
==== Front
JACC Adv
JACC Adv
JACC: Advances
2772-963X
Elsevier

S2772-963X(24)00496-4
10.1016/j.jacadv.2024.101265
101265
Original Research
Impact of Gender-Affirming Hormonal Therapy on Cardiovascular Risk Factors in Transgender Health
An Updated Meta-Analysis
Rahman Saad Ur MD a
Manasrah Nouraldeen MD b
Kumar Nomesh MD c
Hamza Mohammad MD d
Sharma Aakanksha MD e
Patel Neel MD f
Patel Bansari MD g
Naseem Masooma MBBS h
Razzaq Saman MD i
Gill Seemab Imtiaz MD j
Naveed Hamza MD k
Harmouch Khaled M. MD l
Bahar Yasemin MD m
Aamir Muhammad MD n
Sattar Yasar MD o
Alraies M. Chadi MD alraies@hotmail.com
p∗
a Division of Cardiovascular Medicine, Lahey Hospital and Medical Center, Burlington, Massachusetts, USA
b Division of Cardiovascular Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
c Department of Internal Medicine, Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan, USA
d Department of Internal Medicine, Guthrie Medical Group, New York, USA
e Department of Cardiovascular Medicine, Yale University School of Medicine New Haven, Connecticut, USA
f Department of Internal Medicine, New York Medical College/Landmark Medical Center, Woonsocket, Rhode Island, USA
g Department of Internal Medicine, West Virginia University, Morgantown, West Virginia, USA
h Ziauddin Medical College, Ziauddin University, Karachi, Pakistan
i Department of Internal Medicine, Wayne State University/Detroit Medical Center, Detroit, Michigan, USA
j Department of Internal Medicine, Carle Foundation Hospital/Carle Health, Urbana, Illinois, USA
k HCA Houston Kingwood/University of Houston, Texas, USA
l Department of Internal Medicine, Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan, USA
m Wayne State University, Detroit, Michigan, USA
n Division of Cardiovascular Medicine, Lehigh Valley Health Network, Pennsylvania, USA
o Department of Cardiology, West Virginia University, Morgantown, West Virginia, USA
p Cardiovascular Institute, Detroit Medical Center, DMC Heart Hospital, Detroit, Michigan, USA
∗ Address for correspondence: Dr M. Chadi Alraies, Cardiovascular Institute, DMC Heart Hospital, Detroit Medical Center, 311 Mack Avenue, Detroit, Michigan 48201, USA. alraies@hotmail.com
09 9 2024
10 2024
09 9 2024
3 10 10126521 2 2024
13 8 2024
15 8 2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Gender-affirming hormone therapy (GAHT) is common among transgender individuals, but its impact on lipid profile and cardiovascular health is not well studied.

Objectives

The authors performed a systematic review and meta-analysis of existing literature to assess the impact of GAHT on lipid profiles and metabolic cardiovascular risk factors in transgender individuals.

Methods

Online databases including MEDLINE/PubMed, Embase, and Cochrane Central registry were searched to find studies on lipid profile changes in women who are transgender, also referred to as transfeminine (TF), and men who are transgender, also referred to as transmasculine (TM) before and after GAHT. Baseline comorbidities were analyzed using descriptive statistics, and R-statistical software was used to analyze the mean difference in lipid profile change between the two cohorts (pre- and post-GAHT therapy) including transgender patients.

Results

Overall, 1,241 TM and 992 TF patients were included from 12 observational studies and 12 randomized controlled trials. The mean age among TM and TF was 28 years and 30 years, respectively. The mean follow-up duration (including pre- and post-GAHT therapy) was 28 months in TM patients and 39 months in TF patients. When compared to baseline measures, TM patients had a significant increase in low-density lipoprotein, triglyceride levels, and total cholesterol while high-density lipoprotein levels decreased. In TF patients, there was a significant increase in triglyceride levels.

Conclusions

GAHT affects lipid profiles in transgender patients; however, additional studies are needed to determine how these changes impact clinical outcomes.

Central Illustration

Key words

dyslipidemia
hyperlipidemia
gender-affirming hormonal therapy GAHT
lipid profile
trans feminine TF
trans masculine TM
Abbreviations and Acronyms

BMI body mass index

CVD cardiovascular disease

DBP diastolic blood pressure

GAHT gender-affirming hormone therapy

HDL high-density lipoprotein

IM intramuscular

LDL low-density lipoprotein

ROB Risk of Bias

SBP systolic blood pressure

SMD standard mean difference

SQ subcutaneous

TC total cholesterol

TF transfeminine

TG triglyceride

TM transmasculine

VTE venous thromboembolism
==== Body
pmcTransgender is a broad term encompassing individuals whose gender identity differs from the one assigned to them at birth.1 Transgender individuals often go through gender-affirming hormone therapy (GAHT) or surgeries to achieve their desired sex appearance. Transgender men, also referred to as transmasculine (TM) use testosterone to obtain masculine features, while transgender women, also referred to as transfeminine (TF) utilize estrogen and antiandrogen hormones like spironolactone for feminization.2

The use and effects of GAHT have significantly been studied in premenopausal and postmenopausal women and males with hypogonadism. Supplementing androgen to hypogonadal males has been suggested to increase body muscle mass with positive effects on lipid and glycemic profiles or negative outcomes as reported by the World Health Organization controlled trial on the use of combined contraceptive pills that increase the risk of the cardiovascular and thrombotic incident.3, 4, 5 However, there are limited data regarding long-term clinical safety and outcome of hormonal therapy in transgender individuals.

Several studies on GAHT in healthy individuals suggest that estrogen and testosterone may elevate the risk of metabolic syndrome by inducing insulin resistance, dyslipidemia, and increased abdominal fat deposition, which leads to an increased risk of cardiovascular diseases (CVDs).6, 7, 8 However, conflicting conclusions arise from other studies indicating the short-term safety of GAHT for transgender individuals.9 The long-term cardiovascular safety of GAHT remains uncertain, primarily due to the current evidence relying heavily on expert opinion and retrospective case series, utilizing varied GAHT regimens, including older protocols, and occasionally lacking guidelines-based proactive risk management.

Therefore, we conducted a systematic review and meta-analysis of currently available literature to evaluate the influence of GAHT on the lipid profile and metabolic CVD risk factors that can impact cardiovascular outcomes in transgender individuals.

Methods

This systematic review was conducted by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The study eligibility criteria included populations that are either: 1) TF or TM individuals; 2) transgender individuals on GAHT; 3) age >12 years; 4) baseline reporting on metabolic and lipid profiles; and 5) outcomes reporting on changes in metabolic and lipid profiles before and after GAHT use. The exclusion criteria were age <12 years, no reporting of lipid profile or desired outcome, and patient pool not including TF or TM individuals.

A literature search was conducted on Medline/PubMed, Embase, and Cochrane for trials or observational studies with the abovementioned inclusion criteria using a systematic search strategy by PRISMA from inception until January 2023. Search terms employed using Boolean Operators “OR” and “AND” among and between 2 subsets of keywords as “Transgender persons,” “transsexual persons” AND “sex hormones” OR “hyperlipidemias” OR “metabolome.”

