ADLM guidance document on incorporating gender diversity in pathology and laboratory medicine

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Authors

Tiffany A. Thomas
Department of Pathology and Cell Biology
Columbia University
New York, NY

Gabrielle N. Winston-McPherson
University of Wisconsin
Madison, WI

Ina Amarillo
Department of Pathology and Laboratory Medicine
Hershey, PAPenn State Health

Alisha D. Berry
Department of Laboratory Medicine & Pathology
University of Washington
Seattle, WA

Caroline J. Davidge-Pitts
Division of Endocrinology, Diabetes and Nutrition
Mayo Clinic
Rochester, MN

Sridevi Devaraj
Department of Pathology
Baylor College of Medicine and Texas Children's Hospital
Houston, TX

Zil Goldstein
Callen-Lorde Community Health Center
Brooklyn, NY

Brad S. Karon
Department of Laboratory Medicine and Pathology
Mayo Clinic
Rochester, MN

Brooke M. Katzman
Department of Laboratory Medicine and Pathology
Mayo Clinic
Rochester, MN

Department of Laboratory Medicine and Pathology
University of Minnesota
Minneapolis, MN

Hung S. Luu
Department of Pathology
Children’s Health
Dallas, TX

James H. Nichols
Vanderbilt University Medical Center
Nashville, TN

Tracy L. Stockley
Laboratory Medicine Program
University Health Network and University of Toronto
Toronto, Ontario, Canada

Michelle R. Stoffel
Department of Laboratory Medicine and Pathology
University of Minnesota
Minneapolis, MN

Dina N. Greene
Department of Laboratory Medicine & Pathology
University of Washington
Seattle, WA

Matthew D. Krasowski
Department of Pathology
University of Iowa Health Care
Iowa City, IA

Drs. Thomas and Winston-McPherson are co-first authors.
Drs. Greene and Krasowski are co-corresponding authors and co-chaired this project.

This document was approved by the Academy Content Development Committee and Academy Council in February 2026 and the ADLM Board of Directors in March 2026.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Background

The first international clinical standards of care for the gender-diverse population were formulated in the late 1970s. In the last 15 years, multiple subspecialty societies within the United States have developed clinical care guidelines for those with gender dysphoria, including gender-affirming hormone therapy (GAHT) and surgical treatments. To date, there are no pathology- and laboratory medicine–specific recommendations in the United States for the gender-diverse population.

Content

This document outlines pathology- and laboratory medicine–specific recommendations for providing optimal care to the gender-diverse population, with a predominant focus on the adult population. The scope of this document focuses on the following 5 topics: (a) reference intervals and interpretation of laboratory tests impacted by use of GAHT (testosterone for transgender men; estradiol with or without antiandrogens for transgender women), focusing on those stably on GAHT for 6 months or longer; (b) transfusion medicine considerations for the gender-diverse patient population, (c) consideration of gender diversity in autopsy and death investigation, (d) interpretation of histology from tissues that are impacted by GAHT and surgical procedures; and (e) pathology and laboratory medicine informatics challenges and opportunities.

Summary: 
A relatively small group of laboratory tests is significantly impacted by GAHT. The histology of some tissues shows changes attributable to GAHT or to nonhormonal medical procedures. Autopsy and transfusion medicine practices for the gender-diverse population currently lack standardization, although this is evolving. The landscape of pathology informatics related to gender diversity is complicated by varying electronic health record and laboratory informatics systems functionality. Abbott Diagnostics10.13039/100014386Roche Diagnostics10.13039/100016545

INTRODUCTION

The first systematic series of medical and scientific manuscripts related to gender variance was published in the 1950s and 1960s (1). The first published clinical standards of care for what is now termed gender dysphoria were published in 1979 by the Harry Benjamin International Gender Dysphoria Association, Inc., which later became the World Professional Association for Transgender Health (WPATH) (2). The WPATH Standards of Care are now in its eighth version (3). Over the last 15 years, numerous medical societies within the United States have published guidelines or recommendations related to clinical care of the gender-diverse patient population, including endocrinology (4, 5), pediatrics (6), plastic surgery (7), and urology (8).

In Australia, best practice guidelines for pathology testing for transgender and intersex (differences of sex development) individuals have also been published (9).

Within the United States, there have been efforts to provide guidance on handling of surgical specimens collected from transgender and intersex patients, as well as for specimens arriving with either missing or unknown gender or sex markers (10). A working group of the Association for Molecular Pathology recently provided recommendations and considerations for sex- and gender-inclusive collection of specimens for cytogenetics and molecular genomics testing (11, 12). However, to date, there are no published specific recommendations in the United States that broadly cover laboratory medicine, anatomic pathology, and pathology informatics.

To address this need, an expert panel was convened to review the literature as it relates to clinical laboratory and regulatory frameworks. Members included clinical and anatomic pathologists; PhD laboratory medicine experts with training and board certification in areas such as clinical chemistry, laboratory genomics, and molecular genetics; and primary care and endocrinology providers involved in direct clinical care of transgender patients. Panel members were selected to represent geographically diverse institutional environments, including academic medical centers, reference laboratories, and private institutions, to ensure that multiple perspectives were represented. The expert panel met periodically via teleconference as a large group. Subgroups within the broader panel focused on specific areas: anatomic pathology, impact of hormone therapy on laboratory test results and reference intervals, transfusion medicine, and informatics. The objective of this publication is to outline the medical needs of adult transgender people as they specifically relate to laboratory medicine and pathology. Basic definitions relevant to this document are listed in Table 1. Throughout the document, we refer to people using gender-affirming hormones as transgender and are inclusive of nonbinary people within this umbrella term, although some nonbinary people may not identify as transgender.

Table 1. Definitions.

This guidance document intends to (a) review evidence for how gender-affirming hormone therapy (GAHT) impacts laboratory tests and the significance of these changes and propose reference intervals and interpretation for selected clinical laboratory tests for those stably on GAHT for 6 months or longer, (b) discuss transfusion medicine considerations for the gender-diverse patient population, (c) outline best practices related to documentation of gender diversity in autopsy and death investigation, (d) summarize available knowledge on the hormonal and non-hormonal impacts of gender-affirming treatments on cytology and tissue histology, and (e) outline informatics challenges and opportunities for the gender-diverse population including utilization of sexual orientation/gender identity (SOGI) fields within electronic health record (EHR) and laboratory information system (LIS) software.

This guidance focuses on the adult gender-diverse population. For the topics covered in this guidance document, the available literature is evolving and often incomplete, inviting opportunities for future studies. Prospective studies and systematic reviews are relatively rare, although some have been published in recent years (13–20). This guidance document also highlights gaps where additional studies are needed.

LABORATORY TESTS AND POTENTIAL IMPACT BY GAHT

Standard of care for transgender women and men who choose to medically transition includes feminizing GAHT (estradiol with or without antiandrogen medication like spironolactone, finasteride, or cyproterone acetate [CPA]) and masculinizing GAHT (testosterone), respectively (3, 5). This section summarizes available evidence on how GAHT impacts common laboratory assays and applies to those stably on GAHT, defined here as 6 months or longer. In general, there are limited published data on the impact of GAHT on common laboratory tests at timeframes less than 6 months. This is an area for future investigation. Table 2 summarizes the key information relevant to proposed reference intervals for selected assays. Unless otherwise specified, concentrations of analytes referenced in the following discussion refer to those in serum or plasma.

Table 2. Impacts of gender-affirming masculinizing or feminizing hormone therapy on common laboratory tests, along with proposed reference intervals for interpretation.^a

a Mean corpuscular volume.
b White blood cell.

What is the impact of GAHT on laboratory tests for hemostasis and thrombosis and their interpretation?

