Visceral adipose tissue and liver fat on 17-beta estradiol-dominant gender-affirming hormone therapy: A US-based cohort

Ria Talathi; Vencel Juhasz; Matilda Delgado; Thiago Quinaglia; Azin Ghamari; Melissa Wang; Iad Alhallak; Sarah Stinebaugh; Sophia Campbell; Sara L Stockman; Mustafa A Ozturk; Sadia M Ahmadi; Sara E Looby; Hang Lee; Tonia C Poteat; Lidia S Szczepaniak; Markella V Zanni; Tomas G Neilan; Mabel Toribio

doi:10.1210/clinem/dgaf665

. 2025 Dec 12;111(6):1713–1726. doi: 10.1210/clinem/dgaf665

Visceral adipose tissue and liver fat on 17-beta estradiol-dominant gender-affirming hormone therapy: A US-based cohort

Ria Talathi ^1,^#, Vencel Juhasz ^2,^3,^#, Matilda Delgado ⁴, Thiago Quinaglia ⁵, Azin Ghamari ⁶, Melissa Wang ⁷, Iad Alhallak ⁸, Sarah Stinebaugh ⁹, Sophia Campbell ¹⁰, Sara L Stockman ¹¹, Mustafa A Ozturk ¹², Sadia M Ahmadi ¹³, Sara E Looby ¹⁴, Hang Lee ¹⁵, Tonia C Poteat ¹⁶, Lidia S Szczepaniak ¹⁷, Markella V Zanni ¹⁸, Tomas G Neilan ^19,^#, Mabel Toribio ^20,^21,^#,^✉

¹ Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

² Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

³ Heart and Vascular Center, Semmelweis University, Budapest 1122, Hungary

⁴ Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

⁵ Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

⁶ Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

⁷ Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

⁸ Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

⁹ Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

¹⁰ Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

¹¹ Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

¹² Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

¹³ Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA

¹⁴ Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

¹⁵ Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

¹⁶ Division of Healthcare in Adult Populations, Duke University School of Nursing, Durham, NC 27710, USA

¹⁷ MRS Consulting in Biomedical Research, Albuquerque, NM 87112, USA

¹⁸ Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

¹⁹ Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

²⁰ Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

²¹ MGH Transgender Health Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

^✉

Correspondence: Mabel Toribio, MD, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, 50 Staniford Street, Suite 750A, Boston, MA 02114, USA. Email: mptoribio@mgh.harvard.edu.

R.T. and V.J. contributed equally to this manuscript.

T.G.N. and M.T. contributed equally to this manuscript.

PMCID: PMC13183449 PMID: 41383103

Abstract

Context

Data on the metabolic effects of contemporaneous gender-affirming hormone therapy (GAHT) are limited.

Objective

To characterize the metabolic effects of GAHT ie, estradiol with anti-androgen therapy.

Design

Prospective observational study with a 12-month follow-up period.

Setting

Academic medical center in greater Boston, Massachusetts, USA.

Participants

Twenty-six transgender women and nonbinary individuals with no history of cardiovascular disease or diabetes who were either planning to initiate or who had recently initiated GAHT consisting of 17 beta(β)-estradiol and anti-androgen therapy.

Intervention(s)

GAHT.

Main Outcome Measure(s)

The prespecified primary outcome was the change in visceral adipose tissue (VAT). Prespecified secondary outcomes included change in bone density, insulin sensitivity, and intrahepatic triglyceride content (hTG).

Results

Median age of participants was 26 (20, 30) years. After 12 months, VAT mass and volume did not change. While lumbar, total hip, and femoral bone density increased, insulin sensitivity did not change. hTG decreased over 12 months (median change: −0.2 [−1.3, 0.1]%, P = .03). Total lean body mass and the appendicular lean body mass/height² decreased (mean change: −0.31 ± 0.38 kg/m², P = .0003). Systemic triglycerides levels increased, whereas high-density lipoprotein cholesterol and low-density lipoprotein cholesterol, did not change over 12 months. Free testosterone levels at follow-up independently predicted the change in hTG, controlling for estradiol levels, body mass index, and waist-to-hip ratio at follow-up.

Conclusion

Key indices of metabolic health, such as VAT and insulin sensitivity, did not change after 12 months of GAHT. Appendicular lean body mass/height², a predictor of sarcopenia, unfavorably decreased, while hTG favorably decreased. Awareness of the metabolic effects of GAHT may lead to the implementation of strategies aimed at mitigating sarcopenia risk.

Keywords: gender-affirming hormone therapy, estradiol, androgen suppression, transgender women, hepatic fat, body composition

Transgender women on gender-affirming hormone therapy (GAHT) face heightened cardiovascular disease-attributable mortality (1) and cardiometabolic disease risk (2-5). For many transgender women and gender-diverse individuals (TGD individuals), GAHT is continued longitudinally for years as part of their gender-affirming care (6). At least 1 large multicenter study, however, demonstrated that among transgender women receiving GAHT, cardiometabolic disease risk does not decline with ongoing GAHT (2). The heightened cardiometabolic disease risk among transgender women receiving GAHT (2-5), together with the standard practice of longitudinal GAHT (2), provide strong imperatives to better understand the metabolic effects of GAHT and to develop metabolic risk mitigation strategies.

GAHT for transgender women typically consists of a combination of 17 beta (β)-estradiol together with a medication that either suppresses or blocks testosterone/androgens (7). Testosterone blockade/suppression together with estradiol therapy may have complex and competing systemic effects among TGD individuals. Testosterone blockade/suppression, in isolation, may contribute to decreased muscle mass (8, 9) and increased ectopic fat deposition (10). Estradiol therapy, in turn, in isolation, may help preserve muscle mass (11-13) and also has differential effects on lipolysis depending on the fat depot (14-18). In this study, we prospectively recruited transgender women and nonbinary individuals who were planning to initiate or who recently initiated GAHT (clinically prescribed estradiol coupled with anti-androgen therapy) to undergo comprehensive metabolic phenotyping to better understand the complex and competing effects of concomitant estradiol supplementation and anti-androgen therapy. We previously published results on the effects of GAHT on myocardial structure among TGD individuals (19) and now report our findings on body composition, bone density, insulin sensitivity, and systemic cholesterol levels. Given that hepatic steatosis is an independent predictor of cardiovascular disease risk and can contribute to insulin resistance (20), we also examined the effects of estrogen-dominant GAHT on intrahepatic triglycerides.

Material and methods

Study design and participants

For this longitudinal, observational study, TGD individuals were prospectively recruited between August 2021 and March 2023. Individuals underwent baseline study procedures at the Massachusetts General Hospital Translational and Clinical Research Center after a screening visit followed by final study procedures after approximately 12 months from baseline. While all study visits occurred at a single site (Massachusetts General Hospital Translational and Clinical Research Center) in Boston, Massachusetts, United States, we recruited and ultimately enrolled participants living in the Midwest, Northeast, Southeast, Southwest, and West Coast regions of the United States. Individuals were required to be 16 years or older and to start or be within 5 months of starting a combination of 17β-estradiol (oral, sublingual, transdermal, subcutaneous, and/or intramuscular) and anti-androgen therapy (spironolactone, leuprolide, or bicalutamide) through their clinician. As such, participants did not receive GAHT through participation in this study. Individuals with a baseline history of atherosclerotic cardiovascular disease, heart failure, or diabetes were not eligible for the study. Further, individuals with statin use within the last 6 months were also excluded. All participants underwent an informed consent process and signed a consent form. A total of 33 participants signed consent. Two participants were found to be ineligible after signing consent; and 1 participant withdrew after signing consent due to insufficient time to complete the study (Fig. 1). Four participants who underwent baseline study procedures did not return to have their final (12 month) study procedures given that they were no longer on anti-androgen therapy, a requirement of the study. Ultimately, a total of 26 participants completed the study. The study was approved by the Massachusetts General Brigham Institutional Review Board and registered on clinicaltrials.gov (NCT04128488).

