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. 2024 Apr 3;153(5):e2023064380. doi: 10.1542/peds.2023-064380

Laboratory Changes During Gender-Affirming Hormone Therapy in Transgender Adolescents

Kate Millington a,b,*,✉, Janet Y Lee c,d,e,*, Johanna Olson-Kennedy f, Robert Garofalo g, Stephen M Rosenthal c, Yee-Ming Chan h
PMCID: PMC11035161  PMID: 38567424

Abstract

OBJECTIVES

Guidelines for monitoring of medications frequently used in the gender-affirming care of transgender and gender-diverse (TGD) adolescents are based on studies in adults or other medical conditions. In this study, we aimed to investigate commonly screened laboratory measurements in TGD adolescents receiving gender-affirming hormone therapy (GAHT).

METHODS

TGD adolescents were recruited from 4 study sites in the United States before beginning GAHT. Hemoglobin, hematocrit, hemoglobin A1c, alanine transaminase, aspartate aminotransferase, prolactin, and potassium were abstracted from the medical record at baseline and at 6, 12, and 24 months after starting GAHT.

RESULTS

Two-hundred and ninety-three participants (68% designated female at birth) with no previous history of gonadotropin-releasing hormone analog use were included in the analysis. Hemoglobin and hematocrit decreased in adolescents prescribed estradiol (−1.4 mg/dL and −3.6%, respectively) and increased in adolescents prescribed testosterone (+1.0 mg/dL and +3.9%) by 6 months after GAHT initiation. Thirteen (6.5%) participants prescribed testosterone had hematocrit > 50% during GAHT. There were no differences in hemoglobin A1c, alanine transaminase, or aspartate aminotransferase. There was a small increase in prolactin after 6 months of estradiol therapy in transfeminine adolescents. Hyperkalemia in transfeminine adolescents taking spironolactone was infrequent and transient if present.

CONCLUSIONS

Abnormal laboratory results are rare in TGD adolescents prescribed GAHT and, if present, occur within 6 months of GAHT initiation. Future guidelines may not require routine screening of these laboratory parameters beyond 6 months of GAHT in otherwise healthy TGD adolescents.

What’s Known on This Subject:

Guidelines for monitoring gender-affirming hormone therapy (GAHT) in transgender and gender diverse (TGD) youth are based on studies in adults or their use in other medical conditions. These guidelines may not be appropriate for TGD adolescents.

What This Study Adds:

In a cohort of TGD youth in the United States, GAHT was rarely associated with abnormal laboratory parameters. The abnormal laboratory results that did occur did so in the first 6 months of GAHT.

The number of transgender and gender-diverse (TGD) youth presenting for gender-affirming care is increasing.1–5 Despite increased patient numbers, guidelines regarding medical treatment and monitoring for youth receiving gender-affirming hormones (eg, estradiol in transfeminine individuals and testosterone in transmasculine individuals) are based on data from transgender adults and other populations who receive exogenous sex-steroid therapy (eg, hypogonadal cisgender men, hyperandrogenemic cisgender women).6,7 Recent studies have suggested that current monitoring guidelines may be too stringent. For example, despite a recommendation to monitor prolactin in transfeminine adults receiving estradiol on the basis of historical reports of prolactinomas, hyperprolactinemia is rarely seen in this population.8–16 Additionally, treatment-monitoring guidelines that may be appropriate for TGD adults may not be appropriate for TGD youth. Adults generally have a higher burden of other medical comorbidities, may have had treatment with sex steroids associated with higher rates of complications, and may be susceptible to poor outcomes on the basis of age-related changes.17,18 For example, transgender adults treated before 2001, when ethinyl estradiol was commonly used, have an increased risk of venous thromboembolus. However, these data may not accurately represent the risk of contemporary TGD adolescents treated with more physiologic forms of estrogen (eg, 17β estradiol),which are associated with a lower risk of thromboembolism.17 Although laboratory-monitoring data in TGD adults receiving gender-affirming hormone therapy (GAHT) have recently become available,19,20 data in TGD adolescents are still emerging.21–25

