Venous Thromboembolism and Estrogen-Containing Gender-Affirming Hormone Therapy

Abstract

Gender-affirming therapy involves the use of hormones to develop the physical characteristics of the identified gender and suppressing endogenous sex hormone production. Venous thromboembolism (VTE) is a known risk of exogenous estrogen therapy, and while evidence of VTE risk among transgender women using modern gender-affirming hormone therapy (GAHT) is still emerging, it is thought to affect up to 5% of transgender women. Historically, GAHT was associated with a high risk of VTE; however, modern preparations are less thrombogenic mainly due to significantly lower doses used as well as different preparations. This review presents the available literature regarding the following four topics: (1) risk of VTE among transgender women receiving estradiol GAHT, (2) how the route of administration of estradiol affects the VTE risk, (3) perioperative management of GAHT, (4) VTE risk among adolescents on GAHT. There is a need for large, longitudinal studies of transgender women using GAHT to further characterize VTE risk and how this is affected by factors such as patient age, duration of GAHT use, tobacco use, body mass index, and comorbidities. Future studies in these areas could inform the development of clinical guidelines to improve the care of transgender people.

Keywords

transgender - estrogen - venous thromboembolism - hormone therapy - gender

Definitions of Terms

The important terms used in this study have been defined:

Gender: refers to the socially constructed characteristics of women, men, girls, and boys as distinct from the biological and physiological characteristics.[1] Gender identity refers to a person's perception of themselves as male, female, both, or neither and can be the same from their sex assigned at birth (cisgender) or different (transgender).[2]

Transgender: refers to people whose gender identity is different from the traditional gender expectations based on the sex they were assigned at birth. A transgender woman (or transwoman) was assigned male at birth but identifies as having female gender identity and a transgender man (or transman) was assigned female at birth but identifies as having a male identity.[3]

Transgender and gender diverse (TGD): umbrella term for people whose gender identity is different to the sex they were assigned at birth.

Gender transition: the process by which people take actions to align their gender identity with their gender expression and outward appearance. Gender transition includes name and pronoun changes, wearing gender-affirming clothing, taking gender-affirming hormone therapy, and undergoing gender-affirming surgery.

Gender-affirming hormone therapy (GAHT): the use of hormones to aim to align physical characteristics with gender identity and ultimately reduce gender dysphoria and improve wellbeing. These aim to suppress endogenous sex hormone production and maintain sex hormone levels in the physiologic range for the affirmed gender.[4]

Gender-affirming surgery (GAS): refers to surgical procedures intended to align a person's physical anatomy with their gender identity.

Introduction

Transgender and gender diverse (TGD) patients have a gender identity that is different to their sex assigned at birth and their physical characteristics. It is estimated that 0.1 to 2% of the population are TGD; however, significant heterogeneity exists between studies of transgender prevalence.[5] This is largely attributable to a variable “case definition” of transgender, which may be based on self-reported gender identification, use of gender-affirming hormone therapy (GAHT) or gender-affirming surgery (GAS).[6] Transgender health is a relatively new and evolving field and therefore currently recommendations are largely based on consensus opinion. Transgender women use estrogen to develop female characteristics, which is often continued indefinitely in many patients. Venous thromboembolism (VTE) is considered to be the most serious adverse outcome of estradiol therapy among transgender women.[7] Much of the information we have is extrapolated from cisgender women receiving the combined oral contraceptive pill (COCP) or hormone replacement therapy (HRT), but there are important and significant differences between these groups that warrant discussion. VTE is thought to affect up to 5% of transgender women receiving GAHT, with the risk significantly affected by additional factors including increasing age, obesity, smoking, and personal or family history of VTE.[8] Modern estrogen preparations are much less thrombogenic than older versions, mainly due to significantly reduced estrogen dose used, but the role of route of administration on VTE risk is contentious. As the numbers of people who openly identify as transgender increase and seek medical care, health care professionals will need to improve knowledge and skills in managing their care.

This review presents the available literature regarding VTE risk and gender-affirming estradiol therapy in adults and adolescents and the management of GAHT in the perioperative period. Masculinizing therapy, predominantly testosterone, is not considered to carry an increased risk of VTE.[8] Thus, this review will focus on VTE in transgender women. Findings from this review could inform clinical practice and highlight areas for future research.

Background

It is well established that estrogen therapy, in the form of COCP or menopausal HRT, is associated with an increased risk of VTE. This increased risk is shown in [Fig. 1] and is due to: (1) elevated levels of von Willebrand factor, and factors II, VII, VIII, X, and fibrinogen[9] [10]; (2) reduced levels of tissue factor pathway inhibitor and increased thrombin activatable fibrinolysis inhibitor[10]; (3) reduced plasma concentrations of antithrombin and reduced Protein S resulting in the decreased inactivation of factor V[11]; and (4) induction of a pro-inflammatory state with a rise in C-reactive protein, which appears specific to low-dose estrogen exposure such as with the COCP and GAHT.[12] There is also evidence that exposure to exogenous estrogen over time can cause an acquired resistance to protein C.[13] Finally, estrogen in the form of the COCP has been shown to increase platelet aggregation in a dose-dependent manner.[14]

Fig. 1 Changes in the coagulation system due to estrogen. aPC, activated protein C; AT, antithrombin; VWF, von Willebrand factor. Created with biorender.com. (Adapted from Abou-Ismail et al 2020[71].)

These physiological implications of estrogen tip the hemostatic balance into a prothrombotic state, increasing VTE risk. While many of these factors apply to TGD people, there are significant differences in how hormones are used, doses and timing compared with COCP use in cisgender women, and as such these risks are not directly comparable in the TGD setting. GAHT results in an increase in FIX and FXI, an increase in fibrinogen, and an increase in activated protein C ratio.[15] Traditionally, progestogen-containing medications were not thought to play a role in increasing the risk of VTE; however, recent evidence suggests progestogens may also be an independent risk factor for VTE.[16] [17] [18]

What Constitutes GAHT?