Reference intervals and clinical interpretation of common coagulation assays, such as prothrombin time, international normalized ratio, activated partial thromboplastin time, and coagulation factor assays, generally do not differ between cisgender men and women, with the possible exception of protein S, and results can be interpreted independently of sex, gender, or use of GAHT (42). Although there is a complex relationship between estrogen and hemostasis, interpretation of D-dimer concentration does not differ between cisgender men and women and therefore will not differ based on the use of GAHT (43). D-dimer measurements used in algorithms for exclusion of venous thromboembolism are interpreted independently from sex (44). 

Summary

• GAHT does not impact interpretation or clinical decision-making for tests used to evaluate hemostasis and thrombosis, including prothrombin time/international normalized ratio, activated partial thromboplastin time, and D-dimer.

What is the impact of GAHT on hematology parameters and their interpretation?

Androgens stimulate erythropoiesis, resulting in different reference intervals for red blood cell (RBC) indices between postpubertal cisgender men and women. Testosterone stimulates erythropoiesis by increasing the expression of erythropoietin and iron availability (45). This leads to higher concentrations of hemoglobin, hematocrit, and RBC counts in cisgender men relative to cisgender women.

For people taking masculinizing hormone therapy, the increased testosterone concentration will lead to higher hemoglobin, hematocrit, and RBC counts that align with those seen in cisgender adult men (21, 22). For people taking feminizing hormone therapy, testosterone suppression will lead to lower hemoglobin, hematocrit, and RBC counts that align with those seen in cisgender adult women. RBC indices stabilize by 6 months of initiating GAHT (36, 39, 46). There is a lack of published literature on longitudinal changes in hemoglobin, hematocrit, and RBC counts earlier than 6 months after initiating GAHT. Therefore, during the hormone initiation period, the hematology reference interval for SAAB should also be considered, as clinically indicated.

Summary

• Testosterone therapy increases hemoglobin, hematocrit, and RBC counts to values that align with those observed in cisgender men by 6 months; utilize reference intervals for cisgender men to interpret these tests.
• Feminizing therapy decreases hemoglobin, hematocrit, and RBC counts to values that align with those observed in cisgender women by 6 months; utilize reference intervals for cisgender women to interpret these tests.
• Other blood cell parameters are not significantly affected by GAHT.

What is the impact of GAHT on laboratory tests for myocardial injury (cardiac troponins) and heart failure (brain natriuretic peptides)? How should algorithms for assessing acute myocardial injury incorporate gender identity?

The 99th percentile upper reference limit (URL) is the recommended cutoff for the detection of myocardial injury using all cardiac troponin assays, including high-sensitivity cardiac troponin (hs-cTn). In healthy populations with random measurements, cisgender men have higher hs-cTn concentrations than cisgender women, making the 99th percentile URL for cisgender men a higher concentration compared with cisgender women (47). This trend is similar for transgender people, whereby transgender men prescribed testosterone have higher hs-cTn concentrations relative to transgender women, suggesting that sex hormones may influence cardiac physiology (23, 24). The clinical impact of sex-specific 99th percentile URLs in the assessment of acute myocardial infarction (AMI) has been debated, but prospective studies designed to measure long-term consequences of implementing sex-specific thresholds favor their use (48).

On a population level, sex-specific hs-cTn URLs likely improve outcomes and are being further assessed in clinical studies (49, 50). There have been no prospective clinical studies evaluating the influence of sex-specific 99th percentile URLs on long-term cardiac outcomes in transgender patients. However, in a small retrospective cohort evaluating classification of transgender patients based on use of sex-specific hs-cTn URLs, 3 patients with type 2 AMI (myocardial injury due to imbalance between oxygen supply and demand as opposed to coronary artery occlusion) had hs-cTn values that exceeded female but not male 99th percentile URLs. In 2 of these cases, the patients were transgender men, and results would have been falsely negative if using gender identity (male) but a true positive if using sex assigned at birth (SAAB; female). In contrast, the third reclassification was a transgender woman who would have been a true positive if using gender identity (female) but a false negative if using SAAB (male). No patients with type 1 AMI (blockage of the coronary arteries) were reclassified (51).

All four universal definitions of AMI include a rise and/or fall in cardiac troponin with at least one value exceeding the 99th percentile URL needed for the diagnosis of non-ST elevation myocardial infarction, implying that serial hs-cTn measurements to detect a change/delta are critical for diagnosis (52). Unless a specified rapid rule-out hs-cTn protocol is institutionally adopted, all patients presenting with signs and symptoms of AMI should receive serial measurements, and the delta hs-cTn concentration should be assessed and used to determine whether additional cardiac care is required (51). Overall, given the limited current evidence, we emphasize the importance of serial measurements of hs-cTn for the population receiving GAHT. If sex-specific hs-cTn URLs are applied institutionally, we provisionally recommend the use of the 99th percentile that aligns with affirmed gender, recognizing this is an area in need of future study. These recommendations are appropriate for both hs-cTnI and hs-cTnT.

Summary

• Serial measurements of hs-cTn for the population receiving GAHT should be emphasized for AMI risk evaluation and management.
• While GAHT significantly impacts basal levels of hs-cTn, the clinical significance of this for risk assessment of AMI or future cardiovascular events is unclear.
• GAHT does not impact interpretation of laboratory tests related to heart failure.

What is the impact of GAHT on diagnosis and monitoring of chronic kidney disease? How should estimates of the glomerular filtration rate and other markers of kidney function be interpreted in the gender-diverse population?

The impact of sex hormones on kidney health and risk of chronic kidney disease (CKD) has been revealed through cross-sectional, epidemiologic, and animal studies (56). In the cisgender female population, estradiol shows protective effects on glomerular and tubular function, with earlier menarche or later menopause associated with lower risk of CKD (57, 58). In contrast, bilateral oophorectomy in premenopausal women is associated with a higher risk of developing CKD (59). The role of testosterone in kidney function is complex, with some conflicting studies in the literature (60).

Creatinine production is proportional to skeletal muscle mass such that the creatinine reference interval for cisgender adult men has a higher upper and lower limit of normal relative to cisgender women. Although testosterone is a known anabolic steroid that enhances skeletal muscle accrual, a systematic review and meta-analysis illustrated that the changes in creatinine concentration after initiating masculinizing or feminizing GAHT were variable (19). Combined, the analysis indicated that transgender men have a slight increase in creatinine concentration after initiating masculinizing therapy, but that transgender women show no significant change in creatinine concentration from feminizing therapy (33, 61). Interestingly, a study directly measuring the glomerular filtration rate (GFR) using iohexol clearance in transgender women and men showed an increase in measured GFR 3 months after starting feminizing therapy and no change in measured GFR 3 months after starting masculinizing therapy (62).

Clinically, the reference interval for creatinine is less relevant than the use of creatinine concentration in the context of calculating estimated GFR (eGFR), which is ideally calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration or similarly modern eGFR equation (63–65). These equations require input of 3 variables: age, sex, and creatinine concentration. The sex variable influences the numeric output of eGFR by approximately 30%, whereby a creatinine concentration of 1.5 mg/dL (132 µmol/L) for a 40-year-old adult would calculate an eGFR of 98 mL/min/1.73 m2 for an adult male (considered normal) and a value of 73 mL/min/1.73 m2 in an adult female (considered mildly decreased kidney function) (26). Factors other than hormones influence skeletal muscle mass, which can also result in significant differences between measured GFR and eGFR for individual cisgender people. For people receiving GAHT, there is no consensus on the use of SAAB or affirmed gender as most appropriate for eGFR calculations (65, 66). One study illustrated that the Chronic Kidney Disease Epidemiology Collaboration creatinine equation can overestimate eGFR by as much as 50% in transgender men when using the affirmed gender and 30% in transgender women when using SAAB (27).