Current guidelines regarding the care of TGD youth recommend routine monitoring of hemoglobin and hematocrit in patients designated female at birth (DFAB) receiving testosterone because of the increase in these parameters with testosterone therapy. The association of insulin resistance with hyperandrogenic states, such as polycystic ovary syndrome in patients DFAB, has raised concern that exogenous testosterone in the transmasculine population could also lead to dysglycemia. Thus, hemoglobin A1c (HbA1c) monitoring is also routinely performed by some clinicians. Additionally, some clinicians may monitor alanine transaminase (ALT) and aspartate aminotransferase (AST) during testosterone therapy because of the historical association in adult patients between testosterone and abnormal liver enzymes. Potassium monitoring may also be warranted in patients receiving spironolactone, a potassium-sparing diuretic used for its antiandrogen properties in feminization therapy, because of reports of hyperkalemia when spironolactone is used in the treatment of heart failure.6,7,26

In this observational study, we report on changes in laboratory measurements obtained in the clinical setting as TGD youth received care in accordance with accepted guidelines.6,7 These include hemoglobin, hematocrit, HbA1c, liver enzymes, prolactin, and potassium. These data can guide clinicians treating TGD youth and inform future guidelines regarding laboratory monitoring of GAHT in this population.

Methods

Participants were recruited from 4 study sites as part of the Trans Youth Care–United States study and enrolled before initiating GAHT (testosterone or estradiol), which was prescribed by their clinical provider. Laboratory, medication, and anthropometric data were collected as part of routine clinical care and abstracted from the medical record before GAHT and at 6, 12, and 24 months of therapy. Hemoglobin, hematocrit, HbA1c, ALT, AST, prolactin, and potassium measurements were included in this analysis. Laboratory parameters with sex-specific reference ranges (ie, hemoglobin, hematocrit, and prolactin) were compared with both male and female reference ranges. A full description of the study protocol has been published.27 The research protocol was approved by the institutional review boards at all study sites. All study participants and/or their parent/guardians gave written informed consent and/or assent.

Demographic variables were compared using the Wilcoxon sum-rank test. Proportions were compared using Fisher’s exact test. A mixed model repeated measures was applied to model the longitudinal association between the outcome variables adjusting for age at the baseline visit and baseline BMI. This model yields unbiased estimates of the regression parameters even when the outcome is missing at random and allows specifying an unstructured covariance matrix for the residual errors. Tobacco use can change red blood cell parameters; therefore, recent tobacco use was added to the multivariate model for the hemoglobin and hematocrit analysis.28 Because bicalutamide has been associated with increases in ALT, participants prescribed bicalutamide were excluded from the ALT and AST analysis.29 A P value of <.05 was considered significant. Stata Statistical Software: Release 16 (College Station, Texas) was used for analyses.30

Results

Three-hundred and fifteen TGD adolescents were recruited before initiating GAHT, of whom 110 (35%) were designated male at birth (DMAB) and 205 (65%) were DFAB (Table 1). Of these, 22 participants (17 DMAB and 5 DFAB) had a history of gonadotropin-releasing hormone analog use in early puberty (Tanner II and III) and were excluded from the analysis. There were 34 participants DMAB and 31 DFAB who received gonadotropin-releasing hormone analog in late, or after, puberty (Tanner IV or V) and were included in the analysis. The majority of the remaining 293 participants started GAHT in late puberty or after puberty (Tanner IV or V). Most transfeminine individuals were treated with oral (84%) or transdermal (13%) 17β estradiol, and most transmasculine individuals were treated with subcutaneous testosterone injections (97%). For oral estradiol, the median (interquartile range [IQR]) dose calculated over the entire 24-month study period was 4 mg per day (2–4 mg per day), for transdermal estradiol 0.05 mg per day (0.025–0.1 mg per day), and for intramuscular estradiol valerate 20 mg every 2 weeks (20–30 mg every 2 weeks). For subcutaneous testosterone enanthate or cypionate, the median dose was 40 mg per week (26–50 mg per week), and for transdermal testosterone 40.5 mg per day (25–50 mg per day). There were 38 (19%) participants DFAB and 35 (38%) participants DMAB who were prescribed progesterone during GAHT. An additional 22 (11%) of participants DFAB used a combined estrogen–progestin oral contraceptive pill (eg, ethinyl estradiol and a progestin) during GAHT.

