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Mortality and morbidity in trans patients with cross-gender treatment
Abstract
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.
... The first observational study on hormonal therapy and cardiovascular outcome was published in 1989, demonstrating no difference among crude incidence of myocardial infarction (MI) or mortality over a 4-year follow-up [55]. ...
... Contradicting these results, a large observational analysis with a younger cohort by Getahun et al. did not show a significant rise in MI in transgender males [60]. Overall, the available data suggest a higher risk of ischaemic events and cardiovascular risk among transgender populations compared to age-matched non-transgender populations [55]. ...
... Theoretically, the prostate gland undergoes atrophy after hormone therapy. Therefore, only a few people have been documented to have prostate cancer in this population [55]. ...
The transgender concept is described as a clinically significant distress due to the incongruity between the experienced gender and assigned gender. A transgender person carries a gender identity that is different from their assigned sex at birth. Transgender people may be binary: male to female (transgender women) or female to male (transgender men) or genderqueer (non-binary, fluid or variable gender expression). The binary concept has been described in transgender population, where the term transwomen is used to describe people assigned male at birth (AMAB) who are recognized as females during gender transition; with the term transmen where they are assigned female at birth (AFAB) and are then recognized as males in gender transition. According to the DSM-5 classification, gender dysphoria is described when a transgender person develops clinically relevant bio-psychosocial suffering. Currently, the transgender population has gained massive public awareness through social media and gained a considerable level of attention globally. Several studies on transgender populations from different parts of the world have shown real discrimination and stigma towards transgender people, which sometimes acts as a barrier to the provision of the required care for them. Lack of access to the required information, legal issues, lack of solutions to fertility problems, financial constraints, and psychological and emotional obstacles, together with risk of sexually transmitted infections, including human immunodeficiency virus (HIV), all make the life of a transgender person more complicated. Testosterone therapy is a hormone-based therapy for transgender men that provides a body image tallying with the favored gender identification, whereas estrogen and androgen-suppressing agents are used in transgender females to produce changes compatible with their required gender identity. Gender affirmation surgery is a broad term, under which the genital reconstruction is described as a major component. Psychological conditions such as depression, substance abuse, suicidal deaths, and sexually transmitted infections, particularly among males having sex with males, are reported at a significantly higher rate among transgender populations. Cardiovascular morbidity is higher among this population, and continuous medical surveillance is warranted. Medical care provision to transgender populations should be handled with great care, while attending to the unmet needs of this population, as this care should extend beyond routine hormonal therapy and gender reassignment surgery.
... Two early observational studies reported that the crude incidence of myocardial infarction and mortality related to myocardial infarction in transgender women receiving GAHT were not different from sex assigned at birth men [4,5]. Nokoff et al. analyzed the data from a 2015 behavioral risk factor surveillance survey (BRFSS) and found that transgender women on GAHT had a higher risk of myocardial infarction than sex assigned at birth women (OR 2.9; 95% CI 1.6-5.3) ...
... The incidence of cerebrovascular disease in transgender women receiving GAHT was found to be similar to sex assigned at birth men [4] and to the general population [5] in two early retrospective observational studies. In a retrospective cohort study of 966 transgender women receiving GAHT, the mortality related to cerebrovascular disease in transgender women was not statistically different from the general population [10]. ...
... The incidence of hypertension (defined then as BP > 160/90 mmHg) in transgender women receiving GAHT was shown to be similar to sex assigned at birth men (crude incidence 14 [95% CI 7.8-23.1] vs. 18.708) in a study reported in 1989 [4]. A small prospective observational study in 1993 found significantly decreased level of endothelin in transgender women after 4 months of GAHT [19]. ...
Approximately 1.5 million people in the United States currently identify as transgender. The use of gender affirming hormone therapy is integral to routine clinical care of transgender individuals, yet our understanding of the effects of this therapy is limited. There are reasons to believe that gender affirming hormone therapy may have important effects on cardiovascular risk and bone health in transgender individuals. The purpose of this review article is to summarize the evidence for the cardiovascular effects (including coronary artery disease, hypertension and stroke) as well as the effects on bone metabolism associated with gender affirming hormone therapy in both transgender men and transgender women.
... A systematic review and meta-analysis of CV outcomes in transgender people reported few cases of myocardial infarction (MI), stroke, or venous thrombosis; however, the incidence was higher in transgender women compared to transgender men (35,40). ...
... Several studies have observed that despite the negative effects of testosterone therapy on surrogate risks factors of CV disease, these do not translate into a significant effect on CV outcomes ( Table 2). Furthermore, no elevated rates of CV deaths have been observed when compared with cisgender men and women at short and medium follow-up (30,35,40,56). ...
Transgender men and women represent about 0.6 -1.1%% of the general population. Gender affirming hormone therapy (GAHT) helps ameliorate gender dysphoria and promote well-being. However, these treatments’ cardiovascular (CV) effects are difficult to evaluate due to the limited number of extensive longitudinal studies focused on CV outcomes in this population. Furthermore, these studies are mainly observational and difficult to interpret due to a variety of hormone regimens and observation periods, together with possible bias by confounding factors (comorbidities, estrogen types, smoking, alcohol abuse, HIV infection). In addition, the introduction of GAHT at increasingly earlier ages, even before the full development of the secondary sexual characteristics, could lead to long-term changes in CV risk compared to current data.
This review examines the impact of GAHT in the transgender population on CV outcomes and surrogate markers of CV health. Furthermore, we review available data on changes in DNA methylation or RNA transcription induced by GAHT that may translate into changes in metabolic parameters that could increase CV risk.
... Details regarding the age, hormonal therapy regimens, and baseline cardiovascular risk factors indicated therein refer to the entire MTF cohort of each study. [11][12][13][14][15][16][17][18] The sizes of the MTF populations ranged from 49 to 2842 (Mean 1002) while the number of patients who suffered a cerebrovascular event ranged from 1 to 53 (Total 109, Mean 14). Only three studies reported types of stroke. ...
... Only three studies reported types of stroke. 11,12,16 Only a handful of studies were able to specify details regarding hormonal therapy and cardiovascular risk factors in these patients. MTF transgenders received varied preparations of estrogen either orally, transdermally, or via injection with or without antiandrogens. ...
Background:
The effect of hormonal therapy has been extensively studied in women. However, similar data on male-to-female (MTF) transgenders, another important population that receives hormonal therapy is lacking. Existing studies in MTF transgenders are skewed toward mental health and health-harming behaviors while few have focused on chronic health conditions. Our study aims to review the existing data on stroke in MTF transgenders and perform a quantitative analysis on the frequency of this condition in this special population.
Methods:
PubMed, Cochrane, Scopus, Embase, ClinicalTrials.gov, and Web of Science were systematically searched for studies that reported data on the occurrence of cerebrovascular diseases in MTF transgenders. We reported the hormonal regimens, clinical characteristics, and outcomes of stroke in MTF transgenders. A meta-analysis of proportions was performed by the random-effects model to compute for the frequency of cerebrovascular events in MTF transgenders.
Results:
Fourteen studies were included in the qualitative analysis while five studies were included in the quantitative analysis. A total of 109 MTF transgenders (Mean 14; range 1-53) suffered a cerebrovascular event. Random-effect modeling analysis showed an overall estimated frequency of 2% for cerebrovascular events in transgenders with a moderate degree of heterogeneity (I2 = 62%).
Conclusion:
Hormonal therapy in MTF transgenders may confer cardiovascular risks in this population. However, more population-based studies that include clinical characteristics and outcomes of chronic health diseases in MTF transgenders are warranted. Such studies may be crucial in directing future guidelines on the health care and management of MTF transgenders.
... Previous studies found that both in women and transwomen (especially highly dosed) oral preparations induced more procoagulant changes and a higher VTE risk than transdermal preparations. 10,[24][25][26] In this study our aim was threefold. First, to assess whether GAHT has similar effects on the coagulation system as is observed in women using estrogens and men using testosterone, and whether these findings are in line with observations on VTE risk in the transgender population. ...
... The differences between these routes of administration, in terms of change in coagulation profiles, do not appear as substantial in the reports concerning high-dosed oral estrogen in which substantial differences in procoagulant changes and VTE risk were observed for oral formulations compared to transdermal preparations. 10,24,25 It should be mentioned that although various measurements of coagulation are associated with VTE risk, 39 studies that assess the absolute incidence of objectively confirmed symptomatic VTE remain the gold standard. In conclusion, coagulation profiles in transwomen and transmen were influenced by 12 months of GAHT use and affected by route of administration and age to some extent. ...
Background:
The transgender population that uses gender affirmative hormone therapy (GAHT) is rapidly growing. The (side-)effects of GAHT are largely unknown. We examined the effect of GAHT on coagulation parameters associated with venous thromboembolism (VTE) risk.
Methods:
Factor (F)II, FIX, FXI, protein (p)C and free pS, fibrinogen, hematocrit, sex hormone-binding globulin, and normalized activated protein C ratio were measured in 98 transwomen (male sex at birth, female gender identity) and 100 transmen (female sex at birth, male gender identity) before and after 12 months of GAHT (oral or transdermal estradiol and anti-androgens in transwomen, transdermal or intramuscular testosterone in transmen). Mean paired differences in coagulation measurements were estimated with 95% confidence intervals (95%CI). Differences for route of administration and age were assessed with linear regression.
Results:
After GAHT, transwomen had more procoagulant profiles with a mean increase in FIX: 9.6 IU/dL (95%CI 3.1 to 16.0) and FXI: 13.5 IU/dL (95%CI 9.5 to 17.5), and a decrease in pC: -7.7 IU/dL (95%CI -10.1 to -5.2). Changes in measures of coagulation were influenced by route of administration (oral vs. transdermal) and age. A higher SHBG level after 12 months was associated with a lower APCr. In transmen, changes were not procoagulant overall and were influenced by age. Differences for route of administration (transdermal vs. intramuscular) were small.
Conclusions:
GAHT in transmen was not associated with apparent procoagulant changes which provides some reassurance regarding VTE risk. In transwomen GAHT resulted in procoagulant changes, which likely contributes to the observed increased VTE risk.
... Gonadal steroids, in particular estrogen, have a pronounced effect on the areas of the brain responsible for mood and cognition [55]. Exogenous administration of estrogens and androgens can have multiple negative effects on mental health, making individuals more prone to develop depression or anxiety [56]. However, as stated by Colizzi et al., GAHT has a positive effect on psychiatric conditions in both transgender women and transgender men [57]. ...
... In order to lower the dose estrogens and to successfully suppress testosterone levels before surgery, cyproterone acetate may be used. No association has been established between suicide and actual use of cyproterone acetate [56]. ...
The attention to transgender medicine has changed over the last decade and the interest is most likely going to increase in the future due to the fact that gender-affirming treatments are now being requested by an increasing number of transgender people. Even if gender-affirming hormone therapy (GAHT) is based on a multidisciplinary approach, this review is going to focus on the procedures adopted by the endocrinologist in an out-clinic setting once an adult patient is referred by another specialist for ‘gender affirming’ therapy. Before commencing this latter treatment, several background information on unmet needs regarding medical and surgical outcomes should be investigated. We summarized our endocrinological clinical and therapeutic approaches to adult transgender individuals before and during GAHT based on a non-systematic review. Moreover, the possible relationships between GAHT, gender-related pharmacology, and COVID-19 are also reported.
