ArticleLiterature Review

(Patho)physiology of cross-sex hormone administration to transsexual people: The potential impact of male-female genetic differences

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Abstract

There is a limited body of knowledge of desired and undesired effects of cross-sex hormones in transsexual people. Little attention has been given to the fact that chromosomal configurations, 46,XY in male-to-female transsexuals subjects (MtoF) and 46,XX in female-to-male transsexual subjects (FtoM), obviously, remain unchanged. These differences in their genomes cause sex differences in the functions of cells. This study reviews sex differences in metabolism/cardiovascular pathology, immune mechanisms, bone (patho)physiology and brain functions and examines whether they are, maybe partially, determined by genetic mechanisms rather than by (cross-sex) hormones. There do not appear to be major genetic impacts on the changes in bone physiology. Also immune functions are rather unaffected and the evidence for an increase of autoimmune disease in MtoF is preliminary. Brain functions of transsexuals may have differed from controls before cross-sex hormones; they do undergo shifts upon cross-sex hormone treatment, but there is no evidence for changes in sex-specific brain disease. The prevalence of cardiovascular disease is higher in MtoF receiving oestrogens than in FtoM receiving androgens. While type of oestrogen and route of administration might be significant, it is reasonable to speculate that nonhormonal/genetic factors play a role.

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... Reducing transwomen's testosterone levels to under 10 nmol/L potentially reduces muscle mass and oxygen-carrying capacity [7,[13][14][15]. However, hormone therapy will not remodel the male musculoskeletal or cardiovascular and respiratory physiological systems to that of an elite cisfemale athlete [16]. This suggests that the IOC guidelines (2015) afford elite transwomen athletes a performance advantage. ...
... This hormone therapy will increase muscle mass and strength and oxygen-carrying capacity above that of their former female physiology [18]. However, as with transwomen, the hormone therapy taken by transmen will not alter sex-determined musculoskeletal or cardiovascular and respiratory physiological systems [16], suggesting that elite transmen athletes may have a performance disadvantage relative to elite cismen athletes. ...
Article
We support gender equality and freedoms in cases in which ‘like equals like’. Such inclusion is central to a progressive society. However, inclusion could potentially conflict with fairness in cases concerning transgendered athletes in elite sport. Accepted science regarding male and female physiology suggests that transwomen have an advantage over their cisgendered counterparts. This advantage stems from relatively high testosterone levels and prior male physiology of transwomen. Conversely, transmen who wish to compete in the men's division may be disadvantaged in comparison with cismen. Hence, while inclusion supports transwomen and transmen competing in the division that matches their gender identity, this may not satisfy the principle of fairness. We reason that transwomen and cismen are not only advantaged, but unfairly advantaged, and propose that the gender binary in elite sport should be replaced with a nuanced algorithm that accounts for both physiological and social parameters. As the algorithm would be applied to all athletes, it would be both inclusive and fair.
... Few studies showed that transgender's brain is different from their natal sex member's brain and more alike to the opposite sex (Savic et al. 2010;Swaab & Fliers 1985). Transgender's brain seemed to move more towards their experienced gender while receiving hormonal treatment (Gooren et al. 2015). This evidence showed that the brain organisation may be under influence of prenatal sex hormone, which plays a role in the development of the neural circuit (Berenbaum & Beltz 2011;Slabbekoorn et al. 1999). ...
... In this study, it was found that the sexually dimorphic nucleus was 2.5 +/-0.6 times larger, and it contained 2.2+/-0.5 times as many cells in men (Swaab & Fliers 1985). Several studies also showed that sex hormone influenced verbal and spatial ability with androgen hormone favours visuospatial ability and oestrogen favours verbal fluency (Gooren et al. 2015;Slabbekoorn et al. 1999). ...
... A biologic basis of transgenderism is generally accepted. Elucidation of putative biologic underpinnings, likely the result of some combination of genetics, epigenetics, hormonal milieu (perhaps pre-as well as postnatal), influenced by environment factors, is an intriguing and fundamental question that is just beginning to be explored (21). In support of a genetic etiology, it is important to note that monozygotic twins appear to have a higher level of concordance compared to dizygotic twins (22) but that the concordance in monozygotic twins is not 100% (suggesting a role for epigenetic or hormonal modulation, or perhaps even cellular mosaicism). ...
... Despite this increased awareness and acceptance, the transgender community represents one of the most underserved and marginalized populations in health care. The chromosomal configurations, 46 XY in males transitioning to females (henceforth referred to as transwomen) and 46 XX females transitioning to males (referred to as transmen), obviously remains unchanged (Gooren et al., 2015), providing a unique opportunity to determine which metabolic functions are not irreversibly sex differentiated but are determined by the prevailing milieu of sex steroids. ...
... The primary goal of cross-sex hormone treatment is to align the body phenotype of an individual with GD with his/her experienced gender. Cross-sex hormone treatment induces virilization in individuals assigned female at birth (deepening of the voice, male pattern of body hair growth, cessation of menses) and feminization (breast development) of the body in individuals assigned male at birth (Gooren et al. 2015). Transgender individuals report improved feelings of congruence between their gender identity and their body, that is, remission of GD, with cross-sex hormone treatment (Smith et al. 2014), raising the important question as to whether cross-sex hormone treatment also alters the morphology and function of the brain. ...
