Association of Surgical Risk With Exogenous Hormone Use in Transgender Patients: A Systematic Review.

IMPORTANCE: A growing number of transgender patients are receiving gender-affirming hormone treatments. It is unclear whether the evidence supports the current practice of routinely discontinuing these hormones prior to surgery. OBJECTIVE: To determine how medications used in cross-sex hormone treatment (CSHT) affect perioperative risk. EVIDENCE REVIEW: A series of searches were carried out in PubMed and Excerpta Medica Database to identify articles using each of the terms testosterone, estrogen, estradiol, oral contraceptive, spironolactone, cyproterone acetate, finasteride, dutasteride, leuprolide, goserelin, and histrelin, in combination with the terms surgery, perioperative, thrombosis, thromboembolism, and operative. The search was not restricted to perioperative outcomes in transgender populations because many surgeons routinely discontinue hormone use prior to surgery in this population, which makes it impossible to study how hormones affect outcomes. Additional sources were also identified from the texts of reviewed articles. Articles were excluded if they were animal studies or case reports, did not explicitly discuss surgical outcomes, or were restricted to removal of hormonally sensitive tissues. FINDINGS: Eighteen articles addressing perioperative outcomes were identified by this systematic review, including 1 on CSHT, 12 on estrogens and progesterones, 1 on testosterone, and 4 on spironolactone and antiandrogens. Data were limited, but use of exogenous testosterone was not found to be associated with an increased risk of venous thromboembolism or other complications during surgery. Moderate evidence suggests that spironolactone is not associated with negative surgical outcomes. The data linking estrogen use and thrombosis is inconsistent in the perioperative period and does not address the types of estrogens most often used for CSHT. CONCLUSIONS AND RELEVANCE: Current evidence does not support routine discontinuation of all CSHT prior to surgery, particularly given the lack of information on risks associated with resuming these medications after they have been stopped. Evidence suggests there is no need to discontinue either testosterone or spironolactone, although their association with perioperative outcome quality has not been studied in depth. Most of the evidence that supports discontinuation of estrogen prior to surgery is based on oral estrogen regimens that are not typically used in transgender patients, and even with those formulations, there are conflicting reports on perioperative risk. Further research is needed to determine the safety of continuing hormone treatment and elucidate risks of short-term discontinuation.

Long-term follow-up of transsexual persons undergoing sex reassignment surgery: cohort study in Sweden.

CONTEXT: The treatment for transsexualism is sex reassignment, including hormonal treatment and surgery aimed at making the person's body as congruent with the opposite sex as possible. There is a dearth of long term, follow-up studies after sex reassignment. OBJECTIVE: To estimate mortality, morbidity, and criminal rate after surgical sex reassignment of transsexual persons. DESIGN: A population-based matched cohort study. SETTING: Sweden, 1973-2003. PARTICIPANTS: All 324 sex-reassigned persons (191 male-to-females, 133 female-to-males) in Sweden, 1973-2003. Random population controls (10:1) were matched by birth year and birth sex or reassigned (final) sex, respectively. MAIN OUTCOME MEASURES: Hazard ratios (HR) with 95% confidence intervals (CI) for mortality and psychiatric morbidity were obtained with Cox regression models, which were adjusted for immigrant status and psychiatric morbidity prior to sex reassignment (adjusted HR [aHR]). RESULTS: The overall mortality for sex-reassigned persons was higher during follow-up (aHR 2.8; 95% CI 1.8-4.3) than for controls of the same birth sex, particularly death from suicide (aHR 19.1; 95% CI 5.8-62.9). Sex-reassigned persons also had an increased risk for suicide attempts (aHR 4.9; 95% CI 2.9-8.5) and psychiatric inpatient care (aHR 2.8; 95% CI 2.0-3.9). Comparisons with controls matched on reassigned sex yielded similar results. Female-to-males, but not male-to-females, had a higher risk for criminal convictions than their respective birth sex controls. CONCLUSIONS: Persons with transsexualism, after sex reassignment, have considerably higher risks for mortality, suicidal behaviour, and psychiatric morbidity than the general population. Our findings suggest that sex reassignment, although alleviating gender dysphoria, may not suffice as treatment for transsexualism, and should inspire improved psychiatric and somatic care after sex reassignment for this patient group.

A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones.