For image description, please refer to the figure legend and surrounding text. — Consort diagram. The number of participants enrolled and who ultimately completed baseline and final study visits is detailed. Additionally, the number of participants on estrogen-dominant gender-affirming hormone therapy and/or progesterone at baseline is also delineated for participants completing baseline and final study visits.

Study procedures

Clinical assessments

At the time of their screen visit, demographic data, including gender identity, medical history, surgical history, and current medications, were obtained followed by a physical examination. Interval medical history, surgical history, current medications, and physical examination were obtained at the baseline visit and final 12-month visit.

Oral glucose tolerance testing

At the baseline and final 12-month visits, a standard 75-g oral glucose tolerance test was performed with measurement of insulin (immunoassay) and glucose at 0, 30, 60, 90, and 120 minutes. Insulin resistance was quantified by calculating the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and the Matsuda Index (21).

Whole body, lumbar, and total hip dual-energy X-ray absorptiometry

At the baseline and final 12-month visits, whole body, lumbar, and total hip dual-energy X-ray absorptiometry (DEXA) imaging was performed using a Hologic Horizon A DEXA machine (Marlborough, Massachusetts, USA). APEX software version 5.6.0.5 was used to calculate total body and regional fat mass and lean body mass, and lumbar, total hip, and femoral neck bone mineral density, and trabecular bone score per standard techniques (22).

Hepatic magnetic resonance spectroscopy

At the baseline and final 12-month visits, intrahepatic triglyceride content was measured using a 3 Tesla Skyra magnetic resonance imaging scanner (Siemens, Erlangen, Germany). The placement of a volume of interest, voxel of 2 × 2 × 2 cm, was chosen based on sagittal, coronal, and axial localizer abdominal images, through the right hepatic lobe (Fig. 2A). Point RESolved Spectroscopy localization sequence was used for voxel definition. The voxel was selected away from liver margins, avoiding intrahepatic bile ducts and intrahepatic vessels. During hepatic ¹H-magnetic resonance spectroscopy (MRS) data collection, participants breathed freely, and radiofrequency pulses, tracking diaphragm motion (2-dimensional prospective acquisition correction [2D PACE]), were used to trigger spectral acquisition at exhale with the following parameters: echo time—inter-pulse delay time, at least 3 seconds, depending on the participant's breathing rate; echo time—spin echo time—35 ms; 16 acquisitions; and 1024 data points over a 1000-Hz spectral width. Intrahepatic triglyceride content was calculated as a percent of the intrahepatic water signal (Fig. 2B; fat/water ratio percent) and was evaluated by line-fit procedure using NUTS (ACORN NMR, Livermore, California, United States) commercial software (23). The calculations involved exponential relaxation equation I_m (measured signal intensity) = I_o (signal intensity without T2 signal decay) exp (−TE/T2) and considered water and fat signals decay due to T2 relaxation, using average T2 relaxation times for water and fat of 50 and 60 ms, respectively (23).

Laboratory assessments

At the baseline and final 12-month visits, the following laboratory values were assessed through Quest Diagnostics: fasting hemoglobin A1c, cholesterol, estradiol (immunoassay), total testosterone (liquid chromatography-mass spectroscopy), free testosterone (equilibrium dialysis) and SHBG (immunoassay). Assessment of hormone concentrations was not timed to the most recent administration of each participant's GAHT.

Statistical analysis

The primary outcome was change in visceral adipose tissue over 12 months. Secondary outcomes included change over 12 months in the following: total and regional fat and lean body mass, bone mineral density, insulin sensitivity, systemic cholesterol levels, and intrahepatic triglyceride content. A Shapiro-Wilk test was used to assess the normality of the data. The change in these parameters was assessed using either a matched paired t-test for normally distributed data or a Wilcoxon signed-rank test for nonnormally distributed data. Thus, the change in primary and secondary outcomes over 12 months were determined using matched baseline and final endpoints for each participant (ie, matched pairs data). Bivariate analyses relating the change in intrahepatic triglycerides to hormonal parameters (both change in hormone concentrations, hormone concentrations at baseline, and hormone concentrations at follow-up) were performed using robust fit linear regression analyses. Bivariate robust fit regression analyses were also conducted to evaluate whether the change in insulin sensitivity related to the change in intrahepatic triglyceride content. Least squares regression analyses were performed using the change in intrahepatic triglycerides as the dependent variable and estradiol, free testosterone, body mass index (BMI), and waist-to-hip ratio (WHR) at follow-up as independent variables. Based on the results of the multivariable regression analyses, we performed exploratory stratified analyses based on median free testosterone concentrations at follow-up. Given that progesterone use may have influenced the change in our primary and secondary outcomes, sensitivity analyses were performed using either a t-test or Wilcoxon rank-sum test, depending on the normality of the data, to determine if there were differences in primary and secondary outcomes based on progesterone use at the time of follow-up. Analogous sensitivity analyses were also conducted using either a t-test or Wilcoxon rank-sum test, depending on the normality of the data, to determine if there were differences in our primary and secondary outcome parameters at baseline among participants who initiated GAHT before enrollment vs those who initiated GAHT after enrollment. Statistical analyses were completed using JMP software (version 17; SAS Institute).

Results

Participant characteristics

The median interquartile range (IQR) age of study participants was 26 (20, 30) years (Table 1). Eighty-one percent of study participants identified as transgender women, whereas 8% identified as nonbinary and 11% identified as both transgender women and nonbinary. All participants were assigned male sex at birth. The baseline median (IQR) BMI was 25.6 (19.9, 29.6) kg/m². Twenty of 26 participants (77%) were on GAHT prior to enrollment. On average, participants were on GAHT for 2.3 ± 1.7 months at the time of their baseline visit. Aside from 1 participant who started estradiol therapy 5 months before starting spironolactone, the remainder of the study participants started estradiol and anti-androgen therapy simultaneously or within days of each other. No participants had a history of receiving a GnRH analog during puberty or as an older adolescent. At the time of their follow-up visit, participants were on GAHT for 15.2 ± 2.4 months. At follow-up, more than half (61%) of participants were on an oral or sublingual formulation of 17β-estradiol, 27% were on injection 17β-estradiol, and 12% were on transdermal 17β-estradiol. For their androgen suppression at follow-up, 92% were on spironolactone, 4% were on leuprolide, and 4% were on bicalutamide. Furthermore, at follow-up, 54% of participants were on progesterone. Thirteen of these 14 participants were on micronized progesterone and 1 participant was on medroxyprogesterone acetate (Table 2).

Table 1.