Article
Transgender individuals experience incongruence between their gender identity and birth-assigned sex. The resulting gender dysphoria (GD), which some gender-incongruent individuals experience, is theorized to be a consequence of atypical cerebral sexual differentiation, but support for this assertion is inconsistent. We recently found that GD is associated with disconnected networks involved in self-referential thinking and own body perception. Here, we investigate how these networks in trans men (assigned female at birth with male gender identity) are affected by testosterone. In 22 trans men, we obtained T1-weighted, diffusion-weighted, and resting-state functional magnetic resonance imaging scans before and after testosterone treatment, measuring cortical thickness (Cth), subcortical volumes, fractional anisotropy (FA), and functional connectivity. Nineteen cisgender controls (male and female) were also scanned twice. The medial prefrontal cortex (mPFC) was thicker in trans men than controls pretreatment, and remained unchanged posttreatment. Testosterone treatment resulted in increased Cth in the insular cortex, changes in cortico-cortical thickness covariation between mPFC and occipital cortex, increased FA in the fronto-occipital tract connecting these regions, and increased functional connectivity between mPFC and temporo-parietal junction, compared with controls. Concluding, in trans men testosterone treatment resulted in functional and structural changes in self-referential and own body perception areas.
... Once prescribed, XHT is generally chronic and administered indefinitely. Since many physiological systems are both sexsteroid-responsive and sexually dimorphic, the biological ramifications of XHT extend beyond the reproductive tract and alter other biological processes (32). Indeed, the potential negative health effects of XHT include increased incidence of type 2 diabetes in both female-to-male (FtM) and male-tofemale (MtF) transgender people (89), osteoporosis in MtF patients (52,90), and cardiovascular disease in MtF patients (33). ...
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Cross-sex hormone therapy (XHT) is widely used by transgender people to alter secondary sex characteristics to match their desired gender presentation. Here we investigate the long-term effects of XHT on bone health, using a murine model. Female mice underwent ovariectomy at either 6 or 10 weeks, and began weekly testosterone or vehicle injections. Dual-energy X-ray Absorptiometry (DXA) was performed to measure bone mineral density (BMD) and microCT was performed to compare femoral cortical and trabecular bone architecture. The 6-week testosterone group had comparable BMD to controls by DXA, but reduced bone volume fraction, trabecular number, and cortical area fraction, and increased trabecular separation by microCT. 10-week ovariectomy/XHT maintained microarchitecture, suggesting that estrogen is critical for bone acquisition during adolescence, and that late, but not early, estrogen loss can be sufficiently replaced by testosterone alone. Given these findings, we then compared effects of testosterone to effects of weekly estrogen or combined testosterone/low-dose estrogen treatment after a 6-week ovariectomy. Estrogen treatment increased spine BMD and microarchitecture, bone volume fraction, trabecular number, trabecular thickness, and connectivity density, and decreased trabecular separation. Combined testosterone-estrogen therapy caused similar increases in femur and spine BMD and improved architecture (increased bone volume fraction, trabecular number, thickness, and connectivity density) to estrogen therapy, and were superior compared to mice treated with testosterone-only. These results demonstrate estradiol is critical for bone acquisition and suggest a new cross-sex hormone therapy adding estrogens to testosterone treatments, with potential future clinical implications for treating transgender youth or males with estrogen deficiency.
... Because participants had received GAHs for 5 years, prevalence at 22 years was calculated with reference values of the affirmed sex. Although the impact of karyotype cannot completely be ruled out, 39 there is abundant evidence of the effect of GAHs on lipid levels. 40 Therefore, we preferred to use reference values of the affirmed sex. ...
Chapter
Part 3 of this first-of-its-kind 3-part series helps show how pediatric primary care providers (PPCPs) are uniquely situated to screen, identify, and care for transgender and gender-diverse youths.
... Accordingly, the duration of exposure to HT might not be long enough for tumors to manifest and the number of individuals exposed is small. 29 Further, it has been suggested that inconsistency in reporting cancer incidents among transsexuals might lead to an underreporting of cancer in this cohort, 21,30 likely affecting prevalence and incidence rates. ...
Article
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Introduction: Studies of mortality and somatic well-being after sex-reassignment surgery (SRS) of transsexual individuals are equivocal. Accordingly, the present study investigated mortality and somatic morbidity using a sample of transsexual individuals who comprised 98% (n = 104) of all surgically reassigned transsexual individuals in Denmark. Aims: To investigate somatic morbidity before and after SRS and cause of death and its relation to somatic morbidity after SRS in Danish individuals who underwent SRS from 1978 through 2010. Methods: Somatic morbidity and mortality in 104 sex-reassigned individuals were identified retrospectively by data from the Danish National Health Register and the Cause of Death Register. Main Outcome Measures: Somatic morbidity and cause of death. Results: Overall, 19.2% of the sample were registered with somatic morbidity before SRS and 23.1% after SRS (P = not significant). In total, 8.6% had somatic morbidity before and after SRS. The most common diagnostic category was cardiovascular disease, affecting 18 individuals, 9 before and 14 after SRS, and 5 of those 14 who were affected after SRS had cardiovascular disease before and after SRS. Ten individuals died after SRS at an average age of 53.5 ± 7.9 years (male to female) and 53.5 ± 7.3 years (female to male). Conclusion: Of 98% of all Danish transsexuals who officially underwent SRS from 1978 through 2010, one in three had somatic morbidity and approximately 1 in 10 had died. No significant differences in somatic morbidity or mortality were found between male-to-female and female-to-male individuals. Despite the young average age at death and the relatively larger number of individuals with somatic morbidity, the present study design does not allow for determination of casual relations between, for example, specific types of hormonal or surgical treatment received and somatic morbidity and mortality.
... The expected hormonal changes of L were obvious after 6 months of monotherapy: T had decreased by almost 30 % whereas E2 had decreased by almost 60 %. The overall decrease in the estrogenic to androgenic ratio is a common property of all androgenic progestins [15,40,42]. Similarly, cross-sex hormone therapy resulted in mean T levels within the male reference range already after 6 months and with the lowest doses of 50 mg T per 2 weeks only. ...