... The use of steroidal anti-androgens cyproterone acetate and spironolactone for gender affirmation has been well described since the 1980s. 1,2 However, while the doses of cyproterone acetate typically used today are now much lower than historically described (e.g. 10 mg daily vs 50 mg daily) some concerns remain about the risk of mood disturbance, dose-dependent hyperprolactinaemia 3 and an increased risk of meningioma with increasing cumulative dose exposure. 4,5 Similarly, there are theoretical risks of hyperkalaemia, dehydration and renal impairment with the use of spironolactone. ...
Background
There is interest in repurposing bicalutamide for gender-affirming hormone therapy, but little data regarding efficacy and safety in the transgender population.
Objectives
To determine the effect of bicalutamide on serum total testosterone concentrations and liver function. Given bicalutamide is a pure androgen receptor antagonist, we hypothesized that serum total testosterone concentrations would be higher than the cisgender female reference range and those recommended for transgender individuals in consensus guidelines.
Design
Case series.
Methods
We identified transgender people attending outpatient clinics who were using bicalutamide for gender affirmation. The primary outcome was serum total testosterone concentration. Secondary outcomes included serum alanine transferase (ALT) concentration.
Results
Twenty-four transfeminine people prescribed bicalutamide were identified. The median (interquartile range) age was 29 (24–38) years, bicalutamide dose 25 (25–50) mg daily and bicalutamide duration 6 (4–10) months. The median serum total testosterone concentration was 7.7 (0.7–17.5) nmol/L, luteinizing hormone 2.9 (0.5–6.0) IU/L and ALT 20 (13–29) IU/L. One individual had asymptomatic transaminitis. Six individuals discontinued bicalutamide due to a lack of perceived benefit.
Conclusion
Bicalutamide was associated with significant variation in serum total testosterone concentration, likely related to concomitant estradiol or previous anti-androgen therapy. Median serum ALT concentrations remained within the normal reference range. Guideline recommendations for serum total testosterone within the cisgender female reference range may be inappropriate for people using bicalutamide. Further research is needed to establish the longer-term efficacy and safety of bicalutamide in the transfeminine population.
... The use of estrogen for the long term in transfeminine develops the risks of venous thromboembolism, myocardial infarction, and ischemic stroke due to long-term follow-up of estrogen (36,39). Long-term use of estrogen is linked with cardiovascular diseases, leading to mortality (40,41). ...
People who change their gender after birth are known as transgender people. They underwent surgical transformation along with hormonal therapy. Hormonal imbalance is the most common phenomenon in the transgender community due to hormonal therapy and other related issues. Hormonal therapy is essential for gender transformation, but this therapy poses several risks to the individual who is taking this therapy. Transgender people who are under hormonal therapy are more at risk of cardiovascular disorders as certain hormones like estrogen and testosterone, besides their intended function, also induce side effects, due to which individuals taking these hormones become more prone to cardiovascular disorder, irregular blood pressure, brain function, and structure start changing. The cross-sex hormone therapy is also associated with brain tumors, changes in body mass index, and several skin conditions. Such hormones also affect bone density in different individuals due to changes in the deposition pattern of calcium into the bone under hormonal control. Hormonal therapy causes certain metabolic disorders as well, and certain hormones interact with other hormones in a different way when they are not naturally produced in the body. The voice of such people undergoing gender transformation also changes due to the testosterone level. This review summarizes some aspects of hormonal therapy, but whether or not a person undergoes such transition is their choice.
... 3 Many studies and reviews have demonstrated the safety of GAHT in the short and medium term. [4][5][6][7] However, there is a paucity of data on long-term safety and clinical efficacy, especially regarding testosterone (T) therapy in assigned female at birth (AFAB) people, on anthropometric parameters, body composition, and glycolipid metabolism. ...
... Epidemiologic studies have confirmed the anecdotal reports of thrombosis in MTF transgender individuals using GAHT. Retrospective cohort studies from the Netherlands associated a daily regimen of 100-μg ethinyl estradiol and 100-mg cyproterone acetate (which is unavailable in the United States) with a 20-to-45-fold increase in venous thromboembolic risk compared with the general male population [24,25]. In a cohort of 2,236 MTF transgender patients, Gooren et al. [26] found that oral ethinyl estradiol is associated with a 6% to 8% incidence of venous thromboembolism. ...
Gender-affirming hormonal therapies are a critical component of the care of transgender individuals. Transgender people are commonly prescribed estrogen or testosterone to promote male-to-female or female-to-male transitions and to preserve gender-specific characteristics long-term. However, some exogenous hormones, especially certain estrogen preparations, are an established risk factor of thrombosis. As the number of individuals seeking gender-based care is rising, there is an urgent need to identify and characterize the mechanisms underlying hormone-associated thrombosis and incorporate this information into clinical algorithms for diagnosis and management. Herein, we discuss historical evidence on the incidence of thrombosis and changes in plasma composition in transgender and cisgender cohorts. We present 3 case studies to demonstrate knowledge gaps in thrombosis risk stratification and prediction tools. We also present data from in vitro coagulation and fibrinolysis assays and discuss how information from these kinds of assays may be used to help guide the clinical management of transgender individuals.
... [32] The elevation in liver enzymes is usually mild and reversible on temporary discontinuation of testosterone therapy. [33] Serious hepato-toxicity is uncommon with the currently used testosterone preparations; hence frequent liver enzymes screening is not recommended. [32,34] However, alcohol abuse, obesity, known liver disease, or concomitant use of other medications with potential hepatotoxicity may increase the risk of liver injury. ...
... [32] The elevation in liver enzymes is usually mild and reversible on temporary discontinuation of testosterone therapy. [33] Serious hepato-toxicity is uncommon with the currently used testosterone preparations; hence frequent liver enzymes screening is not recommended. [32,34] However, alcohol abuse, obesity, known liver disease, or concomitant use of other medications with potential hepatotoxicity may increase the risk of liver injury. ...
Gender-affirming hormone therapy (GAHT) is the most frequent treatment offered to gender-incongruent individuals, which reduces dysphoria. The goal of therapy among gender-incongruent individuals seeking gender affirmation as male is to change their secondary sex characteristics to affect masculine physical appearances. GAHT greatly improves mental health and quality of life among gender incongruent individuals. India-specific guideline for appropriate care for gender-incongruent individuals is almost absent. This document is intended to assist endocrinologists and other healthcare professionals interested in gender incongruity for individuals seeking gender affirmation as male. A safe and effective GAHT regimen aims to effect masculinising physical features without adverse effects. In this document, we offer suggestions based on an in-depth review of national and international guidelines, recently available evidence and collegial meetings with expert Indian clinicians working in this field. Clinicians represented in our expert panel have developed expertise due to the volume of gender incongruent individuals they manage. This consensus statement provides protocols for the hormone prescribing physicians relating to diagnosis, baseline evaluation and counselling, prescription planning for masculinising hormone therapy, choice of therapy, targets for monitoring masculinising hormone therapy, clinical and biochemical monitoring, recommending sex affirmation surgery and peri-operative hormone therapy. The recommendations made in this document are not rigid guidelines, and the hormone-prescribing physicians are encouraged to modify the suggested protocol to address emerging issues.
... Studies have shown a detrimental association between GAOT use and cardiovascular risk factor, 12 13 although effects may differ by route of GAOT administration. 14 While a lower prevalence of cardiovascular disease was observed in transgender women compared with age-matched and cisgendermatched counterparts, 15 other studies have reported increased rates of venous thromboembolism (VTE), 3 16 myocardial infarction (MI) 17 and cardiovascular-related mortality. 4 Similarly, GAOT has shown conflicting effects on traditional cardiovascular disease risk factors. ...
Introduction:
The use of gender-affirming oestrogen therapy (GAOT) is an integral part of the gender-affirming transition process for transgender women (assigned male at birth who identify as women) and gender-diverse individuals. However, its use may present significant cardiovascular implications, which may be influenced by systemic oestradiol levels. Therefore, we aim to establish the association between serum oestradiol levels and incidence of adverse cardiovascular events in individuals using GAOT.
Methods and analysis:
We will conduct a systematic review addressing the association between serum oestradiol levels and risk of adverse cardiovascular events in individuals using GAOT. Our primary outcome is the incidence of adverse cardiovascular events, our secondary outcome is the incidence of cardiovascular-related mortality and our tertiary outcome is cardiovascular-related risk factors. Electronic databases (Cochrane Central Register of Controlled Trials, Embase, MEDLINE and Web of Science) will be searched from inception until September 2022. Two investigators will independently complete screening to determine appropriateness of inclusion. Extracted data will include information on serum sex hormone levels (oestradiol and testosterone), participants, GAOT (route of administration, formulations, dosages and duration of exposure), incidence of cardiovascular outcomes, study quality and risk of bias. Inter-reviewer reliability will be calculated at both phases. Data will be presented both descriptively and meta-analysed using a random effects model, if appropriate. Heterogeneity will be explored and meta-regressed if noted.
Ethics and dissemination:
Ethics approval is not needed. We will disseminate findings through international conferences, distributions to transgender and gender-diverse support organisations, decision-makers and key stakeholders. The final systematic review will be published in a peer-reviewed journal.
Trial registration number:
CRD42021247717.
... Accordingly, although most studies describe a worsening cardiovascular risk profile in transgender individuals receiving cross-sex hormone therapy, inconsistent data in transgender men have been reported on whether these risk alterations are associated with increased cardiovascular morbidity and mortality [144][145][146] . In transgender women receiving ethinyloestradiol and cyproterone acetate treatment, an increased risk of thromboembolic events compared with cisgender women has consistently been observed across studies [147][148][149] . Likewise, several epidemiological studies suggest that the use of oestrogens in transgender women is associated with an increased risk of MI and ischaemic stroke compared with cisgender women 150 . ...
Despite a growing body of evidence, the distinct contributions of biological sex and the sociocultural dimension of gender to the manifestations and outcomes of ischaemic heart disease and heart failure remain unknown. The intertwining of sex-based differences in genetic and hormonal mechanisms with the complex dimension of gender and its different components and determinants that result in different disease phenotypes in women and men needs to be elucidated. The relative contribution of purely biological factors, such as genes and hormones, to cardiovascular phenotypes and outcomes is not yet fully understood. Increasing awareness of the effects of gender has led to efforts to measure gender in retrospective and prospective clinical studies and the development of gender scores. However, the synergistic or opposing effects of sex and gender on cardiovascular traits and on ischaemic heart disease and heart failure mechanisms have not yet been systematically described. Furthermore, specific considerations of sex-related and gender-related factors in gender dysphoria or in heart-brain interactions and their association with cardiovascular disease are still lacking. In this Review, we summarize contemporary evidence on the distinct effects of sex and gender as well as of their interactions on cardiovascular disease and how they favourably or unfavourably influence the pathogenesis, clinical manifestations and treatment responses in patients with ischaemic heart disease or heart failure.
... In accordance with previous studies, we observed an increased mortality due to HIV-related disease and suicide in transgender women. [12][13][14][15]19 Notably, most of the deaths from HIV-related disease in this study occurred in the first decades studied, indicating an effect of improved HIV treatment over recent years. Moreover, we observed that most suicide cases occurred in the first decades studied. ...