Study selection

All available clinical trials or observational studies were evaluated. Two authors (S.R. and M.H.) independently reviewed the search results for studies that met the eligibility criteria. Any uncertainty regarding study selection was resolved with consensus with a third author (Y.S.).

In the first phase, titles and abstracts were screened and studies fulfilling the inclusion were selected for the second phase. In the second phase, we went through the full texts of the selected studies and further narrowed down our selection based on whether the studies reported items for data extraction.

Primary and secondary outcomes

The primary outcome of the study was the lipid profile of the TF and TM patients including triglyceride (TG) levels, total cholesterol (TC) levels, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Secondary outcomes included other factors that could have impacted CV outcomes including body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP).

Comparison of outcomes

We compared the change in the variables mentioned above from their baseline levels before the initiation of GAHT to their levels after the application of GAHT.

Data collection and statistical analysis

Statistical analysis was performed using the CRAN-R software. Data from each study included after the secondary screening were extracted in a Microsoft Excel sheet. Data elements collected were the number of TF and TM individuals, androgen or estrogen use, and mean age. Other characteristics collected were TG, TC levels, LDL, HDL, BMI, SBP, and DBP before and after GAHT.

A meta-cont module was used along with the inverse variance random effects model to calculate the pooled standard mean difference (SMD) with a probability value of P < 0.05 considered to be statistically significant. The “test for overall effect” was reported as a z-value corroborating the 95% CI's inference. Higgins I-squared (I2) was determined as a measure of statistical heterogeneity where values of ≤50% corresponded to low to moderate heterogeneity while values ≥75% indicated high heterogeneity.10 For heterogeneity of more than 50%, we conducted a leave-one-out analysis to assess for studies contributing the most to heterogeneity using the meta-inf module in CRAN-R software. We also conducted a subgroup analysis based on follow-up duration. Four subgroups were identified: 1) up to 1 year; 2) 1 to 3 years; 3) 3 to 5 years; and 4) 5 to 10 years. The publication bias was depicted graphically and numerically as a forest plot and Begg’s test.11 The quality assessment of the included articles was performed using the Cochrane Risk of Bias (ROB) and Newcastle Ottawa Scale.12, 13, 14

Results

Our search identified 564 articles and following the removal of duplicates (n = 89), 475 records were screened in the first phase. Among them, 431 articles were removed. In the second phase, after removing duplicates and irrelevant studies, a total of 44 articles were selected for a full-length analysis. Of these, 24 studies were included in the final analysis which reported on our desired outcome. A total of 1241 TM and 992 TF individuals were included in our review (Central Illustration, Figure 1, Supplemental S1).Central Illustration Impact of Gender-Affirming Hormonal Therapy on Cardiovascular Risk Factors in Transgender Health: An Updated Meta-Analysis

The outcomes of lipid profile comparison of pre- and post-GAHT use among transmasculine (TM) and transfeminine (TF) populations. Abbreviations as in Figure 2.

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow of the Search Strategy for Systematic Review and Meta-Analysis

We included all GAHT therapies used for gender affirmation that were administered in various formulations such as oral, intramuscular (IM) injections, subcutaneous (SQ) injections, and gel. The GAHT utilized included combination of 17-β-estradiol and cyproterone acetate (oral), ethinyl estradiol (oral), goserelin acetate (SQ), and estradiol valerate (oral) for TF; and testosterone undecanoate (IM), lynestrenol (oral), testosterone cypionate (IM), testosterone enanthate (IM), testoviron depot (IM), anastrozole (oral), and testosterone gel for TM.

The mean follow-up duration for which studies were conducted (including pre- and post-GAHT therapy) was 27.69 months in TM patients and 39.23 months in TF patients. The mean SBP was 120.40 ± 11.31 mm Hg in TM patients and 119.60 ± 14.90 mm Hg in TF patients. The mean diastolic pressure was 73.96 ± 9.07 mm Hg in TM patients and 71.73 ± 10.40 mm Hg in TF patients. The mean age of the TM and TF cohorts was 28 years and 30 years, respectively. Baseline characteristics for TF and TM individuals are shown in Tables 1 and 2, respectively.Table 1 Baseline Demographics, Treatment Regimens, and Follow-Up Duration of Individual Transmasculine (TM) Studies Included

