Volume 36 Number 6 | December 2022

Diane Davis, PhD, MLS(ASCP)CMSCCMSLSCM, ASCLS-Maryland Board Member and ASCLS Region II Treasurer

Diane DavisAccurate reference intervals for transgender patients significantly influence patient safety and are also an ethical obligation of medical laboratory professionals. First, a short vocabulary lesson from GLAAD to ensure that the following information is clear.

  • Transgender women are those whose biological sex at birth is male but identify their gender as female. Transgender men are the reverse.
  • Cisgender is a term to identify those whose biological sex and gender identity match.
  • Non-binary patients identify as neither male nor female, but many of them may undergo therapies similar to those used by transgender people, so laboratory reference intervals determined for transgender populations may also have relevance to non-binary patients.
  • Gender dysphoria is the distress/anxiety transgender people have from the mismatch of their sex at birth and their internal sense of gender identity.

Many transgender people undergo treatments such as genderaffirming hormone therapy and gender-reassignment surgeries to minimize their gender dysphoria. It is these types of treatments that are primarily responsible for the need to research laboratory reference intervals specific to this population.

“Although reference interval studies in the transgender population are daunting, they are ethically necessary. Otherwise, there is potential misinterpretation of laboratory values leading to inappropriate care or withholding of care.”

Developing reference intervals for any laboratory test is no small undertaking. It can be time-consuming and expensive. The reference population must be identified, and then subjects are recruited to participate. Enough people must be recruited to ensure that conclusions are accurate and that innate differences influencing “normal” values can be identified. When data is collected, it is analyzed for variance of values between different sexes, different age groups, different races, and so on. If it is evident, for example, that there should be different reference intervals for males and females, then additional subjects must be recruited so that there is enough data for each sex.

Determining reference intervals for transgender/non-binary persons is even more challenging. As a low prevalence population, there are fewer subjects to recruit, and there is potential hesitation of subjects to participate. Gender-affirming therapy is not well-standardized, and there are multiple options for hormone therapy and surgery. Most published studies are only on subjects on “stable hormone therapy,” since laboratory values in transitioning subjects may be highly variable. Although reference intervals do not apply to biopsy specimens, it must also be noted that the effects of gender-affirming therapy on microscopy of tissue specimens is also not well-researched, and this lack of knowledge has the potential to cause patient harm.

Although reference interval studies in the transgender population are daunting, they are ethically necessary. Otherwise, there is potential misinterpretation of laboratory values leading to inappropriate care or withholding of care. There is also potential legal liability to providers for inappropriate care and to laboratories that do not support clinicians with appropriate reference intervals. For transgender people on stable hormone therapy, data available as of this writing suggests the following practices for using cisgender reference intervals.

  1. Use reference interval for affirmed gender—estradiol, total testosterone, creatinine, eGFR, hemoglobin, hematocrit, iron studies, electrolytes, liver function, and lipid testing.
  2. Use reference interval for sex at birth—high-sensitivity troponin and PSA (unless prostate is removed).
  3. For other routine analytes, differences between sexes are minor, and no known modification is needed as of this writing.

The above guidance is a broad generalization, and it cannot be emphasized enough that transitioning patients will not fall into these neat categories.

Patient safety is most likely to be jeopardized when interpreting analytes that have significant male/female differences and/or are particularly influenced by sex hormones. This includes lingering effects of natural sex hormones prior to transitioning. For example, biological males usually keep higher levels of heart and skeletal muscle mass.

There are cases in the literature where potentially poor patient outcomes have already occurred. These include:

  1. A transgender male identified in the electronic medical record (EMR) as male whose kidney failure diagnosis and eligibility for kidney transplant were delayed (Whitley & Green, 2017)
  2. A near-misdiagnosis of myocardial infarction in a transgender male when the male reference interval for hs-troponin was used on admission (Cheung A, et al, 2021)
  3. A near-miss incident of almost transfusing Rh+ blood to a transgender male during a massive resuscitation protocol (Mays JA, et al, 2018).

