Should Exogenous Estrogens Be Stopped for Surgery in Transgender Women?

Abstract

There are an estimated 700,000 to 1 million transgender individuals living in the United States alone.1, 2 Although these individuals require the same, if not greater, level of surgical care due to the importance of gender-affirming surgery, they often require medical treatment involving cross-sex hormone therapy or medications, which block the effects of endogenous hormones. For transfeminine (male-to-female transgender) individuals, patients are typically counseled to hold medications such as exogenous estrogens due to the concern of increased risk of venous thromboembolism (VTE). This practice is not without risks as stopping treatment can increase dysphoria and lead to symptoms such as hot flashes and mood disruption. Indeed, recent studies have brought to light controversies regarding the appropriateness of stopping medical therapy. This review aims to answer whether or not exogenous estrogens should be stopped prior to surgery in male-to-female transgender individuals. Asscheman et al. performed a 2013 review of the risk of developing VTE in transgender women receiving hormone therapy.1 They found 10 studies reporting VTE in male-to-female subjects treated with cross-sex hormones between 1980 and 2012. They described the decrease in the prevalence and incidence rates of VTE among transgender women over the course of 40 years, likely attributed to safer practices in the formulation and administration of exogenous estrogens, such as the use of transdermal estrogens in patients >40 years of age. Regarding postoperative VTE, the authors compared 1989 and 1997 studies of postoperative VTE prevalence. The later study reported a lower prevalence (<1.0% vs. 1.7%), attributed to the widespread use of perioperative low molecular weight heparin. Although noting that oral contraception (OC) is typically not discontinued by cisgender women before surgery due to the risk of unplanned pregnancy, the authors recommended discontinuing hormonal therapy in transgender women 2 weeks before surgery as they did not carry this risk. They also recommended waiting 3 to 4 weeks before resuming hormonal treatment. Both recommendations were acknowledged as not supported by evidence. Nonetheless, cessation of hormones 2 weeks prior to surgery has become the generally accepted protocol. Similarly, Shatzel et al. conducted a 2017 review of thrombotic issues in transgender medicine, reviewing hormonal interventions and related hematologic complications. Like many reviews on the risks of VTE in transgender individuals, the authors noted the limited data on the thrombotic complications for transfeminine persons. They therefore applied studies on menopausal hormone replacement therapy (HRT) and OC in cisgender women as a biologic correlate. The increased risk of VTE in cisgender women taking these hormone formulations has been well described. For instance, in menopausal therapy, HRT has been shown in pooled prospective and randomized controlled trials to increase the rates of VTE in cisgender women about fourfold, with the greatest risk occurring within the first year of therapy and among smokers.3 The few studies (11 total) that examined VTE risk in transgender patients were all retrospective in nature. The authors further clarified the differences in the rates of thrombosis based on the route and form of estrogen used. The rate of VTE was highest with oral estrogen supplementation, particularly ethinylestradiol, and lowest with transdermal estrogen.3 As with cisgender women, the risk of VTE in transgender women was highest in the first year after starting estrogen supplementation and among smokers. However, the increased risk in the postoperative period is less clear. Guidelines regarding holding HRT in cisgender women are varied with some recommending cessation prior to surgery and others stressing only thromboprophylaxis. Nonetheless, the authors recommended cessation of exogenous estrogens for 2 weeks prior to surgery in transgender women.1, 3 Although the authors also acknowledged the lack of data supporting this practice, they cited the lack of side effects and pregnancy risk with holding hormonal therapy. More recently, in a 2019 systemic review by Boskey et al., 18 articles were reviewed examining how medications used in cross-sex hormone treatment affect perioperative risk.2 Among them, 12 studied the impact of estrogens on perioperative risk ranging from as far back as the 1970s. Due to the lack of robust studies on the effects of hormone therapy on transgender women, all studies investigated the role of exogenous estrogen in cisgender women. Six of the 12 studies, comprising a total of 1,706 total women, demonstrated an increased risk of VTE. Among these, the highest level of evidence was a large prospective study comprising 817 women undergoing spine surgery, which reported that estrogen therapy significantly increased postoperative VTE risk (univariate relative risk, 6.2).4 In contrast, the six remaining studies, comprising a total of 6,598 patients found no difference in increased postoperative VTE risk. For instance, a case–control study of 318 women undergoing hip and knee arthroplasty found no difference in VTE between women undergoing HRT and those who were not.5 Although there exists evidence demonstrating the thrombogenic potential of exogenous estrogens in cisgender women, the authors noted that researchers have questioned whether estrogen increases the risk of VTE in the postoperative period beyond that of undergoing surgery. They also cited the lack of studies and difficulty obtaining data on the perioperative safety of estrogen in transgender women due to their routine discontinuation of hormones despite a lack of evidence supporting the practice.2 Furthermore, as progestins used in combined OCs and HRT may also affect thrombogenic risk and transgender women are generally prescribed unopposed estrogens, they cautioned that extrapolating the results of hormone studies on cisgender women may not be generalizable. While it is true that transgender women do not have to balance the risk of discontinuing hormone therapy with the risk of pregnancy, the authors emphasized the physical and behavioral side effects of discontinuing estrogen, including emotional lability, anxiety, depression, and perimenopausal-like symptoms. Due to the inconsistency of evidence and the lack of studies examining the perioperative risk in transgender women, the authors concluded that decisions on discontinuing estrogen treatment should keep individual risk factors and concerns in mind.2 In the senior author's practice, hormones are held for 2 weeks before surgery unless the patient's endocrinologist states that hormone use may continue. We permit resumption of hormones once the patient returns home and feels their daily activity comfort has reached the preoperative level. Recognizing the lack of transgender-specific evidence regarding the cessation of estrogen, the practice of discontinuing estrogen therapy for 2 weeks prior to surgery should be weighed against individual risk factors, mode of administration, and side effects. Robust transgender-specific prospective studies evaluating the postoperative risks and side effects of discontinuing estrogen therapy are necessary. These recommendations are based on three reviews, which include prospective cohort studies, retrospective cohort studies, case control, and case series studies (level 4 evidence; Table I).