Aligning Laboratory Medicine with Transgender Health Care

Just as respect for the identities of transgender individuals has become a recent topic of social and political importance, the medical community is recognizing the medical implications of care for this group of patients.¹ Clinical practice guidelines published in 2017 by the Endocrine Society represent a significant stride forward in addressing this underserved population by creating an accessible resource for clinicians to assist transgender people with their transition.² 

However, large, robust studies of physiologic changes are lacking. Much of current medical research in transgender populations focuses on mental health and HIV, and while these represent significant comorbidities, aspects of basic health care remain unaddressed. Laboratory medicine is central to monitoring hormone levels and changes in physiology as transgender patients undergo gender-affirming hormone therapy.³ 

Sexually dimorphic traits exist at many levels between males and females. Some traits are phenotypically visible, such as increased height, muscle tone, defined facial structure, or hair growth in males, while others are audible, such as higher vocal pitch in females. During hormone therapy (HT) in transgender patients, some secondary sex characteristic such as hair growth or muscle tone are altered to reflect the desired gender. Other traits are static such as height. Some traits like vocal pitch, are mutable when taking testosterone, but estrogens can’t change voice tone in persons assigned male at birth.⁴ 

As physical changes occur during the hormonal transition process, physiologic changes reflected in blood-derived laboratory values ought to change too. The changes may not be obvious, but alterations can have important long-term impacts on health.

Though many studies have previously described lab values for transgender people, the studies were limited by low numbers of available patients. Now, large and prospective studies have been performed in transgender patients to help establish new reference intervals.^5,6 In particular, our team observed how transgender people’s lab values changed compared to cisgender male and females. Here, I describe some of our results, as well as additional findings, to provide information on what to expect when interpreting lab values of transgender patients.

Hematology

"As physical changes occur during the hormonal transition process, physiologic changes reflected in blood-derived laboratory values ought to change too."

Red blood cell (RBC) parameters are among the most sexually dimorphic of the common laboratory values (RBC count, hemoglobin, and hematocrit). Females may have lower hemoglobin due to unusually heavy menses, but the exact causes are uncertain. When given testosterone therapy, transgender males gain higher levels of hemoglobin and other RBC parameters. As testosterone therapy also suppresses the menstrual cycle, it is possible more blood is retained, which increases hemoglobin levels. 

However, when we looked at transgender women, who do not have menstrual cycles, estrogen HT and spironolactone blockade of androgens (such as testosterone) also resulted in lower hemoglobin.⁵ Furthermore, when RBC levels change on HT, they move into the normal range of cisgender patients. Similarly, if cisgender males are given testosterone therapy, it is not unusual for them to gain excessive hematocrit, demonstrating the effect of HT on RBC levels.⁷ Therefore, our study suggests that sex hormones are the largest driver of RBC levels in transgender patients. 

Kidney function tests

Critical medical management decisions are based on kidney function as estimated by creatinine, including drug dosing, drug toxicity, and qualification for kidney transplantation. Thus, knowing how creatinine changes in transgender patients on hormone therapy is important. 

We observed that creatinine increased in transgender men on testosterone therapy likely due to increased muscle mass, as muscles produce creatinine. However, while creatinine levels statistically decreased in transgender women on feminizing HT, the shift was not clinically significant.⁵ Thus, while creatinine, which is used to calculate kidney function, is affected by HT, the observed shift does not mean that kidney function itself is affected. 

Further characterization of how creatinine changes affect or (more likely) don’t affect kidney function is unresolved, but will have important impacts on the lives of transgender patients. 

Life-threatening lab values

"Overall, if changes in lab values are going to occur in a transgender patient, most happen within six months of initiating HT."

There are several lab values with sex-specific differences that are used to predict life-threatening conditions such as heart attack or cancer. Though these have not been studied in depth, there is a difference in the upper limit of normal in high-sensitivity troponin testing—a measure of heart injury. If the value is above the 99th percentile, patients are at risk of a heart attack due to cardiac tissue damage. 

It is currently unknown whether a transgender person should use the normal range for cisgender males or for cisgender females to determine whether they are having a heart attack. As hormone therapy can affect muscle mass, heart tissue mass could similarly be altered, changing the established value from what would be considered normal in a cisgender person.

For prostate cancer screening, prostate specific antigen levels are lowered by testosterone suppression in transgender women. The extent of this change during HT is still unknown and an area of active investigation. 

Overall, if changes in lab values are going to occur in a transgender patient, most happen within six months of initiating HT. So far, we’ve observed that these values remain stable up to five years out, suggesting that they remain stable long term.⁸ 

By helping health care providers interpret reference values for their transgender patients, the clinical lab can prevent incorrect diagnoses or interpretations of values that may in fact be within the normal range for a transgender person.

References:

1.     Gupta S, Imborek KL, Krasowski MD. Challenges in Transgender Healthcare: The Pathology Perspective. Lab Med. 2016;47(3):180-188. doi:10.1093/labmed/lmw020

2.     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. doi:10.1210/jc.2017-01658

3.     Goldstein Z, Corneil TA, Greene DN. When gender identity doesn’t equal sex recorded at birth: The role of the laboratory in providing effective healthcare to the transgender community. Clin Chem. 2017;63(8):1342-1352. doi:10.1373/clinchem.2016.258780

4.     Gooren LJG, Giltay EJ. Review of studies of androgen treatment of female-to-male transsexuals: effects and risks of administration of androgens to females. J Sex Med. 2008;5(4):765-776. doi:10.1111/j.1743-6109.2007.00646.x

5.     SoRelle JA, Jiao R, Gao E, et al. Impact of hormone therapy on laboratory values in transgender patients. Clin Chem. 2019;65(1). doi:10.1373/clinchem.2018.292730

6.     Greene DN, McPherson GW, Rongitsch J, et al. Hematology reference intervals for transgender adults on stable hormone therapy. Clin Chim Acta. 2019;492:84-90. doi:10.1016/j.cca.2019.02.011

7.     Velho I, Fighera TM, Ziegelmann PK, Spritzer PM. Effects of testosterone therapy on BMI, blood pressure, and laboratory profile of transgender men: a systematic review. Andrology. 2017;5(5):881-888. doi:10.1111/andr.12382

8.     Allen AN, Jiao R, Day P, Pagels P, Gimpel N, SoRelle JA. Dynamic impact of hormone therapy on laboratory values in transgender patients over time. J Appl Lab Med. 2021;6(1):27-40. doi:10.1093/jalm/jfaa192