Demographic and hormone therapy parameters among participants

	Participants
Age (years)	26 (20, 30) N = 26
Race (%)
White	77 (20/26)
Black	4 (1/26)
Asian	11 (3/26)
More than 1 race	4 (1/26)
Other	4 (1/26)
Ethnicity (%)
Hispanic/Latine	4 (1/26)
Not Hispanic/Latine	96 (25/26)
Gender identity (%)
Transgender woman	81 (21/26)
Nonbinary	8 (2/26)
Both transgender woman and nonbinary	11 (3/26)
Duration of GAHT at baseline (months)	2.3 ± 1.7 N = 26
Current smoking (%)
Cigarettes	0 (0/26)
Electronic cigarettes	8 (2/26)
Current hypertension (%)	0 (0/26)
WHR at baseline	0.88 ± 0.08 N = 26
17β-Estradiol at baseline (%)
Oral/sublingual	65 (17/26)
Intramuscular injection	8 (2/26)
Subcutaneous injection	4 (1/26)
Transdermal	8 (2/26)
None	15 (4/26)
17β-Estradiol average doses at baseline^a
Oral/sublingual (total mg daily)	2 (2, 4) N = 17
Intramuscular injection (mg/weekly)	5 ± 0 N = 2
Transdermal (mg/24 hour once weekly)	0.04 ± 0.02 N = 2
17β-Estradiol at follow-up (%)
Oral/sublingual	61 (16/26)
Intramuscular injection	15 (4/26)
Subcutaneous injection	4 (1/26)
Injection	8 (2/26)
Transdermal	12 (3/26)
17β-Estradiol average doses at follow-up^b
Oral/sublingual (total mg daily)	6 (4, 6) N = 15
Injection (mg every week)	6 ± 3 N = 6
Injection (mg every 2 weeks)	20 N = 1
Transdermal (mg/24 hour twice weekly)	0.15 ± 0.05 N = 3
Anti-androgen therapy at baseline (%)
Spironolactone	73 (19/26)
Leuprolide	8 (2/26)
None	19 (5/26)
Anti-androgen therapy average doses at baseline^c
Spironolactone (mg/day)	100 (50, 100) N = 19
Leuprolide (mg/28 days)	3.75 ± 0.00 N = 2
Anti-androgen therapy at follow-up (%)
Spironolactone	92 (24/26)
Leuprolide	4 (1/26)
Bicalutamide	4 (1/26)
Anti-androgen therapy average doses at follow-up
Spironolactone (mg/daily)	125 (100, 200) N = 24
Leuprolide (mg/28 days)	3.75 N = 1
Bicalutamide (mg/daily)	50 N = 1
Progesterone at baseline (%)	8 (2/26)
Progesterone average doses at baseline (mg/daily)	100 ± 0 N = 2
Progesterone at follow-up (%)	54 (14/26)
Progesterone average doses at follow-up (mg/daily)
Micronized progesterone (mg/daily)	100 (100, 100) N = 13
Medroxyprogesterone acetate (mg/daily)	5 N = 1

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Normally distributed variables are presented as mean ± SD; nonnormally distributed variables are presented as median (interquartile range; IQR). Baseline demographic parameters are presented followed by details of the gender-affirming hormone therapy regimens at the time of participants’ baseline and 12-month follow-up visits.

Abbreviations: GAHT, gender-affirming hormone therapy; WHR, waist-to-hip ratio.

^aOne participant did not have a dose available for their 17β-estradiol at baseline and 4 participants had not initiated GAHT at baseline.

^bOne participant did not have a dose available for the 17β-estradiol at follow-up.

^cFive participants had not started anti-androgen therapy at the time of their baseline visit.

Table 2.

Gender-affirming hormone therapy regimens at follow-up

Participant ID	Hormone therapy	Route of administration/hormone type
001	Estradiol	Oral/sublingual
001	Androgen suppressor	Spironolactone
002	Estradiol	Subcutaneous injection
002	Androgen suppressor	Spironolactone
003	Estradiol	Oral/sublingual
003	Androgen suppressor	Spironolactone
005	Estradiol	Oral/sublingual
005	Androgen suppressor	Spironolactone
007	Estradiol	Intramuscular injection
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
008	Estradiol	Transdermal
	Androgen suppressor	Leuprolide
	Adjunctive therapy	Progesterone
009	Estradiol	Oral/sublingual
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
012	Estradiol	Intramuscular injection
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
013	Estradiol	Oral/sublingual
013	Androgen suppressor	Bicalutamide
014	Estradiol	Transdermal
014	Androgen suppressor	Spironolactone
015	Estradiol	Oral/sublingual
015	Androgen suppressor	Spironolactone
016	Estradiol	Intramuscular injection
	Androgen suppressor	Spironolactone
	Adjunctive therapies	Progesterone, Finasteride
017	Estradiol	Oral/sublingual
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Finasteride
018	Estradiol	Oral/sublingual
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
019	Estradiol	Transdermal
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
020	Estradiol	Oral/sublingual
020	Androgen suppressor	Spironolactone
021	Estradiol	Oral/sublingual
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
023	Estradiol	Injection (estradiol valerate)
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
025	Estradiol	Injection (estradiol valerate)
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
026	Estradiol	Oral/sublingual
026	Androgen suppressor	Spironolactone
027	Estradiol	Intramuscular injection
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
028	Estradiol	Oral/sublingual
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
029	Estradiol	Oral/sublingual
029	Androgen suppressor	Spironolactone
030	Estradiol	Oral/sublingual
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
031	Estradiol	Oral/sublingual
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Progesterone
033	Estradiol	Oral/sublingual
	Androgen suppressor	Spironolactone
	Adjunctive therapy	Finasteride

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Participant level hormone regimens including hormone type and route of administration are presented. While some participants changed their regimen during study participation, only their final estrogen-dominant gender affirming hormone regimen is listed for each participant.

Changes in hormone concentrations, insulin sensitivity, and systemic cholesterol levels

After 12 months, estradiol and SHBG concentrations significantly increased, whereas total and free testosterone concentrations decreased (Table 3). Both the HOMA-IR and the Matsuda Index did not change significantly over 12 months. Systemic triglyceride levels, in turn, increased over 12 months but levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol did not significantly change (Table 3).

Table 3.

Change in parameters among participants after 12 months of gender affirming hormone therapy