... Researchers reported a similar incidence across groups for ischemic stroke and myocardial infarction (Getahun et al. 2018). Data from a separate study also displayed safety concerns about the prothrombotic potential of cross gender hormone therapy as transgender women on combined treatment with oral ethinyl estradiol (100 mcg/day) and cyproterone acetate (100 mg/day) were 45 times more likely to have a thromboembolic event compared to a similar reference group of the population not on estrogen (Asscheman et al. 1989). However, an analysis of several studies suggests that the type of oral estrogen, hormone route of administration, and patient demographics and comorbidities may affect estrogen's link with VTE (Goldstein et al. 2019). ...
Incidents of strokes are increased in young women relative to young men, suggesting that oral contraceptive (OC) use is one of the causes of stroke among young women. Long-term exposures to the varying combinations of estrogen and progestogen found in OCs affect blood clotting, lipid and lipoprotein metabolism, endothelial function, and de novo synthesis of neurosteroids, especially brain-derived 17β-estradiol. The latter is essential for neuroprotection, memory, sexual differentiation, synaptic transmission, and behavior. Deleterious effects of OCs may be exacerbated due to comorbidities like polycystic ovary syndrome, sickle cell anemia, COVID-19, exposures to endocrine disrupting chemicals, and conventional or electronic cigarette smoking. The goal of the current review is to revisit the available literature regarding the impact of OC use on stroke, to explain possible underlying mechanisms, and to identify gaps in our understanding to promote future research to reduce and cure stroke in OC users.
... Hence, as shown in Figure 1, 99 studies were identified, of which 18 met the inclusion criteria (17,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49). The studies by Asscheman and colleagues published in 1989 (50) and 2011 (51) were excluded since the population under investigation was already included in the paper by van Kesteren et al., 1997 (47). The studies by Wierckx et al., 2012 (52) and Wierckx et al., 2014 (53) were also excluded because subjects included were considered in the study by Wierckx et al., 2013 (48). ...
Background
Although venous thromboembolism (VTE) is a recognized side effect of some formulations of estrogen therapy, its impact in transgender people remains uncertain. The aim of this study was to define pooled prevalence estimate and correlates of VTE in Assigned Males at Birth (AMAB) trans people undergoing gender affirming hormone therapy.
Methods
A thorough search of MEDLINE, COCHRANE LIBRARY, SCOPUS and WEB OF SCIENCE databases was carried out to identify suitable studies. Quality of the articles was scored using the Assessment Tool for Prevalence Studies. Data were combined using random effects models and the between-study heterogeneity was assessed by the Cochrane’s Q and I².
Results
The eighteen studies included gave information about 11,542 AMAB undergoing gender affirming hormone therapy. The pooled prevalence of VTE was 2% (95%CI:1-3%), with a large heterogeneity (I2 = 89.18%, P<0.0001). Trim-and-fill adjustment for publication bias produced a negligible effect on the pooled estimate. At the meta-regression analysis, a higher prevalence of VTE was significantly associated with an older age (S=0.0063; 95%CI:0.0022,0.0104, P=0.0027) and a longer length of estrogen therapy (S=0.0011; 95%CI:0.0006,0.0016, P<0.0001). When, according to the meta-regression results, the analysis was restricted to series with a mean age ≥37.5 years, the prevalence estimate for VTE increased up to 3% (95%CI:0-5%), but with persistence of a large heterogeneity (I2 = 88,2%, P<0.0001); studies on younger participants (<37.5 years) collectively produced a pooled VTE prevalence estimate of 0% (95%CI:0-2%) with no heterogeneity (I² = 0%, P=0.97). Prevalence estimate for VTE in series with a mean length of estrogen therapy ≥53 months was 1% (95%CI:0-3%), with persistent significant heterogeneity (I2 = 84,8%, P=0.0006); studies on participants subjected to a shorter length of estrogen therapy (<53 months), collectively produced a pooled VTE prevalence estimate of 0% (95%CI:0-3%) with no heterogeneity (I2 = 0%, P=0.76).
Conclusions
The overall rate of VTE in AMAB trans people undergoing gender affirming hormone therapy was 2%. In AMAB population with <37.5 years undergoing estrogen therapy for less than 53 months, the risk of VTE appears to be negligible. Further studies are warranted to assess whether different types and administration routes of estrogen therapy could decrease the VTE risk in AMAB trans people over 37.5 years subjected to long-term therapy.
Systematic Review Registration
[https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42021229916].
... Therapie [11] Zur feminisierenden Hormontherapie wird eine Therapie mit 17β-Estradiol oder 17β-Estradiolvalerat oral oder transdermal empfohlen. Aufgrund des deutlich ungünstigeren Risikoprofils ist der Einsatz von Ethinylestradiol, wie es in den meisten kombinierten oralen Kontrazeptiva enthalten ist, obsolet [6,13,14]. Das Risiko für thromboembolische Komplikationen ist unter oraler Estradioltherapie höher [15], sodass bei zusätzlichen Risikofaktoren, wie Übergewicht, höherem Alter oder Nikotinkonsum, eine transdermale Applikationsform erfolgen sollte. ...
Zusammenfassung
Die Anzahl transidenter Menschen, die sich mit dem Wunsch nach geschlechtsangleichenden Maßnahmen vorstellen, ist, ebenso wie die öffentliche Wahrnehmung des Themas, in den letzten Jahren angestiegen. Trotz einer zunehmenden Akzeptanz verläuft die medizinische Versorgung Betroffener häufig nicht optimal. Aufgrund der weitreichenden und teilweise irreversiblen Konsequenzen sollte eine geschlechtsangleichende Hormontherapie nur bei Erreichen aller notwendigen Voraussetzungen im Konsens mit dem behandelnden Psychiater bzw. Psychotherapeuten und nach ausführlicher Aufklärung durch einen erfahrenen Arzt eingeleitet werden. Vor Therapiebeginn muss ein umfangreiches Screening auf etwaige Risikofaktoren erfolgen und Komorbiditäten sollten adäquat behandelt werden. Die Behandlung erfolgt gemäß der vorliegenden Leitlinienempfehlungen bei Transidentität von Mann zu Frau mit 17β-Estradiol oder 17β-Estradiolvalerat in Kombination mit Cyproteronacetat oder Spironolacton als Antiandrogen, bei Transidentität von Frau zu Mann mit transdermalen oder intramuskulären Testosteronpräparaten. Regelmäßige klinische und laborchemische Verlaufskontrollen auf erwünschte und mögliche unerwünschte Wirkungen der Therapie sind ebenso wie gynäkologische bzw. urologische Früherkennungsuntersuchungen dauerhaft notwendig. Vor Therapiebeginn sollte eine Aufklärung und Beratung zu Fragen der Fertilität und Schwangerschaftsverhütung erfolgen.
Die geschlechtsangleichende Hormontherapie stellt einen wesentlichen Pfeiler der medikamentösen Geschlechtsangleichung dar und mehrere Studien belegen eindeutig ihre positive Auswirkung auf die Lebensqualität der Betroffenen. Bei sorgfältiger Beachtung der notwendigen Vorsichtsmaßnahmen weist die Therapie ein akzeptables Risikoprofil auf.
... In accordance with previous studies, we observed an increased mortality due to HIV-related disease and suicide in transgender women. [12][13][14][15]19 Notably, most of the deaths from HIV-related disease in this study occurred in the first decades studied, indicating an effect of improved HIV treatment over recent years. Moreover, we observed that most suicide cases occurred in the first decades studied. ...
Background:
Increased mortality in transgender people has been described in earlier studies. Whether this increased mortality is still present over the past decades is unknown. Therefore, we aimed to investigate trends in mortality over five decades in a large cohort of adult transgender people in addition to cause-specific mortality.
Methods:
We did a retrospective cohort study of adult transgender people who visited the gender identity clinic of Amsterdam University Medical Centre in the Netherlands. Data of transgender people who received hormone treatment between 1972 and 2018 were linked to Statistics Netherlands. People were excluded if they used alternating testosterone and oestradiol treatment, if they started treatment younger than age 17 years, or if they had ever used puberty-blockers before gender-affirming hormone treatment. Standardised mortality ratios (SMRs) were calculated using general population mortality rates stratified by age, calendar period, and sex. Cause-specific mortality was also calculated.
Findings:
Between 1972 and 2018, 8831 people visited the gender identity clinic. 4263 were excluded from the study for a variety of reasons, and 2927 transgender women and 1641 transgender men were included in the study, with a total follow-up time of 40 232 person-years for transgender women and 17 285 person-years for transgender men. During follow-up, 317 (10·8%) transgender women died, which was higher than expected compared with general population men (SMR 1·8, 95% CI 1·6-2·0) and general population women (SMR 2·8, 2·5-3·1). Cause-specific mortality in transgender women was high for cardiovascular disease, lung cancer, HIV-related disease, and suicide. In transgender men, 44 people (2·7%) died, which was higher than expected compared with general population women (SMR 1·8, 95% CI 1·3-2·4) but not general population men (SMR 1·2, 95% CI 0·9-1·6). Cause-specific death in transgender men was high for non-natural causes of death. No decreasing trend in mortality risk was observed over the five decades studied.
Interpretation:
This observational study showed an increased mortality risk in transgender people using hormone treatment, regardless of treatment type. This increased mortality risk did not decrease over time. The cause-specific mortality risk because of lung cancer, cardiovascular disease, HIV-related disease, and suicide gives no indication to a specific effect of hormone treatment, but indicates that monitoring, optimising, and, if necessary, treating medical morbidities and lifestyle factors remain important in transgender health care.
Funding:
None.
... Individuals who feel unattractive tend to have more social anxiety and to suffer mixed adaptive emotional disorders such as anxiety and depression (Leary & Kowalski, 1995). Because of prejudice and the fear of being disclosed, many patients with gender dysphoria do not seek medical care but often resort to self-medication to affirm the sex with which they self-identify (Asscheman, Gooren & Eklund, 1989). It is known that most transgender women and transvestite self-medicate due to lack of access to health services (Kruger et al., 2019). ...
Pessoas transgênero são aquelas cuja identidade de gênero não se enquadra nas normas impostas pela sociedade quanto ao gênero designado ao nascer, com base na genitália. Obviamente, as características sexuais secundárias dependem dos esteroides sexuais. A redesignação hormonal tem dois objetivos: reduzir as características sexuais secundárias induzidas por hormônios do sexo original e induzir as características sexuais secundárias do novo sexo. O uso desses hormônios esteroides sexuais pode favorecer o desenvolvimento de lesões da mucosa oral, como o granuloma piogênico, que é uma lesão vascularizada não neoplásica, comum na cavidade oral, causada por trauma, irritantes locais ou fatores hormonais. A etiologia atualmente não é clara, mas trauma e aumento do nível de estrogênio e progesterona têm sido sugeridos como potenciais fatores contribuintes. Portanto, o objetivo principal deste artigo é relatar um granuloma piogênico em desenvolvimento em uma mulher transgênero que pode estar associado à terapia hormonal e destacar os efeitos da terapia hormonal nos tecidos orais.
... 51 Initial studies reported a 20-45-fold increase in VTE and/or pulmonary embolism vs the general population. 52,53 However, many of these earlier studies were in patients that used high doses of thrombogenic ethinyl estradiol and did not control for tobacco use. In a more recent cohort study, 2800 transgender women with 10-to-1 matching of cisgender male and female controls found a twofold increase in overall risk of VTE in the transgender population, but the overall risk for VTE was low. ...