TABLE 1.

Baseline Characteristics of Participants

DMAB (n = 93) DFAB (n = 200)
Age, median (IQR), y 17.3 (16.1–18.6) 16.2 (15.1–17.6)
Affirmed gender, n (%)
 Male 0 (0%) 81 (41%)
 Female 36 (39%) 0 (0%)
 Transgender female 52 (56%) 0 (0%)
 Transgender male 0 (0%) 106 (53%)
 Gender fluid 0 (0%) 2 (1%)
 Gender queer 1 (1%) 1 (0.5%)
 Nonbinary 4 (4%) 10 (5%)
Tanner stage at baseline visit, n (%)
 III 3 (3%) 1 (0.5%)
 IV 10 (12%) 17 (9%)
 V 73 (85%) 168 (91%)
Estradiol formulation, n (%)a
 Oral 77 (84%) —
 Transdermal 12 (13%) —
 Intramuscular 3 (3%) —
Estradiol dose at baseline visit, median (IQR)
 Oral administration, mg per day 4 (2–4) —
 Transdermal administration, mg per day 0.0375 (0.025–0.1) —
 Intramuscular, mg every 2 weeks 20 (20–20) —
Estradiol dose at 12-mo visit, median (IQR)
 Oral administration, mg per day 4 (4–4) —
 Transdermal administration, mg per day 0.075 (0.05–0.1) —
 Intramuscular, mg every 2 weeks 28 (20–30) —
Estradiol dose at 24-mo visit, median (IQR)
 Oral administration, mg per day 4 (2–6) —
 Transdermal administration, mg per day 0.05 (0.1–0.2) —
 Intramuscular, mg every 2 weeks 30 (28–30) —
Testosterone formulation, n (%)a
 Subcutaneous — 195 (97%)
 Transdermal gel — 5 (3%)
Testosterone dose at baseline visit, median (IQR)
 Subcutaneous administration, mg per week — 25.0 (25.0–26.0)
 Transdermal administration, mg per day — 25.0 (20.25–25.0)
Testosterone dose 12-mo visit, median (IQR)
 Subcutaneous administration, mg per week — 50.0 (40.0–50.0)
 Transdermal administration, mg per day — 40.5 (37.5–40.5)
Testosterone dose 24-mo visit, median (IQR)
 Subcutaneous administration, mg per week — 50.0 (50.0–60.0)
 Transdermal administration, mg per day — 40.5 (20.25–60.75)
GnRH analog use, n (%)b 34 (37%) 31 (16%)
Spironolactone use, n (%) 59 (63%) —
Progesterone use, n (%)
 Norethindrone acetate — 31 (16%)
 Medroxyprogesterone acetate — 6 (3%)
 Etonogestrel implant — 1 (0.5%)
 Micronized progesterone 35 (38%) —
Combined estrogen and progesterone oral contraceptive use, n (%) — 22 (11%)
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GnRH, gonadotropin hormone-releasing hormone; —, data not applicable.

a

Anticipated formulation at time of baseline visit.

b

Participants who received gonadotropin hormone-releasing hormone analogs in early puberty (Tanner II or III) were excluded. Participants receiving gonadotropin hormone-releasing hormone analogs in late or postpuberty (Tanner IV or V) were included.