Article
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Background: Prior to the start of cross-sex hormone therapy (CSH), androgenic progestins are often used to induce amenorrhea in female to male (FtM) pubertal adolescents with gender dysphoria (GD). The aim of this single-center study is to report changes in anthropometry, side effects, safety parameters, and hormone levels in a relatively large cohort of FtM adolescents with a diagnosis of GD at Tanner stage B4 or further, who were treated with lynestrenol (Orgametril®) monotherapy and in combination with testosterone esters (Sustanon®). Methods: A retrospective analysis of clinical and biochemical data obtained during at least 6 months of hormonal treatment in FtM adolescents followed at our adolescent gender clinic since 2010 (n = 45) was conducted. McNemar's test to analyze reported side effects over time was performed. A paired Student's t test or a Wilcoxon signed-ranks test was performed, as appropriate, on anthropometric and biochemical data. For biochemical analyses, all statistical tests were done in comparison with baseline parameters. Patients who were using oral contraceptives (OC) at intake were excluded if a Mann-Whitney U test indicated influence of OC. Results: Metrorrhagia and acne were most pronounced during the first months of monotherapy and combination therapy respectively and decreased thereafter. Headaches, hot flushes, and fatigue were the most reported side effects. Over the course of treatment, an increase in musculature, hemoglobin, hematocrit, creatinine, and liver enzymes was seen, progressively sliding into male reference ranges. Lipid metabolism shifted to an unfavorable high-density lipoprotein (HDL)/low-density lipoprotein (LDL) ratio; glucose metabolism was not affected. Sex hormone-binding globulin (SHBG), total testosterone, and estradiol levels decreased, and free testosterone slightly increased during monotherapy; total and free testosterone increased significantly during combination therapy. Gonadotropins were only fully suppressed during combination therapy. Anti-Müllerian hormone (AMH) remained stable throughout the treatment. Changes occurred in the first 6 months of treatment and remained mostly stable thereafter. Conclusions: Treatment of FtM gender dysphoric adolescents with lynestrenol monotherapy and in combination with testosterone esters is effective, safe, and inexpensive; however, suppression of gonadotropins is incomplete. Regular blood controls allow screening for unphysiological changes in safety parameters or hormonal levels and for medication abuse.
... Embryonic development may not be the only determinant of gender identity development. While sexual development variations can cause discordant sexual differentiation of the brain and the genitalia and discordance between gender identity and biological sex (Gooren et al. 2015), puberty serves as another key step in gender identity development. In puberty, sex hormone-related brain organization also influences gender identity development (Schulz et al. 2009). ...
Article
Full-text available
Gender identity development is complex and involves several key processes. Transgender people experience incongruence between their biological and identified gender. This incongruence can cause significant impairment in overall functioning and lead to gender dysphoria (GD). The pathophysiology of GD is complex and is poorly understood. A PubMed search based on predetermined eligibility criteria was conducted to review neuropsychiatric articles focused on neurological, biological and neuroimaging aspects of gender development, transgender identity and GD. The information obtained from the literature was then used to formulize a GD model. Distinct gray matter volume and brain activation and connectivity differences were found in individuals with GD compared to controls, suggesting a neurobiological basis of GD; which leads to the concept of brain gender. Individuals with GD encounter a recurrent conflict between their brain gender and the societal feedback; which causes recurrent and ongoing cognitive dissonance, finally leading to GD and functional connectivity and activation changes in the transgender brain. GD has neurobiological basis, but it is closely associated with the individuals’ interaction with the external world, their self-perception and the feedback received in return. We propose a novel model where the development of GD includes cognitive dissonance, involving anterior cingulate cortex and ventral striatum as the key brain structures. This model can be used to generate testable hypotheses using behavioral and neuroimaging techniques to understand the neuropsychobiology of GD.
... For example, hormone therapy will not alter bone structure, lung volume or heart size of the transwoman athlete, especially if she transitions postpuberty, so natural advantages including joint articulation, stroke volume and maximal oxygen uptake will be maintained. 50 While testosterone is the well-recognised stimulator of muscle mass gain, administration of oestradiol has also been shown to activate muscle gain via oestrogen receptor-β activation. [51][52][53][54][55] The combination of oestradiol therapy and a baseline testosterone of 10 nmol/L arguably provides transwomen athletes with an added advantage of increased muscle mass, and therefore power. ...
Article
The inclusion of elite transwomen athletes in sport is controversial. The recent International Olympic Committee (IOC) (2015) guidelines allow transwomen to compete in the women’s division if (amongst other things) their testosterone is held below 10 nmol/L. This is significantly higher than that of cis-women. Science demonstrates that high testosterone and other male physiology provides a performance advantage in sport suggesting that transwomen retain some of that advantage. To determine whether the advantage is unfair necessitates an ethical analysis of the principles of inclusion and fairness. Particularly important is whether the advantage held by transwomen is a tolerable or intolerable unfairness. We conclude that the advantage to transwomen afforded by the IOC guidelines is an intolerable unfairness. This does not mean transwomen should be excluded from elite sport but that the existing male/female categories in sport should be abandoned in favour of a more nuanced approach satisfying both inclusion and fairness.
... Despite this increased awareness and acceptance, the transgender community represents one of the most underserved and marginalized populations in health care. The chromosomal configurations, 46 XY in males transitioning to females (henceforth referred to as transwomen) and 46 XX females transitioning to males (referred to as transmen), obviously remains unchanged (Gooren et al., 2015), providing a unique opportunity to determine which metabolic functions are not irreversibly sex differentiated but are determined by the prevailing milieu of sex steroids. ...
Article
In this Essay, we discuss the critical need to incorporate sex and gender in pre-clinical and clinical research to enhance our understanding of the mechanisms by which metabolic processes differ by sex and gender. This knowledge will allow for development of personalized medicine which will optimize therapies specific for individuals.