	Baseline	Final	Mean/median change	P
Anthropometric measures
Height (cm)	176.5 ± 6.2 N = 26	176.4 ± 6.3 N = 26	−0.17 ± 0.41 N = 26	.049
Weight (kg)	81.0 ± 21.5 N = 26	82.2 ± 21.5 N = 26	1.24 ± 6.8 N = 26	.36
BMI (kg/m²)	25.6 (19.9, 29.6) N = 26	25.5 (20.4, 30.0) N = 26	0.6 (−0.7, 2.0) N = 26	.15
Systolic blood pressure (mm Hg)	122 ± 10 N = 26	121 ± 14 N = 26	−1 ± 18 N = 26	.84
Diastolic blood pressure (mm Hg)	71 ± 8 N = 26	73 ± 14 N = 26	2 ± 14 N = 26	.56
Waist circumference (cm)	89.8 ± 16.3 N = 26	90.4 ± 17.5 N = 26	0.6 ± 6.1 N = 26	.63
Hip circumference (cm)	98.3 (91.7, 109.9) N = 26	100.3 (94.2, 111.6) N = 26	2.1 (−0.7, 4.7) N = 26	.09
Hormone concentration
Estradiol (pg/mL)	81 (44, 259) N = 26	188 (125, 316) N = 26	70 (7, 172) N = 26	.0002
Total testosterone (ng/dL)	116 (37, 522) N = 26	16 (12, 96) N = 26	−95 (−337, -20) N = 26	<.0001
Free testosterone (pg/mL)	17.9 (4.9, 73.1) N = 26	1.9 (1.3, 7.4) N = 26	−16.1 (−55.0, -2.8) N = 26	<.0001
SHBG (nmol/L)	39 (24, 55) N = 26	68 (31, 100) N = 26	16 (6, 43) N = 26	.0001
Bone density
Total lumbar BMD (g/cm²)	0.975 (0.906, 1.031) N = 26	1.022 (0.926, 1.090) N = 26	0.050 (0.022, 0.069) N = 26	<.0001
Total femoral BMD (g/cm²)	0.800 (0.742, 0.925) N = 26	0.842 (0.777, 0.956) N = 26	0.033 (0.008, 0.054) N = 26	.0005
Total hip BMD (g/cm²)	0.930 (0.848, 1.033) N = 26	0.952 (0.881, 1.069) N = 26	0.030 (0.008, 0.044) N = 26	<.0001
Trabecular bone score (Ref cisgender female)	1.436 ± 0.091 N = 26	1.448 ± 0.094 N = 26	0.012 ± 0.057 N = 26	.29
Trabecular bone score (Ref cisgender male)	1.459 ± 0.089 N = 26	1.472 ± 0.088 N = 26	0.013 ± 0.055 N = 26	.23
Body composition on DEXA
Total fat mass (kg)	20.3 (14.6, 28.9) N = 26	24.7 (17.5, 31.1) N = 26	2.8 (0.3, 6.5) N = 26	.002
Total VAT mass (g)	308 (219, 451) N = 26	250 (164, 444) N = 26	−66 (−98, 72) N = 26	.25
Total VAT volume (cm³)	332 (237, 488) N = 26	271 (177, 480) N = 26	−71 (−106, 77) N = 26	.25
Total body fat (%)	27.0 ± 5.7 N = 26	29.9 ± 5.6 N = 26	2.8 ± 3.4 N = 26	.0003
Total fat mass/height² (kg/m²)	6.97 (4.46, 9.10) N = 26	7.54 (5.70, 9.96) N = 26	0.87 (0.085, 2.00) N = 26	.003
Total lean body mass (kg)	57.3 (46.9, 63.6) N = 26	54.7 (47.0, 61.6) N = 26	−0.6 (−3.9, 0.3) N = 26	.02
Total lean body mass/height² (kg/m²)	18.31 ± 3.77 N = 26	17.92 ± 3.63 N = 26	−0.40 ± 0.85 N = 26	.03
Appendicular lean body mass/height² (kg/m²)	8.19 ± 1.76 N = 26	7.88 ± 1.70 N = 26	−0.31 ± 0.38 N = 26	.0003
Insulin sensitivity^a
Glucose at 0 minutes (mg/dL)	83 ± 7 N = 25	83 ± 8 N = 25	0 ± 6 N = 25	.85
Glucose at 30 minutes (mg/dL)	134 ± 21 N = 25	131 ± 23 N = 25	−3 ± 22 N = 25	.45
Glucose at 60 minutes (mg/dL)	133 ± 31 N = 25	124 ± 24 N = 25	−9 ± 31 N = 25	.17
Glucose at 90 minutes (mg/dL)	112 ± 28 N = 24	115 ± 25 N = 24	3 ± 33 N = 24	.61
Glucose at 120 minutes (mg/dL)	93 ± 30 N = 25	100 ± 27 N = 25	7 ± 29 N = 25	.23
Insulin at 0 minutes (µU/mL)	5.8 (4.2, 11.6) N = 25	4.8 (3.7, 8.8) N = 25	−0.6 (−2.2, 3.3) N = 25	.92
Insulin at 30 minutes (µU/mL)	44.8 (28.1, 72.2) N = 25	38.1 (22.9, 69.2) N = 25	−2.7 (−24.4, 16.8) N = 25	.47
Insulin at 60 minutes (µU/mL)	61.7 (39.2, 85.7) N = 24	38.7 (30.5, 54.3) N = 24	−6.5 (−46.7, 11.8) N = 24	.09
Insulin at 90 minutes (µU/mL)	47.1 (24.9, 72.4) N = 25	41.8 (20.4, 57.1) N = 25	−11.0 (−28.8, 9.3) N = 25	.13
Insulin at 120 minutes (µU/mL)	34.1 (22.2, 49.2) N = 25	25.6 (15.0, 48.5) N = 25	−7.0 (−21.5, 14.2) N = 25	.32
Hemoglobin A1c (%)	5.0 ± 0.2 N = 26	5.1 ± 0.2 N = 26	0.0 ± 0.0 N = 26	.60
HOMA-IR	1.1 (0.8, 2.5) N = 25	1.0 (0.7, 1.8) N = 25	−0.1 (−0.4, 0.7) N = 25	.89
Matsuda Index	6.0 (3.5, 9.3) N = 25	8.1 (4.5, 12.3) N = 25	−0.03 (−1.3, 5.4) N = 25	.39
Systemic lipid levels
Total cholesterol (mg/dL)	155 ± 23 N = 26	160 ± 28 N = 26	5 ± 27 N = 26	.37
LDL-C (mg/dL)	89 ± 20 N = 26	90 ± 22 N = 26	1 ± 21 N = 26	.90
HDL-C (mg/dL)	49 ± 11 N = 26	51 ± 8 N = 26	2 ± 9 N = 26	.40
Triglycerides (mg/dL)	69 (60, 84) N = 26	78 (60, 142) N = 26	13 (−11, 38) N = 26	.02
Intrahepatic triglycerides on ¹H-MRS
Intrahepatic triglycerides (%)^b	0.9 (0.7, 4.9) N = 20	0.8 (0.5, 2.0) N = 20	−0.2 (−1.3, 0.1) N = 20	.03

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Normally distributed variables are presented as mean ± SD; nonnormally distributed variables are presented as median (interquartile range; IQR). P values were determined by a paired samples t-test and Wilcoxon signed-rank test for normally distributed and nonnormally distributed variables, respectively. P < .05 values were considered statistically significant and are bolded.

Abbreviations: BMD, bone mineral density; BMI, body mass index; DEXA, dual-energy X-ray absorptiometry; HDL-C; high-density lipoprotein cholesterol; ¹H-MRS, proton magnetic resonance spectroscopy; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; LDL-C, low-density lipoprotein cholesterol; VAT, visceral adipose tissue.

^aOne participant did not complete the baseline glucose tolerance testing. Furthermore, 1 participant did not have a 90-minute glucose level and another participant did not have a 60-minute insulin level due to blood sample issues.

^bThree participants did not have evaluable baseline intrahepatic ¹H-MRS images and 2 participants did not complete the baseline intrahepatic ¹H-MRS, yielding a baseline sample size for intrahepatic triglycerides of 21. Furthermore, 1 participant did not have evaluable final intrahepatic MRS images, yielding a sample size for the final intrahepatic triglycerides of 25. These missing values yielded a total sample size of 20 for the calculated median change of intrahepatic triglycerides.

Changes in lumbar and hip bone density

Bone density increased over 12 months at all sites measured (lumbar, femoral, and total hip; Table 3). The trabecular bone score, a quantitative measure of the bone microarchitecture, referenced using cisgender females and cisgender males, respectively, however, did not significantly change over 12 months (Table 3).

Changes in body composition

Total visceral adipose tissue (VAT) mass and volume did not significantly change (total VAT mass: 308 [219, 451] to 250 [164, 444] g, P = .25; Table 3; Fig. 3A; and total VAT volume: 332 [237, 488] to 271 [177, 480] cm³, P = .25; Table 3). Although total fat mass, percent body fat, and total fat mass/height² (fat mass index; Table 3; Fig. 3B) increased over 12 months, total lean body mass and total lean body mass/height² (lean body mass index; Table 3; Fig. 3C) decreased. Furthermore, the appendicular lean body mass (ALM)/height² (lower levels predictive of sarcopenia) (24) significantly decreased from 8.19 ± 1.76 to 7.88 ± 1.70 over the 12 months (P = .0003; Table 3; Fig. 3D).

Changes in intrahepatic triglyceride content

Intrahepatic triglyceride content decreased from 0.9 (0.7, 4.9)% to 0.8 (0.5, 2.0)% over 12 months (P = .03; Fig. 2C). As demonstrated in Fig. 2C, intrahepatic triglyceride content increased in 1 participant, who had abnormal intrahepatic triglyceride content at baseline and ultimately gained more weight than other participants during the course of the study. Among the entire study cohort, the change in intrahepatic triglycerides did not relate to the change in estradiol, the change in total testosterone, or the change in free testosterone, but the change in intrahepatic triglycerides was inversely related to free testosterone concentrations at follow-up (r = −0.86, P < .0001). Furthermore, free testosterone at follow-up remained an independent predictor of the change in intrahepatic triglycerides in least squares regression analyses with estradiol, free testosterone, BMI, and WHR at follow-up as independent variables (Overall Model R² = 0.77, P = .0001; free testosterone at follow-up β-estimate = −0.09, P < .0001; Table 4). In additional exploratory analyses, we stratified participants into 2 groups based on median free testosterone concentrations at follow-up reflecting varying levels of free testosterone suppression. By design, the below median free testosterone group (“complete testosterone suppression group”) had significantly lower free testosterone concentrations compared to the above median free testosterone group (“incomplete free testosterone suppression group”) (1.2 [0.7, 1.4] vs 3.2 [2.3, 33.4] ng/dL, P = .0002). Estradiol concentrations did not differ between groups (complete testosterone suppression vs incomplete testosterone suppression: 159 [117, 339] vs 191 [145, 265] pg/mL, P = .88). Duration of GAHT at follow-up also did not differ between groups (complete testosterone suppression vs incomplete testosterone suppression: 15.1 ± 2.2 vs 15.2 ± 2.7 months, P = .89). Intrahepatic triglycerides decreased to a greater extent in the incomplete testosterone suppression group (median change: −0.8 [−3.7, −0.2]%) compared to the complete testosterone suppression group (median change: −0.1 [−0.3, 0.2]%; P = .03 for difference in change in intrahepatic triglycerides between testosterone suppression groups). Furthermore, change in HOMA-IR and change in the Matsuda Index, respectively, did not relate to the change in intrahepatic triglycerides content (data not shown).