Patient #	First Author, Year	Follow-Up Duration (months)a	Number of FTM Transgender Individuals	GAHT Regimen Used (Formulation)	Mean Age (y)	Mean BMI (kg/m2)	Mean Systolic Blood Pressure (mm Hg)	Mean Diastolic Blood Pressure (mm Hg)	Mean TG Levels (mg/dL)	Mean LDL Levels (mg/dL)	Mean TC Levels (mg/dL)	Mean HDL Levels (mg/dL)	
1	Abdala et al, 201815	12	30	Testosterone undecanoate (IM) or enanthate (IM)	27 ± 8	25	---	---	88.3 ± 32.8	101.2 ± 25.1	175 ± 42.37	50.1 ± 10.9	
2	Asscheman et al, 199416	6	10	Testosterone undecanoate (IM)	30 ± 5.76	---	---	---	93 ± 31	109.82 ± 28.23	184.45 ± 186	54.52 ± 10.44	
3	Auer et al, 201617	12	20	Testosterone undecanoate (IM)	---	23.49 ± 4.55	---	---	77.95 ± 41.49	106.52 ± 30.39	77.95 ± 41.49	53.1 ± 13.9	
4	Bunck et al, 200618	3	30	Anastrozole (oral)	37.1 ± 7	25.6 ± 2.9	---	---	149.73 ± 147.96	116.1 ± 48.37	186.76 ± 42.57	42.57 ± 12.77	
5	Chandra et al, 201019	12	12	Testosterone, crypionate (IM)/enanthate (IM)	29 ± 9	27.5 ± 5.2	---	---	92 ± 72	113 ± 22	184 ± 26	52 ± 11	
6	Cocchetti et al, 202120	24	165	Testosterone undecanoate (IM), enanthate (IM), and transdermal gel	26.78 ± 7.48	25.06 ± 5.73	116.05 ± 13.62	73.33 ± 10.25	59.16 ± 43.05	102.32 ± 27.42	171.73 ± 30.4	57.57 ± 14.29	
7	Deutsch et al, 201521	6	31	Testosterone cypionate (IM)	27 ± 6.9	29.2 ± 2.8	120 ± 5.75	72 ± 4	75 ± 14	93 ± 8.25	177 ± 9.5	58 ± 5.5	
8	Elbers et al, 200322	12	20	Testosterone esters (IM)	26 ± 6	20.8 ± 2.6	126.9 ± 10.2	70.1 ± 8.5	77.5 ± 12.27	113.3 ± 34.03	170.15 ± 38.67	40.99 ± 8.507	
9	Giltay et al, 200423	4	81	Testosterone esters (IM)/Testosterone undecanoate (IM)	36.7	22.8 ± 4.53	126.62 ± 13.14	79.80 ± 8.00	61.95 ± 9.56	105.2 ± 33.3	176.72 ± 33.64	54.5 ± 16.6	
10	Jacobeit et al, 200724	12	12	Testosterone undecanoate (IM)	33 ± 6	---	---	---	---	140.5 ± 47	215.8 ± 58.5	51.7 ± 10.8	
11	Jacobeit et al, 200925	36	17	Testosterone undecanoate (IM)	34 ± 7	28.3 ± 2.8	---	---	88 ± 14	139 ± 48	218 ± 47	50 ± 11	
12	Klaver et al, 202026	84	121	Mixed testosterone esters “Sustanon”; testosterone propionate, phenylpropionate, isocaproate, and decanoate (IM)	15.2 ± 2	21.6	120	67	70.87	81.2	150.81	58	
13	Korpaisarn et al, 202127	24	39	Testosterone enanthate (IM)	27.8 ± 6	23.6 ± 4.5	---	---	86.4 ± 44.4	131.7 ± 36.8	207.4 ± 40.8	57.2 ± 13.1	
14	Leemaqz et al, 202328	57	196	Testosterone ethanate (IM)/cypionate (IM)	16.4 ± 7.2	---	---	---	85.7 ± 49.1	95.2 ± 27.4	170.8 ± 32.4	58.7 ± 14.2	
15	Liu et al, 202129	27	45	Testosterone cypionate (IM)	26 ± 1.1	20.6 ± 0.4	122.5 ± 2.7	74.1 ± 1.7	85.4 ± 7.7	104.2 ± 3.2	165.1 ± 4.8	63.9 ± 2.6	
16	Milionis et al, 202330	18	33	Testosterone undecanoate (IM)	23.45 ± 5.9	24.47 ± 4.19	---	---	64.93 ± 21.4	88.67 ± 25.69	156.69 ± 23.55	55.5 ± 11.05	
17	Mueller et al, 201031	24	45	Testosterone undecanoate (IM)	30.4 ± 9.1	24.1 ± 4.5	129.3	81	120.5 ± 64	131.2 ± 32.4	185.8 ± 33.4	61.8 ± 16.3	
18	Ott et al, 201132	60	89	Testosterone undecanoate (IM)/lynestrenol (oral)	35.7 ± 11.4	22.6 ± 4.4	---	---	108.6 ± 69.8	111.7 ± 34.2	187.9 ± 45.6	53.2 ± 14.4	
19b	Pelusi et al, 201433	12	15	Testoviron depot (IM)	30.9 ± 5.41	22.3 ± 4.33	---	---	57.4 ± 34.85	92.6 ± 27.44	174.4 ± 28.35	70.2 ± 13.72	
19b	Pelusi et al, 201433	12	15	Testosterone gel	29.4 ± 5.05	23.9 ± 4.87	---	---	60.8 ± 36.81	82 ± 27.44	161.3 ± 28.35	67.8 ± 13.72	
19b	Pelusi et al, 201433	12	15	Testosterone undecanoate (IM)	28.2 ± 4.69	22.1 ± 4.69	---	---	72.5 ± 33.4	83.3 ± 28.89	161.5 ± 28.35	62.9 ± 18.05	
20	Quiros et al, 201534	48	97	Testosterone (IM and transdermal)	28.6 ± 8.6	25 ± 4.7	118.2 ± 9.1	75.2 ± 8.9	70.6 ± 30.7	103.8 ± 38.7	166 ± 35.1	52.2 ± 12.2	
21	Tangpricha et al, 201035	12	12	Testosterone esters (IM), cypionate (IM), and enanthate (IM)	29 ± 9	27.5 ± 5.2	---	---	92 ± 72	113 ± 22	184 ± 26	52 ± 11	
22	Wierckx et al, 201236	120	50	Testosterone esters (IM)	37 ± 8.2	24.8 ± 3.8	124.7 ± 14.4	81.3 ± 10.7	124.1 ± 27.8	---	200.8 ± 10.1	---	
23	Wierckx et al, 201437	12	53	Testosterone undecanoate (IM)	24.5 ± 7.5	---	111.5 ± 12.6	70.2 ± 10.5	69.8 ± 10	98.4 ± 26.3	171.9 ± 28.1	56.3 ± 12.7	
Values are mean ± SD unless otherwise indicated.

BMI = body mass index; FTM = female to male; GAHT = gender-affirming hormone therapy; HDL = high-density lipoprotein; IM = intramuscular; LDL = low-density lipoprotein; TC = total cholesterol; TG = triglyceride.

a Duration refers to follow-up duration which is after initiation of GAHT.

b Pelusi et al, 2014 is a single unique study that has included 3 different testosterone formulations (testosterone depot IM injections, testosterone gel, and testosterone undecanoate). All 3 were separately included to analyze individual effects of the treatment regimen.

Table 2 Baseline Demographics, Treatment Regimens, and Follow-Up of Individual Transfeminine (TF) Studies Included

Patient #	First Author, Year	Follow-Up Duration (months)a	Number of MTF Transgender Individuals	GAHT Regimen Used (Formulation)	Mean Age (y)	Mean BMI (kg/m2)	Mean Systolic Blood Pressure (mm Hg)	Mean Diastolic Blood Pressure (mm Hg)	Mean TG Levels (mg/dL)	Mean LDL Levels (mg/dL)	Mean TC Levels (mg/dL)	Mean HDL Levels (mg/dL)	
1	Auer et al, 201617	12	20	Estradiol valerate (oral), cyproterone acetate (oral)	---	23.9 ± 4.34	---	---	92.32 ± 52.66	112.99 ± 34.16	92.32 ± 52.66	53.95 ± 11.66	
2	Cocchetti et al, 202120	24	144	Estradiol valerate (oral)	31.84 ± 11.46	23.46 ± 4.48	124.92 ± 14.91	76.24 ± 11.06	97.11 ± 89.56	102.83 ± 31.7	176.75 ± 39.08	54.59 ± 13.58	
3	Deutsch et al, 201521	6	16	17-beta estradiol (oral)/estradiol valerate (oral)/spironolactone (oral)	29 ± 9.4	14.55 ± 1.075	71 ± 2.875	49.5 ± 5.25	54.24 ± 9.375	69.5 ± 10.5	110.5 ± 12.5	37.25 ± 4	
4	Dittrich et al, 200538	24	60	Ethinyl estradiol (oral)/17-β-estradiol (oral)	38.37 ± 11.36	24.19 ± 4.34	---	---	110 ± 75.49	---	188 ± 45.81	---	
5	Elbers et al, 200322	12	17	Ethinyl estradiol (oral)	23 ± 5	21.7 ± 3.5	121.4 ± 9.9	67.1 ± 7.5	61.56 ± 9.72	99.38 ± 33.64	162.4 ± 34.8	47.18 ± 12.374	
6	Klaver et al, 202026	84	71	17-β estradiol (oral)	14.6 ± 1.8	20.2	120	65	70.8	73.47	143.07	54.13	
7	Leemaqz et al, 202328	57	170	Estrogen plus spironolactone (oral)	29.9 ± 9.5	---	---	---	111.8 ± 60.2	100.5 ± 33.8	173 ± 37	49.9 ± 13.1	
8	Liu et al, 202129	27	65	Conjugated estrogen and cyproterone acetate (oral)	27.9 ± 0.7	22.6 ± 0.3	119.9 ± 1.9	70.2 ± 1.1	76.7 ± 4.7	124.3 ± 3.7	183.4 ± 3.8	57.9 ± 2.1	
9	Mueller et al, 201031	24	84	Goserelin acetate (SQ)	36.3 ± 11.3	22.3 ± 0.42	---	---	112.9 ± 8.69	115.8 ± 5.96	185.32 ± 6.82	56.75 ± 4.58	
10	Ott et al, 201132	60	80	17-β-estradiol/cyproterone acetate (oral)	26 ± 6.3	23.7 ± 6	---	---	85.5 ± 50.6	107.9 ± 30.1	176.7 ± 38.3	56.6 ± 12.4	
11	Quiros et al, 201534	48	150	Estrogen therapy with antiandrogen activity (oral)	32.4 ± 10.1	24.2 ± 4.3	115.5 ± 11.9	72.9 ± 10.1	90 ± 56.6	104.3 ± 23	164.3 ± 29.1	45.4 ± 12.7	
12	Wierckx et al, 201236	120	50	Cyproterone acetate, exogenous estrogen (oral)	43 ± 10.4	25.3 ± 5.4	124.8 ± 16.6	77.1 ± 10.1	89.5 ± 18.3	---	197.8 ± 17.1	---	
13	Wierckx et al, 201437	12	53	Cyproterone acetate, estradiol valerate (oral)	30.3 ± 14.4	---	125.1 ± 13.8	70.2 ± 10.5	80.4 ± 15.3	99.4 ± 29	171.5 ± 32.7	52.9 ± 13.5	
Values are mean ± SD unless otherwise indicated.