Gender affirmation is a multidisciplinary treatment of which hormone therapy is one component. Aims of GAHT are to suppress endogenous sex hormones determined by the person's genetic/gonadal sex and to maintain sex hormone levels within the normal physiologic range for the person's affirmed gender.[19] For transgender females, treatment with physiologic doses of estrogen alone is insufficient to suppress testosterone into the normal range for females, and as such adjunctive therapies with antiandrogens (spironolactone, cyproterone acetate) or GnRH agonists are required.[20] Estrogen can be used as an oral conjugated estrogen, 17β-estradiol, ethinylestradiol (EE), or transdermal 17β estradiol, although EE is rarely used now for GAHT. Serum estradiol levels can be measured to maintain it at the level for premenopausal females (100–200 pg/mL) and testosterone suppressed to <50 ng/dL.[19] It is the estrogen therapy in GAHT that increases the risk of VTE in transgender women, although whether it has similar pro-coagulant effects to the COCP and HRT has not been extensively studied.[15]

What Is the Role of the Hematologist?

Hematologists are likely to be involved in the care of people undergoing GAHT in two contexts: (1) in the initial risk assessment and discussion of VTE risk, and (2) if and when VTE has already occurred, how to optimally manage anticoagulation and hormone therapy. Thus, it is important that hematologists understand the risks of GAHT, in the context of each individual and other contributors to VTE risk.

Two major clinical practice guidelines by the Endocrine Society and the World Professional Association for Transgender Health provide guidance on health management in TGD patients.[7] [19] These guidelines discuss instigation of hormone therapy, and how to monitor hormone levels to maintain physiologic levels. There are no absolute contraindications for feminizing hormone therapy[7]; relative contraindications that might require a review by a hematologist prior to GAHT include previous VTE, strong family history of VTE or hereditary thrombophilia, or presence of pro-thrombotic comorbidities. Thrombophilia screening prior to initiation of GAHT is not routine and should only be considered if an individual has a personal history of unprovoked VTE, or known family history of an inherited thrombophilia.[19] Although the presence of a thrombophilia would not be a contraindication to GAHT, it may improve risk assessment and explaining risk to the patient. Education and optimization of health prior to commencing GAHT is encouraged, including smoking cessation, healthy diet, and regular exercise.

Management of VTE in transgender women is no different to cisgender women—anticoagulation should be commenced as appropriate to the circumstance of the VTE. Recommendations regarding duration of therapy can be extrapolated from guidelines for hormone-associated VTE in the context of COCP or HRT.[21] It is generally recommended that hormone therapy can be continued concurrently with anticoagulation,[22] and because ceasing GAHT can have significant consequences for the patients physiology and mental/emotional wellbeing, anticoagulation is usually continued for as long as GAHT is continued.[23]

It should be noted that there are substantial limitations to the literature regarding VTE risk associated with the use of GAHT, given these data are limited to retrospective cohort or case-control studies with heterogeneous demographic profiles. Regardless, in the absence of large prospective registry data, the available literature does provide some utility in deciphering risk of VTE particularly with regards to type of hormone and route of administration.

Method

The material in this narrative review is derived from peer-reviewed journals published between September 1989 and July 2022, accessed from the PubMed, Google Scholar, and Cochrane Library databases between May 2 to May 9, 2022. The search terms used were “transgender or transsexual,” “thrombosis or thromboembolism,” “estrogen or oestrogen,” “adolescent,” and “surgery.” References listed in publications were also accessed. Two researchers selected articles, and all relevant articles were included given the low number of findings. We only included articles published in English.

Results

In total, 91 articles were identified based on initial search ([Fig. 2]). In total, 12 observational studies and 4 meta-analyses published between 1989 and 2021 that investigated the association between estrogen therapy and thrombotic events in transgender women were identified. No randomized controlled trials have been published to date. [Table 1] describes the selected articles. The meta-analyses included various combinations of the 12 observational studies we included here, which are specified in [Table 2].