Cystatin C is a skeletal muscle-mass independent analyte that is also used to estimate GFR. Slight differences in cystatin C have been observed between men and women, but the overall impact of these differences on population-derived eGFR equations is significantly less than that of creatinine-based eGFR equations (26). Cystatin C aligns with affirmed gender in those stably on GAHT, whereby use of masculinizing hormone therapy increases cystatin C and feminizing hormone therapy decreases cystatin C (25). These preliminary data support the use of affirmed gender in cystatin C-based eGFR equations. Alternatively, the most recent European Kidney Function Consortium cystatin C–based equation for eGFR does not include a sex variable (67, 68).

Sex is an influential variable in calculating eGFR, and laboratories should strive to provide educational activities that reinforce that muscle mass, sex hormone milieu, SAAB, and gender identity must be considered when interpreting creatinine-based eGFR results. For transgender people, eGFR should ideally be calculated using both male and female variables, although the ability to do this depends on the informatics capability of the LIS and EHR. If the eGFR calculated is 60 mL/min/1.73 m2 in someone on GAHT, additional markers of renal function, such as cystatin C, urine albumin to creatinine ratio (uACR), and direct GFR measurement, should be considered. In line with this, the 2024 Kidney Disease Improving Global Outcomes Chronic Kidney Disease guidance provided Grade 1C evidence using eGFRcr-cys (an eGFR equation incorporating both creatinine and cystatin C measurements) in clinical situations when eGFRcr is less accurate, and GFR estimation affects clinical decision-making (66).

Summary

• Masculinizing therapy with testosterone slightly increases creatinine concentrations, paralleling the concentration range seen in cisgender men.
• Feminizing therapy with estradiol has minimal or no impact on creatinine concentrations.
• There is currently no consensus on whether SAAB or gender identity is more appropriate to be used as the sex variable when calculating eGFR with modern eGFR equations.
• A holistic approach involving additional laboratory monitoring (cystatin C, eGFRcr-cys, uACR) is important for kidney risk assessment for people receiving GAHT.
• An alternative approach, if informatics capabilities permit, is to calculate eGFR using creatinine with both sexes and dual report (e.g., eGFR female, eGFR male) on separate lines for clinicians to observe GAHT-related changes and to allow flagging of abnormal eGFR regardless of sex.

What is the overall impact of GAHT on the hypothalamic–pituitary–gonadal axis?

The hypothalamic–pituitary–gonadal axis (HPGA) is the pathway that regulates sex hormones in humans (71, 72). In response to both environmental and internal cues, the hypothalamus secretes gonadotropin-releasing hormone (GnRH), which acts on the pituitary gland to stimulate the release of the gonadotropins: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In individuals with testes, LH promotes testosterone production. FSH, in conjunction with testosterone, prompts spermatogenesis. For individuals with ovaries, FSH and LH together regulate the menstrual cycle through estradiol and progesterone production. The axis is sensitive to negative feedback, whereby, in general, increased concentrations of testosterone and estradiol (whether endogenous or exogenous) lead to the downregulation of GnRH, LH, and FSH, facilitated by kisspeptin-expressing neurons. GAHT impacts the HPGA by suppressing endogenous hormone expression. The overall effect includes changes to the concentrations of estradiol and testosterone, as well as other hormones and hormone metabolites related to the HPGA. Clinical guidelines related to GAHT for transgender people recommend measuring estradiol and testosterone, although there is debate on the frequency of monitoring and target concentrations (3, 5)

Summary

• GAHT suppresses endogenous production of sex hormones regulated by the HPGA.

What is the impact of feminizing GAHT on concentrations of estradiol and testosterone? What is the evidence for appropriate target concentrations of these hormones in those receiving feminizing GAHT?

Estradiol therapy suppresses GnRH and gonadotropins, with subsequent suppression of testosterone. When prescribed as monotherapy, injectable estradiol can be sufficient to suppress endogenous testosterone, whereas oral and transdermal estradiol monotherapy are often insufficient (16, 73). Consequently, transgender women using these forms of estrogen are often coprescribed antiandrogens if they have not had an orchiectomy (3). In the United States, the most common antiandrogen is spironolactone, whereas CPA is used outside of the United States. GnRH agonists can also be prescribed as antiandrogens, but high cost limits their use. Spironolactone and CPA impart their antiandrogenic activities through different mechanisms (16). Spironolactone primarily acts as an androgen receptor antagonist and only minimally decreases testosterone concentration. Conversely, CPA inhibits GnRH secretion, leading to additional HPGA suppression and significant testosterone concentration reduction. Finasteride is an antiandrogen medication that inhibits 5α-reductase and prevents the conversion of testosterone to dihydrotestosterone. While finasteride is sometimes prescribed to aid in feminization, routine use (except as therapy for other indications such as androgenic alopecia) is not recommended (3). Overall, antiandrogen use is an important factor to consider when evaluating laboratory results for transgender women.

The Endocrine Society and WPATH recommend monitoring estradiol and testosterone every 3 months during the first year of feminizing GAHT or with dose changes until stable dosing is reached, following which sex hormones should be monitored annually or biannually (3, 5). Estradiol and testosterone should be interpreted using a different reference interval than the menstrual cycle phase–specific ones that are used for cisgender women (Table 2) (74). For transgender women, current guidance based on expert opinion recommends that estradiol be maintained in a range of 100 to 200 pg/mL (367–734 pmol/L) (5). However, this interval does not reflect empirical evidence of an adequate therapeutic range, with multiple studies supporting a range wider than 100 to 200 pg/mL (367–734 pmol/L) (20). In addition, estradiol concentrations must be interpreted in the context of key preanalytical factors, such as therapeutic regimen, antiandrogen therapy, mode of hormone administration, time since the last dose, and individualized goals of feminizing therapy (74). More studies are needed to determine expected, toxic, and/or sufficient estradiol concentrations in populations prescribed feminizing therapy. Use of exogenous estradiol is associated with a slightly increased absolute risk of thromboembolism (relative to baseline) and should be evaluated against the goals of therapy using combined informed consent to guide the therapeutic regimen (75, 76).

Clinical guidelines state that for transgender women, total testosterone should be suppressed to <50 ng/dL (<1.7 nmol/L) (5). Circulating testosterone concentrations depend strongly on antiandrogen use and history of orchiectomy. Patients prescribed CPA or who are postorchiectomy typically have testosterone values that approximate concentrations observed in cisgender women, who generally have a total testosterone reference interval of <50 ng/dL (<1.7 nmol/L). Patients prescribed spironolactone may not suppress testosterone to concentrations observed in cisgender women, especially if estradiol concentrations are suboptimal or there is inconsistency with estradiol dosing (16, 17). Because spironolactone primarily works by blocking androgen receptors, desired feminization may be achieved even with relatively higher testosterone concentrations. Feminization goals are personalized and can be accomplished in the setting of testosterone above the cisgender female range (76).

Summary

• Feminizing hormone therapy increases estradiol concentrations. Guidelines from other societies based on expert opinion have recommended 100 to 200 pg/mL (367–734 pmol/L) as the target concentration for estradiol for transgender women. However, published data support a wider range than 100 to 200 pg/mL (367–734 pmol/L), assessed in the context of patient-personalized goals and other factors, such as estradiol formulation, antiandrogen therapy, and concurrent medical conditions.
• Antiandrogen therapy and orchiectomy are important factors for the interpretation of hormonal laboratory results for transgender women. In particular, the use of spironolactone as the only antiandrogen may not achieve testosterone concentrations <50 ng/dL (<1.7 nmol/L), the target set by current clinical guidelines.
• Current clinical guidelines recommend monitoring of estradiol and testosterone every 3 months during the first year of feminizing GAHT or with dose changes and then once or twice a year after reaching maintenance dose. This recommendation aligns with observed physiologic and laboratory changes from GAHT

What is the impact of masculinizing GAHT on concentrations of testosterone and estradiol? What is the evidence for appropriate target concentrations of these hormones in those receiving masculinizing hormone therapy?