MTF = male to female; SQ = subcutaneous; other abbreviations as in Table 1.

a Duration refers to follow-up duration after initiation of GAHT.

TM individuals’ primary and secondary outcomes

TM individuals showed a statistically significant elevation in the primary outcomes when compared to the baseline, including LDL (SMD: 0.28 mg/dl [95% CI: 0.11-0.44] P = <0.01, I2 = 61.1%), TG levels (SMD: 0.42 mg/dL [95% CI: 0.25-0.59] P = <0.01, I2 = 62.8%), TC (SMD: 0.17 mg/dL [95% CI: 0.05-0.29] P = <0.01, I2 = 30.5%) while HDL levels were significantly decreased from baseline (SMD: −0.50 mg/dl [95% CI: −0.67 to −0.32] P = <0.01, I2 = 65.0%) (Figure 2, Table 3).Figure 2 Forest Plots for Primary Outcomes Comparing Lipid Profile Pre- and Post-GAHT Use Among Transmasculine (TM) Individuals

(A) Change in LDL levels pre-GAHT (baseline) and post-GAHT use. (B) Change in HDL levels pre-GAHT (baseline) and post-GAHT use. (C) Change in TG levels pre-GAHT (baseline) and post-GAHT use. (D) Change in TC levels pre-GAHT (baseline) and post-GAHT use. GAHT = gender-affirming hormone therapy; HDL = high-density lipoprotein; LDL = low-density lipoprotein; SMD = standard mean difference; TC = total cholesterol; TG = triglyceride.

Table 3 Pooled Outcomes of CV Risk Factors After GAHT Initiation in Transmasculine Individuals

	Standard Mean Difference (SMD)	95% CI	P Value	I2	
LDL (mg/dL)	0.28	0.11-0.43	<0.01	61.1%	
HDL (mg/dL)	−0.50	−0.67 to −0.32	<0.01	65.0%	
TG (mg/dL)	0.42	0.25-0.60	<0.01	62.8%	
TC (mg/dL)	0.17	0.05-0.29	<0.01	30.5%	
SBP (mm Hg)	−0.09	−0.61 to 0.42	0.72	89.4%	
DBP (mm Hg)	−0.27	−0.76 to −0.21	0.27	88.9%	
BMI (kg/m2)	0.24	0.11-0.38	<0.01	0.0%	
CV = cardiovascular; DBP = diastolic blood pressure; SBP = systolic blood pressure; other abbreviations as in Table 1.

Regarding secondary outcomes, BMI was significantly elevated when compared to the baseline (SMD: 0.24 kg/m2 [95% CI: 0.11-0.38] P = <0.01, I2 = 0.0%). However, no significant relationship between SBP (SMD: −0.09 mm Hg [95% CI: −0.61 to 0.42] P = 0.72, I2 = 89.4%) and DBP (SMD: −0.27 mm Hg [95% CI: −0.76 to 0.21] P = 0.27, I2 = 88.9%) was studied (Supplemental S2, Table 3).

Subgroup analysis

We further performed subgroup analysis to account for follow-up duration as it varied in various studies. Based on subgroup analysis for TM individuals, HDL levels showed significant reduction at up to 1 year, 1 to 3 years, and 3 to 5 years follow-up. However, a nonsignificant reduction was found in 5 to 10 years follow-up. In the case of LDL, significant elevation was seen in up to 1 year and 3 to 5 years follow-up but nonsignificant elevation in 1 to 3 years and 5 to 10 years follow-up. In the case of TG, significant elevation was seen in up to 1 year, 1 to 3 years, and 5 to 10 years follow-up but nonsignificant elevation in 3 to 5 years follow-up. Regarding TC, significant elevation was seen in up to 1 year follow-up but nonsignificant elevation was observed in 1 to 3 years, 3 to 5 years, and 5 to 10 years follow-up. For BMI, up to 1-year follow-up showed significant elevation, however, 1 to 3 years and 3 to 5 years follow-up durations showed nonsignificant elevation. Regarding SBP and DBP, none of the subgroups showed any significant changes. These results are shown in Supplemental S4A.

TF individuals’ primary and secondary outcomes

TF individuals showed a statistically significant increase in TG levels only when compared to the baseline levels (SMD: 0.64 mg/dL [95% CI: 0.01-1.26] P = 0.05, I2 = 91.6%). There was no statistically significant change in the rest of the primary outcomes including LDL (SMD: −0.05 mg/dL [95% CI: −0.56 to 0.46] P = 0.85, I2 = 91.6%), HDL (SMD: 0.25 mg/dL [95% CI: −0.74 to 1.23] P = 0.62, I2 = 97.6%), and TC (SMD: 0.005 mg/dL [95% CI: −0.18 to 0.18] P = 0.96, I2 = 67.2%) (Figure 3, Table 4).Figure 3 Forest Plots for Primary Outcomes Comparing Lipid Profile Pre- and Post-GAHT Use Among Transfeminine (TF) Individuals

(A) Change in LDL levels pre-GAHT (baseline) and post-GAHT use. (B) Change in HDL levels pre-GAHT (baseline) and post-GAHT use. (C) Change in TG levels pre-GAHT (baseline) and post-GAHT use. (D) Change in TC levels pre-GAHT (baseline) and post-GAHT use. Abbreviations as in Figure 2.