Table 1 Summary of studies analyzing VTE in transgender women using GAHT

Reference	Study type and design	Participants (n)	Setting/country	Study duration	Estrogen regimen	Number of VTE (%)
Asscheman et al[42] (1989)	Retrospective cohort, 1972–1986	303 (median age 32 years)	The Netherlands, endocrinology/andrology outpatient department (single center)	Median follow-up: 3.6 years	Ethinylestradiol 100 µg	19 (6.3%)
Van Kesteren et al[41] (1997)	Retrospective cohort, 1975–1994	816	The Netherlands, endocrinology/andrology outpatient department (single center) (overlap with Asscheman et al[42])	7,734 patient-years	Ethinylestradiol 100 µg Transdermal 17β-estradiol 50–100 µg/24 hours (n = 138)	45 (5.5%)
Schlatterer et al[70] (1998)	Retrospective cohort, 1991–1995	46 (median age between 21 and 30 years)	Germany Endocrinological outpatient department (single center)	4 years	Intramuscular estradiol valerate 40–100 mg every 2 weeks	0
Dittrich et al[43] (2005)	Prospective cohort, dates not reported	60	Germany Obstetrics and gynecology department (single center)	2 years	Oral estradiol valerate and gonadotropin-releasing hormone agonist	1 (1.7%)
Ott et al[46] (2010)	Retrospective cohort, 1995–2007	162	Austria Obstetrics and gynecology outpatient department (single center)	Mean follow-up: 5 years	Transdermal estradiol 100 µg	0
Wierckx et al[54] (2012)	Cross-sectional study, invitation to participate if consulted in 2006	50 (median age 43 years)	Belgium Department of Endocrinology (single center)	Median duration of GAHT: 10 years	Transdermal estradiol gel 1.5 mg/24 hours (n = 22), estradiol patch 50 mg/24 hours (n = 3), oral estradiol valerate 2 mg (n = 19), oral estriol 2 mg (n = 1), oral ethinylestradiol 120 mg (n = 2)	2 (4.3%)
Wierckx et al[48] (2013)	Case–control study, 1987–2012	214	Belgium Academic/university hospital (single center)	Mean duration of GAHT: 7.4 years	Transdermal estradiol gel 1.5 mg/24 hours (n = 76), estradiol patch 50 mg/24 hours (n = 29), oral estradiol valerate 2 mg (n = 91), oral estriol 2 mg (n = 1), oral ethinylestradiol 50 mg (n = 2), oral ethinylestradiol oral contraceptive 30–50 mg (n = 5)	9 (4.4%)
Wierckx et al[47] (2014)	Prospective cohort study, 2010–2012	53	Belgium and Norway, academic/university hospitals (multicenter)	1 year	Younger than 45 years: 4 mg estradiol valerate (n = 40); older than 45 years: 100 µg/24 hours transdermal 17-β estradiol patch (n = 13)	0
Arnold et al[44] (2016)	Retrospective study, 2008–2016	676	United States Community health center (single center)	Mean duration of GAHT: 1.9 years	Oral estradiol 4–8 mg (n = 676) Conjugated equine estrogen, dose not specified (n = 42)	1 (0.15%)
Getahun et al[58] (2018)	Cohort study, 2006–2014	2,842	United States Electronic medical record review (multicenter)	Median follow-up: 4.0 years	Not reported	61 (2.1%)
Meyer et al[49] (2020)	Retrospective cohort study, 2009–2017	155 (median age 25 years)	Germany Endocrine outpatient clinic (single center)	Not reported	Transdermal gel 1.5–6 mg/24 hours (n = 73), transdermal patch 0.1 mg/24 hours (n = 9) Oral estradiol valerate 3–10 mg (n = 73)	3 (1.9%)
Mullins et al[35] (2021)	Retrospective chart review, 2013–2019	182 adolescents (median age 17 years)	United States Hospital-associated transgender health clinic (single center)	Median follow-up: 1.5 years	Oral, n = 165 Transdermal, n = 10 Intramuscular, n = 7 (doses and formulation not specified)	0

Abbreviations: GAHT, gender-affirming hormone therapy; VTE, venous thromboembolism.

Table 2 Summary of meta-analyses of VTE among transgender women using GAHT

Reference	Total number of studies included	Observational studies referenced included in meta-analysis	Findings	Heterogeneity	Conclusions
Maraka et al[8] (2017)	10	41, 42, 43, 46, 47, 48, 54, 70	Incidence of VTE was higher among MTF vs. FTM cohorts Risk of VTE among the MTF cohort ranged from 0 to 5%	Significant	Data regarding VTE were insufficient to allow for detailed assessment
Khan et al[38] (2019)	12	41, 43, 44, 46, 47, 48	Incidence of VTE in transgender women on estrogen was 2.3 per 1,000 person-years (95% CI: 0.8–6.9)	Significant	Transgender and cisgender women on estrogen therapy have similar rates of VTE
Totaro et al[37] (2021)	18	35, 41, 43, 44, 46, 48, 49, 58, 70	Overall prevalence of VTE in MTF: 2% (95% CI: 1–3%) Prevalence of VTE in MTF aged >37.5 years: 3% (95% CI: 0–5%) Prevalence of VTE in MTF aged ≤37.5 years: 0% (95% CI: 0–2%)	Significant	Higher prevalence of VTE associated with older age and longer length of estrogen therapy
Kotamarti et al[40] (2021)	22	41, 42, 44, 46, 47, 48, 54, 58	Pooled incidence of VTE in MTF: 42.8 per 10,000 patient-years	Information not available	The rate of VTE among MTF was similar or higher than that in cisgender women on HRT.

Abbreviations: CI, confidence interval; FTM, female to male; GAHT, gender-affirming hormone therapy; HRT, hormone replacement therapy; MTF, male to female; VTE, venous thromboembolism.

Fig. 2 Flowchart of study selection process.

Discussion

What Are the Background Rates of VTE in Cisgender Women?

When calculating the risk of VTE among transgender women taking estrogen therapy, it is important to consider other common thrombotic risk factors. A large part of the risk of VTE is age-dependent—the risk in someone aged <40 years is approximately 1 in 10,000 annually, rising to 5 to 6 per 1,000 annually by age 80.[24] The risk in cisgender men is slightly higher than a cisgender woman not taking hormone therapy.[25]

The use of the COCP increases this age-dependent background risk by two- to ninefold, with the risk based on both estrogen dose and type, and also the type of progestogen.[26] [27] The highest risk of VTE is found with third- and fourth-generation progestogens, such as desogestrel, gestodene, and drospirenone, combined with EE,[27] particularly when combined with higher doses of EE of 30–40 µg.[28] A postmenopausal cisgender woman using transdermal HRT does not have an increased risk of VTE above baseline, but oral HRT increases the risk by two- to threefold, with the highest risk being oral conjugated equine estrogen (CEE) combined with medroxyprogesterone acetate.[29]

Additional specific risk factors include the presence of a hereditary thrombophilia, which can increase the baseline risk by 1.9- to 24-fold, depending on the specific thrombophilia[25]; smoking; and obesity (2–3-fold risk).[30] [31]

Type and Dose of Hormones in COCP and HRT Compared with GAHT

There are significant differences in the dose, type, and delivery of hormones in GAHT compared with the COCP and HRT, which are outlined in [Table 3].[32] [33] Importantly, the synthetic EE is generally used in the COCP, whereas 17β-estradiol is primarily used in GAHT; and second in GAHT estradiol levels are monitored and changed to achieve physiologic levels, whereas in cisgender women COCP dose is generally fixed (i.e., not monitored).[34] [35] Additionally, GAHT is used indefinitely whereas the COCP and HRT are generally time-limited in use. In terms of comparative potency, although difficult to compare, EE is thought to be 500 times more potent than 17-β estradiol, and 650 times more than estradiol valerate.[36]

