madman
Super Moderator
Reference Intervals for Clinical Chemistry Analytes for Transgender Men and Women on Stable Hormone Therapy (2022)
Robert M. Humble, Dina N. Greene, Robert L. Schmidt, Gabrielle Winston McPherson, Jessica Rongitsch, Katherine L. Imborek, Nicole Nisly, Nancy J. Dole, Susan K. Dane, Janice Frerichs, and Matthew D. Krasowski
Background: Gender-affirming hormone therapy with either estradiol or testosterone is commonly prescribed for transgender individuals. Masculinizing or feminizing hormone therapy may impact clinical chemistry analytes, but there is currently a lack of published reference intervals for the transgender population.
Methods: Healthy transgender and nonbinary individuals who had been prescribed either estradiol (n = 93) or testosterone (n = 82) for at least 12 months were recruited from primary care and internal medicine clinics specializing in transgender medical care. Electrolytes, creatinine, urea nitrogen, enzymes (alkaline phosphatase, ALK; alanine aminotransferase, ALT; aspartate aminotransferase, AST; gamma-glutamyltransferase, GGT), hemoglobin A1c, lipids [total cholesterol, high-density lipoprotein (HDL), triglycerides], and high-sensitivity C-reactive protein (hsCRP) were measured on 2 clinical chemistry platforms. Reference intervals (central 95%) were calculated according to Clinical Laboratory Standards Institute guidelines.
Results: There was minimal impact of gender-affirming hormone therapy on electrolytes, urea nitrogen, hemoglobin A1c, and hsCRP. In general, the enzymes studied shifted toward affirmed gender. Creatinine values for both transgender cohorts overlaid the reference interval for cisgender men, with no shift toward affirmed gender for the estradiol cohort. The effects on lipids were complex, but with a clear shift to lower HDL values in the testosterone cohort relative to cisgender women.
Conclusions: Transgender individuals receiving either masculinizing or feminizing hormone therapy showed significant changes in some analytes that have sex-specific variation in the cisgender population. The clearest shifts toward affirmed gender were seen with enzymes for the estradiol and testosterone cohorts and with creatinine and HDL in the testosterone cohort
INTRODUCTION
Transgender people experience incongruence between gender identity (an individual’s personal sense of gender) and sex assigned at birth (1). Transgender men were assigned sex as female at birth but identify as men; conversely, transgender women were assigned sex as male at birth but identify as women. There are also people who identify on the gender spectrum as something other than male or female (often identifying with the umbrella term nonbinary with a number of more specific subterms such as gender-queer, gender fluid, or third gender). A cisgender person is someone whose gender identity is congruent with the sex assigned at birth. Transgender people may seek medical interventions that affirm their gender identity and support psychosocial health. The current standard of care for gender-affirming medical interventions includes hormone therapy and/or surgical procedures as necessary to treat gender dysphoria (2–4)
In terms of hormone therapy, testosterone is prescribed to transgender men or nonbinary people that identify as being masculine of center (“transmasculine”) (5). Testosterone administration promotes masculinizing secondary sex characteristics such as lower vocal pitch, increased muscle mass, increased facial and body terminal hair development, and cessation of menses. Estradiol is the mainstay of hormonal therapy for transgender women or nonbinary people that identify as being feminine of center (“transfeminine”) (6). In addition, a subset of transgender patients prescribed estradiol may also be administered other medications including progesterone (7) or androgen blockers (e.g., bicalutamide, finasteride, spironolactone) (6).