... Sex differentiation of all somatic tissues, including the brain, is driven both by direct genetic influences and gonadal hormones with only minimal environmental effects (Bocklandt and Vilain 2007;Bao and Swaab 2011;Ngun et al. 2011;Lentini et al. 2013;Gooren et al. 2015). Specifically, sex determination or the commitment of an organism to develop toward a female or male phenotype (Bocklandt and Vilain 2007) is mediated via genetic factors, most importantly the presence or absence of the testis-determining gene Sry on chromosome Y (Arnold and Chen 2009). ...
Article
Full-text available
Univariate analyses of structural neuroimaging data have produced heterogeneous results regarding anatomical sex- and gender-related differences. The current study aimed at delineating and cross-validating brain volumetric surrogates of sex and gender by comparing the structural magnetic resonance imaging data of cis- and transgender subjects using multivariate pattern analysis. Gray matter (GM) tissue maps of 29 transgender men, 23 transgender women, 35 cisgender women, and 34 cisgender men were created using voxel-based morphometry and analyzed using support vector classification. Generalizability of the models was estimated using repeated nested cross-validation. For external validation, significant models were applied to hormone-treated transgender subjects (n = 32) and individuals diagnosed with depression (n = 27). Sex was identified with a balanced accuracy (BAC) of 82.6% (false discovery rate [pFDR] < 0.001) in cisgender, but only with 67.5% (pFDR = 0.04) in transgender participants indicating differences in the neuroanatomical patterns associated with sex in transgender despite the major effect of sex on GM volume irrespective of the self-identification as a woman or man. Gender identity and gender incongruence could not be reliably identified (all pFDR > 0.05). The neuroanatomical signature of sex in cisgender did not interact with depressive features (BAC = 74.7%) but was affected by hormone therapy when applied in transgender women (P < 0.001).
... For example, hormone therapy will not alter bone structure, lung volume or heart size of the transwoman athlete, especially if she transitions postpuberty, so natural advantages including joint articulation, stroke volume and maximal oxygen uptake will be maintained. 50 While testosterone is the well-recognised stimulator of muscle mass gain, administration of oestradiol has also been shown to activate muscle gain via oestrogen receptor-β activation. [51][52][53][54][55] The combination of oestradiol therapy and a baseline testosterone of 10 nmol/L arguably provides transwomen athletes with an added advantage of increased muscle mass, and therefore power. ...
... A similar case was published with the development of autoimmune hepatitis associated with estrogen and antiandrogen therapy [19]. However, as concluded in a 2015 cross-HT review, the absolute risk of these effects in the human population is likely to be small and difficult to detect due to the low number of transgender patients in clinical studies [20]. ...
... Because participants had received GAHs for 5 years, prevalence at 22 years was calculated with reference values of the affirmed sex. Although the impact of karyotype cannot completely be ruled out, 39 there is abundant evidence of the effect of GAHs on lipid levels. 40 Therefore, we preferred to use reference values of the affirmed sex. ...
Article
Background and objectives: The effects of endocrinological treatment on cardiovascular risk profile in transgender adolescents are unknown. In this retrospective cohort study, we aim to investigate these effects and assess obesity and dyslipidemia prevalence in transgender adolescents at 22 years compared with peers. Methods: Changes in BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), glucose, homeostatic model assessment for insulin resistance (HOMA-IR), and lipid values during treatment, along with the prevalence of obesity and dyslipidemia at 22 years, were recorded in 71 transwomen and 121 transmen who started gonadotropin-releasing hormone agonists in their adolescence (15 years), with a subsequent addition of sex hormones (17 years). Results: In transwomen, changes in BMI (+3.0; 95% confidence interval [CI] 1.6 to 4.4), SBP (-2 mm Hg; 95% CI -7 to 3), DBP (+10 mm Hg; 95% CI 7 to 14), glucose (0.0 mmol/L; 95% CI -0.2 to 0.2), HOMA-IR (+0.6; 95% CI -0.6 to 1.9), and lipid values were similar or more favorable compared with peers. The same was true for transmen regarding changes in BMI (+2.3; 95% CI 1.7 to 2.9), SBP (+7 mm Hg; 95% CI 3 to 10), DBP (+7 mm Hg; 95% CI 5 to 10), glucose (+0.1 mmol/L; 95% CI -0.1 to 0.3), HOMA-IR (-0.2; 95% CI -0.8 to 0.3), and lipid values. At age 22, obesity prevalence was 9.9% in transwomen, 6.6% in transmen, 2.2% in ciswomen, and 3.0% in cismen. Conclusions: Generally, endocrinological treatment in transgender adolescents is safe regarding cardiovascular risk. Because obesity is more prevalent in transgender adolescents compared with peers, body weight management should be important during the medical trajectory.
... Because participants had received GAHs for 5 years, prevalence at 22 years was calculated with reference values of the affirmed sex. Although the impact of karyotype cannot completely be ruled out, 39 there is abundant evidence of the effect of GAHs on lipid levels. 40 Therefore, we preferred to use reference values of the affirmed sex. ...
... Reviewing the literature on the effects of cross-sex hormone treatment, the brain is astonishingly understudied compared to other body systems and organs (Gooren et al., 2015), despite the fact that the brain is abundant with androgen (Puy et al., 1995) and oestrogen (Osterlund et al., 2000) receptors. If the brain is already sensitive to differences in endogenous levels of sex hormones during the menstrual cycle (Protopopescu et al., 2008) and puberty (Peper et al., 2009), one could imagine that the administration of pharmacological doses of these hormones will have an effect as well. ...