Hemoglobin and Hematocrit

After 6 months of estradiol therapy, participants DMAB experienced a decrease in hemoglobin concentration of 1.4 mg/dL (median [IQR] 15.3 mg/dL [14.9–15.9 mg/dL] to 13.9 mg/dL [13.3–14.6 mg/dL], P < .001) and a decrease in hematocrit of 3.6% (45.2% [43.6%–46.5%] to 41.6% [39.3%–43.2%], P < .001) (Table 2, Fig 1). This represented a relative decrease in hemoglobin of 8.6 ± 4.9% and hematocrit of 7.9 ± 5.2%. There were no further changes in hemoglobin or hematocrit after the first 6 months of treatment. No participants had hemoglobin or hematocrit levels below the typical range for an adult woman (hemoglobin 11.9 mg/dL–14.8 mg/dL, hematocrit 36%–45%)31 during the 24-month follow-up period. There were 19 (20%) participants DMAB who continued to have hemoglobin and/or hematocrit levels above the typical adult female range throughout treatment with estradiol.

TABLE 2.

Laboratory Measurements During Gender-Affirming Hormone Treatment

Baseline 6 mo 12 mo 24 mo
DMAB treated with estrogen (n = 93) median (IQR) (n)
 Hemoglobin (mg/dL) 15.3 (14.9–15.9) (65) 13.9 (13.3–14.6) (40)a 13.9 (13.2–14.7) (38) 14 (13.3–14.6) (29)
 Hematocrit (%) 45.2 (43.6–46.5) (65) 41.6 (39.3–43.2) (40)a 41.7 (39.6–43.7) (38) 42.3 (40.8–43.2) (29)
 HbA1c (%) 5.2 (5.0–5.4) (37) 5.1 (4.9–5.3) (32)a 5.1 (4.9–5.2) (33) 5.1 (5.0–5.3) (22)
 ALT (U/L) 23 (15–38) (65) 21 (15–30) (47) 19 (14–25) (46) 19.5 (12.5–26) (32)
 AST (U/L) 24 (19–32) (65) 24 (19–28) (47) 20.5 (18–25) (45) 22.5 (17.5–28) (32)
 Prolactin (ng/mL) 8.5 (6.2–10.9) (65) 11.5 (8.3–13.6) (48)a 11.9 (8.8–15.9) (45) 10.2 (7.9–12.4) (26)
DFAB treated with testosterone (n = 200) median (IQR) (n)
 Hemoglobin (mg/dL) 13.2 (12.5, 13.9) (189) 14.2 (13.3–15.1) (155)a 14.7 (13.6–15.6) (136)b 15.0 (14.1–15.8) (119)c
 Hematocrit (%) 39.9 (37.8, 41.6) (191) 43.8 (41.6–45.8) (157)a 44.6 (41.6–47.0) (136)b 45.4 (42.9–47.6) (119)c
 HbA1c (%) 5.2 (5.0, 5.4) (105) 5.1 (5.0–5.4) (66) 5.1 (4.9–5.3) (64) 5.1 (4.9–5.3) (59)
 ALT (U/L) 17 (11, 25) (77) 19.5 (14–28) (58) 18 (13–26) (57) 19 (13–27) (42)
 AST (U/L) 20 (17, 25) (77) 23 (19–29) (58) 22 (18–27) (57) 22 (18–28) (42)
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All comparisons are for a multivariate model including age and baseline BMI. Hemoglobin and hematocrit analyses were controlled for recent tobacco use. Participants with diabetes mellitus were excluded from the HbA1c, ALT, and AST analyses. Participants taking bicalutamide were excluded from the ALT and AST analyses.

a

P < .05 for change between 6 months and baseline measurement.

b

P < .05 for change between 6- and 12-month measurement.

c

P < .05 for change between 12- and 24-month measurement.

FIGURE 1.