The physiologic and metabolic changes from gender-affirming hormone therapy may impact the concentrations of analytes in commonly ordered laboratory tests (8, 9). One hypothesis is that significant changes in laboratory values due to gender-affirming hormone therapy would be more likely in laboratory tests such as hemoglobin/hematocrit and creatinine that have significant differences between cisgender males and females (8). The impact of gender-affirming hormone therapy on laboratory tests may also be influenced by pharmacokinetic differences in various pharmaceutical formulations for both estradiol (oral, intramuscular, subcutaneous, topical) and testosterone (topical, subcutaneous, intramuscular). An example of this is illustrated by differences in estrone concentrations for different estradiol preparations used by transgender women (10). Progesterone and androgen blockers may also impact laboratory tests. For instance, spironolactone has an effect on mineralocorticoid receptors that can lead to changes in sodium and potassium concentrations (6)
The existing literature on the effects of gender-affirming therapy on laboratory tests has been mostly from retrospective analyses (11–17) or observational studies that followed transgender people for a variety of physiologic and laboratory parameters after initiation of gender-affirming therapies (18–24). Both approaches have been useful in identifying relative changes in laboratory tests; however, these cohorts include some people with a pathophysiology that make it difficult to define normative laboratory ranges. More recent prospective studies with defined inclusion and exclusion criteria have provided data on the impact of gender-affirming hormone therapy on hematology (25) and reproductive endocrinology tests (26, 27). The most clear-cut changes with gender-affirming therapy have been observed with hemoglobin/hematocrit and red blood cell count (25). For these parameters, the reference intervals essentially “flip” to those for the opposite sex (i.e., adopt the reference interval for the affirmed gender). For example, the distribution of hemoglobin/hematocrit values of adult transgender men on stable testosterone therapy aligns with adult cisgender men and not adult cisgender women. Similarly, the distribution of hemoglobin/hematocrit values of adult transgender women on stable estrogen administration aligns with adult cisgender women and not adult cisgender men.
The objective of this study was to establish reference intervals for common clinical chemistry analytes in transgender people receiving either masculinizing or feminizing hormone therapy. The analytes studied include electrolytes, enzymes (alkaline phosphatase, ALK; alanine aminotransferase, ALT; aspartate aminotransferase, AST; gamma-glutamyltransferase, GGT), hemoglobin A1c, lipids, urea nitrogen, and creatinine. Some of these analytes, such as creatinine, commonly have sex-specific reference intervals in the cisgender population. An additional objective was to evaluate these analytes on 2 different automated clinical chemistry platforms.
DISCUSSION
Establishing proper reference ranges is a complicated area of laboratory medicine. In the present study, we determine reference intervals in the adult transgender population for common clinical chemistry analytes including electrolytes, enzymes, lipids, and creatinine. In Supplemental Tables 3 and 4, we compare the results of our study with the findings in prior retrospective and observational (including longitudinal) studies in the transgender population (11–24). In comparing between the present and prior studies, it is important to point out that conditions that were exclusions in our study (e.g., severe cardiovascular disease, diabetes, obesity, cigarette smoking) were typically not exclusions for the retrospective and observational studies.
*There are some limitations to our study. First, samples were collected at a single time interval, limiting observations over time. Second, the sample size was limited to 93 participants taking feminizing hormones and 82 participants taking masculinizing hormones. Study recruitment was challenging even at 2 separate sites providing LGBTQ care, and future studies would benefit from larger initiatives, as done through international collaborations for pediatric biochemical reference ranges (39). Larger sizes are also necessary to resolve subgroup differences we could not resolve in our study, including the impact of medication dosage and route of administration. Third, 36.6% of the estradiol cohort in our study was prescribed spironolactone as an antiandrogen. There is considerable variability in antiandrogen use in transgender women, with spironolactone more common in the USA and cyproterone more common in some parts of Europe (6). Even within the USA, there can be variable prescribing practices, and other institutions may see higher or lower proportions of spironolactone antiandrogen therapy than in our study. Fourth, we applied the Wilcoxon rank sum, a nonparametric test that makes no assumptions about the underlying distribution, across all tests. This approach increases the risk of Type II errors (failure to detect a difference when one exists) but avoids the complex alternative to finding best-fit parametric distributions for all data series in our study. Last, some of the exclusion criteria for our prospective study are for conditions that may be more common in the transgender population, including diabetes, obesity, and tobacco use (40–42). These exclusion criteria impacted recruitment. There are significant opportunities for future studies on the interaction of disease and social factors with laboratory testing in the transgender population
In summary, we have established reference intervals for commonly measured clinical chemistry analytes in the transgender population. These reference intervals can aid laboratories and healthcare providers in providing evidence-based care for the transgender population.