Summary

• Masculinizing hormone therapy increases testosterone concentration. Published literature supports using the cisgender male reference intervals for total testosterone for transgender men.
• Estradiol concentrations in transgender men show a higher URL than those derived from cisgender men.
• Current clinical guidelines recommend monitoring testosterone every 3 months during the first year of masculinizing GAHT and once or twice a year after establishing a maintenance dose. This recommendation aligns with observed physiological and laboratory changes from masculinizing GAHT.

What preanalytical and analytical factors impact the measurement of estradiol and testosterone?

Patient factors that can impact estradiol and testosterone concentrations include hormone formulation, mode of administration, frequency of dosing, time since the last dose, use of antiandrogen (for feminizing GAHT), and individualized goals of GAHT (Table 3). Estradiol and testosterone immunoassay measurements are susceptible to interferences stemming from the preanalytical and analytical phases of testing (79). These factors are not unique to GAHT but can complicate the interpretation of hormone concentrations. Measurement error or assay interference should be considered if reported hormone concentrations are unexpectedly high or low. Immunoassays for estradiol and testosterone may lack the analytical sensitivity to measure low hormone concentrations. Mass spectrometry–based confirmatory methods should be considered in cases where immunoassay measurements yield unexpected results or where determination of hormone concentrations below immunoassay analytical sensitivity is clinically indicated (88, 89).

Circulating concentrations of total testosterone are affected by concentrations of sex hormone–binding globulin (SHBG). A variety of clinical conditions and medications are associated with abnormal concentrations of SHBG, including thyroid disorders, polycystic ovarian syndrome, insulin resistance, and exogenous hormones (94). Measurement of free testosterone may be useful when total testosterone concentrations yield confusing or unexpected results (95, 96). In transgender men, cisgender male reference intervals for free testosterone can be used for interpretation (18). There is currently insufficient evidence to guide the interpretation of free testosterone concentrations in transgender women.

Summary

• Measurement of estradiol and testosterone by immunoassay is subject to preanalytical factors and analytical interferences seen in all patient populations. Mass spectrometry-based methods are alternatives for the measurement of estradiol or testosterone in cases with unusual or conflicting laboratory results.
• Measurement of free testosterone may be useful in some circumstances. However, there is scant published literature on free testosterone and those receiving GAHT.

What is the impact of GAHT on concentrations of sex hormone–binding globulin?

SHBG is useful for the calculation of free testosterone using mathematical models such as the Vermeulen equation or other calculators (95, 96). Although routine measurement of SHBG is not recommended by WPATH or the Endocrine Society (3, 5), estradiol stimulates SHBG; therefore, SHBG concentrations often increase in people taking feminizing hormone therapy and decrease in people taking masculinizing therapy (17, 18, 29). This is most pronounced with oral estradiol treatment (17, 29). The reference interval for SHBG for transgender women, as determined in a single study, spanned a wider concentration range than the corresponding reference intervals for either cisgender women or cisgender men (17). The reference interval for SHBG in transgender men most closely approximated the reference interval for cisgender men (18). However, as the primary use of SHBG is to calculate free testosterone, these changes are clinically relevant in their influence on testosterone interpretation.

Summary

• The primary utility of SHBG is to aid in the calculation of free testosterone; routine monitoring of SHBG in isolation is rarely indicated.
• For isolated interpretation of SHBG, feminizing GAHT results in a wider reference interval than seen in either cisgender men or women, with overall higher SHBG concentrations. This is an area in need of further study. For transgender men, the SHBG reference interval for cisgender men can be used.

What is the impact of GAHT on concentrations of follicle-stimulating hormone and luteinizing hormone? What clinical value does the measurement of these hormones have for the gender-diverse population?

Measurement of LH and FSH may be clinically indicated in instances where estradiol or testosterone concentrations are unexpectedly high or low and/or when phenotypic effects are insufficient relative to goals of GAHT (97). LH and FSH can provide context for estradiol or testosterone values measured at a single time point (i.e., is the HPGA suppressed, balanced, or activated?) and can be trended over time as a measure of hormone stability. There are few data investigating the exact impact of feminizing or masculinizing therapy on FSH and LH, but changes likely depend on surgical history, antiandrogen use, progestogen use, and the temporal relationship between estradiol or testosterone administration and the response to exogenous hormone therapy (30).

Guidance documents from the Endocrine Society and WPATH do not suggest routinely monitoring LH and FSH in adults prescribed GAHT (3, 5). There have been studies that support LH suppression as a correlate to a positive body image and quality of sex life (98) and others indicating that adequate feminizing therapy is usually accompanied by an LH concentration less than 1.0 mIU/mL (99). In cisgender people, elevated FSH has been shown to predict bone loss (100). Understanding the relationship between GAHT and LH and FSH concentration in transgender people is an important area of future study.

Summary

• Measurement of LH and FSH can provide context to isolated estradiol or testosterone concentrations, especially if results are unexpected or discordant with the clinical assessment.
• Current clinical guidelines do not recommend routine measurement of LH or FSH in those receiving GAHT. This is an area in need of future research.

What is the impact of GAHT on concentrations of progesterone? What clinical value does the measurement of progesterone have for the gender-diverse population?

Studies of progesterone in those taking GAHT have been largely limited to the influence of progesterone on pregnancy in transgender men and not on the phenotypic influence of progesterone on physiological processes in transgender men or women. For transgender men using masculinizing hormones, use of testosterone should inhibit progesterone production (18). However, since ovulation may still spontaneously occur, progesterone may be transiently detected (31). Early follicular phase reference intervals applied to cisgender women can be used as a guide to ensure adequate progesterone suppression in transgender men, if clinically indicated (18).

Transgender women may be coprescribed progesterone with estradiol to enhance feminization (particularly breast development) or improve other health aspects such as sleep or libido (32, 101, 102). There is an absence of data to indicate what concentrations of progesterone would be ideal as a treatment goal for those receiving feminizing GAHT, but a recent study indicated that patient satisfaction may be improved by coprescription of progesterone (32).

Summary

• Expected concentrations of progesterone have not been clearly defined for the population taking GAHT, including those coprescribed progesterone with feminizing hormone therapy.
• Current clinical guidelines do not recommend routine measurement of progesterone in transgender men or women. This is an area in need of future research.

What is the impact of GAHT on concentrations of dehydroepiandrosterone sulfate and anti-Müllerian hormone?

Changes in dehydroepiandrosterone sulfate (DHEAS) and anti-Müllerian hormone concentrations from GAHT appear to be complex, and there is insufficient data indicating how masculinizing or feminizing therapy affects these analytes. For DHEAS, the concentration ranges observed in transgender women and men more closely parallel the reference intervals associated with SAAB as opposed to affirmed gender (17, 18, 103). The impact of GAHT on adrenal hormones such as DHEAS may be multifaceted and is incompletely understood (104). The interpretation of anti-Müllerian hormone as a marker of ovarian reserve in transgender men receiving testosterone is also an area of evolving study (105).

Summary

• Current clinical guidelines do not recommend routine measurement of DHEAS and anti-Müllerian hormone in transgender men or women. This is an area in need of future research.
• Given current evidence, reference intervals associated with SAAB most closely approximate DHEAS ranges observed in transgender men and women.