FIGURE 1

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Change in hemoglobin (A) and hematocrit (B) from baseline during GAHT. Solid circles and solid lines represent participants DMAB treated with estradiol, and open circles and dotted lines represent participants DFAB treated with testosterone. Symbols represent the means and lines represent standard deviations. Light gray shading represents the typical range for adult cisgender women (hemoglobin 11.9–14.8 mg/dL, hematocrit 35%–43%), and hashed shading represents the typical range for adult cisgender men (hemoglobin 13.3–16.9 mg/dL, hematocrit 40%–50%). There was a decrease in hemoglobin and hematocrit in participants DMAB after 6 months of estradiol. There was an increase in hemoglobin and hematocrit in participants DFAB after 6 months of testosterone, and a smaller increase after 12 and 24 months (P < .001 for all comparisons). (C) There were 12 participants DFAB who had hematocrit measurements >50% during GAHT. Each line represents the course of 1 participant.

After 6 months of testosterone treatment, participants DFAB experienced a 1.0 mg/dL rise in hemoglobin (13.2 mg/dL [12.5–13.9 mg/dL] to 14.2 mg/dL [13.3–15.2 mg/dL], P < .001) and a 3.9% rise hematocrit (39.9% [37.8%–41.6%] to 43.8% [41.6%–45.8%], P < .001), increases comparable in degree to the decreases seen with estradiol. From 6 to 12 months of follow-up, there was a smaller additional rise in both hemoglobin (14.2 mg/dL [13.3–15.1 mg/dL] to 14.7 mg/dL [13.6–15.6 mg/dL], P < .001) and hematocrit (43.8% [41.6%–45.8%] to 44.6% [41.6%–47.0%], P < .001), and from 12 to 24 months, there was an additional small increase in both hemoglobin (14.7 mg/dL [13.6–15.6 mg/dL] to 15.0 mg/dL [14.1–15.8 mg/dL], P = .01) and hematocrit (44.6% [41.6%–47.0%] to (45.4% [42.9%–47.6%], P = .03). This represented a relative increase in hemoglobin of 11.0 ± 9.7% and hematocrit of 11.7 ± 8.4% over the first year of testosterone treatment and of 12.6 ± 9.0% and 12.8 ± 7.5%, respectively, over the 24-month follow-up period. There were 53 (27%) participants DFAB who continued to have hemoglobin and/or hematocrit levels below the typical adult male range throughout treatment with testosterone.

Higher serum testosterone levels were associated with higher hematocrit in participants DFAB in a model including BMI and age (R2 = 0.27, P < .001).

There were 13 participants (6.5%) DFAB, 1 of whom had recent tobacco use, who had hematocrit above the typical cisgender male range (hematocrit 40%–50%)31 during treatment with testosterone, ranging from 50.1% to 53.1% (Supplemental Table 3, Fig 1). No participants had a hematocrit > 54%, which has been cited as the upper limit of normal by some sources.32 Apart from a decrease in the testosterone dose, there were no other clinical interventions (eg, therapeutic phlebotomy) required to address the increased hematocrit in this cohort.

Hemoglobin A1c

There were 5 participants, all DFAB, with preexisting diabetes mellitus who were excluded from the HgbA1c analysis. In participants DMAB, there was a small decrease in HbA1c of 0.1% (5.2% [5.0%–5.4%] to 5.1% [4.9%–5.3%], P = .001) after 6 months of estradiol treatment (Table 2). Two DMAB participants had slightly elevated HbA1c measurements of 5.8% at the baseline visit. One of these participants did not have additional HbA1c measurements, and the other had a subsequently normal HbA1c measurement. An additional 2 DMAB participants had HbA1c levels of 5.7% at the 12- and 24-month follow-up visits. Neither of these participants had baseline HbA1c measurements recorded. One participant treated with estradiol had an increase in HbA1c from 5.0% at baseline to 6.0% at the 24-month follow-up. This participant did not have a BMI in the obese range (BMI throughout study 24 kg/m2). In total, there were 5 (5.4%) participants DMAB who had an elevated HbA1c measurement at any point during the study period.