Table 3 Types and doses of estrogen and other agents used in combination in the COCP, HRT, and GAHT

	COCP[26] [27] [34]	HRT[33]	GAHT[19] [35]
Type of estrogen used	Ethinylestradiol (EE) Estradiol valerate	Conjugated equine estrogen (CEE) 17β-estradiol	17β-Estradiol Estradiol valerate
Delivery mechanism	Oral	Oral or transdermal	Oral or transdermal
Typical doses used	20–35 µg/d EE 1–2 mg/d estradiol valerate	1 mg 17-β estradiol oral 0.05 mg/d transdermal 0.625 mg/d CEE	2–6 mg/d oral 17β estradiol 0.025–0.2 mg/d transdermal 2–4 mg/d oral estradiol valerate
Other agents used in combination	First- and second-generation progestogens: norethisterone, medroxy progesterone, and levonorgestrel Third-generation progestogens: gestodene desogestrel and norgestimate	Combine with a progestogen if no previous hysterectomy—oral natural micronized progesterone 200 mg/d cyclical or 100 mg continuous; medroxyprogesterone 5–20 mg/d	Cyproterone acetate Spironolactone GnRH agonists

Abbreviations: COCP, combined oral contraceptive pill; GAHT, gender-affirming hormone therapy; HRT, hormone replacement therapy.

What Is the Risk of VTE in Transgender Women?

Four meta-analyses of VTE risk among transgender women using GAHT have been published to date and are summarized in [Table 2]. All reported significant heterogeneity of included studies and insufficient data to conduct detailed analysis. Additionally, only one study adjusted for, or reported, incidence based on age, reporting a 0 and 3% prevalence among transgender women aged ≤37.5 and ≥37 years, respectively.[37] A review of 12 studies estimated the incidence of VTE as 2.3 per 1,000 person-years[38] and another review reported a 0 to 5% risk of VTE among transgender women using GAHT.[8] A Cochrane review[39] from 2020 found no published studies meeting inclusion criteria, thus no comment could be made on any safety outcomes of GAHT for transgender women. A contemporary systematic review[40] of data from over 9,000 transgender and 103,000 cisgender people reported a fourfold increase in the risk of VTE among transgender women compared with transgender men. Comparison with cisgender groups revealed that the rate of VTE was similar or higher among transgender women compared with cisgender women on HRT.[40]

Does the Type of Estrogen Affect Risk of VTE?

As outlined previously, there are several different formulations of estrogen. Oral administration options include micronized 17β-estradiol, CEE, and estradiol valerate, as well as EE which is widely used for the COCP but no longer recommended in GAHT.[19] The studies presented are difficult to directly compare due to differing types, doses, and mode of delivery of estrogen used, outlined in [Table 1]. Observational studies suggest the type of estrogen does affect VTE risk, with EE used as the initial form of estrogen in GAHT being associated with a high incidence of VTE (5.5–6%) but it was being used at a very high dose of 100 µg (compared with the dose of up to ∼35 µg used in the COCP).[41] [42] The use of EE in the setting of GAHT is generally no longer recommended.[19] Additionally, it is not possible to measure serum levels of EE, being a synthetic estrogen.

Other oral estrogens such as CEE appear to have a lower risk of VTE. A cohort study of 60 transgender women taking oral synthetic estrogen reported only one case of VTE which occurred in the setting of an inherited thrombophilia.[43] Similarly, a large study of 676 women taking CEE, followed-up for a median of 1.9 years, reported only one case of VTE.[44] Another small study of 50 young transgender women reported no cases of VTE with CEEs at a dose of 0.625 mg/d use over a 4-year period.[45]

Does the Route of Administration Affect VTE Risk?

There is conflicting evidence regarding the effect of route of estrogen administration on VTE risk. A study of 816 transgender women in 1997 identified a 50% reduction in VTE incidence if all transgender women ≥40 years of age switched from oral EE to transdermal estradiol.[41] However, the elevated risk of VTE observed among participants taking oral EE was likely due to the EE formulation itself, not the route of administration. Age was also a likely confounder in this study.[41] A later study of 162 women using transdermal estradiol reported no cases of VTE over a 5-year period.[46]

In contrast, a multicenter prospective study[47] allocated 40 transgender women aged <45 years to receive 4 mg oral estrogen valerate and 13 transgender women aged ≥45 years to receive 100 µg transdermal estradiol daily. Both groups were also using 50 mg cyproterone daily. No cases of VTE were reported during 1 year of follow-up. Although conclusions about the comparative risk of oral and transdermal estradiol cannot be made from this study due to the lack of control groups and small sample size, these findings do not suggest any significant difference between the two routes of administration.[47] A case–control study[48] of 214 transgender women on GAHT for a median of 7.4 years identified 11 cases of VTE, one-third of which occurred in people using transdermal estradiol. Similarly, two of three cases of VTE in a retrospective cohort study[49] of 155 transgender women occurred in people using transdermal preparations. In both studies, other risk factors were present among those affected (older age, higher body mass index [BMI], immobility following GAS); therefore, the causative link between route of estrogen administration and VTE is not clear. Analysis of coagulation assays among transgender women receiving transdermal or oral estradiol for GAHT (excluding EE) found the estradiol route did not influence coagulation parameters.[50] However, there have not been any head-to-head studies or studies of sufficient duration in GAHT to make strong conclusions either way.

It is well established that the use of transdermal estrogen in the HRT setting is not associated with an increased risk of VTE. A nested case–control study of over 80,000 women found no increased risk of VTE with the use of transdermal preparations.[29] A narrative review similarly found no increased risk of VTE with transdermal HRT even in women considered higher risk, including those with previous VTE, obesity, proinflammatory conditions, or prothrombotic genetic polymorphisms.[51]

Do Antiandrogens Play Any Role in VTE Risk?