Table 4.

Regression modeling for change in intrahepatic triglycerides

Whole model R² = 0.77, P = .0001
Covariate	β-estimate	β-SE	P
BMI at follow-up	.17	.16	.31
WHR at follow-up	−9.8	10.8	.38
Free testosterone at follow-up	−.09	.01	<.0001
Estradiol at follow-up	.0004	.002	.88

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In least squares regression modeling with BMI, WHR, free testosterone, and estradiol at follow-up as independent variables, free testosterone remained an independent predictor of the change in intrahepatic triglycerides. P < .05 value was considered statistically significant and is bolded.

Abbreviations: BMI, body mass index; β-SE, beta standard error; WHR, waist-to-hip ratio.

Sensitivity analyses for progesterone use and timing of GAHT initiation

In our sensitivity analyses comparing differences in primary and secondary outcomes based on progesterone use, the median change in HOMA-IR differed based on progesterone use, with progesterone users having a positive median change as compared to a negative median change among progesterone nonusers (progesterone users vs progesterone nonusers: 0.6 [−0.3, 0.9] vs −3.9 [−0.6, −0.1], P = .02). Furthermore, the median change in the Matsuda Index also differed based on progesterone use, with progesterone users having a negative median change vs a positive median change among progesterone nonusers (progesterone users vs progesterone nonusers: −0.4 [−3.4, 2.0] vs 2.4 [−0.3, 7.3], P = .0487). Furthermore, there was also a trend toward a difference in the mean change in total cholesterol among progesterone users vs progesterone nonusers, with progesterone users having a positive mean change and progesterone nonusers having a negative mean change (P = .0968). Other primary and secondary outcomes did not differ between progesterone users vs progesterone nonusers (data not shown).

In our sensitivity analyses comparing differences in primary and secondary outcomes at baseline among participants who initiated GAHT prior to enrollment vs those who initiated GAHT after enrollment, systemic HDL-C levels were lower among participants who initiated GAHT after enrollment (GAHT after enrollment vs GAHT prior to enrollment: 42 ± 5 vs 51 ± 12 ng/mL, P = .04). Furthermore, participants who initiated GAHT after enrollment had higher total fat mass/height² compared to those who initiated GAHT prior to enrollment (GAHT after enrollment vs GAHT prior to enrollment: 10.67 [7.77, 14.15] vs 5.95 [4.41, 8.10], P = .04). Additionally, baseline total fat mass, total body fat, total lean body mass, lean body mass/height², appendicular lean body mass/height², and intrahepatic triglycerides tended to be higher among participants who initiated GAHT after enrollment vs those who initiated GAHT prior to enrollment (data not shown).

Discussion

In this study of TGD individuals either newly or recently initiated on gender-affirming estradiol therapy together with anti-androgen therapy, we observed no change in our primary outcome of change in visceral adipose tissue over the course of 12 months of GAHT as well as several secondary endpoints (insulin sensitivity, total cholesterol, HDL-C, and low-density lipoprotein cholesterol). We did, however, observe significant changes in select cardiometabolic secondary endpoints. Although some changes have the potential to adversely affect the health of TGD individuals (unfavorable body composition changes such as a decrease in total and appendicular lean body mass and systemic triglycerides), we also demonstrate changes that could potentially positively impact the health of this population (decrease in intrahepatic fat and increase in bone density). Retrospective studies demonstrating heightened cardiometabolic disease (2-5) and cardiovascular disease-attributable mortality (1) among transgender women on GAHT emphasize the need for prospective studies, such as ours, with the aim of ultimately optimizing the cardiometabolic health of individuals receiving GAHT. Our results highlight the complex biology of GAHT with estradiol and anti-androgen therapy and underscore the need for adjunctive measures to preserve lean body mass and, in turn, mitigate progression to sarcopenia, with this form of GAHT.

Although regimens of GAHT among transgender women may differ globally, they often include an anti-androgen therapy combined with estradiol therapy. Of relevance to body composition, estrogen and testosterone balance influences fat and lean body mass (8, 9, 25, 26). Studies using earlier GAHT regimens, which included ethinyl estradiol, demonstrated increases in VAT among transgender women after GAHT (27, 28). Studies using contemporary GAHT regimens containing 17β-estradiol, in contrast, have demonstrated either a reduction (29, 30) or no change in VAT (31, 32), analogous to the current study. Furthermore, the majority of participants in these other studies (29-32) included anti-androgen therapies that differed from our study participants, who largely were on spironolactone for their anti-androgen therapy. Despite these differences in anti-androgen therapy, however, study participants across these studies similarly had either a reduction or no change in VAT. Together, our results and those of other recent studies highlight the need to assess the metabolic effects of contemporary regimens as their effects differ from those previously studied.

Differences in study findings on estrogen-dominant GAHT effects on bone health also highlight that there can be regimen-specific metabolic effects. Studies that have demonstrated decreased bone density after estrogen-dominant GAHT initiation, for example, included regimens where androgen suppression initiation preceded (in certain studies for 1 year) the initiation of estrogen therapy (33, 34). Our findings of increased bone density with estrogen-dominant GAHT, in turn, are in line with other studies (32, 35) that included concomitant initiation of estrogen with androgen suppression and underscores a potential beneficial effect of estrogen-dominant GAHT. Additional research is needed to determine whether or not the improvements in bone density with certain estrogen-dominant GAHT regimens ultimately affects fracture risk in this population.

With respect to lean body mass, we demonstrated that ALM/height² (a DEXA-derived measure, with lower values predicting sarcopenia (24)), decreased after 12 months of GAHT in our relatively young cohort of participants. Sarcopenia is a condition characterized by the loss of muscular mass, strength, and function (24, 36) and is associated with increased mortality and adverse health outcomes (37-42). Although none of our participants had a final ALM/height² that was below the normative cutoff for cisgender women (ALM/height² of 5.5 kg/m²), 7 participants (27%) had a final ALM/height² that was lower than the normative cutoff for cisgender men (ALM/height² of 7.0 kg/m²) (24). Because this study was limited to 12 months of follow-up time, it is unclear if the reduction in ALM/height² progresses with longitudinal GAHT or if additional participants may also experience these adverse body composition changes with continued therapy. These results nonetheless highlight the need for early recognition of the changes in body composition after initiation of GAHT because they provide potential avenues to intervene and abrogate untoward downstream health effects.

In addition to effects on fat and lean body mass, estrogen and testosterone balance also significantly impacts ectopic fat deposition (10, 18). In line with our findings, Tebbens et al previously demonstrated a reduction in intrahepatic triglycerides among a smaller cohort of individuals receiving estrogen-dominant GAHT for 1 year with anti-androgen therapy achieved by either a GnRH analog or the cyproterone acetate, an anti-androgenic progesterone (43). In another European cohort, Sluková et al, in turn, found a nonsignificant reduction in intrahepatic triglycerides after 6 months of a GAHT regimen containing cyproterone acetate as the form of anti-androgen therapy. The latter study's shorter duration of follow-up after GAHT may have contributed to their findings not reaching statistical significance (30). Together, although our study differed in the forms of anti-androgen therapy used compared to prior European studies, we also demonstrated a reduction in intrahepatic triglycerides, highlighting a potential beneficial effect of estrogen-dominant GAHT on ectopic fat deposition spanning different hormone therapy regimens.