Article
The current review gives an overview of brain studies in transgender people. First, we describe studies into the aetiology of feelings of gender incongruence, primarily addressing the sexual differentiation hypothesis: does the brain of transgender individuals resemble that of their natal sex, or that of their experienced gender? Findings from neuroimaging studies focusing on brain structure suggest that the brain phenotypes of trans women (MtF) and trans men (FtM) differ in various ways from control men and women with feminine, masculine, demasculinized and defeminized features. The brain phenotypes of people with feelings of gender incongruence may help us to figure out whether sex differentiation of the brain is atypical in these individuals, and shed light on gender identity development. Task-related imaging studies may show whether brain activation and task performance in transgender people is sex-atypical. Second, we review studies that evaluate the effects of cross-sex hormone treatment on the brain. This type of research provides knowledge on how changes in sex hormone levels may affect brain structure and function.
... No que concerne à presença e participação de atletas trans no esporte, cabe frisar que esta temática não é nova, muito embora seja difícil ter acesso a registros históricos oficiais envolvendo atletas trans, já que a participação deste público sempre foi invisibilizada desses registros (CAMARGO, 2018b Também podem ocorrer distúrbios psiquiátricos, do sistema nervoso, cardiovasculares, gastrintestinais e musculoesqueléticos (GOOREN et al., 2015), que são fatores muito importantes a se incluir nessas intervenções epistemológicas acerca do desempenho e treinabilidade de todo/a e qualquer atleta transgênero. ...
Article
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As recomendações para a participação de atletas transgênero no esporte RESUMO Neste ensaio, pretendemos descrever e refletir sobre o desenvolvimento das recomendações esportivas que versam sobre a participação de atletas transgênero no esporte. Perguntamos: como vêm se desenvolvendo tais recomendações, por quem e em quais localidades? Pudemos inferir que, mesmo as recomendações esportivas sendo elaboradas por especialistas na temática e através de dados científicos, o assunto "transgênero no esporte" não é inovador, carecendo de mais investigações no campo empírico e acionando unicamente a testosterona como principal hormônio anabólico responsável pelas diferenças entre homens e mulheres cisgênero, entendimento que é estendido para o rendimento de corpos transgêneros de forma ainda pouco conclusiva.
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Introduction Studies have shown that transgender women (TGW) are disproportionately affected by HIV, with an estimated HIV prevalence of 19.1% among TGW worldwide. After receiving a diagnosis, HIV-positive TGW have challenges accessing effective HIV treatment, as demonstrated by lower rates of virologic suppression and higher HIV-related mortality. These adverse HIV outcomes have been attributed to the multiple sociocultural and structural barriers that negatively affect their engagement within the HIV care continuum. Guidelines for feminizing hormonal therapy among TGW recommend combinations of oestrogens and androgen blockers. Pharmacokinetic studies have shown that certain antiretroviral therapy (ART) agents, such as protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and cobicistat, interact with ethinyl estradiol, the key oestrogen component of oral contraceptives (OCPs). The goal of this article is to provide an overview of hormonal regimens used by TGW, to summarize the known drug-drug interactions (DDIs) between feminizing hormonal regimens and ART, and to provide clinical care recommendations. Methods The authors identified English language articles examining DDIs between oestrogen therapy, androgen blockers and ART published between 1995 and 2015 using PubMed, Cumulative Index to Nursing and Allied Health Literature and EBSCOhost. Results and Discussion Published articles predominantly addressed interactions between ethinyl estradiol and NNRTIs and PIs. No studies examined interactions between ART and the types and doses of oestrogens found in feminizing regimens. DDIs that may have the potential to result in loss of virologic suppression included ethinyl estradiol and amprenavir, unboosted fosamprenavir and stavudine. No clinically significant DDIs were noted with other anti-retroviral agents or androgen blockers Conclusions There are insufficient data to address DDIs between ART and feminizing hormone regimens used by TGW. There is an urgent need for further research in this area, specifically pharmacokinetic studies to study the direction and degree of interactions between oral, injectable and transdermal estradiol and ART. Clinicians need to be vigilant about possible interactions and monitor hormone levels if concerns arise. More research is also needed on the provision of hormone therapy and gender-affirming care on the long-term health outcomes of HIV-positive TGW.
Article
Transgender individuals experience unique challenges with regards to discrimination and access to health care. Further, their unique health-care needs and challenges lead to greater rates of morbidity. This article seeks to review the unique biology of transgender patients and the effects of cross-sex hormone therapy on ophthalmic and non-ophthalmic pathology. Attention is given to topics in neuro-ophthalmology, oculoplastics, and retinal disease.
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The current literature shows growing evidence of a link between gender dysphoria (GD) and autism spectrum disorder (ASD). This study reviews the available clinical and empirical data. A systematic search of the literature was conducted using the following databases: PubMed, Web of Science, PsycINFO and Scopus; utilizing different combinations of the following search terms: autism, autism spectrum disorder (ASD), Asperger's disorder (AD), co-morbidity, gender dysphoria (GD), gender identity disorder (GID), transgenderism and transsexualism. In total, 25 articles and reports were selected and discussed. Information was grouped by found co-occurrence rates, underlying hypotheses and implications for diagnosis and treatment. GD and ASD were found to co-occur frequently - sometimes characterized by atypical presentation of GD, which makes a correct diagnosis and determination of treatment options for GD difficult. Despite these challenges there are several case reports describing gender affirming treatment of co-occurring GD in adolescents and adults with ASD. Various underlying hypotheses for the link between GD and ASD were suggested, but almost all of them lack evidence.