Cyproterone acetate, spironolactone, and GnRH agonists are used in this setting to suppress testosterone levels. While cyproterone acetate has been shown to have a similar VTE risk to other higher VTE-risk progestogens when used with EE, its risk when combined with low-dose estradiol in GAHT is not well described.[52] Spironolactone is not known to increase VTE risk.[4]

What Is the Role of Other Risk Factors in VTE?

The body of literature on transgender women using GAHT suggests that increasing age, smoking status, and BMI are also important in ascertaining VTE risk.[37] This is consistent with findings from studies of cisgender women using the COCP and HRT.[53] A small study[54] of 50 transgender women in Belgium reported three cases (incidence 6%) of VTE during hormone treatment (two cerebral and one deep vein thrombosis). The participants who experienced a VTE were ≥40 years of age, one had a history of VTE and pulmonary embolism, one was taking EE, and two of three were current smokers. Another study[48] in Belgium reported 11 cases of VTE in their population, only one of which occurred in the absence of other risk factors. Both of these publications reported higher rates of VTE than other studies, which may be partially attributable to the older age of study participants (median age ≥40 years) and high prevalence of risk factors such as smoking. Wierckx et al also noted that age at onset of GAHT and BMI were higher among people who developed a VTE while on GAHT compared with the overall cohort.[47] In contrast, a meta-analysis[37] which included over 11,000 patients concluded no major impact of BMI or smoking on VTE risk, but that increasing age and longer length of estrogen therapy did have an association.

Only one larger study[46] to date has investigated the VTE risk among transgender women receiving GAHT with an underlying inherited thrombophilia. This retrospective cohort study of 162 transgender women using transdermal estradiol reported no cases of VTE over a 5-year study period. A small proportion of this cohort (7.2%) had a thrombophilia, most of which were the lower risk heterozygous factor V Leiden mutation with only one protein S deficiency. A 2022 case series[55] included 7 transgender people with an underlying thrombophilia who received estrogen therapy, three of whom experienced a VTE over a 20-year study period (one case of VTE was provoked by surgery, the other two were considered unprovoked). The finding that underlying thrombophilia increases the risk of VTE is consistent with larger studies of cisgender women taking exogenous estrogen but it appears the risk is still lower in the transgender population. A systematic review and meta-analysis of cisgender women taking the COCP identified significantly increased rates of VTE among participants with an underlying thrombophilia compared with those without, with between four- and 15-times increased risk of VTE depending on the thrombophilia.[56] The reason for this difference between the cisgender and transgender populations is unclear but may be related to the fact that there are much fewer studies and with smaller sample size in transgender compared with cisgender women taking the COCP, as well as differences in dose and population characteristics.

Does the Duration of Hormone Therapy Affect VTE Risk?

It is thought that the highest risk period for developing a VTE is within the first 3 to 12 months of starting the COCP and HRT and stabilizes thereafter,[57] but it appears the risk actually increases with increasing duration of hormone use in transgender woman.[58] [59] Up to 2 years after initiation of estrogen, the adjusted hazard ratio for VTE was 1.5 (95% confidence interval [CI]: 0.5–5.1) compared with reference cisgender men, and 1.7 (95% CI: 0.5–5.5) compared with reference cisgender women.[58] This increased to 5.1 (95% CI: 2.1–12.6) compared with cisgender men and 3.2 (95% CI: 1.3–7.6) at >2 years of follow-up.[58] One meta-analysis (which included the aforementioned study) also found a higher estimate prevalence for VTE in those using estrogen for >53 months compared with <53 months, although suggested that it is confounded by both age and potentially closer monitoring.[37]

How Should GAHT Be Managed in the Setting of Gender-Affirming Surgery?

There exists a debate within the literature and clinicians as to whether GAHT should be ceased prior to GAS. Estrogen therapy, surgery itself, and postoperative reduced mobility are individually associated with an increased VTE risk. Historically, surgeons recommended discontinuation of GAHT 2 to 6 weeks prior to GAS.[60] This recommendation was based on extrapolation of data from studies involving EE regimes which are no longer used. Additionally, cessation of hormone therapy can cause adverse emotional and physiological effects including exacerbation of gender dysphoria, mood swings, hot flushes, and increased facial and body hair and the potential risks of ceasing and restarting GAHT are unknown.[61] [62] [63]

Current guidelines from the American Society of Plastic Surgeons Executive Committee Venous Thromboembolism Task Force Report[62] state that there is “insufficient evidence to create an all-inclusive VTE prophylaxis recommendation” and that VTE risk should be assessed on an individual basis using the Caprini score. The Caprini score integrates several demographic, medical, and surgical risk factors to develop a score of VTE risk.[64] A Caprini score ≥7 warrants risk-reduction strategies including discontinuation of GAHT, and a score ≥9 warrants consideration of chemoprophylaxis.[65] Potential risk factors for VTE in the setting of GAS include type/duration of surgery (for example, pelvic surgery has a higher risk of VTE than other procedures), patient age, underlying medical conditions, history of recent surgery, thrombotic history, thrombophilia, and BMI.[60]

A 2022 systematic review comparing the risk of VTE among patients who continued or ceased GAHT prior to undergoing vaginoplasty found no increased VTE risk if estrogen therapy was continued perioperatively.[66] Nolan et al reported a higher incidence of VTE among the hormone discontinuation group compared with the continuing group; however, this was not statistically significant.[67] Similarly, Kozato et al reported one case of VTE among 407 participants which occurred following 1 week of GAHT cessation prior to surgery.[68] Overall, the risk of perioperative VTE among TGD patients is comparable to that reported for patients undergoing benign gynecological procedures, irrespective of whether GAHT is suspended or continued. It is recommended that the decision on perioperative management of GAHT is individualized, taking into account the patient's preference and individual risks of VTE balanced against the known potential emotional and physiologic effects of hormone cessation.