OBJECTIVE: Adverse effects of long-term cross-sex hormone administration to transsexuals are not well documented. We assessed mortality rates in transsexual subjects receiving long-term cross-sex hormones. DESIGN: A cohort study with a median follow-up of 18.5 years at a university gender clinic. Methods Mortality data and the standardized mortality rate were compared with the general population in 966 male-to-female (MtF) and 365 female-to-male (FtM) transsexuals, who started cross-sex hormones before July 1, 1997. Follow-up was at least 1 year. MtF transsexuals received treatment with different high-dose estrogen regimens and cyproterone acetate 100 mg/day. FtM transsexuals received parenteral/oral testosterone esters or testosterone gel. After surgical sex reassignment, hormonal treatment was continued with lower doses. RESULTS: In the MtF group, total mortality was 51% higher than in the general population, mainly from increased mortality rates due to suicide, acquired immunodeficiency syndrome, cardiovascular disease, drug abuse, and unknown cause. No increase was observed in total cancer mortality, but lung and hematological cancer mortality rates were elevated. Current, but not past ethinyl estradiol use was associated with an independent threefold increased risk of cardiovascular death. In FtM transsexuals, total mortality and cause-specific mortality were not significantly different from those of the general population. CONCLUSIONS: The increased mortality in hormone-treated MtF transsexuals was mainly due to non-hormone-related causes, but ethinyl estradiol may increase the risk of cardiovascular death. In the FtM transsexuals, use of testosterone in doses used for hypogonadal men seemed safe.

Mortality and morbidity in transsexual subjects treated with cross-sex hormones.

OBJECTIVE: The optimum steroid hormone treatment regimes for transsexual subjects has not yet been established. We have investigated the mortality and morbidity figures in a large group of transsexual subjects receiving cross-sex hormone treatment. DESIGN: A retrospective, descriptive study in a university teaching hospital. SUBJECTS: Eight hundred and sixteen male-to-female (M-->F) and 293 female-to-male (F-->M) transsexuals. INTERVENTIONS: Subjects had been treated with cross-sex hormones for a total of 10,152 patient-years. OUTCOME MEASURES: Standardized mortality and incidence ratios were calculated from the general Dutch population (age- and gender-adjusted) and were also compared to side effects of cross-sex hormones in transsexuals reported in the literature. RESULTS: In both the M-->F and F-->M transsexuals, total mortality was not higher than in the general population and, largely, the observed mortality could not be related to hormone treatment. Venous thromboembolism was the major complication in M-->F transsexuals treated with oral oestrogens and anti-androgens, but fewer cases were observed since the introduction of transdermal oestradiol in the treatment of transsexuals over 40 years of age. No cases of breast carcinoma but one case of prostatic carcinoma were encountered in our population. No serious morbidity was observed which could be related to androgen treatment in the F-->M transsexuals. CONCLUSION: Mortality in male-to-female and female-to-male transsexuals is not increased during cross-sex hormone treatment. Transdermal oestradiol administration is recommended in male-to-female transsexuals, particularly in the population over 40 years in whom a high incidence of venous thromboembolism was observed with oral oestrogens. It seems that in view of the deep psychological needs of transsexuals to undergo sex reassignment, our treatment schedule of cross-sex hormone administration is acceptably safe.

The lethal paraphiliac syndrome. Accidental autoerotic deaths in Denmark 1933-1990.

A new definition of accidental autoerotic death (AAD) is proposed. A death is an AAD if it is solitary, accidental, and caused by a lethal paraphilia. On the basis of a series of 46 AADs, all occurring among men in the period 1933-1990 in Denmark, the definition cannot be rejected. A paraphilia is regarded as lethal if it is inherently life-threatening. The results of this study have been related to previous reports of similar autoerotic deaths in the literature. It is suggested that the present distinction between asphyxial AAD as typical and nonasphyxial ADD as atypical be replaced with lethal paraphilia with accompanying nonlethal paraphilia or props as typical AAD and lethal paraphilia with no accompanying nonlethal paraphilia or props as atypical AAD.

Mortality and morbidity in transsexual patients with cross-gender hormone treatment.

Sex steroid treatment is associated with side effects. The number of deaths and morbidity cases in 425 transsexual patients treated with cross-gender hormones were evaluated retrospectively and compared with the expected number in a similar reference group of the population. The number of deaths in male-to-female transsexuals was five times the number expected, due to increased numbers of suicide and death of unknown cause. Combined treatment with estrogen and cyproterone acetate in 303 male-to-female transsexuals was associated with a 45-fold increase of thromboembolic events, hyperprolactinemia (400-fold), depressive mood changes (15-fold), and transient elevation of liver enzymes. Androgen treatment in 122 female-to-male transsexuals was associated with weight increase greater than 10% (17.2%) and acne (12.3%). In both groups persistent liver enzyme abnormalities could be attributed to other causes than sex steroids (hepatitis B and alcohol abuse). Much of the morbidity was minor and reversible with appropriate treatment or temporary discontinuation of hormone treatment. Thus, the dilemma of prescribing cross gender hormones in view of the needs of these patients is not resolved. Explanation of possible side effects and careful clinical judgment remain the cornerstone of the clinical decision to prescribe cross-gender hormones. Furthermore, follow up of this relatively young population to disclose long-term side effects and to elucidate the association of sex steroids with coronary heart disease, as well as efforts to reduce the risk of thromboembolic events, are required.