Transgender people do not experience gender as consistent with their birth sex. The non-correlation between experienced gender and biological sex, known as gender incongruence (1), can lead to stigma, depression, body uneasiness, social margination for Assigned Males at Birth (AMAB) and Assigned Females at Birth (AFAB) trans people (“gender dysphoria”). For those who want to change all/some physical features can start gender affirming care (hormonal and/or surgical treatment).

According to a meta-analysis by Collin and colleagues, the overall prevalence estimates for transgender diagnoses were 2.5 per 100,000 for AFAB and 5.8 per 100,000 for AMAB, although prevalence may vary based on different definitions (2).

World Professional Association for Transgender Health (WPATH) guidelines define hormone treatment as medically necessary for transgenders asking for medical interventions to affirm their gender (3). The Endocrine Society recommends oral, transdermal, or intramuscular 17β-estradiol for AMAB trans people (4). Oral administration includes micronized 17β-estradiol, conjugated estrogens and estradiol valerate, quickly cleaved to 17β-estradiol, while ethinyl estradiol is no longer recommend because of the poor safety profile (5). Co-administration with androgen inhibitors (cyproterone, spironolactone, progesterone) is often chosen to foster feminization (6, 7). However, the lack of international standardization of specific hormone regimens for gender affirming therapy in AMAB trans people hinders the knowledge of the side effects of hormone treatment, including venous thromboembolism (VTE).

The incidence rate of VTE in young women who do not use estrogens is about 1 in 10,000 per year (8–10). Much of the available data on thrombotic risk associated to estrogen treatment steams from studies on cisgender women treated with combined oral contraceptives (COCs), or with hormone replacement therapy (HRT) (11). In cisgender women, COC increases the risk of VTE by approximately 2–4 fold (10, 12) and a higher risk would result from increases in estrogen dose (13). Transdermal estrogen formulations used for HRT in postmenopausal women do not seem to be associated with a significant increase in the VTE risk (12, 14–16) and had showed a low thrombogenic profile in AMAB trans people, although there are no head-to-head studies with other estrogen formulations (17, 18). However, thrombophilia, smoking, obesity, age, major surgery and fractures are well-recognized risk factors in the general population and could contribute, alone or in combination, to promote VTE in COC and HRT users (19–22).

Results of studies on the thrombotic risk in cisgender women under COC or HRT should not be translated to AMAB trans people due to differences in age, estrogen formulations and doses (23); cisgender women and AMAB trans people do have genetic differences and AMAB usually also use androgen inhibitors. Furthermore, many data on the risk of VTE in AMAB trans people undergoing feminizing hormone treatment have been produced in case reports or small series, thus reaching a low statistical power (18). In a meta-analysis by Khan and colleagues (7), the incidence rate for VTE was 2.3 per 1,000 person-years (95% CI: 0.8 – 6.9). However, this estimate was burdened with a large and unexplained between-study heterogeneity (I ² = 74%; P = 0.0039). More recently, a systematic review pointed to a significantly higher incidence of VTE in treated AMAB compared to AFAB trans people (42.8 vs 10.8 VTE per 10,000 patient years; P = 0.02) (24). Again, a large between-study heterogeneity arose, and the qualitative approach did not allow the identification of covariates potentially able to influence the pooled data.

Given the large unexplained heterogeneity among the studies, the actual impact and risk of VTE in AMAB trans people receiving gender affirming hormone therapy remains uncertain. In this light, we aimed to perform a systematic review and a meta-analysis of available studies to define pooled prevalence estimate and correlates of VTE in AMAB undergoing hormone feminizing therapy.

The study was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) (25). It also complies with the guidelines of Meta-Analyses and Systematic Reviews of Observational Studies (MOOSE) (26). The PRISMA-P and MOOSE checklists have been presented as Supplementary Table 1 (A and B). The study is registered in the PROSPERO (International Prospective Register of Systematic Reviews) with the number CRD42021229916. (https://www.crd.york.ac.uk/PROSPERO/).

To our knowledge, this is the largest meta-analysis performed on VTE risk in AMAB trans people under gender-affirming hormone therapy: it included 18 studies, collectively giving information about 11,542 AMAB trans people. The overall pooled VTE prevalence estimate was 2%, but with large heterogeneity. Our results were similar to those of Khan and colleagues (7), who reported an incidence rate for VTE in AMAB treated with estrogens of 2.3 per 1,000 person-years, resulting from the analysis of a smaller number of studies. According to a recent systematic review by Kotamarti et al. (24), the incidence of VTE in AMAB would be significantly higher than in AFAB trans people.