As demonstrated above, development of EMRs that can capture all information relevant to caring for a patient is needed. To neglect such software development would be unethical. Currently, some EMRs have limited ability to capture:

  1. Birth sex and current gender
  2. Chosen names/pronouns
  3. Sexual orientation
  4. Prior procedures from other providers
  5. Specialized reference intervals for the transgender and other populations

This is further complicated because some patients prefer not to disclose their transgender status and/or sexual orientation, especially if they are transitioning. Some patients may withhold their use of illicit gender affirming therapy. Incomplete patient history and information does impact laboratory output as well in a variety of ways including:

  1. eGFR calculations only for stated sex
  2. Reference interval inappropriate for patient status
  3. Auto-cancellation of tests when gender doesn’t match

The power of complete and accurate information cannot be overstated for appropriate patient care. Information systems must expand to capture all data that has significant patient impact.

What are the next moves for any laboratory to address the patient safety/ethical issues raised in this article? The analytes most impacted by inadequate/incorrect information leading to misdiagnosis are serum creatinine, eGFR, and high sensitivity troponin, so practices related to these analytes take priority. The limitations of a site’s EMR should be identified regarding the ability to capture and utilize gender information. The ability of the lab to calculate an eGFR for the opposite sex upon request should be explored.

Most labs don’t have the ability to perform reference interval studies, but an alert could be placed on the report with the reference interval of these analytes. An example is: “Studies have shown this reference interval may not apply to sexual/gender minorities. Contact the lab if assistance is needed interpreting these values.” The laboratory should then maintain resources to give clinicians. A list of good resources is provided below, not just for clinicians, but also for medical laboratory professionals who care about patient safety and doing the right thing.

  1. Allen A, et al. Dynamic impact of hormone therapy on laboratory values in transgender patients over time. JALM. 6(01): 27-40. 2021.
  2. Bunch D. Modern reference intervals. Clinical Laboratory News. July 2021.
  3. Caughey A, et al. USPSTF Approach to Addressing Sex and Gender When Making Recommendations for Clinical Preventive Services. JAMA. 326(19):1953-61. 2021.
  4. Cheung A, et al. Approach to Interpreting Common Laboratory Pathology Tests in Transgender Individuals. J of Clin Endocrinology & Metabolism. 106(3): 893–901. 2021.
  5. Greene DN, et al. Hematology reference intervals for transgender adults on stable hormone therapy. Clin Chem Acta. 492: 84-90. 2019.
  6. Greene DN, et al. Reproductive endocrinology reference intervals for transgender men on stable hormone therapy. JALM. 6(01): 41-50. 2021.
  7. Greene DN, et al. Reproductive endocrinology reference intervals for transgender women on stable hormone therapy. JALM. 6(01): 15-26. 2021.
  8. Hranilovich J, et al. Headache in transgender and genderdiverse patients: A narrative review. Headache. 61(7): 1040-50. 2021.
  9. Humble R, et al. Common hormone therapies used to care for transgender patients influence laboratory results. JALM. 3(05): 799-814. 2019.
  10. Mays JA, et al. Transfusion support for transgender men of childbearing age. Transfusion. 58(3): 823-825. 2018.
  11. Ozarda Y. Reference intervals: current status, recent developments and future considerations. Biochemica Medica. 26(1): 5-16. 2016.
  12. Salzer A. Fecundity in transgender men. J of Amer Acad of PA’s. 34(10): 51-3. 2021.
  13. thepathologist.com/outside-the-lab/driving-care-for-our-transpatients.
  14. Whitley C, Green, D. Transgender Man Being Evaluated for a Kidney Transplant. Clin Chem. 63(11): 1680–3. 2017.

Diane Davis is Faculty Emeritus at Salisbury University Medical Laboratory Science Program in Salisbury, Maryland, and is a Consultant for Spectra Laboratories.