Penile inversion vaginoplasty helps to alleviate gender dysphoria and improve quality of life in many transgender individuals. Overall, the procedure is associated with high post‐operative satisfaction, even when complications occur. Adverse events related to vaginoplasty are commensurate with other genitourinary reconstructive procedures performed for other diagnoses (i.e. cancer or congenital issues). Here, we explore the incidence of complications following vaginoplasty, emphasizing the challenges in defining and managing these adverse events. In addition, outcome measures to assess patient satisfaction will be reviewed.
... Multiple studies demonstrated an increased risk of venous thromboembolism (VTE) and stroke among TGW using estrogen GAHT. [9][10][11][12] However, other studies reported minimal rates of thrombosis with estrogen GAHT. [13][14][15][16][17] Exogenous estrogen may produce a prothrombotic state through multiple mechanisms, including increased synthesis of hemostatic factors, suppression of inhibitors of coagulation, and/or inhibition of fibrinolysis. ...
Background and objectives:
Many transgender youth experience gender dysphoria, a risk factor for suicide. Gender-affirming hormone therapy (GAHT) ameliorates this risk but may increase the risk for thrombosis, as seen from studies in adults. The aim with this study was to examine thrombosis and thrombosis risk factors among an exclusively adolescent and young adult transgender population.
Methods:
This retrospective chart review was conducted at a pediatric hospital-associated transgender health clinic. The primary outcome was incidence of arterial or venous thrombosis during GAHT. Secondary measures included the prevalence of thrombosis risk factors.
Results:
Among 611 participants, 28.8% were transgender women and 68.1% were transgender men. Median age was 17 years at GAHT initiation. Median follow-up time was 554 and 577 days for estrogen and testosterone users, respectively. Individuals starting GAHT had estradiol and testosterone levels titrated to physiologic normal. Multiple thrombotic risk factors were noted among the cohort, including obesity, tobacco use, and personal and family history of thrombosis. Seventeen youth with risk factors for thrombosis were referred for hematologic evaluation. Five individuals were treated with anticoagulation during GAHT: 2 with a previous thrombosis and 3 for thromboprophylaxis. No participant developed thrombosis while on GAHT.
Conclusions:
In this study, we examined thrombosis and thrombosis risk factors in an exclusively adolescent and young adult population of transgender people receiving GAHT. These data suggest that GAHT in youth, titrated within physiologic range, does not carry a significant risk of thrombosis in the short-term, even with the presence of preexisting thrombosis risk factors.
... It is biologically plausible that transgender women experience a similar risk. In 1989, one group demonstrated a 45fold increased risk in their population of transgender women who were on hormonal therapy (35). Ten years later, the same group identified a 20-fold increased risk, mostly in transgender women over the age of 40 (36). ...
Individuals who identify with a gender not typically associated with their sex assigned at birth are a growing population worldwide. Guidelines to help healthcare providers navigate the care of gender minorities are often aimed at primary care providers and may be too general for subspecialists. Pulmonologists may see gender minority individuals for a variety of reasons and no reference exists which contains relevant information about gender minority-specific care, including unique conditions to consider. A systematic review was completed to identify unique characteristics in caring for gender minority patients with a pulmonary complaint.
... Studies have shown that CPA can cause liver injury in 1-5.7% of prostate cancer patients and in women with hirsutism (8,9). In a transgender study population with transgender women using 100 mg cyproterone acetate and 100 mg ethinylestradiol/day, only 0.06% showed persistent elevations of transaminases that could not be attributed to alcohol abuse or a hepatitis B infection (10). Also, oestrogen therapy can potentially cause intrahepatic cholestasis, an idiosyncratic type of DILI, as well as peliosis hepatitis (11,12). ...
Context: Individuals with gender dysphoria can receive gender-affirming hormone therapy. Different guidelines mention a severe risk of liver injury within the first months after the start of treatment with anabolic androgenic steroids, antiandrogens, and oral contraceptives, which is potentially fatal.
Objective: The incidence of liver injury in a transgender population using gender-affirming hormone therapy.
Design: Multicentre prospective study with 1933 transgender individuals, who started with hormone therapy between 2010 and 2020.
Methods: The following parameters were analysed before hormone therapy, after 3 months, and after 12 months of hormone therapy: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT). Both male and female reference values were considered. Liver injury was defined as either an elevation of 2x upper limit of normal (ULN) of ALP, 3xULN of ALT, or 3x ULN of AST.
Results: 889 transgender women and 1044 transgender men were included in the analysis. The incidence of liver injury within 12 months after start of hormone therapy, without attribution to alcohol abuse, medical history, or co medication was 0.1% and 0.0% in transgender women according to female and male reference intervals respectively, and 0.6% and 0.4% in transgender men (female and male reference intervals).
Conclusion: The incidence of liver injury is found to be very low. We therefore conclude that liver enzyme monitoring within the frame of the risk of liver injury due to hormone therapy is not necessary in a transgender population.
Research regarding the hematologic sequelae of estrogen and testosterone therapy for transgender people is an emerging area. While estrogen therapy has been widely studied in cisgender women, studies in transgender individuals are limited, revealing variable adverse effects influenced by the dose and formulation of estrogen used. Thrombotic risk factors in transgender and gender-diverse individuals are multifactorial, involving both modifiable and nonmodifiable factors. Management of venous thromboembolism (VTE) in individuals receiving gender-affirming estrogen entails standard anticoagulation therapy alongside shared decision-making regarding hormone continuation and risk factor modification. While data and guidance from cisgender women can offer a reference for managing thrombotic risk in transgender individuals on hormone therapy, fully applying these insights can be challenging. The benefits of gender-affirming hormone therapy include significantly reducing the risk of suicide and depression, highlighting the importance of a contemplative approach to the management of hormonal therapy after a VTE event. Although limited, the available data in the literature indicate a low thrombotic risk for transgender individuals undergoing gender-affirming testosterone therapy. However, polycythemia is a common adverse effect necessitating monitoring and, occasionally, adjustments to hormonal therapy. Additionally, iron deficiency may arise due to the physiological effects of testosterone or health care providers' use of phlebotomy, an aspect that remains unstudied in this population. In conclusion, while the set of clinical data is expanding, further research remains vital to refine management strategies and improve hematologic outcomes for transgender individuals undergoing gender-affirming hormone therapy.
Background
Gender-affirming hormone therapy (GAHT) is common among transgender individuals, but its impact on lipid profile and cardiovascular health is not well studied.
Objectives
The authors performed a systematic review and meta-analysis of existing literature to assess the impact of GAHT on lipid profiles and metabolic cardiovascular risk factors in transgender individuals.
Methods
Online databases including MEDLINE/PubMed, Embase, and Cochrane Central registry were searched to find studies on lipid profile changes in women who are transgender, also referred to as transfeminine (TF), and men who are transgender, also referred to as transmasculine (TM) before and after GAHT. Baseline comorbidities were analyzed using descriptive statistics, and R-statistical software was used to analyze the mean difference in lipid profile change between the two cohorts (pre- and post-GAHT therapy) including transgender patients.
Results
Overall, 1,241 TM and 992 TF patients were included from 12 observational studies and 12 randomized controlled trials. The mean age among TM and TF was 28 years and 30 years, respectively. The mean follow-up duration (including pre- and post-GAHT therapy) was 28 months in TM patients and 39 months in TF patients. When compared to baseline measures, TM patients had a significant increase in low-density lipoprotein, triglyceride levels, and total cholesterol while high-density lipoprotein levels decreased. In TF patients, there was a significant increase in triglyceride levels.
Conclusions
GAHT affects lipid profiles in transgender patients; however, additional studies are needed to determine how these changes impact clinical outcomes.
Gender-affirming hormone therapy (GAHT) is used by many transgender and gender-diverse adults to align physical characteristics with their gender identity, reduce gender incongruence and improve psychological functioning. This narrative review provides an overview of the initiation and monitoring of GAHT in an Australian context. Trans individuals treated with testosterone typically receive standard testosterone doses and formulations recommended for cisgender men, whereas those receiving estradiol GAHT are typically treated with estradiol in combination with an anti-androgen in those without orchidectomy. Proactive monitoring and mitigation of cardiovascular risk factors is pertinent in all transgender and gender-diverse adults and bone health is an important consideration in those using estradiol GAHT.
Clinicians have long lacked guidance on how to appropriately manage transgender patients perioperatively. This chapter aims to provide guidance on the safe management of transgender patients in the preoperative, intraoperative, and postoperative phases of surgical procedures. Understanding how gender transition influences anatomy and physiology is essential for the optimization of surgical outcomes and patient safety. Many parameters differ for cisgender and transgender patients, while others stay similar. As the practice of medicine evolves, implementing guidelines from new data on traditionally understudied patient populations, such as LGBT+ individuals, will translate to improved healthcare outcomes and decreased healthcare disparities in these populations. This chapter will focus specifically on the perioperative considerations for patients undergoing a gender transition, also known as transgender patients or (formerly) known as transsexual patients. This information will also be effective in better caring for patients who were born intersex, as they often have had similar surgical procedures and medical treatments as transgender individuals. Overall, we aim to present a brief analysis of critical physiologic, anatomical, procedural, and pharmacological considerations for transgender patients when they require surgical care.
Context
Transgender and gender diverse (TGD) individuals have greater access to genital surgery (GS) with improved insurance coverage and access to trained surgeons and interdisciplinary gender-affirming providers.
Objective
To determine perioperative medical and behavioral health outcomes in transfeminine (TF) individuals undergoing GS, with use of a specific gender-affirming hormone therapy (GAHT) algorithm based on individualized risk factor assessment.
Methods
In this retrospective observational cohort study, we collected preoperative and postoperative data from 183 TF individuals at a single tertiary referral center from 2017 to 2022, grouping patients by those who continued estradiol (Group 1) vs those who had temporarily discontinued estradiol for 2 to 6 weeks preoperatively (Group 2). Data included clinical and biochemical assessment, GAHT regimens, validated behavioral health measures, and postoperative complications. Main outcomes included venous thromboembolism (VTE) incidence, non-VTE postoperative complication incidence, and change in behavioral health assessments.
Results
The majority of individuals continued estradiol perioperatively (Group 1; 138 [75.4%]). Individuals who temporarily held estradiol preoperatively (Group 2; 45 [24.6%]) were statistically older (P < .01), had higher incidence of cardiometabolic comorbidities (P < .01), and higher Caprini scores (P < .01). Group 1 was statistically more likely to use oral estradiol (P < .01). One episode (0.05%) of VTE occurred (Group 1). There was no significant difference in postoperative complications or behavioral health measures between groups.
Conclusion
An individualized algorithm for preoperative hormone management for TF GS resulted in perioperative continuation of GAHT for the majority of individuals without significantly increasing the risk for postoperative surgical complications, while maintaining stable behavioral health measures perioperatively.
Objective:
Participation in athletics is essential for the overall well-being of transgender athletes and should be included as part of gender-affirming care. Surveys show physicians and athletic trainers want to provide appropriate care for transgender athletes but lack the proper knowledge and training to do so. Gender Affirming Hormone Therapy (GAHT) is part of gender-affirming care, yet the effects of GAHT on the cardiovascular and musculoskeletal health of transgender athletes is not well-understood. The purpose of this review was to discuss important musculoskeletal and cardiovascular considerations unique to transgender athletes and improve physician understanding in caring for transgender athletes.
Methods:
A representative selection of literature on the effects of GAHT on cardiovascular and musculoskeletal health was included in this review.
Results:
Estrogen therapy may increase the risk of venous thromboembolism (VTE) and stroke, and decrease blood pressure levels among transgender women, while studies on lipid profile are inconsistent among both transgender men and women. Transgender women receiving GAHT may also be at greater risk for bone fracture and ligamentous injuries.