In our study, free testosterone at follow-up remained an independent predictor of the change in intrahepatic triglycerides after adjusting for estradiol, BMI, and WHR at follow-up. Data from preclinical rodent models provide mechanistic insights into our observation that higher free testosterone concentrations were associated with a greater reduction in intrahepatic triglycerides. In male liver-targeted androgen receptor knockout mice, intrahepatic triglyceride accumulation occurred despite normal circulating testosterone concentrations. Mechanistically, this rodent model was associated with an upregulation of lipogenic genes and reduced β-oxidation implicating androgen receptor activation in lipid homeostasis (44, 45). Rodent models have also demonstrated the important role of estrogen signaling in intrahepatic lipid metabolism. Hart-Unger et al found that intrahepatic triglyceride accumulation significantly increased in global ERα knockout male and female mice, whereas liver-specific ERα knockout mice did not exhibit increased intrahepatic triglyceride accumulation (46, 47). This discrepancy suggests that the protective effects of estrogen signaling may not be mediated solely by the hepatic ERα, but rather through broader systemic metabolic pathways influenced by estrogen signaling or interactions with other hepatic receptors, such as androgen receptors (46). Together, the evidence from preclinical studies highlight a dynamic interplay between androgen and estrogen signaling in hepatic lipid regulation, providing a mechanistic framework for interpreting population-based patterns.

Although direct evidence remains limited, particularly regarding testosterone's role in hepatic lipid metabolism among cisgender women, population-based studies highlight the differing effects of testosterone's influence on intrahepatic triglyceride accumulation in cisgender men and cisgender women, respectively. In a large retrospective cohort study, androgen deprivation therapy in cisgender men was associated with dose-dependent increases in metabolic dysfunction-associated steatotic liver disease (48). Albhaisi et al, on the other hand, reported that 16 weeks of treatment with an oral testosterone prodrug in testosterone-deficient cisgender men led to reductions in hepatic fat independent of BMI (49). Conversely, in cisgender women with polycystic ovary syndrome, elevated total testosterone has been identified as an independent risk factor for intrahepatic triglyceride accumulation and associated metabolic dysfunction-associated steatotic liver disease (50, 51). Together, studies among cisgender populations suggest that intrahepatic triglyceride deposition is highly influenced by the hormonal milieu, with testosterone deficiency being associated with intrahepatic triglyceride accumulation in cisgender men and testosterone excess being associated with intrahepatic triglyceride accumulation in cisgender women with polycystic ovary syndrome.

In the context of GAHT, our exploratory stratified analysis suggests that incomplete free testosterone suppression yielded greater reductions in intrahepatic triglycerides than those with complete suppression, despite similar estradiol concentrations and duration of GAHT. This finding adds nuance to our understanding of testosterone's role in intrahepatic triglyceride metabolism by suggesting that moderate residual free testosterone concentrations, when coupled with estradiol therapy, may have protective hepatic effects in TGD individuals. In contrast to our findings, Nelson et al found that transgender women on GAHT and an orchiectomy had lower levels of intrahepatic triglycerides compared to transgender women without a history of orchiectomy and on anti-androgen therapy, suggesting a protective effect of orchiectomy (52). Notably, in this prior study, the transgender women with a history of orchiectomy had higher estradiol concentrations and lower testosterone concentrations compared to the group without a history of orchiectomy. As such, differences in estradiol concentrations, in addition to differences in testosterone concentrations, could have contributed to the between-group difference in intrahepatic triglycerides observed. Furthermore, an important distinction between this study and our study is that this prior study examined participants that were longitudinally on GAHT rather than newly on or about to start GAHT. Together, the differences in our study results highlight the complexity of the metabolic effects of GAHT. It also underscores the need for further research into hormone-specific mechanisms of ectopic fat deposition to optimize GAHT regimens and reduce long-term metabolic risk.

Additionally, our exploratory analyses on differences in outcomes based on progesterone use suggested that progesterone use may be associated with adverse effects on insulin sensitivity. Overall, the adverse effects of progesterone use among TGD individuals on estrogen-dominant GAHT are not as well studied as the effects of estradiol and anti-androgen therapy. Studies among cisgender individuals suggest that both endogenous (53, 54) and exogenous (55, 56) progesterone can adversely affect insulin sensitivity. Together, the results of our analyses warrants further investigation to establish whether the addition of progesterone among TGD individuals on estrogen-dominant GAHT may have adverse metabolic effects, such as worsening insulin sensitivity.

Our study was limited by the relatively small sample size. Although all study visits occurred at Massachusetts General Hospital, our study population was recruited from multiple geographic regions spanning across the United States. Our study included gender-diverse participants who were initiated on both estradiol and anti-androgen therapy, which may not necessarily be standard clinical practice. Further, formulations of estradiol differed across study participants; and estradiol doses were adjusted clinically for participants. Thus, even if participants were on the same estradiol formulation, doses may have differed across participants. The majority of our study participants received variable doses of spironolactone for their anti-androgen therapy, limiting the generalizability of our results to other regimens, while still enhancing the generalizability on a population level, given that spironolactone is the most commonly prescribed form of anti-androgen therapy in the United States (57). Additionally, 54% of participants were on progesterone; and progesterone use could have affected our primary and secondary outcomes, as suggested by our exploratory analyses. Although 30 study participants completed their 6-month check-in, 4 of those participants did not complete final 12-month study procedures, thereby reducing the sample size for our primary and secondary outcomes. Furthermore, while the majority of our study participants had newly initiated GAHT at the time of their baseline assessment, we were still able to enroll participants within a few months of initiation. As this would be expected to bias our results toward the null, it is notable that we were still able to demonstrate significant changes in key cardiometabolic parameters in addition to significant changes in estradiol and testosterone concentrations during our 12-month study period.

Investigators from several health care systems have demonstrated that GAHT is typically continued longitudinally beyond the 12 months we observed in our study cohort (58-60). Furthermore, the increased risk of adverse outcomes with GAHT is not solely limited to the first few years of GAHT but can extend several years beyond GAHT initiation (2). As such, our study findings within the context of a growing global population receiving GAHT (61) underscores the need for larger prospective studies examining the cardiometabolic effects of GAHT longitudinally. Moreover, our results suggest the potential need for adjunctive interventions (exercise, dietary, and/or pharmacological) to be initiated in concert with GAHT to optimize the metabolic health of TGD individuals. Finally, the results also highlight that minor adjustments in how we prescribe GAHT (ie, slightly less testosterone suppression, which still ultimately results in low systemic testosterone concentrations) may potentially impact the cardiometabolic health of our patients.

Acknowledgments

The authors thank the participants of this study and the Massachusetts General Hospital (MGH) Translational and Clinical Research Center. They also thank Jacob Calkins, Alexander Robertson, and Lynelle Ferreira of the MGH Martinos Imaging Center.

Abbreviations

2D-PACE: 2-dimensional prospective acquisition correction
ALM: appendicular lean body mass
BMI: body mass index
DEXA: dual-energy X-ray absorptiometry
GAHT: gender-affirming hormone therapy
HDL-C: high-density lipoprotein cholesterol
HOMA-IR: Homeostatic Model Assessment of Insulin Resistance
IQR: interquartile range
MRS: magnetic resonance spectroscopy
TGD: transgender women and gender-diverse individuals
VAT: visceral adipose tissue
WHR: waist-to-hip ratio

Contributor Information

Ria Talathi, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Vencel Juhasz, Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Heart and Vascular Center, Semmelweis University, Budapest 1122, Hungary.