Are There Any Differences in Adolescents?

It is estimated that 2.5 to 8.4% of young people worldwide identify as TGD and numbers are increasing.[69] To date, only one study[35] analyzing the thrombosis risk in transgender adolescents receiving GAHT has been published. This study involved 611 participants aged 13 to 24 years, 29% of whom were undergoing feminizing hormone therapy with oral or transdermal estradiol preparations.[35] In addition, 17 adolescents were referred for hematological evaluation prior to commencement of GAHT due to the presence of thrombotic risk factors, 5 of whom were treated with anticoagulation. No cases of VTE were reported over 1.5 years of follow-up; however, due to the very low baseline risk of VTE in adolescents and the relatively short follow-up period, as well as the fact less than one-third were transgender females, it means that this study was inadequately powered to identify an increased risk. However, it does suggest that hematological involvement in high-risk patients can guide care, evaluate VTE risk, and implement preventative strategies as appropriate.

Research Gaps and Areas for Future Research

Transgender health is a relatively new health care domain with minimal data and low case numbers. A 2020 Cochrane review[39] on the use of antiandrogen and/or estradiol treatment in the transition of transgender women identified no completed studies that met inclusion criteria. It concluded that there was insufficient evidence to comment on the safety or efficacy of GAHT. Increasing age is a known risk factor for VTE among all patient populations, including transgender women. The use of GAHT in TGD is a relatively new phenomenon, and we do not fully know the effects of GAHT in transgender people beyond middle age. Longitudinal studies are needed to provide insight into the age-related benefits and risks of GAHT and at what point this balance tips toward harm.

Historically, guidelines for GAHT were extrapolated from studies of VTE risk in postmenopausal cisgender women on HRT or cisgender women using the COCP. This had three main flaws: (1) the estradiol preparations used in HRT and COCP differ from those currently recommended for GAHT, (2) higher doses of estradiol are needed to maintain the recommended serum concentrations in transgender women compared with those used in HRT, and (3) the physiology of transgender women is not well researched and cannot be assumed to be identical to that of cisgender women. Several studies have assessed different routes and types of estradiol and have made conclusions about the comparative safety and VTE risk. However, in many of these studies it is unclear whether VTE risk varies due to the route of estradiol administration or the dose. There also appears to be a gap between the evidence and clinical practice when prescribing GAHT, particularly regarding the use of higher doses of estradiol than that in studies.[17]

There is early evidence that the risk of thrombosis increases with duration of GAHT; however, further longitudinal studies are needed for validation and clarification. Other long-term effects of GAHT are currently being researched; however, many studies have low numbers of participants and are unable to report statistically significant results in sub-analysis. A registry which would allow long-term follow-up and reflect “real-world” management may be of particular utility. The body of evidence for GAHT in adolescents is emerging. In many cases, findings from adult studies may be extrapolated to adolescents and young adults; however, specific studies of these age groups would provide higher value care and evidence-based guidelines.

Conclusion

Transgender women using modern oral and transdermal estradiol therapy are at a slightly increased risk of VTE; however, current evidence is based on retrospective reviews and observational studies. It does appear that most cases of VTE in this context occur in older age and/or in the presence of other thrombotic risk factors. VTE risk does not appear to be elevated in adolescents using GAHT compared with adults; however, further studies are required to fully delineate this. Although the body of evidence on transgender health is quickly expanding, large studies with sufficient data to conduct statistically significant analyses are needed. This review highlights several areas for future research, including the effects of GAHT in adolescents, the long-term effects of GAHT on VTE risk, and the role of route and type of estrogen on VTE risk. Although there are risks associated with estradiol therapy, these must be weighed against the increased quality of life associated with GAHT and patients should be empowered to make decisions about their health care and their acceptable level of risk with the input of a multidisciplinary team.

Conflict of Interest

None declared.

Authors' Contribution

M.M. performed the literature review and wrote the manuscript; C.D. performed the literature review and wrote the manuscript. J.D.M. wrote and reviewed the manuscript. H.T. wrote and reviewed the manuscript.