What is the impact of GAHT on concentrations of lipids and lipoproteins? How do these changes impact clinical interpretation of these laboratory tests for the gender-diverse population?

Interpretation of lipid parameters is largely independent of sex, with clinical guidelines applying the same treatment thresholds for most lipid values regardless of gender (106). The primary exception is HDL cholesterol (HDL-C), which historically has had higher optimal target concentrations in females (>50 mg/dL [>1.3 mmol/L] for female; >40 mg/dL [>1.0 mmol/L] for males). In transgender patients receiving GAHT, lipoprotein concentrations often shift in the direction of the affirmed gender (33). Estrogen therapy in transgender women may increase HDL-C and slightly decrease LDL cholesterol and triglycerides. Conversely, testosterone therapy in transgender men may reduce HDL-C and slightly increase LDL cholesterol and triglycerides (34, 35). These changes generally stabilize within 6 to 12 months of initiating therapy (33, 39, 46).

Despite hormone-related effects on lipoprotein metabolism, clinical management should focus on target concentrations and overall cardiovascular risk, rather than sex-based reference intervals. Routine monitoring of lipoproteins is recommended, particularly during the early stages of GAHT, to guide individualized risk assessment and treatment planning. Specific guidance on the timing or frequency of monitoring lipid measurements is lacking, but most changes in response to hormone therapy will take at least several weeks to significantly change. There is currently no consensus on how to utilize lipid markers to estimate long-term cardiovascular risk in the population receiving GAHT; this is an area of active inquiry with a need for future research (107, 108).

Summary

• The most consistent impact of GAHT on common lipid parameters is on HDL-C, which is decreased by testosterone and increased by estradiol.
• Clinical management of hyperlipidemia focuses on target lipid concentrations and overall cardiovascular risk, not sex-based reference intervals.
• Future studies are needed to determine how to utilize lipid markers and other data to estimate cardiovascular risk in the gender-diverse population taking gender-affirming hormones.

What is the impact of GAHT on concentrations of laboratory tests commonly used to assess liver function? How do these changes affect clinical [KP1.1]interpretation of these laboratory tests for the gender-diverse population?

Summary

• Reference intervals corresponding to affirmed gender should be used to interpret ALP, ALT, and AST in transgender people on long-term GAHT.
• Available data indicate that GAHT does not significantly impact liver function or increase the risk of liver injury or pathology.
  
   

What is the impact of GAHT on concentrations of prolactin? What is evidence for routine measurement of prolactin for those receiving feminizing GAHT?

Prolactin production by the anterior pituitary is stimulated by estrogen. Hyperprolactinemia is one of the most common disorders of the hypothalamic–pituitary axis and is associated with hypogonadism in both men and women (111). Upper reference limits for prolactin are higher in cisgender women relative to cisgender men, but there is significant overlap between these sex-specific reference intervals. Multiple reports suggest that feminizing therapy regimens using estradiol and CPA modestly increase prolactin from baseline (38, 112–115). There is evidence that CPA is the causative factor for the observed increase (112, 113).

The 2017 Endocrine Society guidelines recommend routine monitoring of prolactin to screen for hyperprolactinemia in those receiving GAHT (5), but there is insufficient evidence linking estradiol therapy itself (as opposed to CPA) with an increased risk of hyperprolactinemia or prolactinoma (20). CPA is not approved for clinical use in the United States; therefore, the antiandrogen used needs to be considered. While there is no guidance for what concentration of prolactin is expected in transgender women, in the rarely reported instances of symptomatic hyperprolactinemia, prolactin concentrations were several-fold higher than the upper limit of normal for cisgender women (116). Based on available evidence, cisgender female reference intervals for prolactin can be used for those receiving feminizing GAHT. Routine prolactin monitoring is not recommended for individuals prescribed GAHT unless they are experiencing signs and symptoms of hyperprolactinemia or prolactinoma (40).

Summary

• Some clinical guidelines have recommended routine monitoring of prolactin in transgender women; however, published data indicate increases in prolactin are likely a function of CPA antiandrogen therapy. CPA is not approved for use in the United States.
• Routine measurement of prolactin in transgender women is not recommended.
• Prolactin should be measured if clinical evaluation indicates signs and symptoms consistent with hyperprolactinemia.

What are the current challenges and opportunities with respect to cervical cancer screening for transgender men? Which diagnostic tests are available, and what are their potential advantages?

There is a global deficiency in cervical cancer screening. Within the United States, underscreening is particularly pronounced in the transgender population (117, 118). Pap testing has traditionally been the mainstay of cervical cancer screening. There are, however, some challenges to Pap testing in transgender men, including a high rate of unsatisfactory Pap tests (119) as well as cytologic changes from long-term testosterone therapy. Cervical and vaginal epithelial changes from masculinizing GAHT can mimic the effects of human papillomavirus (HPV) infection, making it difficult to distinguish HPV-related changes from hormone-related tissue atrophy (120–122).

HPV primary screening is an effective approach to screen for precancerous cervical lesions and to prevent the development of cervical cancer (123, 124). This screening method relies on the detection of HPV nucleic acid sequences, which can be detected from vaginal specimens and therefore does not initially require collection of a cervical specimen. This contrasts with the Pap test, which requires collection of a cervical specimen for cytologic analysis (123). The enhanced negative predictive value of HPV primary screening allows for approximately 90% of screening individuals to be triaged without collection of a cervical specimen.

Vaginal specimens, which involve superficial insertion and rotation of a swab in the vaginal canal, are uniquely positioned for self-collection with or without the need for a clinical encounter. Most people are comfortable with self-collection of vaginal specimens and can perform the collection process in a nonclinical setting, like at home or in a private area at a clinic or health fair (125). Additionally, multiple studies have illustrated a preference for vaginal self-collection among transgender people (126,127). HPV primary screening with the option for vaginal swab self-collection would be ideal for transgender people with a cervix (128, 129).

Summary

• Cervical cancer screening should be performed for transgender men with a cervix.
• Pap testing has limitations in transgender men, including a high rate of unsatisfactory Pap tests and difficulty in interpreting abnormal cytology related to HPV from hormone-related tissue atrophy.
• Primary HPV screening, including self-collection protocols, is a good option to expand cervical cancer screening, particularly for this population.

What are the recommendations for prostate cancer screening in transgender women? How should prostate-specific antigen concentrations be interpreted?

Prostate-specific antigen (PSA) plays a role in both the diagnosis and monitoring of prostate cancer. Generally, prostate cancer screening for transgender adults should be performed in accordance with local guidelines (3). Considering that transgender women retain their prostate even following orchiectomy and/or vaginoplasty, clinical recommendations for prostate cancer screening should be followed. Currently, PSA values for transgender women are evaluated using cisgender male interpretive ranges. While there is a paucity of data evaluating the impact of feminizing hormone therapy on PSA concentrations, there is evidence that transgender women have significantly lower baseline PSA values relative to cisgender men, and a PSA cutoff of 4.0 ng/mL may not have appropriate sensitivity to screen for prostate cancer in transgender women prescribed estradiol (130). A lower PSA threshold of 1.0 ng/mL has been proposed for transgender women (131), but the caveats for PSA as a cancer screening marker still apply (132). This is an area in need of future research, including the study of long-term outcomes. Interpreting prostate biopsies should follow guidelines for cisgender men (130, 133). Transgender men do not have prostates; therefore, PSA is not detectable in this population, and testing is not clinically indicated.

Summary

• Prostate cancer screening for transgender women should follow local guidelines for cisgender men.
• Preliminary data suggest a lower PSA threshold for transgender women; this is an area in need of additional research.