Matilda Delgado, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Thiago Quinaglia, Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Azin Ghamari, Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Melissa Wang, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Iad Alhallak, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Sarah Stinebaugh, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Sophia Campbell, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Sara L Stockman, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Mustafa A Ozturk, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Sadia M Ahmadi, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA.

Sara E Looby, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Hang Lee, Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Tonia C Poteat, Division of Healthcare in Adult Populations, Duke University School of Nursing, Durham, NC 27710, USA.

Lidia S Szczepaniak, MRS Consulting in Biomedical Research, Albuquerque, NM 87112, USA.

Markella V Zanni, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Tomas G Neilan, Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Mabel Toribio, Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; MGH Transgender Health Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.

Funding

This study was funded through grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI) [1K23HL147799-01] and the American Heart Association-Harold Amos Medical Research Faculty Development Program by the Robert Wood Johnson Foundation.

Disclosures

R.T., V.J., M.D., T.Q., A.G., M.W., I.A., S.S., S.C., S.L.S., M.A.O., S.M.A., S.E.L., T.P., L.S.S., and M.T. have nothing to disclose. H.L. is on the Statistical Reviewer Board for the Journal of Clinical Endocrinology & Metabolism and played no role in the Journal's evaluation of the manuscript. M.V.Z. is principal investigator of grant funding from Gilead to her institution. T.G.N. reports the receipt of grant funding from BMS and Abbott and consulting fees from BMS, Pfizer, Sanofi, Roche, and Genentech. All disclosures are unrelated to the current work.

Data availability

Some or all datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request and after approval of the Massachusetts General Brigham Institutional Review Board.

Clinical Trial Information

NCT registration: NCT04128488

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32. Yun Y, Kim D, Lee ES. Effect of cross-sex hormones on body composition, bone mineral density, and muscle strength in trans women. J Bone Metab. 2021;28(1):59‐66. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Wierckx K, Mueller S, Weyers S, et al. Long-term evaluation of cross-sex hormone treatment in transsexual persons. J Sex Med. 2012;9(10):2641‐2651. [DOI] [PubMed] [Google Scholar]
34. Lapauw B, Taes Y, Simoens S, et al. Body composition, volumetric and areal bone parameters in male-to-female transsexual persons. Bone. 2008;43(6):1016‐1021. [DOI] [PubMed] [Google Scholar]
35. Van Caenegem E, Wierckx K, Taes Y, et al. Preservation of volumetric bone density and geometry in trans women during cross-sex hormonal therapy: a prospective observational study. Osteoporos Int. 2015;26(1):35‐47. [DOI] [PubMed] [Google Scholar]
36. Cruz-Jentoft AJ, Sayer AA. Sarcopenia. Lancet. 2019;393(10191):2636‐2646. [DOI] [PubMed] [Google Scholar]
37. Beaudart C, Zaaria M, Pasleau F, Reginster JY, Bruyere O. Health outcomes of sarcopenia: a systematic review and meta-analysis. PLoS One. 2017;12(1):e0169548. [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Yuan S, Larsson SC. Epidemiology of sarcopenia: prevalence, risk factors, and consequences. Metabolism. 2023;144:155533. [DOI] [PubMed] [Google Scholar]
39. Lee SJ, Park YJ, Cartmell KB. Sarcopenia in cancer survivors is associated with increased cardiovascular disease risk. Support Care Cancer. 2018;26(7):2313‐2321. [DOI] [PubMed] [Google Scholar]
40. Foley RN, Wang C, Ishani A, Collins AJ, Murray AM. Kidney function and sarcopenia in the United States general population: NHANES III. Am J Nephrol. 2007;27(3):279‐286. [DOI] [PubMed] [Google Scholar]
41. Lee YH, Kim SU, Song K, et al. Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: Nationwide surveys (KNHANES 2008-2011). Hepatology. 2016;63(3):776‐786. [DOI] [PubMed] [Google Scholar]
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43. Tebbens M, Schutte M, Troelstra MA, et al. Sex steroids regulate liver fat content and body fat distribution in both men and women: a study in transgender persons. J Clin Endocrinol Metab. 2023;109(1):e280‐e290. [DOI] [PMC free article] [PubMed] [Google Scholar]
44. Lin HY, Yu IC, Wang RS, et al. Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor. Hepatology. 2008;47(6):1924‐1935. [DOI] [PubMed] [Google Scholar]
45. Palmer CN, Hsu MH, Griffin KJ, Raucy JL, Johnson EF. Peroxisome proliferator activated receptor-alpha expression in human liver. Mol Pharmacol. 1998;53(1):14‐22. [PubMed] [Google Scholar]
46. Hart-Unger S, Arao Y, Hamilton KJ, et al. Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice. Int J Obes. 2017;41(6):945‐954. [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Zhu L, Martinez MN, Emfinger CH, Palmisano BT, Stafford JM. Estrogen signaling prevents diet-induced hepatic insulin resistance in male mice with obesity. Am J Physiol Endocrinol Metab. 2014;306(10):E1188‐E1197. [DOI] [PMC free article] [PubMed] [Google Scholar]
48. Gild P, Cole AP, Krasnova A, et al. Liver disease in men undergoing androgen deprivation therapy for prostate cancer. J Urol. 2018;200(3):573‐581. [DOI] [PubMed] [Google Scholar]
49. Albhaisi S, Kim K, Baker J, et al. LPCN 1144 resolves NAFLD in hypogonadal males. Hepatol Commun. 2020;4(10):1430‐1440. [DOI] [PMC free article] [PubMed] [Google Scholar]
50. Mahmoud M, Kawtharany H, Awali M, Mahmoud N, Mohamed I, Syn WK. The effects of testosterone replacement therapy in adult men with metabolic dysfunction-associated steatotic liver disease: a systematic review and meta-analysis. Clin Transl Gastroenterol. 2025;16(1):e00787. [DOI] [PMC free article] [PubMed] [Google Scholar]
51. Falzarano C, Lofton T, Osei-Ntansah A, et al. Nonalcoholic fatty liver disease in women and girls with polycystic ovary syndrome. J Clin Endocrinol Metab. 2022;107(1):258‐272. [DOI] [PubMed] [Google Scholar]
52. Nelson MD, Szczepaniak LS, Wei J, et al. Transwomen and the metabolic syndrome: is orchiectomy protective? Transgend Health. 2016;1(1):165‐171. [DOI] [PMC free article] [PubMed] [Google Scholar]
53. Yeung EH, Zhang C, Mumford SL, et al. Longitudinal study of insulin resistance and sex hormones over the menstrual cycle: the BioCycle study. J Clin Endocrinol Metab. 2010;95(12):5435‐5442. [DOI] [PMC free article] [PubMed] [Google Scholar]
54. Greenhill C. Progesterone in pregnancy. Nat Rev Endocrinol. 2025;21(6):328. [DOI] [PubMed] [Google Scholar]
55. Shadoan MK, Kavanagh K, Zhang L, Anthony MS, Wagner JD. Addition of medroxyprogesterone acetate to conjugated equine estrogens results in insulin resistance in adipose tissue. Metabolism. 2007;56(6):830‐837. [DOI] [PubMed] [Google Scholar]
56. Kahn HS, Curtis KM, Marchbanks PA. Effects of injectable or implantable progestin-only contraceptives on insulin-glucose metabolism and diabetes risk. Diabetes Care. 2003;26(1):216‐225. [DOI] [PubMed] [Google Scholar]
57. UCSF Gender Affirming Health Program DoFaCM; University of California San Francisco . Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People. 2nd ed. Deutsch MB, ed. 2016. Available at transcare.ucsf.edu/guidelines. [Google Scholar]
58. Roberts CM, Klein DA, Adirim TA, Schvey NA, Hisle-Gorman E. Continuation of gender-affirming hormones among transgender adolescents and adults. J Clin Endocrinol Metab. 2022;107(9):e3937‐e3943. [DOI] [PubMed] [Google Scholar]
59. van der Loos M, Hannema SE, Klink DT, den Heijer M, Wiepjes CM. Continuation of gender-affirming hormones in transgender people starting puberty suppression in adolescence: a cohort study in The Netherlands. Lancet Child Adolesc Health. 2022;6(12):869‐875. [DOI] [PubMed] [Google Scholar]
60. Gupta P, Cunha LM, Diego D, Tangpricha V. Continuation of gender-affirming hormone therapy in transgender and gender-diverse individuals: a systematic review. Endocr Pract. 2024;30(12):1206‐1211. [DOI] [PubMed] [Google Scholar]
61. Das RK, Dusetzina SB. Gender-affirming hormone therapy spending and use in the USA, 2013-2019. J Gen Intern Med. 2023;38(1):260‐262. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