Table 4 Pooled Outcomes of CV Risk Factors After GAHT Initiation in Transfeminine Individuals

	Standard Mean Difference (SMD)	95% CI	P Value	I2	
LDL (mg/dL)	−0.05	−0.56 to 0.46	0.85	91.6%	
HDL (mg/dL)	0.25	−0.74 to 1.23	0.62	97.6%	
TG (mg/dL)	0.64	0.01-1.27	0.05	91.6%	
TC (mg/dL)	0.004	−0.18 to 0.18	0.96	67.2%	
SBP (mm Hg)	−0.51	−1.44 to 0.43	0.29	96.6%	
DBP (mm Hg)	−0.01	−0.81 to 0.79	0.97	88.1%	
BMI (kg/m2)	0.38	−0.13 to 0.88	0.14	91.9%	
Abbreviations as in Tables 1 and 3.

Regarding secondary outcomes, there was no statistically significant change observed in SBP when compared to the baseline (SMD: −0.51 mm Hg [95% CI: −1.44 to 0.43] P = 0.29, I2 = 96.6%), DBP (SMD: −0.01 mm Hg [95% CI: −0.81 to 0.78] P = 0.97, I2 = 88.1%), and BMI (SMD: 0.38 kg/m2 [95% CI: −0.13 to 0.88] P = 0.14, I2 = 91.9%) (Supplemental S3, Table 4).

Subgroup analysis

For TF individuals, the impact of follow-up duration on HDL levels did not show any significant change. LDL showed no significant changes in up to 1 year, 1 to 3 years, and 3 to 5 years follow-up, and only showed mild statistically significant reduction in 5 to 10 years follow-up. For TG, similarly up to 1 year, 1 to 3 years, and 3 to 5 years follow-up did not show any significant change, and only mild significant change was observed in 5 to 10 years follow-up. Regarding SBP, no subgroup showed any significant results. For DBP, only 1 to 3 years follow-up showed mild significant elevation. Up to 1 year follow-up showed nonsignificant elevation but 3 to 5 years and 5 to 10 year follow-up subgroups showed nonsignificant reduction. Thus, overall, the result is nonsignificant. Regarding BMI, all the subgroups showed nonsignificant elevation. The results of the subgroup analysis are shown in Supplemental S4B.

Publication bias

To ascertain the bias, we plotted funnel plots and then used Begg’s test to assess for funnel plot asymmetry.11 The plot's vertical axis uses standard error to estimate the sample size of the study, thereby, plotting larger studies at the top and smaller studies at the bottom. The horizontal spread depicts the power and effect sizes of the included studies. We did a numerical assessment of the funnel plot scatter using Begg’s test that did not show any publication bias or small study effects (Supplemental S5).

Quality assessment

Bias assessment of randomized controlled trials was done using the Cochrane ROB tool.12 In all of the intervention studies, there was no blinding because of the interventional nature of GAHT and parallel single-arm designs with no intergroup comparison. This raises a concern for selection bias. In most of the studies, data regarding matching are also not available. There is minimal risk of detection bias as all the outcomes were laboratory measures and robust data regarding laboratory methods are available. The risk of reporting bias was minimal due to adequate reporting of outcomes. The overall risk of bias was high. The detailed ROB tool assessment of the intervention studies is given in Supplemental S6.

Quality assessment of non-randomized studies was assessed by the Newcastle-Ottawa Scale.14 In all non-interventional studies, the quality of study population selection, comparability of the selected sample with the general population, and methods of measuring the outcome were assessed as depicted in Supplemental S7. The overall risk of bias for the observational studies included in the study was low.

Heterogeneity

In general, the high heterogeneity observed in the outcomes studied in our analysis is likely due to several factors. Firstly, it encompasses studies utilizing diverse GAHT approaches. Secondly, most of the studies in our analysis exhibited notable selection bias, both in non-randomized observational studies and even in randomized controlled trials, contributing to a high risk of overall bias. Thirdly, such pronounced heterogeneity may be explained by sampling bias.

To further assess heterogeneity, we conducted a leave-one-out analysis. In TM individuals, the outcomes with >50% heterogeneity were HDL, LDL, TG, SBP, and DBP. For HDL, almost all studies contributed equally to heterogeneity except Liu et al.29 Omitting this study resulted in an overall pooled HDL of −0.55 mg/dL (95% CI: −0.7 to −0.40; P < 0.01) compared to the baseline and a decrease in I2 value to 50%. For LDL, the study contributing the most to heterogeneity was again Liu et al.29 Omitting this study led to a pooled LDL increase of 0.35 mg/dL (95% CI: 0.24 to 0.49; P < 0.01) from baseline and a resultant heterogeneity of 31%. The rest of the studies contributed equally to heterogeneity. For TG, all the studies contributed to heterogeneity except Wierckx et al.37 Omitting this study led to a total heterogeneity of 51% and a pooled increase in TG from a baseline of 0.389 mg/dL (95% CI: 0.24-0.53; P < 0.01). Regarding SBP, the study contributing to heterogeneity was again Liu et al29 while all other studies contributed equally to heterogeneity. Omitting Liu et al29 decreased heterogeneity to 68% and a change in SBP of 0.12 mm Hg (95% CI: −0.15 to 0.37; P = 0.38) from baseline. Regarding DBP, all studies contributed equally to heterogeneity except Liu et al.29 Omitting this study led to a decrease in heterogeneity to 50% and a final pooled change in DBP of −0.02 mm Hg (95% CI: −0.23 to 0.19; P = 0.85) from baseline. Supplemental S8A.

In TF individuals, regarding HDL, all studies contributed equally to heterogeneity. Regarding LDL, Liu et al29 contributed most to heterogeneity. Omitting it led to a decrease in heterogeneity to 72% and a pooled LDL difference of −0.18 mg/dL (95% CI: −0.43 to 0.06; P = 0.15) from baseline. Regarding TC, Cocchetti et al20 and Wierckx et al37 contributed the most to heterogeneity. Removing Cocchetti et al decreased heterogeneity to 51% with pooled TC of 0.06 mg/dL (95% CI: -0.11 to 0.23; P = 0.48) as compared to baseline; while removing Wierckx et al decreased heterogeneity to 54% with pooled TC of 0.07 mg/dL (95% CI: -0.09 to 0.22; P = 0.40) from baseline. Regarding TG, all studies contributed almost equally to heterogeneity. Regarding SBP, Liu et al29 contributed the most to heterogeneity. Its omission led to a decreased heterogeneity to 90% with a pooled SBP difference of −0.08 mm Hg (95% CI: -0.60 to 0.44; P = 0.77) compared to baseline. For DBP, Deutsch et al21 contributed the most to heterogeneity. Its omission led to a decrease in I2 levels to 68% and pooled DBP changed to about 0.33 mm Hg (95% CI: 0.08-0.05; P = 0.01). Here omission of the most heterogeneous study changed the results to a statistically significant increase in DBP as compared to baseline. Deutsch et al had a short follow-up duration, which likely skewed the overall effect and contributed to the normalization of DBP. Also, medication adherence was not consistently tracked among most patients, a limitation acknowledged within the study. Regarding BMI, Mueller et al31 was the most heterogeneous study and its omission led to a decrease in I2 value to 57% and pooled BMI differed by 0.20 kg/m2 (95% CI: −0.04 to 0.43; P = 0.10) from baseline Supplemental S8B.