Conclusion:
Exercise is essential for the well-being of transgender individuals and special considerations regarding the cardiovascular and musculoskeletal health of transgender athletes should be incorporated into standard medical education. Educational programs for transgender patients and their support team should focus on preventative measures that can be taken to reduce the risk of adverse musculoskeletal and cardiovascular events. The PPE is an invaluable tool available to physicians to monitor the health and safety of transgender athletes and should be regularly updated as research on the health of transgender individuals continues to grow. Longitudinal and prospective studies should examine the effects of GAHT on the musculoskeletal and cardiovascular health of transgender athletes. Lastly, health care providers play an important role in the advancement of gender-neutral policies.
This chapter will describe five noncommunicable diseases (NCDs) and their implications for the sexual and gender minority (SGM) population: cardiovascular diseases (CVD), cancer, diabetes mellitus (DM), asthma, and chronic obstructive pulmonary disease (COPD). These were selected due to their high relative prevalence among NCDs (World Health Organization, Fact sheet: noncommunicable diseases. https://www.who.int/news-room/fact-sheets/detail/noncommunicable-diseases . Accessed 25 Nov 2022, 2018). An extensive literature review was undertaken to uncover studies that reported on NCD prevalence among the SGM population, globally. For SM studies, nine countries that are considered mature from an economic perspective represented almost all of the findings. For transgender studies, almost all studies about cancer were case and case series reports, and these represented numerous countries around the world. The limited data representing a global perspective among sexual minorities hints at the possibility of a similar burden for CVD, cancer (excluding HIV/AIDS-related cancers), DM, COPD, and asthma (among SM men) compared to heterosexual and/or cisgender populations. The same seems to be true for transgender populations, with some evidence of elevated CVD risk among transfeminine populations.
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 4 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 children and adolescents on GAHT. There is a need for large, longitudinal studies of transgender women using GAHT to further characterise VTE risk and how this is affected by factors such as patient age, duration of GAHT use, tobacco use, BMI, and comorbidities. Future studies in these areas could inform the development of clinical guidelines to improve the care of transgender people.
The growing number of people who identify themselves as transgender has gained increased attention in recent years and will certainly impact personalized clinical practices and healthcare worldwide. Transgender and gender non-conforming individuals frequently undergo gender-affirming hormone therapy (GAHT), i.e. they use sex hormones to align their gender identity with their biological characteristics. Testosterone is the main compound used in GAHT by transmasculine people, leading to the development of male secondary sexual characteristics in these individuals. However, sex hormones, testosterone included, also influence hemodynamic homeostasis, blood pressure, and cardiovascular performance by direct effects in the heart and blood vessels, and by modulating several mechanisms that control cardiovascular function. In pathological conditions and when used in supraphysiological concentrations, testosterone is associated with harmful cardiovascular effects, requiring close attention in its clinical use. The present review summarizes current knowledge on the cardiovascular impact of testosterone in biological females, focusing on aspects of testosterone use by transmasculine people (clinical goals, pharmaceutical formulations, and impact on the cardiovascular system). Potential mechanisms whereby testosterone may increase cardiovascular risk in these individuals are discussed, and the influence of testosterone on the main mechanisms that control blood pressure and that potentially lead to hypertension development and target-organ damage are also reviewed. Additionally, current experimental models, which are key to reveal testosterone mechanistic aspects and potential markers of cardiovascular injury, are reviewed. Finally, research limitations and the lack of data on cardiovascular health of transmasculine individuals are considered, and future directions for more appropriate clinical practices are highlighted.
Transgender and nonbinary (TGNB) patients who desire gender-affirming therapy are often treated with hormones to help align their external appearance with their gender identity. This practice is generally safe, and studies have shown that gender-affirming therapy has positive physical and psychological effects for many TGNB individuals. Masculinizing hormone therapy involves administration of exogenous testosterone. Expected changes include cessation of menses, deepening of the voice, and development of terminal facial and body hair. Testosterone therapy increases the risk of polycythemia. Feminizing hormone therapy typically involves the use of estrogen and an anti-androgen, and can produce physical changes such as breast growth, changes in fat distribution, and redistribution of hair growth. Transfeminine individuals may have an increased risk of breast cancer and thromboembolism based on recent cohort studies, although this has yet to be confirmed with randomized controlled trials. Regular surveillance is essential to establish the proper hormone dosage and detect complications. Important long-term considerations include metabolic, cardiovascular, and skeletal health. Gender-affirming surgeries are also available and may improve outcomes in some patients. Gender dysphoric adolescents entering puberty can opt for reversible pubertal suppression, which may make future gender-affirming treatment easier to accomplish. High-quality, long-term studies on the effectiveness and safety of gender-affirming treatments in both adults and adolescents are lacking, but the current evidence suggests that they are overall safe and effective with appropriate oversight.
This book discusses the global prevalence as well as the geographic distribution of HIV-1 and HIV-2 infections and updates on recent shared global initiatives. The demographic trends in HIV in the United States, especially regarding gender, sexuality, race, ethnicity, age, injection-drug use, socioeconomic status, and recent initiatives are reviewed. Special attention is paid to HIV among communities of color, as well as women, children, and adolescences. The role of HIV in men who have sex with men and the transgender community is reviewed in detail. HIV Testing and Counselling lists and describes the various types of HIV testing available. The book also presents an overview of HIV counselling. HIV testing terminology and algorithms are presented to the reader along with descriptive figures. Laboratory markers for HIV are reviewed. The chapter describes who should be tested, as well as pre and post-test counselling elements. A section of the chapter is dedicated to special populations and environments (blood supply screening, prenatal screening, testing settings) Strategies to improve uptake of HIV testing are discussed.
The use of gender-affirming hormone therapy is found almost universally in transgendered and nonbinary patients presenting for gender-affirming surgical procedures of the face, neck, and voice. Surgeons caring for this population need to be aware of the effects, reasonable expectations, and limitations as well as potential perioperative risks of both continuation and discontinuation of hormone therapy.
There is a growing interest in the healthcare community to focus on the healthcare needs of lesbian, gay, bisexual, transgender, or genderqueer (LGBTQ) patients, particularly transgender and gender diverse (TGD) patients. TGD individuals have historically experienced rejection and mistreatment by healthcare providers yet have significant health needs, highlighting the need for providing affirming care. Medication therapy for TGD individuals involves many nuances and special considerations for managing concomitant therapies and drug interactions. Additionally, approaches to caring for TGD patients involve both medical interventions as well as social and legal processes. Pharmacists can assist and facilitate the care for TGD patients through a variety of mechanisms. This narrative review describes strategies to recognize and address many aspects of the care for TGD individuals, including destigmatizing care, affirmation strategies, and an overview of therapeutic misconceptions and concerns. Ultimately, this manuscript serves as a guide for pharmacists to care holistically for TGD patients. This article is protected by copyright. All rights reserved.
Background: Venous thromboembolism (VTE) is a rare side effect of hormonal therapy in transgender persons. Prothrombotic genetic variants can increase this risk. For this reason, previous VTE and/or genetic thrombophilia may be considered by some as contraindications to hormonal treatment.
Aim: To formulate directions for clinical practice about the indications for thrombophilia screening and when to consider combination therapy of therapeutic anticoagulation and hormonal treatment as a safe alternative to withholding hormonal treatment.
Methods: We conducted a literature search and describe a case series. All adult patients with gender dysphoria and a known prothrombotic genetic variant or history of VTE were invited by letter to participate in this study.
Results: In our center, thrombophilia screening before start of hormonal treatment was restricted to those with a personal or family history of VTE. Sixteen individuals with a history of VTE and/or an underlying prothrombogenic condition were described. The time of follow up varied from 4 months to 20 years. Seven trans women had a positive thrombophilia screening (2 Factor V Leiden (FVL), 1 FVL + anticardiolipin antibodies, 1 FVL + high Factor VIII coagulant activity, 1 protein C deficiency, 1 prothrombin mutation, 1 positive lupus anticoagulant). Three trans women experienced an unprovoked VTE after start of hormonal therapy of which one lead to a positive thrombophilia screening. One VTE event in a trans woman was assumed to be provoked by surgery. Five trans men were identified with a prothrombogenic mutation (3 FVL, 1 protein C deficiency, 1 prothrombin mutation). One trans man, with a negative thrombophilia screen, experienced multiple provoked VTE events before start of hormonal therapy.
Conclusion: Based on our literature review and case series we offer guidance when confronted with patients with previous VTE and/or genetic thrombophilia requesting hormonal interventions.
Purpose
Identifying the health-related needs in transgender (TG) people can help to formulate strategies for providing appropriate and accessible health services and promoting health and social justice, as well as human rights in these populations. This systematic review aims to determine health-related needs, problems and barriers, as well as ways to solve them in TG people from the viewpoint of TG individuals and health policymakers.
Design/methodology/approach
All international electronic databases such as PubMed (Medline), Embase, CINAHL, Scopus, Web of Sciences, Cochrane, PsycInfo and Google Scholar (Gray Literature) were searched from December 1990 to December 2019. After the search, the articles were screened based on their title, abstract and full text. The quality of articles was assessed using the Strengthening the reporting of observational studies in epidemiology (STROBE), Consolidated Standards of Reporting Trials (CONSORT) and Standards for Reporting Qualitative Research (SRQR) checklists. The search strategy, data extraction and quality evaluation of articles were independently performed by two researchers.
Findings
The general health-related needs identified in TG individuals from the viewpoint of themselves included access to legal hormone therapy, psychological and psychiatric counseling, privacy, health and hygiene needs, equality and freedom of expression. General health-related needs in TG individuals from the viewpoint of health policymakers included screening tests to detect sexually transmitted diseases, especially HIV, cancers and other diseases, as well as training service providers (physicians, nurses, health workers, etc.).
Research limitations/implications
One of the limitations of this study was nonreporting of health-related needs in initial articles by different TG groups because these groups have had different needs and different barriers to accessing health-care services. In this study, health-related needs and barriers to satisfy them were categorized from the viewpoint of TG populations and health policymakers around the world, which may influence future decisions to provide services to TG populations. The results of this systematic review can help to develop different strategies by considering all TGs from individual, family and social aspects to better provide services for this group. However, given the dynamics and changes in the existing communities and the limited studies on gender minorities in developing countries, further research is required to comprehensively address the subject.
Originality/value
The findings can be used as an incentive to improve existing conditions and to address problems and shortcomings. The results of this systematic review formulate strategies for providing appropriate and accessible health services and better lives for TGs, planning for more effective participation of these individuals in local communities, improving their physical problems and mental health through counseling, as well as promoting health and social justice, and human rights for these populations.
Background
Feminizing and masculinizing hormone treatments are established components of management in transgender patients. Exogenous hormones have been associated with hemostatic effects, which are well-studied in cis-gender individuals on hormone replacement therapy (HRT). Unfortunately, comprehensive understanding of their effects on venous thromboembolism (VTE) risk in the transgender population is lacking.
Aim
This manuscript aims to identify the risk of VTE among transgender individuals undergoing cross-sex hormone therapy.
Methods
A Systematic review of the literature was performed in March 2020 for studies reporting VTE rates in transgender patients undergoing hormone treatment and rates in cis-gender patients on HRT. Data regarding demographics, hormone therapy, and VTE incidence were collected and pooled for analysis.
