research, not to mention room assignments and, state legislative bills aside, bathrooms. “When you start out, you don’t think about all these nuances.” Like a strong piece of theater, it demands attention, with the power to discomfit as well as transform.

Dina Greene, PhD, assistant professor and associate director, chemistry, University of Washington Department of Laboratory Medicine, Seattle, has immersed herself in transgender health care. The topic is hardly new to her, but she doesn’t hesitate to suggest that laboratories start with the basics. In presentations and talks with colleagues, she says, “My role is often Gender 101. There is no shortage of care providers who think they know something but are actually confused” about terms like sex (often based on phenotypic appearance of genitalia at birth and chromosomal type), gender (a person’s sense of their gender, which may not match the sex assigned at birth), and cisgender (a person whose gender identity matches the sex assigned at birth).

Laboratories can also raise their level of care by figuring out how to lower barriers for transgender patients. Though Dr. Greene has worked for health care systems that take transgender health seriously, often in areas of the country typically considered to be liberal, she’s seen her fair share of missteps, including pregnancy tests canceled on transgender males, or failures to flag PSA tests on transgender women when results were greater than the reference interval.

Most barriers are system based, Dr. Greene says, and use rules-based settings derived from the sex/gender field. But there’s also the system of the mind, she suggests. “You need to make sure you’re not making rules that exclude a percentage of the population because their reproductive organs don’t match what you’ve been socialized to believe they should.” And remember, she adds: “Once someone’s transitioned, they very much look like their gender. So it would be really silly to have someone who’s listed as female [who’s] walking in with a beard and big, broad shoulders.”

Changing systems “is always harder than you think,” Dr. Greene concedes. “But being aware of the need for change is” a big step in the right direction. “That’s definitely part of our responsibility as a laboratory,” she says.

Some might argue, reasonably enough, that the main responsibility of laboratories is to perform testing and provide accurate, useful results.

In transgender medicine, however, “accurate” and “useful” aren’t always synonymous.

Becoming more familiar with the basics of cross-sex hormone therapy is a good place for laboratories to start, says Tim Cavanaugh, MD, co-medical director for the transgender health program, Fenway Health, Boston. “That’s really what we’re talking about here,” he says. He points to the primary care protocols on the topic from the University of California, San Francisco’s Center of Excellence for Transgender Health (http://transhealth.ucsf.edu/protocols), which were revised and published last year. He calls them “incredibly well researched and referenced,” noting that they include a section on both feminizing and masculinizing hormone therapy. “If I had to give somebody one resource for some basic information, that would be it.” The protocols cover titration and monitoring of BUN/Cr/K+, estradiol, total testosterone, sex hormone binding globulin, albumin, and prolactin.

Not everything is a complete and utter mystery. With experience, Dr. Cavanaugh says, physicians have learned that estradiol and the forms of testosterone used for hormone therapy do not have a big impact on liver health, so monitoring liver transaminases is no longer considered useful.

But once care providers start thinking about transgender care, the questions come as fast as presidential tweets. Does it make sense for a transgender woman to continue taking hormonal therapy in her later, traditionally postmenopausal decades? If she does, what is the long-term impact on the body?

Not surprisingly, says Dr. Greene, almost every area of transgender health is in need of more study. “There are a few important analytes that we’re better trying to understand in the trans population,” she says. That would include creatinine, hemoglobin/hematocrit, and lipid profiles. “How can you tell if a trans woman is anemic?” Dr. Greene asks. “In a hematologic profile of a trans man, what indicates a blood cell disorder? What needs to be monitored?”

Basic hormone concentrations are critical yet difficult. “Estrogens are really complicated to measure in general,” says Dr. Greene. Interestingly, trans women on estrogen will often have elevated prolactin concentrations. “But at what point might that be physiologically inappropriate?” she asks. Testosterone reference levels are also complicated. “That’s another area that needs clarity,” she says, “because we’re treating these folks with exogenous hormones, and it would be nice if there were a target.” Moreover, she notes, concentrations are linked to route of administration, whether subcutaneous or topical hormone treatment versus oral or intramuscular injection. Most of the information to date has been observed empirically by physicians who treat transgender patients, but studies are lacking.

Dr. Greene says it’s fine to start small—a study looking at patients within a certain age range who are one year post-hormone therapy, for example, and the type of administration, to see if variation exists. “If the group needs to be broken down further, we can do that. But even just starting there would give a nice data set that just doesn’t exist.”

Transfusion can have its own challenges, says Dr. Greene, since transfusions in people of childbearing age who have ovaries and a uterus have a special protocol, especially in emergent cases involving a massive transfusion. “Then you would want to treat a trans man of childbearing age—if he’s retained his ovaries and uterus—the same way you would treat a cis woman.” If the patient is identified in the EHR as male, however, and is being treated outside a gynecology suite, providers may not know how to treat appropriately.

Kidney transplants also require closer scrutiny, since creatinine and eGFR are sex-based. Because there can be strict thresholds for placing a patient on a transplant list, says Dr. Greene, it’s possible that a trans male with low muscle mass might need to be evaluated with the female adjusted equation. Dr. Greene recently had a case report on this topic accepted for publication in Clinical Chemistry.

Transitioning itself, whether from female to male or male to female, gives to labs another set of puzzles to solve. The process may occur early in a person’s life and involve the use of puberty blockers; many patients transition much later in life. Needless to say, that can feel like another curveball thrown at the lab.

For many trans individuals, says Dr. Cavanaugh, hormone therapy is expected to be lifelong, though in keeping with the theme of personalized medicine, it varies tremendously by individual. For patients who have had their testes or ovaries removed and stop hormone therapy, he says, the impact on cardiovascular and bone health, as well as general vigor, can be considerable. There is debate as to whether transgender women should stop hormone therapy in their 50s or 60s, when cisgender women would be in menopause.

“But it depends a great deal on when a patient has started their hormone therapy,” he continues. Many transgender people don’t start hormone therapy until their 30s, 40s, or 50s. “We’ve had patients in their 60s starting on hormones.” Not surprisingly, when to stop or lower hormones has not been well established. But while current practice is to keep patients on hormones indefinitely, patients may decide to stop for any of a number of reasons.

One would be the growing number of patients who don’t identify as male or female, but instead as gender fluid. “They see themselves as in the middle of the spectrum, so we have patients who decide very consciously to be on testosterone for a period of time and then stop the therapy once they’ve experienced the changes they want,” says Dr. Cavanaugh. Or, patients may use very low doses of hormones to achieve partial masculinization or feminization. “How will that affect their health and interpretations of hemoglobin and creatinine?”

Male-to-female transitioning patients on hormone therapy, who experience a decrease in muscle mass, might be expected to have a drop in creatinine levels, given that they’re higher in men due to their greater muscle mass. In one study looking at interpreting lab tests in transgender patients (Roberts TK, et al. Am J Med. 2014;127[2]:159–162), researchers observed the opposite effect. At the same time, they noted, alkaline phosphatase, which decreases in response to hormone therapy in postmenopausal women, could be expected to drop also in those male-to-female trans patients. Instead, they found that levels resembled controls in male patients.