What are the recommended practices for screening for sexually transmitted infections in the gender-diverse population?

Optimal specimen types to screen for certain sexually transmitted genital infections differ between cisgender men and women, whereby mid-stream first-void urine is the specimen of choice for people with a penis, and vaginal swabs are the specimen of choice for those without (13). There are currently no studies identifying the optimal specimen type in transgender men and women prescribed GAHT regardless of genital surgery, but expert consensus suggests people should be sampled at anatomic sites about which they have concerns of exposures (134–137). Ensuring flexibility in the laboratory operational design, whereby vaginal swabs from men and urine samples from women are acceptable sample types, is important to ensure optimal access to testing and timely result reporting across genders (13, 129). Future studies should determine the optimal specimen types from transgender people. In addition, some assays do not have US Food and Drug Administration (FDA) approval for some specimen types, necessitating laboratory-developed test validations. An expansion of FDA-approved assays for multiple specimen types would be beneficial across patient populations.

Summary

• Determining the optimal specimen types for sexually transmitted infection screening in the transgender patient population is an ongoing area of study.
• Laboratory and informatics operational design should have flexibility to allow optimal access to sexually transmitted infection testing.

TRANSFUSION MEDICINE CONSIDERATIONS FOR THE GENDER-DIVERSE POPULATION

How should sex assigned at birth and gender identity factor into the criteria for blood donors and blood product recipients? What are the specific challenges in the transgender population who can become pregnant?

The 2023 change in FDA guidance toward a gender-neutral and risk-based donor history questionnaire has improved several aspects of donor eligibility assessment (138). For instance, since all potential donors are asked about pregnancy history regardless of gender identity, the residual risk of transfusion-related acute lung injury from transgender men donating plasma is considered minimal (139). However, important clinical and operational considerations remain that may affect the safety of both transgender donors and transfusion recipients. These include limitations in existing information systems, differences in physiologic parameters based on sex and hormone therapy, and gaps in standardized approaches to donor and recipient classification.

A persistent limitation in transfusion medicine is the inability of most blood establishment information systems to separately record gender identity and SAAB. Per FDA guidance, gender may be self-identified and self-reported but must be limited to the binary options of male or female (138). Consequently, most blood centers do not offer an option for nonbinary donors who do not identify as either gender (140).

Donor eligibility criteria are traditionally based on sex-specific physiologic parameters, including hemoglobin and hematocrit reference intervals. Recording both gender identity and SAAB as distinct data points would allow for more accurate donor evaluation and safer collections; however, determining gender-neutral hemoglobin ranges or donation intervals that err on the side of safety could potentially eliminate the need to collect both gender and SAAB and make it possible to allow a wider range of gender options (140–142). The latter approach would also benefit donation practices in hypogonadal cisgender people.

For transgender recipients of blood products, accurate SAAB documentation remains essential for blood product selection, particularly in emergencies. When the recipient’s ABO type is unknown, group O RBCs are administered. Because D-negative units are a limited resource, they are prioritized for patients with potential for pregnancy to reduce the risk of D alloimmunization and hemolytic disease of the fetus and newborn. In emergent settings, reproductive history and gender identity may not be available. Institutional policies often address this uncertainty by assuming reproductive potential in cisgender women up to a defined age threshold, which may inadvertently exclude some patients or lead to inconsistent application of safety precautions. Rh-positive blood products should also be avoided for transgender men who retain a uterus to prevent alloimmunization and potential complications in future pregnancies (143). Conversely, transgender women who were assigned male at birth do not share these reproductive risks and can safely receive Rh-positive blood if needed, provided that this information is available for blood bank staff to make the appropriate substitution according to institutional standard operating procedures.

Summary

• Transfusion medicine practices involving transgender donors and recipients would benefit from standardized, evidence-based approaches to maintain safety and equity.
• Gender-neutral policies should be implemented whenever possible, incorporating physiological and reproductive considerations to optimize safety outcomes across all patient populations.

AUTOPSY AND MEDICOLEGAL DEATH INVESTIGATION CONSIDERATIONS

What are the recommended practices for autopsy and medicolegal death investigation of gender-diverse decedents?

Medicolegal death investigations lack standardized guidance on documenting gender identity, which often results in inaccurate or absent reporting of gender identity in official records (144, 145). Inconsistent or absent data on gender identity makes research on transgender and nonbinary decedents challenging and affects the accuracy of mortality surveillance, especially for deaths from violence or suicide, which can make it difficult to identify health disparities and patterns of violence (146, 147).

Forensic pathologists should document both the legal and chosen/correct name and gender, with the legal name being used for legal or administrative purposes and the chosen/correct name used whenever possible. Gender identity should be verified using medical and legal records, chosen family, or other designated decision makers, and should not be limited to family of origin (144). When discrepancies occur, reports can include clarifying statements such as “The decedent identified as a transgender man and used the name [affirmed name].”

Anatomic findings should be described neutrally using inclusive terminology such as SAAB instead of biological sex and phenotypic male/female genitalia instead of gendered labels. Pathologists should note evidence of gender-affirming care (e.g., surgical scars, implants, hormonal changes) without speculation (144). Despite frequently appearing in forensic pathology textbooks, terminology such as crossdresser or transvestite is not synonymous with transgender identity. These terms are outdated and inaccurate and should be avoided (144).

Over half of transgender and gender-diverse decedents in Oregon had incorrect gender identity on death certificates, creating discordance between medical examiner data and vital records (145). Death certificates should reflect affirmed identity whenever possible, with the narrative and investigative reports providing clarification when legal requirements prevent this.

Training initiatives demonstrate that SOGI data can be collected accurately with structured education and leadership support (148). Scene investigators can also facilitate accurate gender-identity reporting. Several jurisdictions now have laws regarding gender identity after death, including California (149), New York City (150), New Jersey (151), Colorado (152), and the District of Columbia (153).

Summary

• Autopsy and medicolegal death investigation currently lacks standardization of practices related to the gender-diverse population, with documentation of gender identity often missing.
• Autopsy reports should ideally verify and document both legal sex and gender identity, with the use of affirmed names and pronouns in reports and narratives.
• Anatomic findings in autopsy reports can use gender-neutral, inclusive, and objective terminology.
• There is an opportunity to expand the use of more flexible SOGI data fields, policies, and training to facilitate accurate postmortem gendering and improve mortality surveillance for the gender-diverse population.
  
   

SURGICAL PATHOLOGY

GAHT and/or surgical procedures impact secondary sexual characteristics and organ histology. This section summarizes tissue-based changes associated with GAHT or gender-affirming surgeries. As part of the examination of the resected tissues, the pathologist will evaluate and document these findings. Other clinical scenarios exist where a pathologist may examine tissue specimens from transgender individuals without knowledge of their transgender status or hormone therapy history. For example, pathologists may receive prostate gland biopsies from transgender women or oophorectomy specimens from transgender men for reasons unrelated to the individual’s gender affirmation. When gender-affirming surgery is preceded by long periods of GAHT, hormone-related histologic changes are seen (14, 15).

What are gross examination and tissue processing considerations for specimens from patients who have received GAHT and/or surgical procedures?

For transgender men undergoing reduction mammoplasty, specific guidelines for the gross examination and subsequent tissue submission of mastectomy specimens have not been standardized. There is currently no evidence to suggest that GAHT increases the incidence of breast cancer in transgender men (154). Accordingly, local institutional protocols for reduction mammoplasty specimens from cisgender women may be followed, with additional tissue evaluated if atypical proliferations are identified on initial examination. Documenting the size and weight of the product of a mastectomy, along with what exactly was removed, is important since surgery does not necessarily remove all identifiable breast tissue. There is a lower incidence of breast cancer in transgender men receiving testosterone than in cisgender women. However, there is a higher risk of breast cancer in transgender women receiving estradiol compared with cisgender men (155). Long-term follow-up studies are needed to better understand the risk of breast cancer in this population; thus, future studies may facilitate refinement of pathology procedures.