A number of factors could contribute to the variable VTE risk in transgender people undergoing gender affirming treatment, including the type of estrogen and the route of administration, age at the estrogen therapy onset, length of therapy, concomitant conditions such as smoking, obesity, thrombophilia and comorbidities (16, 20–22, 54–56). In the present study, meta-regression analyses showed no significant relationship of VTE with BMI, smoking, diagnosis of T2DM, dyslipidemia and hypertension, albeit with the due caution this subject deserves due to the lack of information about these variables in many studies ( Table 1 and Supplementary Table 3 ). Indeed, it is known that obesity increases the risk of VTE in cisgender women using COCs (21) and the combination of COCs and smoking could exert a synergistic effect (22). Interestingly, consistent with our findings, in the recent systematic review by Kotamarty et al. (24), although AMAB trans people exhibited a lower BMI and an almost 2-fold higher prevalence of smoking compared to cisgender women, these variables were not correlated with the risk of VTE. Moreover, in the present meta-analysis, neither estrogen valerate nor oral estrogen use was related to VTE risk. Unfortunately, the dearth of information about type of estrogen and route of administration ( Supplementary Table 3 ) did not allow us to carry out sub-group analyses with these variables.

Worth noting and previously not reported was the here revealed significant association of VTE with an older age of participants and a longer length of estrogen therapy, thus indicating that the longer the exposure time to therapy, the greater the rate of thromboembolic complications for AMAB trans people. Accordingly, when we restricted the analyses to younger series (mean age <37.5 years) and those under estrogen therapy for less than 53 months, the risk was wiped out with no between-study heterogeneity. Therefore, we surmise that the enrollment of series with different mean age and different length of estrogen therapy contributed to the large between-study heterogeneity. Although statistical analyses produced an overall VTE prevalence of 0% in sub-groups younger than 37.5 years and under estrogen therapy for less than 53 months, a complete absence of risk would be unrealistic in these populations. Our results should instead suggest that a not negligible rate of VTE, albeit low, has to be taken into account after 4-5 years of estrogen therapy, especially in older AMAB trans people. This latter finding, if on one hand could be due to an actual thrombophilic effect of prolonged estrogen treatment regimens (54), on the other, it could reflect a higher number of VTE diagnoses arising over time from regular control visits which usually trans people undergo in clinical settings. The persistence of a large between-study heterogeneity in these sub-analyses might be related to the different prevalence of comorbidities in the study populations, as well as to other variables, including the possible influence of different regimens of antiandrogens.

This study has some limitations. First, as mentioned above, the paucity of available data did not allow to perform reliable quantitative analyses to assess the best estrogen treatment regimen associated with the lowest risk for VTE in this population. However, transdermal estrogens and oral estradiol valerate are recommended by the current WPATH guidelines in people with VTE risk factors (3) while the use of ethinyl estradiol formulation is not recommended (18). Furthermore, the impact of inherited risk factors for VTE in AMAB trans people undergoing gender affirming hormone therapy remains uncertain as only five studies reported results of thrombophilia screening ( Table 1 ). Finally, the trim-and-fill analysis revealed a possible publication bias, suggesting that published studies might be not fully a representative sample of the available evidence. Nevertheless, the corrected pooled OR, taking into account the putative missing studies, demonstrated that publication bias did not substantially affect the overall estimate.

In conclusion, the overall rate of VTE in AMAB trans people undergoing gender-affirming hormone therapy was 2%. Our analyses revealed that in AMAB series with younger age (<37.5 years) and under estrogen therapy for less than 53 months the risk of VTE appears to be negligible. Further studies investigating type and modalities of estrogen therapy are warranted to better manage the risk of VTE in this population.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

MT and AB conceived the concept and design. MT, SP, and AB evaluated the full text of all selected studies for eligibility. AP, SP, FD’A, and DT were involved in the acquisition of the data. MT, AB, and CC were involved in evaluation of quality assessment. MT and AB were involved in the statistical analysis and interpretation of the data. MT wrote the article under SF supervision. MB and SF critically reviewed the article. All authors contributed to the article and approved the submitted version.

This research was supported by the Ministero dell’Istruzione, Università e Ricerca (MIUR), grant number: 2017XLFJAX.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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