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O objetivo deste trabalho é compreender o percurso histórico de Valkyria Montes no esporte e, a partir daí, problematizar a participação de mulheres trans em competições esportivas, sejam elas oficiais ou não. Para tanto, desenvolvemos um estudo de caso caracterizado como descritivo e de cunho qualitativo. Para coleta de dados, realizamos uma entrevista com roteiro semiestruturado que foi posteriormente transcrita e analisada pela técnica de análise de conteúdo. Como resultados, encontramos que, embora a participação de Valkyria no voleibol seja híbrida, já que ela participa de competições tanto pelo naipe masculino quanto feminino, ainda encontra resistências significativas para poder atuar entre as mulheres cisgênero, com base em aspectos legais, morais e éticos que contornam as premissas de igualdade e justiça nas esferas do esporte. Palavra-chave: Corpo humano; Esportes; Gênero; Pessoas transgênero; Estudo de caso.
Chapter
Most preclinical and clinical, animal, and human research has been biased with respect to sex and even more so with respect to gender. In fact, little is known about the impact of sex and even less about the influence of gender on overall metabolic processes. The National Institutes of Health has recognized this gap in scientific knowledge and now mandates that studies be conducted in both sexes and to include gender as variables influencing physiological processes such as metabolism. It is therefore critical to understand and appreciate how to incorporate sex and gender in preclinical and clinical research in order to enhance our understanding of the mechanisms by which metabolic processes differ by sex and gender. In this chapter, we define sex and gender and discuss when sex and gender are not aligned, such as that which occurs in transgender individuals, and how this impacts metabolic processes. We discuss the importance of understanding the influence and interactions between sex hormones and sex chromosomes rather than focusing on their relative contributions to metabolism in isolation. This knowledge will optimize therapies specific for individuals which need to encompass sex and gender.
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Introduction Transgender women are at high risk for the acquisition and transmission of HIV. However, there are limited empiric data characterizing HIV‐related risks among transgender women in sub‐Saharan Africa. The objective of these analyses is to determine what factors, including sexual behaviour stigma, condom use and engagement in sex work, contribute to risk for HIV infection among transgender women across three West African nations. Methods Data were collected via respondent‐driven sampling from men who have sex with men (MSM) and transgender women during three‐ to five‐month intervals from December 2012 to October 2015 across a total of six study sites in Togo, Burkina Faso and Côte d'Ivoire. During the study visit, participants completed a questionnaire and were tested for HIV. Chi‐square tests were used to compare the prevalence of variables of interest between transgender women and MSM. A multilevel generalized structural equation model (GSEM) was used to account for clustering of observations within study sites in the multivariable analysis, as well as to estimate mediated associations between sexual behaviour stigma and HIV infection among transgender women. Results In total, 2456 participants meeting eligibility criteria were recruited, of which 453 individuals identified as being female/transgender. Transgender women were more likely than MSM to report selling sex to a male partner within the past 12 months (p<0.01), to be living with HIV (p<0.01) and to report greater levels of sexual behaviour stigma as compared with MSM (p<0.05). In the GSEM, sexual behaviour stigma from broader social groups was positively associated with condomless anal sex (adjusted odds ratio (AOR)=1.33, 95% confidence interval (CI)=1.09, 1.62) and with selling sex (AOR=1.23, 95% CI=1.02, 1.50). Stigma from family/friends was also associated with selling sex (AOR=1.42, 95% CI=1.13, 1.79), although no significant associations were identified with prevalent HIV infection. Conclusions These data suggest that transgender women have distinct behaviours from those of MSM and that stigma perpetuated against transgender women is impacting HIV‐related behaviours. Furthermore, given these differences, interventions developed for MSM will likely be less effective among transgender women. This situation necessitates dedicated responses for this population, which has been underserved in the context of both HIV surveillance and existing responses. 10.7448/IAS.19.3.20774 © 2016 Stahlman S et al; licensee International AIDS Society Received 28 October 2015; Revised 14 April 2016; Accepted 25 April 2016; Published 17 July 2016 Corresponding author: Shauna Stahlman, E7133, 615 N Wolfe St, Baltimore, MD 21205, USA. Tel: +1 443 287 2370; Fax: +1 410 614 8371. (sstahlm1@jhu.edu)
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Aspects of osteoporosis in men, such as screening and identification strategies, definitions of diagnosis and intervention thresholds, and treatment options (both approved and in the pipeline) are discussed. Introduction: Awareness of osteoporosis in men is improving, although it remains under-diagnosed and under-treated. A European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) workshop was convened to discuss osteoporosis in men and to provide a report by a panel of experts (the authors). Methods: A debate with an expert panel on preselected topics was conducted. Results and conclusions: Although additional fracture data are needed to endorse the clinical care of osteoporosis in men, consensus views were reached on diagnostic criteria and intervention thresholds. Empirical data in men display similarities with data acquired in women, despite pathophysiological differences, which may not be clinically relevant. Men should receive treatment at a similar 10-year fracture probability as in women. The design of mixed studies may reduce the lag between comparable treatments for osteoporosis in women becoming available in men.
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Improvements in neuroimaging technologies, and greater access to their use, have generated a plethora of data regarding male/female differences in the developing brain. Examination of these differences may shed light on the pathophysiology of the many illnesses that differ between the sexes and ultimately lead to more effective interventions. In this review, we attempt to synthesize the anatomic magnetic resonance imaging (MRI) literature of male/female brain differences with emphasis on studies encompassing adolescence - a time of divergence in physical and behavioral characteristics. Across all ages total brain size is consistently reported to be about 10% larger in males. Structures commonly reported to be different between sexes include the caudate nucleus, amygdala, hippocampus, and cerebellum - all noted to have a relatively high density of sex steroid receptors. The direction and magnitude of reported brain differences depends on the methodology of data acquisition and analysis, whether and how the subcomponents are adjusted for the total brain volume difference, and the age of the participants in the studies. Longitudinal studies indicate regional cortical gray matter volumes follow inverted U shaped developmental trajectories with peak size occurring one to three years earlier in females. Cortical gray matter differences are modulated by androgen receptor genotyope and by circulating levels of hormones. White matter volumes increase throughout childhood and adolescence in both sexes but more rapidly in adolescent males resulting in an expanding magnitude of sex differences from childhood to adulthood.