Outcome
The primary outcome of interest was the development of a VTE event in association with concurrent hormone administration.
Results
Overall, 22 studies were included with 11 reporting VTE rates among transgender patients, 6 in cis-female patients, and 5 in cis-male patients. Data from 9,180 transgender patients (6,068 assigned male at birth [AMAB] and 3,112 assigned female at birth [AFAB]) undergoing hormone treatment and 103,713 cis-gender patients (18,748 female and 84,965 male) undergoing HRT were pooled. The incidence of VTE was higher in AMAB patients compared to AFAB patients (42.8 vs 10.8 VTE per 10,000 patient years; P = .02). The rate of VTE incidences in AMAB patients appears similar or higher than the rate demonstrated in cis-females on HRT. VTE incidence in AFAB patients, however, is similar to the published rates in cis-males on HRT.
Clinical Implications
AMAB patients on hormone therapy have higher VTE rates than AFAB patients. AMAB and AFAB patients may have similar VTE incidence to cis-female and cis-male patients on hormone replacement therapy, respectively.
Strengths & Limitations
This is the first study to aggregate and quantify the development of VTE events in association with hormone therapy in transgender patients. It places these values in the context of rates published in more widely studied populations. It is limited by its retrospective data and heterogenic data.
Conclusion
Surgical planning regarding perioperative and postoperative VTE prophylaxis or cessation of hormone therapy should take into account each patient's Caprini risk assessment and the nature of each intervention.
Kotamarti VS, Greige N, Heiman AJ, et al. Risk for Venous Thromboembolism in Transgender Patients Undergoing Cross-Sex Hormone Treatment: A Systematic Review. J Sex Med 2021;XX:XXX–XXX.
Context
Cyproterone acetate (CPA) is a competitive inhibitor of the androgen receptor and exerts negative hypothalamic feedback. It is often used in combination with estrogens in trans women to achieve feminization. However, CPA has been associated with side effects such as changes in liver enzyme concentrations and increases in prolactin concentrations. The question is whether testosterone lowering, as well as these side effects, are dose-dependent.
Objective
To assess the lowest effective dose of CPA in trans women to prevent side effects.
Design
This longitudinal study is part of the European Network for the Investigation of Gender Incongruence (ENIGI), a multicenter prospective cohort study.
Setting
Gender identity centers in Amsterdam, Ghent, and Florence
Participants
Trans women (n = 882) using estrogens only or in combination with 10mg, 25mg, 50mg, or 100mg CPA daily.
Intervention
Different doses of CPA.
Main Outcome measure
The concentration of testosterone at 3 and/or 12 months of hormone therapy.
Results
Using estrogens only (without CPA) led to testosterone concentrations of 5.5nmol/L (SEM 0.3). All doses of CPA resulted in testosterone concentrations below the pre-defined threshold of suppression of 2nmol/L (10mg: 0.9nmol/L, SEM 0.7; 25mg: 0.9nmol/L, SEM 0.1; 50mg: 1.1nmol/L, SEM 0.1; 100mg: 0.9nmol/L, SEM 0.7). Higher prolactin and lower high-density lipoprotein concentrations were observed with increasing doses of CPA. No differences in liver enzyme concentrations were found between the doses.
Conclusions
Compared to higher doses of CPA, a daily dose of 10mg is equally effective in lowering testosterone concentrations in trans women, while showing fewer side effects.
This review discusses the current evidence regarding perioperative hormone therapy for transgender individuals, with an emphasis on strategies to reduce the risk of perioperative venous thromboembolism. Historically, surgeons routinely discontinued estrogen therapy in the perioperative period with the goal of reducing the risk of venous thromboembolism. However, abrupt estrogen cessation may also lead to adverse emotional and physiologic effects, including an exacerbation of one's gender dysphoria. The data on the relationship of feminizing hormones and venous thromboembolism in the perioperative setting are largely based on extrapolation of hormone regimens that are no longer in use and may not accurately reflect the actual risk of venous thromboembolism. Future studies will allow surgeons to engage in evidence-based, patient-centered, informed consent while also minimizing the risk of complications, such as venous thromboembolism.
We sought to systematically review the effect of gender-affirming hormone therapy on psychological outcomes among transgender people. We searched PubMed, Embase, and PsycINFO through June 10, 2020 for studies evaluating quality of life (QOL), depression, anxiety, and death by suicide in the context of gender-affirming hormone therapy among transgender people of any age. We excluded case studies and studies reporting on less than 3 months of follow-up. We included 20 studies reported in 22 publications. Fifteen were trials or prospective cohorts, one was a retrospective cohort, and 4 were cross-sectional. Seven assessed QOL, 12 assessed depression, 8 assessed anxiety, and 1 assessed death by suicide. Three studies included trans-feminine people only; 7 included trans-masculine people only, and 10 included both. Three studies focused on adolescents. Hormone therapy was associated with increased QOL, decreased depression, and decreased anxiety. Associations were similar across gender identity and age. Certainty in this conclusion is limited by high risk of bias in study designs, small sample sizes, and confounding with other interventions. We could not draw any conclusions about death by suicide. Future studies should investigate the psychological benefits of hormone therapy among larger and more diverse groups of transgender people using study designs that more effectively isolate the effects of hormone treatment.
Background:
Limited research suggests that rates of suicide death among transgender people may be higher than their nontransgender peers.
Objective:
The objective of this study was to compare rates of suicide deaths by different means between transgender and nontransgender patients.
Research design:
This secondary analysis used VHA administrative and electronic health record (EHR) data from October 1, 1999 through December 31, 2016.
Subjects:
Transgender patients (n=8981) were categorized as such based on a set of International Classification of Disease codes, and a comparison sample was selected by randomly choosing 3 nontransgender patients (n=26,924).
Measures and analyses:
Cause and date of death data are from the National Death Index. Because of low frequencies amid different methods of suicide death, we combined categories into self-poisoning; hanging, strangulation and suffocation; discharge of firearms; and self-harm by all other and unspecified means. We conducted Cox regression analyses to model time-to-event for each method of suicide, adjusted for age, sex based on EHR, race, ethnicity, marital status, and whether patients had ever been diagnosed with depression.
Results:
Among transgender patients, 73 died by suicide (22 female EHR-based sex, 51 male EHR-based sex), and among nontransgender patients, 71 died by suicide (4 female EHR-based sex, 67 male EHR-based sex). In adjusted models, transgender patients had significantly greater hazards of death by self-poisoning and firearms than their nontransgender peers.
Conclusions:
Differences in methods of suicide death suggest that firearms and self-poisoning may be specific areas of concern for transgender individuals experiencing suicidal crisis, which underscore needs for examining effective delivery of evidence-based care.
One hundred consecutive patients aged up to 75 with newly diagnosed cancer of the prostate suitable for hormonal treatment were included in a controlled study of the cardiovascular effects of oestrogen versus orchidectomy. In all cases pre-existing cardiovascular morbidity was excluded. Of the 100 patients, 91 were strictly randomised to receive either oestrogen (n = 47) or orchidectomy (n = 44) and 9 (6 given oestrogen, 3 orchidectomy) either chose their own treatment (five cases) or had it selected for them by the urologist (four). Oestrogen was given in the lowest recommended dosage in Sweden--namely, as 160 mg polyestradiol phosphate intramuscularly every month for the first three months, then 80 mg monthly, plus ethinyloestradiol 1 mg by mouth daily for the first two weeks, then 150 micrograms daily. At entry to the study the two treatment groups showed no difference in demographic characteristics or conventional risk factors for cardiovascular disease. During the first year, however, 13 (25%) of the patients given oestrogen suffered major cardiovascular events as compared with none of the patients after orchidectomy. Patients in the oestrogen treatment group who did not have minor signs of atherosclerosis at entry to the study suffered a similar incidence of cardiovascular complications to those who did have these signs at entry. The substantially increased risk of cardiovascular complications in patients given oestrogen for prostatic cancer warrants careful consideration when choosing treatment for this disorder.
An analysis has been made of the 249 deaths that have been reported during the course of the Royal College of General Practitioners' prospective study of the health associations of oral contraception. As previously, women who had used the pill were reported to have a 40% higher death rate than women who had never taken oral contraceptives. Virtually all the excess mortality was due to diseases of the circulatory system. Women who had used the pill had a relative risk of 4.3 for deaths attributed to vascular diseases. Most of these were from ischaemic heart disease (relative risk 4.1) and subarachnoid haemorrhage (relative risk 4.0). The larger number of cases now reported has permitted greater discrimination than was possible earlier between subjects with high and low risks. There were few deaths under 35 years of age and the excess annual death rates of 1 per 77 000 women in non-smokers and 1 per 10 000 women in smokers have wide confidence limits, and could have arisen by chance. For women aged 35-44 years the excess annual death rate was 1 per 6700 women in non-smokers and 1 per 2000 women in smokers; at 45 years and above the risks were 1 in 2500 and 1 in 500, respectively. There is now no evidence that the risk is associated with duration of oral contraceptive use. The demonstrated positive association of risk with parity in pill users needs confirmation. Former-users were noted to have an increased risk of death from vascular disease, but it was not possible to determine whether this represents a residual effect of oral contraceptives on the vascular system.
As noted in two previous reports from the Coronary Drug Project,1,2 physicians face a difficult dilemma concerning pharmacologic therapy of hyperlipidemia-hyperlipoproteinemia in an attempt to prevent first or recurrent episodes of clinical coronary heart disease. It is known that susceptibility to premature coronary heart disease is directly related to serum levels of cholesterol, and of low-density and very-low-density lipoproteins. It is also known that elevated serum levels of lipids-lipoproteins frequently can be influenced over long periods of time by available drugs. However, answers to key questions about these pharmaceutical agents are lacking. Do they prevent coronary heart disease and prolong life? Are they reasonably safe in long-term usage?
The Coronary Drug Project—a nationwide collaborative study sponsored by the National Heart and Lung Institute—is the most extensive effort ever undertaken to answer these questions with regard to men who have already experienced one or more episodes of myocardial infarction.¹⁻⁵
The clinicopathological findings in a patient who developed breast carcinoma ten years after male-to-female sexual reassignment are reported. Only two other cases of transsexual men with breast carcinoma have been reported previously. All three patients received oral estrogens for prolonged periods to maintain secondary female characteristics. The controversies relating to hormonal influences in the etiology of breast cancer in men are discussed herein.
(JAMA 1988;259:-2278-2280)
There is limited published literature on the risk of breast cancer in transgender patients. We report a case of an aggressive triple negative inflammatory breast cancer in a male-to-female transsexual. This patient had a complicated psychiatric history with significant antipsychotic use, and the case raises several questions about the pathogenesis of this breast cancer. The literature on breast cancer in transgender patients and in relation to hyperprolactinaemia is reviewed. © 2013 The Authors. Internal Medicine Journal
Summary— Cardiovascular complications in patients with carcinoma of the prostate have been studied in relation to 3 methods of treatment, namely stilboestrol, estramustine phosphate (Estracyt) and bilateral orchiectomy. One hundred and sixteen patients were studied over a 4-year period on a prospective basis, 48 being treated with stilboestrol, 31 with estramustine and 37 with bilateral orchiectomy. The incidence of the cardiovascular side effects of these 3 treatment regimes in the first year of treatment was recorded after the patients had been divided into those with localised (MO) disease and advanced disease with metastases (Ml).