In our population of DFAB adolescents, there was no change in median HbA1c across the cohort during testosterone therapy (P = .3). There were 10 (5.1%) participants DFAB with baseline HbA1c measurements in the prediabetes range (5.7%–6.4%). Of these, 3 participants did not have additional follow-up measurements, 5 had subsequently normal measurements, and 2 had persistently elevated HbA1c measurements of 5.7%. Five (2.5%) participants DFAB had elevated HbA1c measurements during the treatment period. Three of these participants did not have baseline HgbA1c measurements recorded, so it is possible that they had an elevated HbA1c before beginning treatment. One DFAB participant had an increase in HbA1c from 5.4% to 5.7% over the 24-month treatment period. This participant also had an increase in BMI from 24.5 to 27.8 kg/m2. Another DFAB participant had an increase in HbA1c from 5.6% to 6.1% at the 12-month follow-up visit, but HbA1c was in the normal range at the 24-month follow-up visit (4.3%). This participant also had a baseline BMI in the obese range (32.0 kg/m2). There were 15 (7.7%) total DFAB participants who had an elevated HbA1c measurement at any point during the study period.

ALT and AST

There was no change in median ALT or AST in participants DMAB treated with estradiol (Table 2, Fig 2). One participant DMAB had an increase in ALT and AST during treatment with estradiol (range 98–235 U/L). This participant was not taking any additional medications associated with liver toxicity, but did have a BMI in the obese range that increased further after estradiol was initiated (31.9–35.1 kg/m2).

FIGURE 2.

FIGURE 2

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ALT and AST values in participants DMAB receiving estradiol (A and C, respectively) and participants DFAB receiving testosterone (B and D, respectively) at baseline and during study follow-up. The box represents the 25th to 75th percentile, horizontal line the median, and whiskers are the minimum and maximum values after outliers were removed. Outlier measurements are represented by solid circles. There were no significant changes in ALT or AST during GAHT. Participants treated with bicalutamide and those with diabetes mellitus were excluded.

We did not find any change in median ALT or AST during testosterone therapy in transmasculine participants DFAB over 24 months of treatment. Four (2%) participants DFAB had elevations in liver enzymes >2 times the upper limit of normal during testosterone therapy (range 118–263 U/L). All 4 participants were receiving concurrent treatment with other medications that have been associated with abnormal liver function tests (ie, isotretinoin,33 quetiapine,34 lamotrigine, bupropion,35). Three of these 4 participants had subsequent ALT and AST measurements that returned to normal during the study visit. The fourth participant, who was taking isotretinoin and sertraline, continued to have elevated ALT at the 24-month follow-up visit.

Prolactin

In this cohort of transfeminine adolescents, we found an increase in median (IQR) prolactin level after 6 months of estrogen treatment (8.5 ng/mL [6.2–10.9 ng/mL] to 11.5 ng/mL [8.3–13.6 ng/mL], P < .001, Table 2). One participant had a prolactin >40 ng/mL. This participant had a mildly elevated prolactin level at baseline (20.6 ng/mL) and was prescribed medications associated with hyperprolactinemia (escitalopram36). This participant had a prolactin level of 48.3 ng/mL at the 24-month follow-up visit. Two additional participants had prolactin levels between 20 ng/mL and 40 ng/mL, both of whom were prescribed medications associated with hyperprolactinemia (escitalopram,36 venlafaxine,37 and fluoxetine38).39 Both of these participants had prolactin levels <20 ng/mL at the 24-month follow-up visit.