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Introduction. Long-term effects and side effects of cross-sex hormone treatment in transsexual persons are not well known. Aim. The aim of this study is to describe the effects and side effects of cross-sex hormone therapy in both transsexual men and women. Main Outcome Measures. Hormone levels were measured by immunoassays. Physical health was assessed by physical examination and questionnaires on general health and specific side effects, areal bone parameters by dual energy X-ray absorptiometry. Methods. Single center cross-sectional study in 100 transsexual persons post-sex reassignment surgery and on average 10 years on cross-sex hormone therapy. Results. Transsexual men did not experience important side effects such as cardiovascular events, hormone-related cancers, or osteoporosis. In contrast, a quarter of the transsexual women had osteoporosis at the lumbar spine and radius. Moreover, 6% of transsexual women experienced a thromboembolic event and another 6% experienced other cardiovascular problems after on average 11.3 hormone treatment years. None of the transsexual women experienced a hormone-related cancer during treatment. Conclusion. Cross-sex hormone treatment appears to be safe in transsexual men. On the other hand, a substantial number of transsexual women suffered from osteoporosis at the lumbar spine and distal arm. Twelve percent of transsexual women experienced thromboembolic and/or other cardiovascular events during hormone treatment, possibly related to older age, estrogen treatment, and lifestyle factors. In order to decrease cardiovascular morbidity, more attention should be paid to decrease cardiovascular risk factors during hormone therapy management. Wierckx K, Mueller, S, Weyers S, Van Caenegem E, Roef G, Heylens G, and T'Sjoen G. Long-term evaluation of cross-sex hormone treatment in transsexual persons. J Sex Med **;**:**–**.
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Background: Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment. Methods: We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. Results: The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. Conclusions: In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)
Article
Objectives: To examine plasma homovanillic acid (pHVA) levels in first-episode schizophrenia, to compare pHVA levels in patients and controls, and to assess the association of pHVA levels with psychopathology and treatment response.Methods: Forty-one patients entered the study, and pHVA levels were measured at baseline and on a weekly basis for up to 6 weeks of open standardized neuroleptic treatment. Psychopathology was evaluated with the Schedule for Affective Disorders and Schizophrenia, the Scale for Assessment of Negative Symptoms, and the Clinical Global Impressions scale. Ten healthy controls were used for comparison of baseline pHVA levels.Results: No differences were observed between patients and controls. Baseline pHVA level was not associated with psychopathology but was associated with time to reach remission. Baseline pHVA levels and week-1 pHVA levels were higher in responders than nonresponders. Regardless of responsiveness, female participants had higher pHVA levels than male participants throughout the study. The pattern of pHVA levels with treatment was similar in all patients with a short-term rise initially and then a decrease toward baseline values.Conclusions: These findings suggest that pHVA levels have prognostic significance for response and time to reach remission. Qualitative and quantitative differences between first-episode patients' pHVA levels and studies using a long-term, neuroleptic-exposed population suggest that changes occur with neuroleptic treatment or the progression of the illness.
Article
Objective Circulating testosterone, oestradiol and oestrone concentrations vary considerably between men. Although a substantial proportion of this variation may be attributed to morbidity and behavioural factors, these cannot account for its entirety, suggesting genetic inheritance as a potential additional determinant. The analysis described here was intended to estimate the heritability of male circulating total testosterone (TT), calculated free testosterone (cFT), oestrone (E1), oestradiol (E2) and sex hormone binding globulin (SHBG), along with the genetic correlation between these factors. DesignCross-sectional, observational analysis of data from male members of the Offspring and Generation 3 cohorts of the Framingham Heart Study. Data were collected in the years 1998-2005. ParticipantsA total of 3367 community-dwelling men contributed to the analysis, including 1066 father/son and 1284 brother pairs among other family relationships. MeasurementsLevels of serum sex steroids (TT, E1 and E2) were measured by liquid chromatography-tandem mass spectrometry, SHBG by immunofluorometric assay and cFT by mass action equation. Heritability was obtained using variance components analysis with adjustment for covariates including age, diabetes mellitus, body mass index and smoking status. ResultsAge-adjusted heritability estimates were 019, 040, 040, 030 and 041 for cFT, TT, E1, E2 and SHBG, respectively. Adjustment for covariates did not substantially attenuate these estimates; SHBG-adjusted TT results were similar to those obtained for cFT. Genetic correlation coefficients ((G)) indicated substantial genetic association between TT and cFT ((G)=068), between TT and SHBG (pG=087), between E1 and E2 ((G)=046) and between TT and E2 ((G)=048). Conclusion Circulating testosterone, oestradiol and oestrone concentrations exhibit substantial heritability in adult men. Significant genetic association between testosterone and oestrogen levels suggests shared genetic pathways.