• References

• 1 Human Rights Campaign. Sexual orientation and gender identity definitions. Accessed April 3, 2023 at: https://www.hrc.org/resources/sexual-orientation-and-gender-identity-terminology-and-definitions
• 2 World Health Organisation (WHO). Gender and health. Accessed April 3, 2023 at: https://www.who.int/health-topics/gender#tab=tab_1
• 3 American Psychological Association (APA). Answers to your questions about transgender people, gender identity and gender expression 2014. Accessed April 19, 2023 at: https://www.apa.org/topics/lgbtq/transgender
• 4 Connors JM, Middeldorp S. Transgender patients and the role of the coagulation clinician. J Thromb Haemost 2019; 17 (11) 1790-1797
• 5 Goodman M, Adams N, Corneil T, Kreukels B, Motmans J, Coleman E. Size and distribution of transgender and gender nonconforming populations: a narrative review. Endocrinol Metab Clin North Am 2019; 48 (02) 303-321
• 6 Collin L, Reisner SL, Tangpricha V, Goodman M. Prevalence of transgender depends on the “case” definition: a systematic review. J Sex Med 2016; 13 (04) 613-626
• 7 Coleman E, Radix AE, Bouman WP. et al. Standards of care for the health of transgender and gender diverse people, Version 8. Int J Transgender Health 2022; 23 (Suppl. 01) S1-S259
• 8 Maraka S, Singh Ospina N, Rodriguez-Gutierrez R. et al. sex steroids and cardiovascular outcomes in transgender individuals: a systematic review and meta-analysis. J Clin Endocrinol Metab 2017; 102 (11) 3914-3923
• 9 Harrison RL, McKee PA. Estrogen stimulates von Willebrand factor production by cultured endothelial cells. Blood 1984; 63 (03) 657-664
• 10 Middeldorp S, Meijers JC, van den Ende AE. et al. Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study. Thromb Haemost 2000; 84 (01) 4-8
• 11 Cosman F, Baz-Hecht M, Cushman M. et al. Short-term effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature. Thromb Res 2005; 116 (01) 1-13
• 12 van Rooijen M, Hansson LO, Frostegård J, Silveira A, Hamsten A, Bremme K. Treatment with combined oral contraceptives induces a rise in serum C-reactive protein in the absence of a general inflammatory response. J Thromb Haemost 2006; 4 (01) 77-82
• 13 Rosing J, Tans G, Nicolaes GA. et al. Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives. Br J Haematol 1997; 97 (01) 233-238
• 14 Norris LA, Bonnar J. Effect of oestrogen dose on whole blood platelet activation in women taking new low dose oral contraceptives. Thromb Haemost 1994; 72 (06) 926-930
• 15 Scheres LJJ, Selier NLD, Nota NM, van Diemen JJK, Cannegieter SC, den Heijer M. Effect of gender-affirming hormone use on coagulation profiles in transmen and transwomen. J Thromb Haemost 2021; 19 (04) 1029-1037
• 16 Barsoum MK, Heit JA, Ashrani AA, Leibson CL, Petterson TM, Bailey KR. Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. Thromb Res 2010; 126 (05) 373-378
• 17 Goldstein Z, Khan M, Reisman T, Safer JD. Managing the risk of venous thromboembolism in transgender adults undergoing hormone therapy. J Blood Med 2019; 10: 209-216
• 18 de Bastos M, Stegeman BH, Rosendaal FR. et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev 2014; (03) CD010813
• 19 Hembree WC, Cohen-Kettenis PT, Gooren L. et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2017; 102 (11) 3869-3903
• 20 Gooren LJ, Giltay EJ, Bunck MC. Long-term treatment of transsexuals with cross-sex hormones: extensive personal experience. J Clin Endocrinol Metab 2008; 93 (01) 19-25
• 21 Baglin T, Bauer K, Douketis J, Buller H, Srivastava A, Johnson G. SSC of the ISTH. Duration of anticoagulant therapy after a first episode of an unprovoked pulmonary embolus or deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost 2012; 10 (04) 698-702
• 22 Martinelli I, Lensing AW, Middeldorp S. et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood 2016; 127 (11) 1417-1425
• 23 Baker KE, Wilson LM, Sharma R, Dukhanin V, McArthur K, Robinson KA. Hormone therapy, mental health, and quality of life among transgender people: a systematic review. J Endocr Soc 2021; 5 (04) bvab011
• 24 Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158 (06) 585-593
• 25 Cushman M, Tsai AW, White RH. et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004; 117 (01) 19-25
• 26 Stegeman BH, de Bastos M, Rosendaal FR. et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ 2013; 347: f5298
• 27 LaVasseur C, Neukam S, Kartika T, Samuelson Bannow B, Shatzel J, DeLoughery TG. Hormonal therapies and venous thrombosis: considerations for prevention and management. Res Pract Thromb Haemost 2022; 6 (06) e12763
• 28 Dragoman MV, Tepper NK, Fu R, Curtis KM, Chou R, Gaffield ME. A systematic review and meta-analysis of venous thrombosis risk among users of combined oral contraception. Int J Gynaecol Obstet 2018; 141 (03) 287-294
• 29 Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2019; 364: k4810
• 30 Abdollahi M, Cushman M, Rosendaal FR. Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use. Thromb Haemost 2003; 89 (03) 493-498
• 31 Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med 2005; 118 (09) 978-980
• 32 Kemmeren JM, Algra A, Grobbee DE. Third generation oral contraceptives and risk of venous thrombosis: meta-analysis. BMJ 2001; 323 (7305) 131-134
• 33 Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev 2004; 2004 (04) CD002978
• 34 Thorogood M, Villard-Mackintosh L. Combined oral contraceptives: risks and benefits. Br Med Bull 1993; 49 (01) 124-139
• 35 Mullins ES, Geer R, Metcalf M. et al. Thrombosis risk in transgender adolescents receiving gender-affirming hormone therapy. Pediatrics 2021; 147 (04) e2020023549
• 36 Helgason S, Damber MG, von Schoultz B, Stigbrand T. Estrogenic potency of oral replacement therapy estimated by the induction of pregnancy zone protein. Acta Obstet Gynecol Scand 1982; 61 (01) 75-79
• 37 Totaro M, Palazzi S, Castellini C. et al. Risk of venous thromboembolism in transgender people undergoing hormone feminizing therapy: a prevalence meta-analysis and meta-regression study. Front Endocrinol (Lausanne) 2021; 12: 741866
• 38 Khan J, Schmidt RL, Spittal MJ, Goldstein Z, Smock KJ, Greene DN. Venous thrombotic risk in transgender women undergoing estrogen therapy: a systematic review and metaanalysis. Clin Chem 2019; 65 (01) 57-66