In patients treated with stilboestrol 29% had cardiovascular complications with a mortality rate of 1 6%. With estramustine 25% had complications with a 1 6% mortality rate, but with orchiectomy the complication rate was only 8% with a 3% mortality rate. It is recommended that stilboestrol and estramustine phosphate should not be used in the presence of cardiovascular disease and that the primary form of treatment in prostatic carcinoma should be bilateral orchiectomy, especially in patients with localised disease.
The effect of Cyproteron-Acetate was followed in 329 patients with idiopathic hirsutism, acne, seborrhoea oleosa or androgenetic alopecia. Cyproteron-acetate is known to act as an antiandrogen with a strong progestin effect. Treatment was done in form of a “reverse sequence-therapy”: 100 mg cyproteron-acetate from day 5 to 14 and 50μg ethinylestradiol from day 5 to 25 and in a combination of 2 mg cyproteron-acetate and 50 mg ethinyl estradiol from day 5 to 25 of the cycle. The medication was continued for at least three months up to three years. In patients with acne and seborrhoea oleosa in more than 90% an improvement or a complete disappearance of the symptoms was observed after three months treatment. The effect in hirsutism and androgenetic alopecia was retarded. After 6 to 9 month of medication in nearly all cases a significant improvement could be obtained. Side effects during administration of cyproteronacetat mainly were of subjective nature and mostly disappeared after three months. Only in 2,5% therapy had to be interrupted because of the intensity of the side effects. In 2000 treatment cycles no pregnancy occured.
Lipid and lipoprotein values, including fasting triglycerides and high density lipoproteins (HDL), low density lipoproteins (LDL) and total cholesterol levels, were obtained on 2,815 men and women aged 49 to 82 years chiefly between 1969 and 1971 at Framingham. In the approximately four years following the characterization of lipids, coronary heart disease developed in 79 of the 1,025 men and 63 of the 1,445 women free of coronary heart diseases. At these older ages the major potent lipid risk factor was HDL cholesterol, which had an inverse association with the incidence of coronary heart disease (p less than 0.001) in either men or women. This lipid was associated with each major manifestation of coronary heart disease. These associations were equally significant even when other lipids and other standard risk factors for coronary heart disease were taken into consideration. A weaker association with the incidence of coronary heart disease (p less than 0.05) was observed for LDL cholesterol. Triglycerides were associated with the incidence of coronary heart disease only in women and then only when the level of other lipids was not taken into account. At these ages total cholesterol was not associated with the risk of coronary heart disease.
This study was undertaken to investigate the effect of various forms of hormone replacement therapy (HRT) upon postmenopausal women while controlling as many variables as possible. It was felt that the age, duration of amenorrhoea and the general health of the patients should be as comparable as possible and that each patient should provide her own pretherapy and post-therapy control data. In addition, it was felt that any placebo effect should be investigated and the patients were therefore randomly allocated to placebo tablets or one of six available forms of HRT. The age/sex registers of two large general practices were scrutinized and all women between 49 and 54 years of age were asked to cooperate; for a variety of reasons only 56 women were suitable and willing to take part in the project, yielding 8 women for each of the seven possible therapy groups. Blood samples were taken at 7-day intervals three times before therapy was given and the mean of the three values was used as the control value. The women returned on day 21 of each subsequent therapy cycle for six consecutive months and finally three months after discontinuing therapy. From the data the following broad conclusions can be drawn: (i) some women have classic symptoms of hot flushes and sweating despite high endogenous oestrogen concentrations; (ii) vaginal cytology is a relatively poor indicator of endogenous oestrogen status; (iii) while follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations are reduced on HRT neither is decreased to anywhere near premenopausal values while prolactin is unaffected; (iv) plasma cholesterol levels are reduced on HRT, the pulse rate is slower and both systolic and diastolic blood pressure are reduced to a small but significant extent; (v) there is no adverse effect upon blood clotting; and (vi) most women experience significant or complete relief of symptoms on all forms of HRT as do some women taking a placebo. The combined preparations containing an oestrogen and progestogen produced vaginal bleeding in only 80 per cent of the women. Thus protection by regular endometrical shedding may not be afforded to all women. As vaginal bleeding is unacceptable to most women if they can achieve the same symptomatic relief without inducing menstruation, it is suggested that women have a low dose oestrogen preparation prescribed cyclically for 6 to 12 months. If therapy is to be maintained for a longer time, uterine curretage should be undertaken at regular intervals to exclude the possibility of endometrial carcinoma developing.
The Collaborative Study Group for the Study of Stroke in Young Women studied 598 women from age 15 to 44 years with cerebrovascular disease. They found that the use of oral contraceptives was significantly more prevalent in women who had suffered a thrombotic stroke than in women who had not had strokes. The risk of thrombotic stroke was estimated to be nine times greater in users of oral contraceptives than in nonusers. We report a case in which a previously healthy man who was using an oral contraceptive drug developed middle cerebral artery occlusion. In the absence of other predisposing factors in this case, it appears that the cerebrovascular occlusion was related to estrogen administration. The occurrence of persistent severe headaches in patients using estrogenic hormones may be a clue to impending cerebrovascular occlusion.
THE ASSOCIATION of the use of oral contraceptive pills with increased risk of thromboembolism in women has been well documented.1 This report describes the occurrence of pulmonary embolism in a normal, healthy man taking estrogens to alter secondary sex characteristics.
Report of a Case
A 29-year-old phenotypic and genotypic man was admitted to the hospital with a history of short-term onset of right shoulder and chest pain accompanied by shortness of breath, diaphoresis, and hemoptysis. The patient did not have any history of varicosities, injuries, or prolonged inactivity, but he felt "muscle cramps" in both legs prior to the onset of pain. He was being seen at the San Francisco Community Health Center for Special Problems for therapy of transsexualism, which included psychotherapy and diethylstilbestrol, 5 mg every day for two years, in preparation for a sex-reassignment operation.Initial examination showed a feminineappearing man with gynecomastia and atrophic testes.
The clinicopathological findings in a patient who developed breast carcinoma ten years after male-to-female sexual reassignment are reported. Only two other cases of transsexual men with breast carcinoma have been reported previously. All three patients received oral estrogens for prolonged periods to maintain secondary female characteristics. The controversies relating to hormonal influences in the etiology of breast cancer in men are discussed herein.
PRL levels were evaluated during long-term treatment with cyproterone acetate 100 mg and ethinyloestradiol 100 micrograms/day orally or depot-oestrogens in 214 male-to-female transsexuals. PRL levels increased above normal in all subjects (normal less than 300 mU/l). In 46 (21.4%) subjects PRL levels rose to greater than 1000 mU/l. The incidence of PRL levels greater than 1000 mU/l was 3.7-7.2% per treatment year. Grossly elevated PRL levels were associated with high doses of oestrogens (P less than 0.05) and advanced age at the start of treatment (P less than 0.05). In 23 subjects PRL levels greater than 1000 mU/l decreased by more than 50% spontaneously (n = 5) or after dose reduction (n = 18). In five of the subgroup of 15 subjects with persistent PRL levels greater than 1000 mU/l enlargement of the pituitary gland was shown by CT-scanning. These data suggest that the lowest possible oestrogen dose and lifelong follow-up of hormone-treated male-to-female transsexuals is essential.
In a case-control study of the risk of adenocarcinoma of the endometrium in relation to conjugated-estrogen use, we found that 31 per cent of 425 women with endometrial cancer and 15 per cent of 792 controls reported having used conjugated estrogens; the rate-ratio estimate was 3.5 with a 95 per cent confidence interval of 2.6 to 4.7. For use that lasted at least one year, the rate-ratio estimate for Stage I or II cancer was 5.2 (95 per cent confidence interval, 3.7 to 7.2), and for Stages III and IV combined it was 3.1 (1.5 to 6.4). Among women who had used estrogen for at least one year and then discontinued it, the risk of endometrial cancer remained significantly elevated even after estrogen-free intervals of over 10 years. The findings suggest that long-term use of conjugated estrogen increases the risk of both localized and widespread endometrial cancer. The data also suggest that women who have taken conjugated estrogen for one or more years remain at increased risk for at least 10 years after they discontinue use. Such women should be considered for long-term gynecologic surveillance.
The physical and hormonal characteristics of 60 male-to-female transsexuals and 30 female-to-male transsexuals were measured before or during treatment with commonly used forms and dosages of hormones. Only two patients (both female-to-male) had either a congenital defect in hormonal production or abnormal genital development. Patients were seen at 3- to 6-month intervals for an average of 18 months. The response to therapy was examined over time; physical parameters, hormonal concentrations, liver function tests, lipids, and glucose were measured. Three patients were changed from ethinyl estradiol to conjugated estrogen because of liver enzyme elevations. Ethinyl estradiol (0.1-0.5 mg/day) was equal to conjugated estrogen (7.5-10 mg/day) in its ability to suppress testosterone and gonadotropins and to promote breast growth. Maximum breast growth required 2 years of therapy. During treatment with testosterone, female-to-male transsexuals had a significant mild elevation of cholesterol and triglyceride. The female-to-male transsexuals receiving testosterone cypionate, 200 mg every 2 weeks, ceased to have menstrual periods and became progressively masculinized. A mean maximal clitoral length of 4.6 cm which achieved by 1 year of therapy. Based on the data generated by this study, we recommend as hormonal therapy 0.1-0.5 mg/day of ethinyl estradiol or 7.5-10 mg/day of conjugated estrogen for male-to-female transsexuals, and intramuscular testosterone cypionate, 200 mg every 2 weeks, for female-to-male transsexuals.
One hundred consecutive patients aged up to 75 with newly diagnosed cancer of the prostate suitable for hormonal treatment were included in a controlled study of the cardiovascular effects of oestrogen versus orchidectomy. In all cases pre-existing cardiovascular morbidity was excluded. Of the 100 patients, 91 were strictly randomised to receive either oestrogen (n = 47) or orchidectomy (n = 44) and 9 (6 given oestrogen, 3 orchidectomy) either chose their own treatment (five cases) or had it selected for them by the urologist (four). Oestrogen was given in the lowest recommended dosage in Sweden--namely, as 160 mg polyestradiol phosphate intramuscularly every month for the first three months, then 80 mg monthly, plus ethinyloestradiol 1 mg by mouth daily for the first two weeks, then 150 micrograms daily. At entry to the study the two treatment groups showed no difference in demographic characteristics or conventional risk factors for cardiovascular disease. During the first year, however, 13 (25%) of the patients given oestrogen suffered major cardiovascular events as compared with none of the patients after orchidectomy. Patients in the oestrogen treatment group who did not have minor signs of atherosclerosis at entry to the study suffered a similar incidence of cardiovascular complications to those who did have these signs at entry. The substantially increased risk of cardiovascular complications in patients given oestrogen for prostatic cancer warrants careful consideration when choosing treatment for this disorder.
A three-phase study tested the hypothesis that the decrease in the high-density lipoprotein cholesterol (HDL-C) level observed in boys at puberty is related to an increase in the plasma testosterone concentration. In phase I, 57 boys aged 10 to 17 years were categorized into four pubertal stages based on clinical parameters and plasma testosterone levels. These four groups showed increasing plasma testosterone values and decreasing HDL-C levels. In phase II, 14 boys with delayed adolescence were treated with testosterone enanthate (100, 200, and 200 mg/mo, respectively, for three months). Plasma testosterone levels during therapy were in the adult male range. Levels of HDL-C decreased by a mean of 7.4 mg/dL (0.20 mmol/L) and 13.7 mg/dL (0.35 mmol/L), respectively, after the first two doses. In phase III, 13 boys with delayed adolescence demonstrated increasing plasma testosterone levels and decreasing HDL-C levels (-12.0 mg/dL [-0.30 mmol/L]) during spontaneous puberty. Levels of HDL-C and apolipoprotein A-1 were correlated during induced and spontaneous puberty. Testosterone should be considered a significant determinant (not necessarily directly causal) of plasma HDL-C levels during pubertal development.
