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?
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?
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
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.
What is known about this topic?
-
Transgender women using gender-affirming hormone therapy (GAHT) do appear to be at
increased risk of venous thromboembolism (VTE).
-
Available studies are of poor quality, with significant heterogeneity.
What does this paper add?
-
The risk of VTE is modified by type, dose, and route of estrogen; and duration of
therapy, increasing age, high BMI, and smoking.
-
Although there are risks associated with estradiol therapy, these must be weighed
against the increased quality of life associated with gender-affirming hormone therapy
(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.
-
The feasibility of performing large prospective studies powered to conduct statistically
significant analyses should be explored, to understand precise risk, and how individual
and estrogen-related modifiers interact, to allow for potential interventions to minimize
VTE risk.