Robert M. Humble, Dina N. Greene, Robert L. Schmidt, Gabrielle Winston McPherson, Jessica Rongitsch, Katherine L. Imborek, Nicole Nisly, Nancy J. Dole, Susan K. Dane, Janice Frerichs, and Matthew D. Krasowski
Background: Gender-affirming hormone therapy with either estradiol or testosterone is commonly prescribed for transgender individuals. Masculinizing or feminizing hormone therapy may impact clinical chemistry analytes, but there is currently a lack of published reference intervals for the transgender population.
Methods: Healthy transgender and nonbinary individuals who had been prescribed either estradiol (n = 93) or testosterone (n = 82) for at least 12 months were recruited from primary care and internal medicine clinics specializing in transgender medical care. Electrolytes, creatinine, urea nitrogen, enzymes (alkaline phosphatase, ALK; alanine aminotransferase, ALT; aspartate aminotransferase, AST; gamma-glutamyltransferase, GGT), hemoglobin A1c, lipids [total cholesterol, high-density lipoprotein (HDL), triglycerides], and high-sensitivity C-reactive protein (hsCRP) were measured on 2 clinical chemistry platforms. Reference intervals (central 95%) were calculated according to Clinical Laboratory Standards Institute guidelines.
Results: There was minimal impact of gender-affirming hormone therapy on electrolytes, urea nitrogen, hemoglobin A1c, and hsCRP. In general, the enzymes studied shifted toward affirmed gender. Creatinine values for both transgender cohorts overlaid the reference interval for cisgender men, with no shift toward affirmed gender for the estradiol cohort. The effects on lipids were complex, but with a clear shift to lower HDL values in the testosterone cohort relative to cisgender women.
Conclusions: Transgender individuals receiving either masculinizing or feminizing hormone therapy showed significant changes in some analytes that have sex-specific variation in the cisgender population. The clearest shifts toward affirmed gender were seen with enzymes for the estradiol and testosterone cohorts and with creatinine and HDL in the testosterone cohort
INTRODUCTION
Transgender people experience incongruence between gender identity (an individual’s personal sense of gender) and sex assigned at birth (1). Transgender men were assigned sex as female at birth but identify as men; conversely, transgender women were assigned sex as male at birth but identify as women. There are also people who identify on the gender spectrum as something other than male or female (often identifying with the umbrella term nonbinary with a number of more specific subterms such as gender-queer, gender fluid, or third gender). A cisgender person is someone whose gender identity is congruent with the sex assigned at birth. Transgender people may seek medical interventions that affirm their gender identity and support psychosocial health. The current standard of care for gender-affirming medical interventions includes hormone therapy and/or surgical procedures as necessary to treat gender dysphoria (2–4)
In terms of hormone therapy, testosterone is prescribed to transgender men or nonbinary people that identify as being masculine of center (“transmasculine”) (5). Testosterone administration promotes masculinizing secondary sex characteristics such as lower vocal pitch, increased muscle mass, increased facial and body terminal hair development, and cessation of menses. Estradiol is the mainstay of hormonal therapy for transgender women or nonbinary people that identify as being feminine of center (“transfeminine”) (6). In addition, a subset of transgender patients prescribed estradiol may also be administered other medications including progesterone (7) or androgen blockers (e.g., bicalutamide, finasteride, spironolactone) (6).