• 39 Haupt C, Henke M, Kutschmar A. et al. Antiandrogen or estradiol treatment or both during hormone therapy in transitioning transgender women. Cochrane Database Syst Rev 2020; 11 (11) CD013138
• 40 Kotamarti VS, Greige N, Heiman AJ, Patel A, Ricci JA. Risk for venous thromboembolism in transgender patients undergoing cross-sex hormone treatment: a systematic review. J Sex Med 2021; 18 (07) 1280-1291
• 41 van Kesteren PJ, Asscheman H, Megens JA, Gooren LJ. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 1997; 47 (03) 337-342
• 42 Asscheman H, Gooren LJ, Eklund PL. Mortality and morbidity in transsexual patients with cross-gender hormone treatment. Metabolism 1989; 38 (09) 869-873
• 43 Dittrich R, Binder H, Cupisti S, Hoffmann I, Beckmann MW, Mueller A. Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist. Exp Clin Endocrinol Diabetes 2005; 113 (10) 586-592
• 44 Arnold JD, Sarkodie EP, Coleman ME, Goldstein DA. Incidence of venous thromboembolism in transgender women receiving oral estradiol. J Sex Med 2016; 13 (11) 1773-1777
• 45 Prior JC, Vigna YM, Watson D. Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism. Arch Sex Behav 1989; 18 (01) 49-57
• 46 Ott J, Kaufmann U, Bentz EK, Huber JC, Tempfer CB. Incidence of thrombophilia and venous thrombosis in transsexuals under cross-sex hormone therapy. Fertil Steril 2010; 93 (04) 1267-1272
• 47 Wierckx K, Van Caenegem E, Schreiner T. et al. 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 2014; 11 (08) 1999-2011
• 48 Wierckx K, Elaut E, Declercq E. et al. Prevalence of cardiovascular disease and cancer during cross-sex hormone therapy in a large cohort of trans persons: a case-control study. Eur J Endocrinol 2013; 169 (04) 471-478
• 49 Meyer G, Mayer M, Mondorf A, Flügel AK, Herrmann E, Bojunga J. Safety and rapid efficacy of guideline-based gender-affirming hormone therapy: an analysis of 388 individuals diagnosed with gender dysphoria. Eur J Endocrinol 2020; 182 (02) 149-156
• 50 Lim HY, Leemaqz SY, Torkamani N. et al. Global coagulation assays in transgender women on oral and transdermal estradiol therapy. J Clin Endocrinol Metab 2020; 105 (07) dgaa262
• 51 Sobel TH, Shen W. Transdermal estrogen therapy in menopausal women at increased risk for thrombotic events: a scoping review. Menopause 2022; 29 (04) 483-490
• 52 Spitzer WO. Cyproterone acetate with ethinylestradiol as a risk factor for venous thromboembolism: an epidemiological evaluation. J Obstet Gynaecol Can 2003; 25 (12) 1011-1018
• 53 Nightingale AL, Lawrenson RA, Simpson EL, Williams TJ, MacRae KD, Farmer RD. The effects of age, body mass index, smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives. Eur J Contracept Reprod Health Care 2000; 5 (04) 265-274
• 54 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
• 55 Kerrebrouck M, Vantilborgh A, Collet S, T'Sjoen G. Thrombophilia and hormonal therapy in transgender persons: a literature review and case series. Int J Transgender Health 2022; 23 (04) 377-391
• 56 Wu O, Robertson L, Langhorne P. et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Thromb Haemost 2005; 94 (01) 17-25
• 57 de Moreuil C, Le Mao R, Le Moigne E. et al. Long-term recurrence risk after a first venous thromboembolism in men and women under 50 years old: a French prospective cohort. Eur J Intern Med 2021; 84: 24-31
• 58 Getahun D, Nash R, Flanders WD. et al. Cross-sex hormones and acute cardiovascular events in transgender persons: a cohort study. Ann Intern Med 2018; 169 (04) 205-213
• 59 Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008; 336 (7655) 1227-1231
• 60 Hontscharuk R, Alba B, Manno C. et al. Perioperative transgender hormone management: avoiding venous thromboembolism and other complications. Plast Reconstr Surg 2021; 147 (04) 1008-1017
• 61 Lawrence AA. Patient-reported complications and functional outcomes of male-to-female sex reassignment surgery. Arch Sex Behav 2006; 35 (06) 717-727
• 62 Murphy Jr RX, Alderman A, Gutowski K. et al. Evidence-based practices for thromboembolism prevention: summary of the ASPS Venous Thromboembolism Task Force Report. Plast Reconstr Surg 2012; 130 (01) 168e-175e
• 63 Boskey ER, Taghinia AH, Ganor O. Association of surgical risk with exogenous hormone use in transgender patients: a systematic review. JAMA Surg 2019; 154 (02) 159-169
• 64 Cronin M, Dengler N, Krauss ES. et al. Completion of the updated caprini risk assessment model (2013 Version). Clin Appl Thromb Hemost 2019; 25: 1076029619838052
• 65 Pannucci CJ, MacDonald JK, Ariyan S. et al. Benefits and risks of prophylaxis for deep venous thrombosis and pulmonary embolus in plastic surgery: a systematic review and meta-analysis of controlled trials and consensus conference. Plast Reconstr Surg 2016; 137 (02) 709-730
• 66 Badreddine J, Lee MH, Mishra K. et al. Continuing perioperative estrogen therapy does not increase venous thromboembolic events in transgender patients: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci 2022; 26 (07) 2511-2517
• 67 Nolan IT, Haley C, Morrison SD, Pannucci CJ, Satterwhite T. Estrogen continuation and venous thromboembolism in penile inversion vaginoplasty. J Sex Med 2021; 18 (01) 193-200
• 68 Kozato A, Fox GWC, Yong PC. et al. No venous thromboembolism increase among transgender female patients remaining on estrogen for gender-affirming surgery. J Clin Endocrinol Metab 2021; 106 (04) e1586-e1590
• 69 Zhang Q, Goodman M, Adams N. et al. Epidemiological considerations in transgender health: a systematic review with focus on higher quality data. Int J Transgender Health 2020; 21 (02) 125-137
• 70 Schlatterer K, Yassouridis A, von Werder K, Poland D, Kemper J, Stalla GK. A follow-up study for estimating the effectiveness of a cross-gender hormone substitution therapy on transsexual patients. Arch Sex Behav 1998; 27 (05) 475-492
• 71 Abou-Ismail MY, Citla Sridhar D, Nayak L. Estrogen and thrombosis: a bench to bedside review. Thromb Res 2020; 192: 40-51

Publikationsverlauf

Eingereicht: 14. Juni 2023

Angenommen: 09. Oktober 2023

Accepted Manuscript online:
10. Oktober 2023

Artikel online veröffentlicht:
02. November 2023