A total of 10,550 'normal' adults (8450 men and 2100 women) in the general population were screened by a paired assay method for serum PRL and 40 subjects with hyperprolactinaemia (greater than 75 micrograms/l) were detected. Of these, five patients (three men and two women) with pituitary prolactinoma, one man with empty sella syndrome, 10 cases of 'big' prolactinaemia, seven pregnant women and 13 subjects with drug-induced hyperprolactinaemia were found. The patients with prolactinoma had few if any complaints (asymptomatic prolactinoma).
We describe the management of a genotypic female who developed hyperlipidaemia and premature coronary artery disease following bilateral oophorectomy and methyltestosterone administration, and present evidence to suggest that the therapeutic androgenization involved in the sex-change was responsible for the hyperlipidaemia.
To clarify the possible role of postmenopausal estrogen use in coronary heart disease, we surveyed 121,964 female nurses, aged 30 to 55 years, with mailed questionnaires, beginning in 1976. Information on hormone use and other potential risk factors was updated and the incidence of coronary heart disease was ascertained through additional questionnaires in 1978 and 1980, with a 92.7 per cent follow-up. End points were documented by medical records. During 105,786 person-years of observation among 32,317 postmenopausal women who were initially free of coronary disease, 90 women had either nonfatal myocardial infarctions (65 cases) or fatal coronary heart disease (25 cases). As compared with the risk in women who had never used postmenopausal hormones, the age-adjusted relative risk of coronary disease in those who had ever used them was 0.5 (95 per cent confidence limits, 0.3 and 0.8; P = 0.007), and the risk in current users was 0.3 (95 per cent confidence limits, 0.2 and 0.6; P = 0.001). The relative risks were similar for fatal and nonfatal disease and were unaltered after adjustment for cigarette smoking, hypertension, diabetes, high cholesterol levels, a parental history of myocardial infarction, past use of oral contraceptives, and obesity. These data support the hypothesis that the postmenopausal use of estrogen reduces the risk of severe coronary heart disease.
The decrease of the number of deaths from ischaemic heart disease which has been reported earlier appears to be continuing. This gratifying phenomenon cannot be solely due to a rising quality of medical treatment; a falling incidence is undoubtedly playing a part. Comparison of the mortality figures from a number of years reveals that women between the ages of 45 and 49 years constitute the only age group with a rising mortality from acute ischaemic heart disease. The probably transient character of this rise is one of the reasons why it should be investigated further before far-reaching conclusions are drawn from it.
The mortality from atherosclerotic diseases of the brain, roughly combined under the heading 'cerebrovascular accident' is found to have decreased substantially in the last few decades. At the same time, the frequency of hospitalization has shown a fairly marked rise, but the average duration of hospitalization has decreased. In women aged 45-49 years and in men of approximately the same age group, the decrease has been less pronounced, or has started later. Study of the data arranged according to age shows that the factors that influence the decrease of the mortality and (or) the increase of the frequency of hospitalization are not the same for men and for women. There are grounds to assume that the frequency of the above-mentioned category of diseases among the population is decreasing. This trend appears to be international.
Liver function of patients with cancer of the prostate gland was studied while they were receiving oestrogen therapy. When synthetic oestrogens were given, raised values of serum aspartate and alanine amino-transferase (S.G.O.T. and S.G.P.T.) were found in about 30-50% of them. As treatment continued the increased values usually returned to normal levels. No serious liver damage was observed, though the serum bilirubin content rose temporarily in some patients.
We report on a 30-year-old male-to-female transsexual who had been treated with diethylstilbestrol and Premarin from 1954 to the present. A sex change operation was done. In May 1979 transurethral resection was performed for obstruction due to the enlargement of the verumontanum. Transurethral resection was repeated in January 1983 for obstructive symptoms. The interesting effect of the estrogens on the verumontanum and prostate is described and illustrated. The squamous metaplasia is compared to that seen in the prostate of a true hermaphrodite.
An analysis of vasomotor, psychological, and physical symptoms of 136 women who were receiving piperazine oestrone sulphate (Ogen) and conjugated equine oestrogens (Premarin) after menopause has shown differences in responses which can be explained only if it is accepted that the two oestrogenic compounds have differing effects on various parts of the body. Premarin (0.625 mg) was found to be more potent at inducing withdrawal bleeding than Ogen (1.25 mg), whereas Ogen was more effective than Premarin in alleviating hot flushes and some psychological symptoms. A hypothesis involving metabolism of oestrone to the catecholamine, 2-hydroxyoestrone, is postulated, which explains why these differences occur. It is further suggested that better selection of oestrogens to suit particular postmenopausal symptoms should be encouraged when prescribing oestrogen for women after menopause.
• An estrogen-dependent genetic-male transsexual had an extensive anterior wall myocardial infarction, despite insignificant coronary artery disease, a subsequent mural thrombosis, and resultant multiple cardioarterial thromboembolic events, despite heparin therapy. With an otherwise lack of cardiac risk factors, the patient was demonstrated to have an antithrombin III deficiency that resolved when conjugated estrogen therapy was withdrawn. Although congenital, plasminogen-activator dysfunction, or heparin-induced etiologies could not be ruled out, we believe this case demonstrated an estrogen-induced—antithrombin III deficiency culminating in thrombotic diathesis. This identifies a previously unrecognized population at risk. Prophylactic and therapeutic considerations are discussed.
(Arch Intern Med 1984;144:1082-1083)
Because testosterone is rapidly metabolized by the liver, it is necessary either to administer androgens by injection in the form of testosterone esters that are absorbed slowly into the circulation or to administer by mouth derivatives that are slowly metabolized by the liver. The later derivatives, however, have deleterious side effects that limit their usefulness. Long-acting parenteral androgen esters are the treatment of choice in the replacement therapy of male hypogonadism. Because these esters must be hydrolyzed to the free hormone prior to exerting their cellular actions the effectiveness of therapy can be monitored by following plasma testosterone levels. All known effects of the endogenous hormone can be duplicated except for the induction and maintenance of normal spermatogenesis. Androgens have been tried in a variety of clinical situations other than male hypogonadism in the hopes that the nonvirilizing actions would outweigh any detectable side effects. The only disorders in which a salutary effect has been documented are hereditary angioneurotic edema and some patients with anemia due to failure off the bone marrow.
Vital statistics and epidemiologic studies in Great Britain and the U.S. have shown that among nonpregnant women of reproductive age who are not using OCs (oral contraceptives) the risks of myocardial infarction and stroke increase substantially with age and in the presence of such risk factors as cigarette smoking and hypertension. The same statistics and studies show that OCs multiply instead of adding to the effects of age and these other risk factors. The pathogenesis of myocardial infarction that is attributable to OCs involves the effects of current use which are unrelated to duration and which disappear when OCs are discontinued and the effects of past use which are related to duration of use and which persist when OCs are discontinued. OCs are known to elevate blood pressure and decrease glucose tolerance slightly in most women. The net effect on high-density-lipoprotein cholesterol depends on the composition of the specific OC compounds. Among women under 35 who do not smoke the risks of death associated with OC cardiovascular effects are lower than the risks associated with complications of pregnancy and risks associated with other methods of contraception. Over 35 the risk of OC-related mortality rises substantially. For smokers the risk is even greater. Introduction of the very low dose estrogenic compounds may reduce these risks. Screening of susceptible high-risk women may also reduce OC-associated mortality.
Current information suggests that oral contraceptives increase both the risk of overt venous thromboembolic disease and the occurrence of subclinical venous thromboembolic disease, primarily by increasing the size of the intravenous clots formed in response to endothelial injury or other stimuli that lead to thrombin formation. This effect appears to be primarily due to the estrogenic component of oral contraceptives, to involve decreased antithrombin III activity, and probably to be exacerbated in women who do not have an appropriate increase in fibrinolytic activity in response to increased intravenous clotting.
Atherosclerotic diseases of the heart and in the statistics of causes of deaths
- Hoogendoorn
Hoogendoorn D: Atherosclerotic diseases of the heart and in the statistics of causes of deaths. Ned Tijdschr Geneeskd 129:
1827-1833, 1985
Atherosclerotic diseases of the brain as seen in hospitals and in the national statistics of causes of death; the cerebrovascular accident (CVA) Oliemans AP: Morbidity in the general practice
- Hoogendoorn
Hoogendoorn D: Atherosclerotic diseases of the brain as seen in hospitals and in the national statistics of causes of death; the cerebrovascular accident (CVA). Ned Tijdschr Geneeskd 129: 1883-1887,1985 34. Oliemans AP: Morbidity in the general practice. Doctoral thesis, Leiden, Stenfert Kroese, 1969
Breast cancer in a male-to-female transsexual Ffrench-Constant CK, Spengel FA, Thompson GR: Hyperlip-idaemia and premature coronary artery disease associated with sex-change in a female
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Pritchard TJ, Pankowsky DA, Crowe JP, et al: Breast cancer in a male-to-female transsexual. JAMA 259:2278-2280, 1988 16. Ffrench-Constant CK, Spengel FA, Thompson GR: Hyperlip-idaemia and premature coronary artery disease associated with sex-change in a female. Postgrad Med 61:61-63.1985
Prolactin levels and pituitary enlargement in hormone-treated male-to-female trans-sexuals Coronary Drug Project Research Group: Findings leading to discontinuation of the 2.5 mg/day estrogen group
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Asscheman H, Gooren LJG, Assies J, et al: Prolactin levels and pituitary enlargement in hormone-treated male-to-female trans-sexuals. Clin Endocrinol (Oxf) 28:583-588, 1988 21. Coronary Drug Project Research Group: Findings leading to discontinuation of the 2.5 mg/day estrogen group. JAMA 226: 652-657,1973
Standards of care. The hormonal and surgical sex reassignment of gender dysphoric persons.
- Walker P
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Walker P, Berger J, Green R, et al: Standards of care. The hormonal and surgical sex reassignment of gender dysphoric per
sons. Arch Sex Behav 14:79-90,1985
Remarkable changes of the epidemiological pattern of cholithiasis, cholecystitis and gall-bladder cancer
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Hoogendoorn D: Remarkable changes of the epidemiological pattern of cholithiasis, cholecystitis and gall-bladder cancer. Ned
TijdschrGeneeskd 132:1243-1248, 1988
Endocrine treatment of male and female transsexualism
- Hamburger
Hamburger C: Endocrine treatment of male and female transsexualism, in Green R, Money J (eds): Transsexualism and Sex
Reassignment. Baltimore, John Hopkins University, 1969, pp 291-307
Prevalentie, opsporing en behandeling van hypertensie in Lelystad (1982–1984); is “de regel van de helften” nog steeds van toepassing?.
- Van Loo JML
- Drenthen AJM
- Peer PGM
Van Loo JML, Drenthen AJM, Peer PGM, et al: Prevalentie, opsporing en behandeling van hypertensie in Lelystad (1982-1984);
is "de regel van de helften" nog steeds van toepassing? Ned Tijdschr Geneeskd 131:624-627, 1987