The physiologic and metabolic changes from gender-affirming hormone therapy may impact the concentrations of analytes in commonly ordered laboratory tests (8, 9). One hypothesis is that significant changes in laboratory values due to gender-affirming hormone therapy would be more likely in laboratory tests such as hemoglobin/hematocrit and creatinine that have significant differences between cisgender males and females (8). The impact of gender-affirming hormone therapy on laboratory tests may also be influenced by pharmacokinetic differences in various pharmaceutical formulations for both estradiol (oral, intramuscular, subcutaneous, topical) and testosterone (topical, subcutaneous, intramuscular). An example of this is illustrated by differences in estrone concentrations for different estradiol preparations used by transgender women (10). Progesterone and androgen blockers may also impact laboratory tests. For instance, spironolactone has an effect on mineralocorticoid receptors that can lead to changes in sodium and potassium concentrations (6)
The existing literature on the effects of gender-affirming therapy on laboratory tests has been mostly from retrospective analyses (11–17) or observational studies that followed transgender people for a variety of physiologic and laboratory parameters after initiation of gender-affirming therapies (18–24). Both approaches have been useful in identifying relative changes in laboratory tests; however, these cohorts include some people with a pathophysiology that make it difficult to define normative laboratory ranges. More recent prospective studies with defined inclusion and exclusion criteria have provided data on the impact of gender-affirming hormone therapy on hematology (25) and reproductive endocrinology tests (26, 27). The most clear-cut changes with gender-affirming therapy have been observed with hemoglobin/hematocrit and red blood cell count (25). For these parameters, the reference intervals essentially “flip” to those for the opposite sex (i.e., adopt the reference interval for the affirmed gender). For example, the distribution of hemoglobin/hematocrit values of adult transgender men on stable testosterone therapy aligns with adult cisgender men and not adult cisgender women. Similarly, the distribution of hemoglobin/hematocrit values of adult transgender women on stable estrogen administration aligns with adult cisgender women and not adult cisgender men.
The objective of this study was to establish reference intervals for common clinical chemistry analytes in transgender people receiving either masculinizing or feminizing hormone therapy. The analytes studied include electrolytes, enzymes (alkaline phosphatase, ALK; alanine aminotransferase, ALT; aspartate aminotransferase, AST; gamma-glutamyltransferase, GGT), hemoglobin A1c, lipids, urea nitrogen, and creatinine. Some of these analytes, such as creatinine, commonly have sex-specific reference intervals in the cisgender population. An additional objective was to evaluate these analytes on 2 different automated clinical chemistry platforms.
DISCUSSION
Establishing proper reference ranges is a complicated area of laboratory medicine. In the present study, we determine reference intervals in the adult transgender population for common clinical chemistry analytes including electrolytes, enzymes, lipids, and creatinine. In Supplemental Tables 3 and 4, we compare the results of our study with the findings in prior retrospective and observational (including longitudinal) studies in the transgender population (11–24). In comparing between the present and prior studies, it is important to point out that conditions that were exclusions in our study (e.g., severe cardiovascular disease, diabetes, obesity, cigarette smoking) were typically not exclusions for the retrospective and observational studies.
*There are some limitations to our study. First, samples were collected at a single time interval, limiting observations over time. Second, the sample size was limited to 93 participants taking feminizing hormones and 82 participants taking masculinizing hormones. Study recruitment was challenging even at 2 separate sites providing LGBTQ care, and future studies would benefit from larger initiatives, as done through international collaborations for pediatric biochemical reference ranges (39). Larger sizes are also necessary to resolve subgroup differences we could not resolve in our study, including the impact of medication dosage and route of administration. Third, 36.6% of the estradiol cohort in our study was prescribed spironolactone as an antiandrogen. There is considerable variability in antiandrogen use in transgender women, with spironolactone more common in the USA and cyproterone more common in some parts of Europe (6). Even within the USA, there can be variable prescribing practices, and other institutions may see higher or lower proportions of spironolactone antiandrogen therapy than in our study. Fourth, we applied the Wilcoxon rank sum, a nonparametric test that makes no assumptions about the underlying distribution, across all tests. This approach increases the risk of Type II errors (failure to detect a difference when one exists) but avoids the complex alternative to finding best-fit parametric distributions for all data series in our study. Last, some of the exclusion criteria for our prospective study are for conditions that may be more common in the transgender population, including diabetes, obesity, and tobacco use (40–42). These exclusion criteria impacted recruitment. There are significant opportunities for future studies on the interaction of disease and social factors with laboratory testing in the transgender population
In summary, we have established reference intervals for commonly measured clinical chemistry analytes in the transgender population. These reference intervals can aid laboratories and healthcare providers in providing evidence-based care for the transgender population.