Documenting the inclusion of the cervix and fallopian tubes in hysterectomy specimens from transgender men is important for future cancer screening plans, including cervical cancer screening and ovarian-related oncology (e.g., BRCA mutation or family diagnosis of ovarian cancer), respectively.

Orchiectomy specimens from transgender women can be serially sectioned for the identification of any grossly identifiable lesion. A spermatic cord en face margin and 2 or 3 cross-sections, including both rete testis/epididymis are submitted for histopathologic examination (156).

Summary

• For transgender men undergoing reduction mammoplasty, follow local institutional protocols for mastectomy procedures in cisgender women and document the extent of breast tissue removed.
• For transgender men undergoing hysterectomy, document whether the cervix and fallopian tubes were removed, since the presence of these organs impacts future cancer screening and risk.
• For transgender women undergoing orchiectomy, serially section the testes and examine for grossly identifiable lesions; submit 2 or 3 cross-sections for histopathologic examination.

What are the histologic changes in tissues associated with GAHT?

In hysterectomy specimens from transgender men on long-term masculinizing GAHT, the endometrium may show expanded endometrial stroma with endometrial glandular atrophy (157), areas with decidua-like changes and occasional vacuolated cells, and glandular paucity (Fig. 1A) (158). Rarely, endometrial polyps showing hyperplasia without atypia are seen (159). Changes in cervical epithelium from masculinizing therapy with testosterone include ectocervical epithelial atrophy, transitional cell metaplasia (Fig. 1B) (158), and, rarely, prostate-type glands at the base of ectocervical epithelium (160). From salpingo-oophorectomy specimens, periadnexal tissue may show the presence of virilized mesonephric duct remnants (160). Changes in ovaries from masculinizing therapy include large follicular cysts lined by nonluteinized granulosa cells (161), higher follicular density than typical for chronologic age (158), thickening of the tunica albuginea, and stromal hyperplasia (Fig. 1C) (161). Testosterone therapy induces histologic changes in vaginal mucosa that include epithelial atrophy, transitional cell metaplasia, and prostate-type glands at the base of the ectocervical epithelium (Fig. 1D) (162). In mastectomy specimens from transgender men, histologic changes can include lobular atrophy with fewer lobules, gynecomastoid changes (163), stromal fibrosis, fibrocystic changes, and microcalcifications (Fig. 2) (164). Table 4 summarizes histologic changes seen in tissues from long-term masculinizing GAHT. 

Fig. 1. Androgen-related histologic changes seen in hysterectomy and vaginectomy specimens. (A), Specimens feature plump endometrial stromal cells with ample cytoplasm and sparse inactive small glands; (B), Ectocervical epithelium resembles urinary bladder epithelium with nuclear grooves, umbrella-like cells on the surface, and a virtual absence of the cuboidal palisaded basal layer; (C), Ovaries exhibit large cortical follicular cysts lined by nonluteinized granulosa cells, accompanied by a relatively higher number of primordial follicles for the individual’s age; (D), Vaginal mucosa is typically atrophic with transitional cell metaplasia and benign prostate-like glands at the epithelial–stromal junction.

Fig. 2. Androgen-related histologic changes seen in mastectomy specimens. (A), Specimens feature lobular atrophy with atrophic ductal epithelium and stromal hyalinization/fibrosis; (B), Fibrocystic changes with apocrine metaplasia and calcification could also be present.

Table 4. Histologic changes seen in tissues in those with gender-affirming gonadectomy preceded by long-term gender-affirming masculinizing hormone therapy.

a Differential diagnosis of epithelial atrophy and transitional cell metaplasia of the ectocervix and vagina. Special attention is given not to overdiagnose these lesions as high-grade intraepithelial lesions. Umbrella-like cells could be seen on the surface, and these cells feature nuclear grooves. P16 immunohistochemical staining shows patchy, weak positive staining.
b Differential diagnosis of prostate-like glands (prostatic metaplasia). These cells are positive for NKX3.1, PSA, and p501s. They exhibit no nuclear atypia. Special attention must be given to not mistake prostate-type glands in the cervix for dysplasia or glandular proliferative abnormalities.

Fig. 3. Estrogen-related histologic changes seen in orchiectomy and penectomy specimens. (A), There is testicular atrophy with increased stromal/basement membrane fibrosis, reduction of Leydig cell numbers, and Sertoli cell cytoplasmic vacuolization; (B), Typically, penile urethral epithelium undergoes squamous cell metaplasia.

Table 5. Histologic changes seen in tissues in those with gender-affirming gonadectomy preceded by long-term gender-affirming feminizing hormone therapy. 

Summary

• Long-term testosterone therapy in transgender men can lead to histologic changes in vaginal mucosa, endometrium, cervix, periadnexal tissue, ovaries, and breast tissue. Characteristic changes include expanded endometrial stroma, ectocervical epithelial atrophy, cervical transitional cell metaplasia, large follicular ovarian cysts lined by nonluteinized granulosa cells, vaginal epithelial atrophy with transitional cell metaplasia, and breast lobular atrophy with gynecomastia changes.
• Long-term estradiol therapy in transgender women can lead to testicular fibrosis and atrophy, reduce Leydig cell numbers, and squamous cell metaplasia of urethral epithelium.

What are the histologic changes resulting from nonhormonal gender-affirming medical procedures?

Gender-affirming surgery with or without prior GAHT may generate tissues submitted to pathology with nonhormone-related changes. Complications of masculinizing surgeries may include urethral stenosis, fistulae, sinus tracts, and abscess formation (167). Tissues resulting from the gender-affirming surgery itself or managing its complications are handled in the pathology laboratory as per the local protocols similar to those received from cisgender persons. Some augmentation procedures can be associated with foreign body reactions to exogenous material injections and silicone implants (Fig. 4).

Summary

• Gender-affirming surgery can result in complications, including stenosis, fistulae, sinus tracts, and abscesses.
• Foreign body reactions may occur from nonsurgical cosmetic procedures.
• Tissues can be processed following local protocols used for cisgender patients.

INFORMATICS

Informatics has a significant impact on how laboratory medicine and pathology can provide affirming care for the transgender population. As with the general public, healthcare professionals may not be familiar with terminology and concepts related to sex and gender (168). As highlighted in the following discussion, the capabilities of software used in healthcare, including LIS systems for clinical laboratories, are also highly variable with respect to functionality related to gender-diverse patient identity and who has permission to change SOGI status within the EHR.

What are informatics considerations related to name and other common patient identifiers for the gender-diverse population?

Patient names in legal documents, date of birth, and medical record numbers are primary patient identifiers within the healthcare setting, including insurance billing and reporting of information to public health authorities (168–171). Transgender patients may adopt a different name than their birth name to align with their gender identity. Transgender patients may elect to change their name on identity documents and/or in the medical record. In the healthcare setting, a change of patient name in legal documents can follow patient identification policies that apply in other situations, such as marital name changes. However, given that these changes require effort and expense, the birth name may still be the name in the medical record.