Potassium in Participants Taking Spironolactone

In this cohort, there were 59 participants DMAB treated with spironolactone in addition to estradiol. The median potassium in this group remained within the normal range for potassium (3.5–5.0 mmol/L); median (IQR) potassium during the entire 24-month treatment course 4.3 mmol/L (4.1–4.6 mmol/L). Five participants who had elevated potassium values during estradiol and spironolactone treatment (Supplemental Table 4), ranging from 5.1 mmol/L to 5.2 mmol/L. Four of the 5 participants with hyperkalemia had repeat potassium levels that were normal when rechecked after 6 or 12 months. One participant with a potassium level of 5.2 mmol/L after 6 months of estradiol had no follow-up levels available.

Discussion

We report here laboratory follow-up data for a large observational cohort of TGD adolescents receiving GAHT for 24 months. In general, our data are in line with previous reports that GAHT in adolescents is safe and that laboratory abnormalities are transient when they do occur.26,40 Additionally, laboratory values that are known to differ between cisgender men and women, such as hemoglobin, shift into the reference range on the basis of gender after 6 months in transgender men and 12 months in transgender women. This pattern in laboratory values that show differences between females and males has been previously reported in TGD individuals receiving GAHT.23,25,41,42 The additional data we present here add to the growing body of literature supporting the laboratory safety of GAHT in TGD adolescents.

We found no increases in HbA1c with GAHT in adolescents. Early reports of GAHT in transgender adults suggested that GAHT, specifically estrogen therapy in transgender women, was associated with increases in insulin resistance.43–45 The known association between insulin resistance and type 2 diabetes mellitus in hyperandrogenic states, such as polycystic ovarian syndrome46 in cisgender women, has also led to concern about increased risk of insulin resistance in transgender men receiving testosterone.18,47 Two recent large epidemiologic studies in transgender adults, 1 from the Study of Transition, Outcomes, and Gender cohort in the United States and another from researchers in the Netherlands, did not find an increase in the incidence of type 2 diabetes in transgender men when compared with either cisgender women or cisgender men.48,49 The US study did find an increase in type 2 diabetes incidence in transgender women when compared with cisgender women, but not when compared with cisgender men. Recent estimates of prediabetes prevalence in US adolescents range from 9.5% in females to 22.4% in males.50 Thus, the prevalences in our study, 7.7% and 5.4% in transmasculine and transfeminine adolescents, respectively, may represent the background prevalence of prediabetes in US adolescents. The American Diabetes Association currently recommends screening for prediabetes in adolescents with overweight or obesity who have an additional risk factor for type 2 diabetes.51 These screening guidelines also apply to TGD individuals, but our results suggest that TGD adolescents do not need additional diabetes screening for the indication of GAHT alone.

Transgender women receiving GAHT have been thought to be at higher risk of prolactinomas because of reports of elevated prolactin and development of prolactinomas in transwomen treated with estradiol and the antiandrogen cyproterone acetate or with high-dose estradiol.8,9,52–54 The increase in prolactin in these reports was ultimately attributed to cyproterone acetate and not estradiol use.55,56 Smaller studies of transfeminine adolescents did not find any increase in prolactin during estradiol treatment.40,57 A similar-sized study of nearly 98 transfeminine adults, likewise, found no difference in prolactin levels during estradiol treatment.16 In our study, we found a small increase in prolactin after 6 months of estradiol treatment (difference of means 3 ng/mL) that is unlikely to be clinically significant. Only 1 participant developed clinically significant hyperprolactinemia (prolactin >40 ng/mL) after 6 months of estradiol treatment. This participant was also taking escitalopram, which has been associated with an increase in prolactin levels.36 We suggest obtaining prolactin levels only in patients with symptoms of hyperprolactinemia before or during estradiol therapy.

There have now been multiple studies of the incidence of hyperkalemia in TGD adolescents and adults taking spironolactone.19,21,58,59 These reports found that hyperkalemia was a rare event (prevalence of hyperkalemia 2.2%–2.5% in adolescents and adults, respectively). In our cohort, there were 5 participants (8.5%) taking spironolactone who had a potassium level >5.0 mmol/L at some point in their estradiol treatment course. In all but 1 participant, who did not have follow-up levels, the potassium level resolved on subsequent measurement without intervention. There were no participants with potassium levels >5.2 mmol/L, which some major laboratories have as the upper limit of normal.60,61 Because of the retrospective nature of the study, we do not have information about the degree of hemolysis in the samples. This finding agrees with previous reports that spironolactone-related hyperkalemia in transfeminine adolescents is rare and transient.