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[dgaf665-B35] 35. Van Caenegem E, Wierckx K, Taes Y, et al. Preservation of volumetric bone density and geometry in trans women during cross-sex hormonal therapy: a prospective observational study. Osteoporos Int. 2015;26(1):35‐47. [DOI] [PubMed] [Google Scholar]

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[dgaf665-B40] 40. Foley RN, Wang C, Ishani A, Collins AJ, Murray AM. Kidney function and sarcopenia in the United States general population: NHANES III. Am J Nephrol. 2007;27(3):279‐286. [DOI] [PubMed] [Google Scholar]

[dgaf665-B41] 41. Lee YH, Kim SU, Song K, et al. Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: Nationwide surveys (KNHANES 2008-2011). Hepatology. 2016;63(3):776‐786. [DOI] [PubMed] [Google Scholar]

[dgaf665-B42] 42. Du Y, Oh C, No J. Associations between sarcopenia and metabolic risk factors: a systematic review and meta-analysis. J Obes Metab Syndr. 2018;27(3):175‐185. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dgaf665-B43] 43. Tebbens M, Schutte M, Troelstra MA, et al. Sex steroids regulate liver fat content and body fat distribution in both men and women: a study in transgender persons. J Clin Endocrinol Metab. 2023;109(1):e280‐e290. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dgaf665-B44] 44. Lin HY, Yu IC, Wang RS, et al. Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor. Hepatology. 2008;47(6):1924‐1935. [DOI] [PubMed] [Google Scholar]

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[dgaf665-B46] 46. Hart-Unger S, Arao Y, Hamilton KJ, et al. Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice. Int J Obes. 2017;41(6):945‐954. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dgaf665-B47] 47. Zhu L, Martinez MN, Emfinger CH, Palmisano BT, Stafford JM. Estrogen signaling prevents diet-induced hepatic insulin resistance in male mice with obesity. Am J Physiol Endocrinol Metab. 2014;306(10):E1188‐E1197. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dgaf665-B48] 48. Gild P, Cole AP, Krasnova A, et al. Liver disease in men undergoing androgen deprivation therapy for prostate cancer. J Urol. 2018;200(3):573‐581. [DOI] [PubMed] [Google Scholar]

[dgaf665-B49] 49. Albhaisi S, Kim K, Baker J, et al. LPCN 1144 resolves NAFLD in hypogonadal males. Hepatol Commun. 2020;4(10):1430‐1440. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dgaf665-B50] 50. Mahmoud M, Kawtharany H, Awali M, Mahmoud N, Mohamed I, Syn WK. The effects of testosterone replacement therapy in adult men with metabolic dysfunction-associated steatotic liver disease: a systematic review and meta-analysis. Clin Transl Gastroenterol. 2025;16(1):e00787. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dgaf665-B51] 51. Falzarano C, Lofton T, Osei-Ntansah A, et al. Nonalcoholic fatty liver disease in women and girls with polycystic ovary syndrome. J Clin Endocrinol Metab. 2022;107(1):258‐272. [DOI] [PubMed] [Google Scholar]

[dgaf665-B52] 52. Nelson MD, Szczepaniak LS, Wei J, et al. Transwomen and the metabolic syndrome: is orchiectomy protective? Transgend Health. 2016;1(1):165‐171. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dgaf665-B53] 53. Yeung EH, Zhang C, Mumford SL, et al. Longitudinal study of insulin resistance and sex hormones over the menstrual cycle: the BioCycle study. J Clin Endocrinol Metab. 2010;95(12):5435‐5442. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dgaf665-B54] 54. Greenhill C. Progesterone in pregnancy. Nat Rev Endocrinol. 2025;21(6):328. [DOI] [PubMed] [Google Scholar]

[dgaf665-B55] 55. Shadoan MK, Kavanagh K, Zhang L, Anthony MS, Wagner JD. Addition of medroxyprogesterone acetate to conjugated equine estrogens results in insulin resistance in adipose tissue. Metabolism. 2007;56(6):830‐837. [DOI] [PubMed] [Google Scholar]

[dgaf665-B56] 56. Kahn HS, Curtis KM, Marchbanks PA. Effects of injectable or implantable progestin-only contraceptives on insulin-glucose metabolism and diabetes risk. Diabetes Care. 2003;26(1):216‐225. [DOI] [PubMed] [Google Scholar]

[dgaf665-B57] 57. UCSF Gender Affirming Health Program DoFaCM; University of California San Francisco . Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People. 2nd ed. Deutsch MB, ed. 2016. Available at transcare.ucsf.edu/guidelines. [Google Scholar]

[dgaf665-B58] 58. Roberts CM, Klein DA, Adirim TA, Schvey NA, Hisle-Gorman E. Continuation of gender-affirming hormones among transgender adolescents and adults. J Clin Endocrinol Metab. 2022;107(9):e3937‐e3943. [DOI] [PubMed] [Google Scholar]

[dgaf665-B59] 59. van der Loos M, Hannema SE, Klink DT, den Heijer M, Wiepjes CM. Continuation of gender-affirming hormones in transgender people starting puberty suppression in adolescence: a cohort study in The Netherlands. Lancet Child Adolesc Health. 2022;6(12):869‐875. [DOI] [PubMed] [Google Scholar]

[dgaf665-B60] 60. Gupta P, Cunha LM, Diego D, Tangpricha V. Continuation of gender-affirming hormone therapy in transgender and gender-diverse individuals: a systematic review. Endocr Pract. 2024;30(12):1206‐1211. [DOI] [PubMed] [Google Scholar]

[dgaf665-B61] 61. Das RK, Dusetzina SB. Gender-affirming hormone therapy spending and use in the USA, 2013-2019. J Gen Intern Med. 2023;38(1):260‐262. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Visceral adipose tissue and liver fat on 17-beta estradiol-dominant gender-affirming hormone therapy: A US-based cohort

Ria Talathi

Vencel Juhasz

Matilda Delgado

Thiago Quinaglia

Azin Ghamari

Melissa Wang

Iad Alhallak

Sarah Stinebaugh

Sophia Campbell

Sara L Stockman

Mustafa A Ozturk

Sadia M Ahmadi

Sara E Looby

Hang Lee

Tonia C Poteat

Lidia S Szczepaniak

Markella V Zanni

Tomas G Neilan

Mabel Toribio

Abstract

Context

Objective

Design

Setting

Participants

Intervention(s)

Main Outcome Measure(s)

Results

Conclusion

Material and methods

Study design and participants

Figure 1.

Study procedures

Clinical assessments

Oral glucose tolerance testing

Whole body, lumbar, and total hip dual-energy X-ray absorptiometry

Hepatic magnetic resonance spectroscopy

Figure 2.

Laboratory assessments

Statistical analysis

Results

Participant characteristics

Table 1.

Table 2.

Changes in hormone concentrations, insulin sensitivity, and systemic cholesterol levels

Table 3.

Changes in lumbar and hip bone density

Changes in body composition

Figure 3.

Changes in intrahepatic triglyceride content

Table 4.

Sensitivity analyses for progesterone use and timing of GAHT initiation

Discussion

Acknowledgments

Abbreviations

Contributor Information

Funding

Disclosures

Data availability

Clinical Trial Information

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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