Some healthcare organizations have adopted a trauma-informed option that allows patients to provide a chosen/correct name that signifies how the patient wants to be addressed, including in waiting areas (172). Use of the chosen/correct name to identify patients in the healthcare setting is beneficial for all patients and may be especially important to transgender patients to avoid use of a name with which they no longer identify. There are challenges that need to be reviewed and managed in healthcare environments to ensure the proper use of the chosen/correct name and identification (170). Common practical challenges include display and visibility of the chosen/correct name on specimen labels and computer displays for the EHR and LIS. Hospital and clinical laboratory policies and procedures should specify whether the legal name is required for certain activities, such as collecting laboratory specimens, or when a chosen/correct name may substitute.

Summary

• Laboratory and informatics operational design should include procedures for the use of the chosen/correct name, if this functionality is available. This benefits all patient populations.
• Patient-facing areas of pathology, such as phlebotomy waiting areas, should utilize the chosen/correct name when possible. Standard operating procedures can include clear guidance for when a legal name is required for specific tasks.

What are SOGI data fields, and how can they enhance care for the gender-diverse patient population?

Functionality for SOGI data elements in records, commonly known as SOGI fields, has become available in some EHRs and LISs in recent years (170, 171, 173–176). SOGI fields include options for patients to voluntarily provide sexual orientation, SAAB, gender identity, and pronouns (e.g., he/him/his, she/her/hers, they/them/theirs). More advanced functionality includes fields that document current use of GAHT, history of gender-affirming surgeries, and organ inventories. Information in the SOGI fields can facilitate optimal interpretation of laboratory tests and analysis of anatomic pathology specimens (11, 170, 177). Some institutions do not utilize SOGI fields for a variety of reasons, including the absence of SOGI functionality in the specific EHR for the institution, lack of informatics resources to implement this functionality, or restriction by laws or policies related to gender identity (178). Table 6 summarizes applications and potential challenges with the use of SOGI fields in laboratory medicine and pathology.

For those institutions that have implemented SOGI functionality in the EHR, published literature on the extent of patient use of these SOGI fields varies, with data coming mainly from larger institutions (176, 179, 180). Typical rates for patient volunteering of SOGI information, such as gender identity, SAAB, and sexual orientation, are approximately 20% to 30% at larger institutions that have implemented SOGI functionality, although rates can be higher for the gender-diverse patient population. Institutional factors that impact clinical use of SOGI fields include EHR capability, decisions to implement specific SOGI functionality, and workflows for the collection of SOGI data. Patient factors include health literacy, understanding of SOGI terminology, use of EHR patient portals (if these allow SOGI data input), and comfort with providing the information (168, 176, 179–181). SOGI information can present risks to patient privacy and confidentiality if viewed by individuals who can access the patient record (171, 182–186). EHR regulations in the United States around SOGI information include the privacy, security, and confidentiality considerations that apply to all sensitive health data; however, like all electronic health data, there are security risks to including this information in the EHR (187, 188).

Pathology personnel can facilitate optimal use of SOGI-related demographic data. There are limited available data on the state of cultural competency and the need for training clinical laboratory personnel (169, 189). But at a high level, pathology and informatics staff can help evaluate the EHR, LIS, and middleware software for SOGI functionality and how it might impact pathology results (170). For some institutions, the EHR and LIS have differences in SOGI functionality, especially if the EHR and LIS are from different vendors. Thus, even if SOGI information is available in the EHR, the LIS or laboratory middleware software may not be capable of utilizing that information. In that scenario, a clinical laboratory that assigns reference intervals in the LIS will be unable to incorporate SOGI logic. Additionally, even if an institutional EHR and LIS have SOGI functionality, the SOGI data fields may be inaccessible to reference laboratories that analyze specimens from that institution.

Summary

• SOGI fields are a relatively new functionality available within some EHRs. If available, these fields provide information, including gender identity, SAAB, and organ inventories, that may be useful to pathology.
• SOGI field functionality may not be available at some institutions due to a variety of practical and legal factors.

What are the considerations and downstream impacts for sex and gender markers in the electronic health record for the gender-diverse population?

The legal sex marker in the EHR and administrative documents has traditionally been the main sex identifier used in healthcare (173). Legal sex is typically displayed together with name and date of birth on patient identification labels and medical record documentation. For laboratory tests that have sex-specific reference intervals or calculations, legal sex impacts which intervals or calculations are used for interpretation and subsequent medical decision-making (180, 190–192). Institutional protocols and EHR alerts may also utilize logic based on this documented sex. For example, health maintenance and decision support algorithms in the EHR may utilize legal sex in the logic for sex-specific reminders and alerts for cervical or prostate cancer screening, pregnancy testing prior to surgery, mammography, and cardiovascular risk assessment.

Some transgender patients elect to change their gender marker on identity documents, a process influenced by laws and policies at international, national, and local levels (193, 194). Healthcare organizations have varying policies for how to change legal sex within the medical record; prior change of 1 or more identity documents may be required. Within the United States and its territories, the ability to change the gender marker on identity documents is mainly subject to federal and state laws. Some states within the United States do not allow any change of the gender designation marker on motor vehicle and other state identity documents, while other states permit this change (194).

Change of legal sex within the medical record may include a change from male to female or female to male or to another sex marker, such as unknown (U), *, X, or nonbinary (if institutional practice offers these options) (180, 195, 196). A change of legal sex in the EHR has downstream consequences in terms of sex-specific reference intervals, billing for procedures that have coding based on a binary sex classification (e.g., pregnancy screening, PSA testing), healthcare maintenance alerts, and decision support logic. One important consideration is that changes in EHR legal sex and/or gender identity markers can occur even for those not receiving GAHT or who discontinue or pause GAHT at some point. This adds a layer of complexity to interpreting laboratory tests that have sex-specific reference intervals. Consider the situation where a transgender man has gone through the process to change his legal sex in the EHR to male. All logic for sex-specific reference intervals, health maintenance alerts, and procedural billing will use male as the legal sex. In the absence of EHR logic that recognizes the patient as transgender, alerts and decisions based on a female SAAB would be missed. These include pregnancy testing prior to procedures, health maintenance alerts for cervical cancer screening or mammography, and use of Rh-negative blood for emergency administration. In this scenario, a SOGI field for SAAB would be beneficial and practical.

Tissue specimens from transgender patients may be misidentified when the legal sex does not match the expectation (e.g., prostate specimen from a transgender woman who has changed legal sex to female; cervical biopsy from a transgender man who has changed legal sex to male) (170, 191, 192). There are also people with nonbinary or similar gender identities. As mentioned previously, some EHRs allow for options like *, X, and nonbinary in the legal sex field, a scenario that can create challenges with sex-specific reference range assignment, including potential safety issues, if no reference interval gets applied to specific testing in the event that legal sex is something other than male or female (195).

Summary

• Legal sex is typically the sex marker used for EHR and LIS sex-specific logic.
• Some gender-diverse patients change their legal sex in the EHR, a practice influenced by institutional policies and state/national laws. This change can impact reference intervals, calculations, health maintenance alerts, and billing codes that utilize sex-specific logic.
• Clinical laboratory personnel should be aware of what SOGI data are available in the health system (i.e., whether SOGI fields are available or not) for procedural interpretation and to reduce the risk for patient misidentification, inappropriate cancellation of tests, and billing errors.

Informatic approaches and challenges related to displaying reference intervals in the electronic health record

There are multiple approaches for reporting reference intervals/ranges that may be impacted by GAHT (Fig. 5 and Table 7). There is a relatively short list of common laboratory tests significantly impacted by GAHT based on current evidence (Table 2). Of common nonhormonal laboratory tests, hemoglobin/hematocrit/RBC count demonstrates the clearest shift toward affirmed gender for those stably receiving either feminizing or masculinizing hormone therapy.

Table 7. Approaches for handling reference ranges/intervals for tests with sex-specific reference intervals.

a Reference interval.
b Information technology.