Compared to other studies, Liu et al29 differed significantly in methodology, potentially contributing to high heterogeneity. While other studies included some patients with baseline dyslipidemia, Liu et al29 opted to exclude individuals with dyslipidemia. Follow-up duration was variable in Liu et al29 with some participants monitored at 3 months, others at 6 months, and some for even longer periods. Moreover, loss to follow-up was high as compared to the other studies, also contributing to high heterogeneity.

Discussion

We performed a systematic review and meta-analysis to outline the effect of GAHT on lipid profile in transgender patients. Our results show a statistically significant increase in TG levels in transgender women with no significant changes in TC, LDL, HDL levels, or changes in SBP and DBP when compared to the baseline levels. On the other hand, transgender men had a statistically significant increase in TG, LDL, and TC levels and a decrease in HDL levels with no significant changes in SBP or DBP as compared to the baseline levels.

The primary class of estrogen (17-β estradiol) and ethinyl estradiol were the most commonly used regimens given to transgender women in our selected studies. The amount of estrogen used in transgender individuals is much higher than in women on hormone replacement therapy or oral contraceptive pills (5 mg estradiol/24 h compared to 100 μg estradiol/24 h) which could explain the variability of the results on lipid profiles.39 For instance, in a study by Walsh et al postmenopausal women on low-dose estrogen (1.25 mg/day) have favorable outcomes in lipid profile as there was a 19% increase in HDL and an 18% reduction in LDL level, which could protect women against atherosclerosis.40 In addition to that, the mode of delivery may be another contributing factor, as transdermal 17-estradiol is the safest method of administration in terms of thromboembolic events, which might have mitigated effects on lipid profiles in comparison to the oral form.7,41 On the other hand, studies by New et al42 found an increased level of HDL and TC and lower LDL in transgender women compared to men who are not on treatment which correlates with our study findings.

Testosterone therapy in eugonadal cisgender men might increase TG levels and reduce TC, LDL, and HDL levels in cisgender eugonadal men. On the other hand, androgen deficiency is linked with an increase in TG, TC, LDL, and HDL levels.43,44 However, the effect of testosterone on lipid profile in transgender men in our meta-analysis shows a significant increase in TG, LDL, and TC levels and a decrease in HDL levels. Our results correlate with a large retrospective study performed on 89 transgender men individuals who had GAHT and reported that TGs, TC, and LDL levels were increased, while HDL was decreased.45

GAHT can adversely affect lipid profiles, potentially increasing the risk of myocardial infarction and ischemic stroke. This risk is attributed to alterations in cholesterol levels resulting from hormone therapy. Moreover, GAHT has been associated with an increased risk of venous thromboembolism (VTE).46, 47, 48 The use of oral ethinyl estradiol in transgender women carries a significant 20-fold increased risk of spontaneous VTE.49 Notably, all VTE cases occurred in patients using oral ethinyl estradiol, except for a single case using transdermal 17-β-estradiol in the latter study.45 Estradiol valerate is a novel estrogen with fewer side effects than ethinyl estradiol and is now the most commonly prescribed form of estrogen in transgender women.50

Numerous studies have explored the metabolic impacts of GAHT in transgender individuals, but findings are frequently conflicting and inconclusive. This is largely due to the observational and retrospective nature of the studies, which involve populations with varied hormone regimens, often without medical supervision.51, 52, 53, 54 While our analysis suggests an association of GAHT with dyslipidemia, which could potentially indicate a higher cardiovascular mortality risk, it remains uncertain whether transgender individuals have a higher cardiovascular mortality rate compared to the general population.55

A previous meta-analysis conducted by Elamin et al in 2010 concluded that current level of evidence is of low quality, characterized by significant imprecision and heterogeneity.56 Similarly, previous systematic reviews suggest that the current data on GAHT in transgender patients are limited and of low quality.22,52,57,58

In summary, our meta-analysis reveals statistically significant changes in lipid profiles among transgender individuals undergoing GAHT. However, the clinical implications of GAHT on lipid profiles remain unclear. Current evidence is insufficient to draw definitive conclusions about its impact. Additional research is essential to determine if these changes affect cardiovascular morbidity and mortality. Long-term studies with extended follow-up are crucial to gain a comprehensive understanding of these potential impacts.

Study Limitations

We did not have a long-term follow-up of data and CVD data available including myocardial infarction and major adverse cardiovascular events due to dyslipidemia in the transgender population. Individual genetic, dietary, and lifestyle factors can act as confounders and effect modifiers that can alter the results. The study includes data sets from older studies that used ethinyl estradiol as part of GAHT. Ethinyl estradiol is known to be pro-thrombotic, which is why it is no longer used in GAHT. Limited evidence from small studies with diverse hormone treatments and follow-up durations makes drawing definitive conclusions challenging.

Because of high heterogeneity, even statistically significant results do not translate into clinical significance. A similar observation was made by a meta-analysis done 14 years ago.56 The available evidence regarding the effects of GAHT in TM and TF individuals remains low in quality with a lot of imprecisions precluding its clinical use.

Conclusions

Our meta-analysis found that the initiative of GAHT in TM individuals was associated with increases in LDL, TGs, TC, and a decrease in HDL levels. In TF individuals, GAHT was associated with an increase in TG levels only. There was no impact on blood pressure or BMI. Whether these changes in lipids after GAHT translate into unfavorable clinical outcomes is yet to be determined.PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Our analysis encompassed data from a substantial cohort of TM and TF patients, revealing notable alterations in lipid levels following GAHT.

COMPETENCY IN PATIENT CARE: It is critical to stratify cardiovascular risk based on alterations in lipid profiles and BMI, and devising appropriate management strategies tailored to individual patient needs, to optimize cardiovascular health outcomes in transgender patients undergoing GAHT.

TRANSLATIONAL OUTLOOK: Health care providers should consider comprehensive lipid profile assessments and cardiovascular risk stratification in the management of transgender patients. Additionally, further research endeavors are imperative to elucidate the long-term clinical implications of these lipid profile changes and optimize therapeutic strategies to mitigate cardiovascular risk in this population.