In our cohort of TGD adolescents taking testosterone, hemoglobin and hematocrit increased as expected and entered the higher end of the male reference range. In our study, 9% (n = 18 of 200) of the adolescents prescribed testosterone had hematocrit >50% at any time during their treatment course; none had hematocrit >54%, and no interventions were required aside from dose modification. Other studies have reported similar findings, with the most pronounced increases in hematocrit within the first 3 months of testosterone therapy.19,62–66 In our cohort, some hematocrit values were >50% after 24 months of GAHT, so it would be prudent to continue monitoring hemoglobin and hematocrit while on testosterone therapy, in line with existing guidelines.6,7,67

A small proportion of TGD adolescents receiving testosterone had changes in liver enzymes during therapy: 4 participants (2.0%), all of whom were taking other medications associated with liver enzyme alterations. Most of these participants (3 of 4, 75%) had normal ALT values upon repeat testing. One TGD adolescent receiving estrogen who had an elevated ALT level also had an elevated BMI, putting them at risk for nonalcoholic fatty liver disease and would have required ALT screening on the basis of the diagnosis of obesity independent of their estrogen exposure. No testosterone therapy had to be stopped in our cohort because of liver enzyme elevation. Again, these data are in line with other studies of liver enzymes in TGD adults receiving testosterone, with some noting modest increases that could be associated with other exposures or conditions such as alcohol use and obesity.19,65,68 On the basis of the low incidence of liver enzyme elevation not attributable to other factors in TGD adults receiving GAHT, some groups have advocated for excluding liver enzyme monitoring.69 For TGD adolescents receiving GAHT, our results suggest that it is reasonable to exclude liver enzyme monitoring unless there are additional risk factors for liver injury such as bicalutamide use, alcohol use or abuse, dyslipidemia, or obesity.

This study is limited by its observational study design. The study design introduced missing data, which may skew our results. This study was conducted at large, urban, tertiary care centers with clinics specializing in the care of TGD youth, and may not represent all TGD youth, especially those from minority backgrounds, lower socioeconomic status, or living in rural settings.

In summary, we found that TGD adolescents receiving 24 months of GAHT starting in late puberty did not have significant laboratory abnormalities. Some of the recommended laboratory monitoring for GAHT in TGD adolescents may not be necessary given the relatively low rates of abnormal values. Longer-term studies will be needed to determine whether abnormal laboratory values do occur as TGD adolescents age into adulthood while receiving GAHT, and when monitoring should change in terms of frequency or stop altogether.

Supplementary Material

Supplemental Information
peds.2023-064380SupplementaryData.pdf (403.1KB, pdf)

Glossary

ALT

alanine transaminase

AST

aspartate aminotransferase

DFAB

designated female at birth

DMAB

designated male at birth

GAHT

gender-affirming hormone therapy

HbA1c

hemoglobin A1c

IQR

interquartile range

TGD

transgender/gender-diverse

Footnotes

Dr Millington performed the data analysis, interpreted the data, and drafted the initial manuscript; Dr Lee participated in the interpretation of data and drafted the initial manuscript; Drs Olson-Kennedy, Garofalo, Rosenthal, and Chan conceptualized the study and supervised data collection; and all authors critically reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

FUNDING: Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD082554); the Doris Duke Charitable Foundation grant 2019119; the Biostatistics Core at the Saban Research Institute, Children’s Hospital Los Angeles; and by grants UL1TR001855 and UL1TR000130 from the National Center for Advancing Translational Science of the US National Institutes of Health. The sponsors had no role in the design or conduct of this study, and the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose.

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