Funding support and author disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Supplementary data

Supplementary material

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

Appendix

For the research question, PICO, and search strategy as well as supplemental tables and figures, please see the online version of this paper.
==== Refs
References

1 Unger C.A. Hormone therapy for transgender patients Transl Androl Urol 5 6 2016 877 884 10.21037/tau.2016.09.04 28078219
2 Banos G. Guarner V. Perez-Torres I. Sex steroid hormones, cardiovascular diseases and the metabolic syndrome Cardiovasc Hematol Agents Med Chem 9 3 2011 137 146 21745183
3 Saad F. Kamischke A. Yassin A. More than eight years' hands-on experience with the novel long-acting parenteral testosterone undecanoate Asian J Androl 9 3 2007 291 297 10.1111/j.1745-7262.2007.00275.x 17486268
4 Whitsel E.A. Boyko E.J. Matsumoto A.M. Anawalt B.D. Siscovick D.S. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis Am J Med 111 4 2001 261 269 10.1016/s0002-9343(01)00833-6 11566455
5 Hulley S.B. Grady D. The WHI estrogen-alone trial--do things look any better? JAMA 291 14 2004 1769 1771 10.1001/jama.291.14.1769 15082705
6 Berenson A.B. Rahman M. Wilkinson G. Effect of injectable and oral contraceptives on serum lipids Obstet Gynecol 114 4 2009 786 794 10.1097/AOG.0b013e3181b76bea 19888036
7 Moore E. Wisniewski A. Dobs A. Endocrine treatment of transsexual people: a review of treatment regimens, outcomes, and adverse effects J Clin Endocrinol Metab 88 8 2003 3467 3473 10.1210/jc.2002-021967 12915619
8 Polderman K.H. Gooren L.J. Asscheman H. Bakker A. Heine R.J. Induction of insulin resistance by androgens and estrogens J Clin Endocrinol Metab 79 1 1994 265 271 10.1210/jcem.79.1.8027240 8027240
9 T'Sjoen G. Arcelus J. Gooren L. Klink D.T. Tangpricha V. Endocrinology of transgender medicine Endocr Rev 40 1 2019 97 117 10.1210/er.2018-00011 30307546
10 Moher D. Liberati A. Tetzlaff J. Altman D.G. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement PLoS Med 6 7 2009 e1000097 10.1371/journal.pmed.1000097
11 Lin L. Chu H. Quantifying publication bias in meta-analysis Biometrics 74 3 2018 785 794 10.1111/biom.12817 29141096
12 Egger M. Davey Smith G. Schneider M. Minder C. Bias in meta-analysis detected by a simple, graphical test BMJ 315 7109 1997 629 634 10.1136/bmj.315.7109.629 9310563
13 Cumpston M.S. McKenzie J.E. Welch V.A. Brennan S.E. Strengthening systematic reviews in public health: guidance in the cochrane handbook for systematic reviews of interventions, 2nd edition J Public Health 44 2022 e588 e592 10.1093/pubmed/fdac036
14 Lo C.K. Mertz D. Loeb M. Newcastle-Ottawa Scale: comparing reviewers' to authors' assessments BMC Med Res Methodol 14 2014 45 10.1186/1471-2288-14-45 24690082
15 Abdala R. Nagelberg A. Silveira F. Otero P. Mormandi E. Short-term safety profile of cross-hormonal therapy in trans-male subjects Medicina (Argentina) 78 6 2018 399 402
16 Asscheman H. Gooren L.J.G. Megens J.A.J. Nauta J. Kloosterboer H.J. Eikelboom F. Serum testosterone level is the major determinant of the male-female differences in serum levels of high-density lipoprotein (HDL) cholesterol and HDL2 cholesterol Metab Clin Exp 43 8 1994 935 939 10.1016/0026-0495(94)90170-8 8052149
17 Auer M.K. Cecil A. Roepke Y. 12-months metabolic changes among gender dysphoric individuals under cross-sex hormone treatment: a targeted metabolomics study Sci Rep 6 2016 37005 10.1038/srep37005
18 Bunck M.C.M. Toorians A.W.F.T. Lips P. Gooren L.J.G. The effects of the aromatase inhibitor anastrozole on bone metabolism and cardiovascular risk indices in ovariectomized, androgen-treated female-to-male transsexuals Eur J Endocrinol 154 4 2006 569 575 10.1530/eje.1.02126 16556720
19 Chandra P. Basra S.S. Chen T.C. Tangpricha V. Alterations in lipids and adipocyte hormones in female-to-male transsexuals Internet J Endocrinol 2010 2010 945053 10.1155/2010/945053
20 Cocchetti C. Castellini G. Iacuaniello D. Does gender-affirming hormonal treatment affect 30-year cardiovascular risk in transgender persons? A two-year prospective European study (ENIGI) J Sex Med 18 4 2021 821 829 10.1016/j.jsxm.2021.01.185 33745831
21 Deutsch M.B. Bhakri V. Kubicek K. Effects of cross-sex hormone treatment on transgender women and men Obstet Gynecol 125 3 2015 605 610 10.1097/aog.0000000000000692 25730222
22 Elbers J.M.H. Giltay E.J. Teerlink T. Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects Clin Endocrinol 58 5 2003 562 571 10.1046/j.1365-2265.2003.01753.x
23 Giltay E.J. Toorians A.W.F.T. Sarabjitsingh A.R. de Vries N.A. Gooren L.J.G. Established risk factors for coronary heart disease are unrelated to androgen-induced baldness in female-to-male transsexuals J Endocrinol 180 1 2004 107 112 10.1677/joe.0.1800107 14709149
24 Jacobeit J.W. Gooren L.J. Schulte H.M. Long-acting intramuscular testosterone undecanoate for treatment of female-to-male transgender individuals J Sex Med 4 5 2007 1479 1484 10.1111/j.1743-6109.2007.00556.x 17635694
25 Jacobeit J.W. Gooren L.J. Schulte H.M. Safety aspects of 36 months of administration of long-acting intramuscular testosterone undecanoate for treatment of female-to-male transgender individuals Eur J Endocrinol 161 5 2009 795 798 10.1530/EJE-09-0412 19749027
26 Klaver M. De Mutsert R. Van Der Loos M.A.T.C. Hormonal treatment and cardiovascular risk profile in transgender adolescents Pediatrics 145 3 2020 e20190741 10.1542/peds.2019-0741 32102929
27 Korpaisarn S. Chiewchalermsri D. Arunakul J. Chinthakanan O. Poomthavorn P. Sriphrapradang C. Effects of testosterone treatment on transgender males: a single-institution study SAGE Open Medicine 9 2021 10.1177/20503121211051546
28 Leemaqz S.Y. Kyinn M. Banks K. Sarkodie E. Goldstein D. Irwig M.S. Lipid profiles and hypertriglyceridemia among transgender and gender diverse adults on gender-affirming hormone therapy J Clin Lipidol 17 1 2023 103 111 10.1016/j.jacl.2022.11.010 36473821
29 Liu Y.H. Wu T.H. Chu C.H. Lin Y.C. Lin L.Y. Metabolic effects of cross-sex hormone therapy in transgender individuals in Taiwan J Chin Med Assoc 84 3 2021 267 272 10.1097/jcma.0000000000000475 33350652
30 Milionis C. Ilias I. Venaki E. Koukkou E. The metabolic effects of hormonal treatment in transgender males: safety of the testosterone gender-affirming therapy Int J Risk Saf Med 34 1 2023 21 28 10.3233/jrs-200087 35964205
31 Mueller A. Haeberle L. Zollver H. Effects of intramuscular testosterone undecanoate on body composition and bone mineral density in female-to-male transsexuals J Sex Med 7 9 2010 3190 3198 10.1111/j.1743-6109.2010.01912.x 20584125
32 Ott J. Aust S. Promberger R. Huber J.C. Kaufmann U. Cross-sex hormone therapy alters the serum lipid profile: a retrospective cohort study in 169 transsexuals J Sex Med 8 8 2011 2361 2369 10.1111/j.1743-6109.2011.02311.x 21595834
33 Pelusi C. Costantino A. Martelli V. Effects of three different testosterone formulations in female-to-male transsexual persons J Sex Med 11 12 2014 3002 3011 10.1111/jsm.12698 25250780
34 Quirós C. Patrascioiu I. Mora M. Effect of cross-sex hormone treatment on cardiovascular risk factors in transsexual individuals. Experience in a specialized unit in Catalonia Endocrinol Nutr 62 5 2015 210 216 10.1016/j.endonu.2015.02.001 25790747
35 Tangpricha V. Chandra P. Basra S.S. Chen T.C. Alterations in lipids and adipocyte hormones in female-to-male transsexuals Int J Endocrinol 2010 2010 10.1155/2010/945053
36 Wierckx K. Mueller S. Weyers S. Long-term evaluation of cross-sex hormone treatment in transsexual persons J Sex Med 9 10 2012 2641 2651 22906135
37 Wierckx K. Van Caenegem E. Schreiner T. Cross-sex hormone therapy in trans persons is safe and effective at short-time follow-up: results from the European network for the investigation of gender incongruence J Sex Med 11 8 2014 1999 2011 10.1111/jsm.12571 24828032
38 Dittrich R. Binder H. Cupisti S. Hoffmann I. Beckmann M.W. Mueller A. Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist Exp Clin Endocrinol Diabetes 113 10 2005 586 592 10.1055/s-2005-865900 16320157
39 van Kesteren P. Lips P. Gooren L.J. Asscheman H. Megens J. Long-term follow-up of bone mineral density and bone metabolism in transsexuals treated with cross-sex hormones Clin Endocrinol 48 3 1998 347 354 10.1046/j.1365-2265.1998.00396.x
40 Walsh M.N. Women as leaders in cardiovascular medicine Clin Cardiol 41 2 2018 269 273 10.1002/clc.22920 29485719
41 Adlercreutz H. Tenhunen R. Some aspects of the interaction between natural and synthetic female sex hormones and the liver Am J Med 49 1970 630 648 10.1016/s0002-9343(70)80130-9 4924590
42 New G. Timmins K.L. Duffy S.J. Long-term estrogen therapy improves vascular function in male to female transsexuals J Am Coll Cardiol 29 7 1997 1437 1444 10.1016/S0735-1097(97)00080-6 9180101
43 Haddad R.M. Kennedy C.C. Caples S.M. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials Mayo Clin Proc 82 1 2007 29 39 10.4065/82.1.29 17285783
44 Traish A.M. Abdou R. Kypreos K.E. Androgen deficiency and atherosclerosis: the lipid link Vascul Pharmacol 51 5-6 2009 303 313 10.1016/j.vph.2009.09.003 19818414
45 van Kesteren P.J. Asscheman H. Megens J.A. Gooren L.J. Mortality and morbidity in transsexual subjects treated with cross-sex hormones Clin Endocrinol 47 3 1997 337 342 10.1046/j.1365-2265.1997.2601068.x
46 Chan Swe N. Ahmed S. Eid M. Poretsky L. Gianos E. Cusano N.E. The effects of gender-affirming hormone therapy on cardiovascular and skeletal health: a literature review Metabol Open 13 2022 100173 10.1016/j.metop.2022.100173
47 Getahun D. Nash R. Flanders W.D. Cross-sex hormones and acute cardiovascular events in transgender persons: a cohort study Ann Intern Med 169 4 2018 205 213 10.7326/m17-2785 29987313
48 Asscheman H. Giltay E.J. Megens J.A. de Ronde W.P. van Trotsenburg M.A. Gooren L.J. A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones Eur J Endocrinol 164 4 2011 635 642 10.1530/eje-10-1038 21266549
49 de Blok C.J.M. Wiepjes C.M. Nota N.M. den Heijer M. Hormone treatment of transgender people: long-term health effects and safety Ned Tijdschr Geneeskd 164 2020 D4481 32757514
50 Morssinkhof M.W.L. Wiepjes C.M. Bosman B.W. Sex hormones, insomnia, and sleep quality: subjective sleep in the first year of hormone use in transgender persons Sleep Med 107 2023 316 326 10.1016/j.sleep.2023.04.028 37271109
51 Asscheman H. T'Sjoen G. Lemaire A. Venous thrombo-embolism as a complication of cross-sex hormone treatment of male-to-female transsexual subjects: a review Andrologia 46 7 2014 791 795 10.1111/and.12150 23944849
52 Maraka S. Ospina N.M.S. Rodriguez-Gutierrez R. Davidge-Pitts C.J. Nippoldt T.B. Murad M.H. Effect of sex steroids on lipids, venous thromboembolism, cardiovascular disease and mortality in transgender individuals: a systematic review and meta-analysis Endocr Rev 37 2 2016 10.1210/endo-meetings.2016.RE.15.FRI-136
53 Asscheman H. Gooren L.J. Eklund P.L. Mortality and morbidity in transsexual patients with cross-gender hormone treatment Metabolism 38 9 1989 869 873 10.1016/0026-0495(89)90233-3 2528051
54 Maraka S. Mwangi R. McCoy R.G. Thyroid hormone treatment among pregnant women with subclinical hypothyroidism: US national assessment BMJ 356 2017 i6865 10.1136/bmj.i6865
55 Masumori N. Nakatsuka M. Cardiovascular risk in transgender people with gender-affirming hormone treatment Circ Rep 5 4 2023 105 113 10.1253/circrep.CR-23-0021 37025940
56 Elamin M.B. Garcia M.Z. Murad M.H. Erwin P.J. Montori V.M. Effect of sex steroid use on cardiovascular risk in transsexual individuals: a systematic review and meta-analyses Clin Endocrinol 72 1 2010 1 10 10.1111/j.1365-2265.2009.03632.x
57 Velho I. Fighera T.M. Ziegelmann P.K. Spritzer P.M. Effects of testosterone therapy on BMI, blood pressure, and laboratory profile of transgender men: a systematic review Andrology 5 5 2017 881 888 10.1111/andr.12382 28709177
58 Aranda G. Mora M. Hanzu F.A. Vera J. Ortega E. Halperin I. Effects of sex steroids on cardiovascular risk profile in transgender men under gender affirming hormone therapy Endocrinol Diabetes Nutr (Engl Ed) 66 6 2019 385 392 10.1016/j.endinu.2018.11.004 30704917