Article
Guidelines for cross-sex hormone treatment of transsexual people are now in place. However, little attention has been paid to the issue of treatment suitability for older people. Does existing treatment need to be adapted as subjects age, and does it make a difference if treatment is only started when the subject is already older? To assess the necessity of adapting cross-sex hormone administration for elderly transsexual people. Risks/benefits of continued use of cross-sex hormones with regard to bone health, cardiovascular risks, and malignancies. Due to lack of data on the subject population, sex hormone treatment of other conditions in older non-transsexual people has been taken as the best available analogy to determine the extent to which these might be applicable to comparable transsexual persons. Findings in transsexual people receiving cross-sex hormone treatment sometimes modified the above approach of applying guidelines for the elderly to the aging transsexual population. Testosterone administration to female-to-male transsexual persons (FtoM) carries little risk with regard to cardiovascular disease and cancer. For those with high hematocrit or cardiac insufficiency the dose can be reduced. Administration of estrogens to male-to-female transsexual persons (MtoF), particularly when combined with progestins, does significantly increase the risk of developing cardiovascular disease (almost a twofold incidence compared with the general population). This may require dose adjustment or changing from oral to safer transdermal estrogens. Tumors of the breasts, prostate and pituitary may occur. In FtoM, breast cancer can occur even after breast ablation. Older subjects can commence cross-sex hormone treatment without disproportionate risks. Cross-sex hormones may be continued into old age but monitoring for cardiovascular disease and malignancies, both of the old and new sex, is recommended. MtoF will have more health complications in old age than FtoM requiring adaptations of treatment. Gooren L and Lips P. Conjectures concerning cross-sex hormone treatment of aging transsexual persons. J Sex Med **;**:**-**.
Article
Mutations in PLS3 have been identified as a cause of bone fragility in children but the bone phenotype associated with PLS3 mutations has not been reported in detail. PLS3 is located on the X chromosome and encodes the actin-binding protein plastin 3. Here we describe skeletal findings in four boys from two families with mutations in PLS3 (c.994_995delGA; p.Asp332* in Family 1; c.1433T > C; p.Leu478Pro in Family 2). When first evaluated between 4 and 8 years of age, these boys had a history of one to four long-bone fractures. Mild vertebral compression fractures were identified in each boy. No obvious extraskeletal disease manifestations were present. Lumbar spine areal bone mineral density (LS-aBMD) z-scores ranged from -1.7 to -3.5 but height was normal. Iliac bone histomorphometry in two patients showed low trabecular bone volume and a low osteoid maturation time but normal bone formation rate and osteoclast surface. Quantitative backscattered electron imaging did not reveal a major abnormality in bone mineralization density distribution. The two boys from Family 1 received oral alendronate for 6 years, which normalized LS-aBMD. The mothers of the four boys did not have a history of fractures and had normal LS-aBMD. However, one of these mothers had low bone mass at the distal radius, as measured by peripheral quantitative computed tomography. In conclusion, hemizygous mutations in PLS3 are associated with osteoporosis and bone fragility in childhood, but in contrast to bone fragility caused by mutations in collagen type I encoding genes, there is no hypermineralization of mineralized bone matrix. © 2014 American Society for Bone and Mineral Research.
Article
A central issue when designing multidimensional biological and psychosocial interventions for children who are exposed to multiple developmental risks is identification of the age period(s) in which such interventions will have the strongest and longest lasting effects (sensitive periods). In this paper, we review nutritional, neuroscientific, and psychological evidence on this issue. Nutritional evidence is used to identify nutrient-sensitive periods of age-linked dimensions of brain development, with specific reference to iron deficiency. Neuroscience evidence is used to assess the importance of timing of exposures to environmental stressors for maintaining neural, neuroendocrine, and immune systems integrity. Psychological evidence illustrates the sensitivity of cognitive and social-emotional development to contextual risk and protective influences encountered at different ages. Evidence reviewed documents that the early years of life are a sensitive period when biological or psychosocial interventions or exposure to risk or protective contextual influences can produce unique long-term influences upon human brain, neuroendocrine, and cognitive or psychosocial development. However, the evidence does not identify the early years as the sole sensitive time period within which to have a significant influence upon development. Choice of age(s) to initiate interventions should be based on what outcomes are targeted and what interventions are used.
Article
Why is popular understanding of female-male differences still based on rigid models of development, even though contemporary developmental sciences emphasize plasticity? Is it because the science of sex differences still works from the same rigid models?
Article
This article is part of a Special Issue "Puberty and Adolescence".This article aims to provide an outline of what is currently known on trajectories, and contributing factors to gender identity development in adolescence. We give a historical overview of the concept of gender identity, and describe general identity development in adolescence, gender identity development in the general population and in gender variant youth. Possible psychosocial (such as child and parental characteristics) and biological factors (such as the effects of prenatal exposure to gonadal hormones and the role of genetics) contributing to a gender variant identity are discussed. Studies focusing on a number of psychosocial and biological factors separately, indicate that each of these factors influence gender identity formation, but little is known about the complex interplay between the factors, nor about the way individuals themselves contribute to the process. Research into normative and gender variant identity development of adolescents is clearly lagging behind. However, studies on persons with gender dysphoria and disorders of sex development, show that the period of adolescence, with its changing social environment and the onset of physical puberty, seems to be crucial for the development of a non-normative gender identity.
Article
Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age. The infrequency of SLE in men and disease onset in prepubertal or postmenopausal women suggests a role of estrogen in the predisposition to the disease. Patients with hypergonadotrophic hypogonadism are prone to the development of SLE, and the use of exogenous estrogens in women increases the relative risk of SLE onset and disease flares. These observations provide indirect evidence for an opposite role of estrogens and androgens in the pathogenesis of SLE. We report on a male-to-female transsexual who developed SLE 20 years after sex-reassignment surgery and prolonged estrogen therapy. The role of sex hormones in SLE is revisited.
Article
Osteoprotegerin (OPG) is a recently identified member of the tumor necrosis factor (TNF) receptor superfamily that regulates bone mass through an inhibitory action on osteoclast differentiation and function. To determine its potential roles of OPG in pathological changes in bone metabolism caused by estrogen deficiency, we investigated effects of estrogen on OPG expression by a mouse stromal cell line, ST-2, in vitro. Treatment of ST-2 cells with 17β-E2 resulted in up-regulation of OPG expression at both the messenger RNA and protein levels. The effect was time and dose dependent and steroid specific. The stimulatory action of 17β-E2 on OPG expression appeared to be mediated by the estrogen receptor-α (ERα) subtype because stable overexpression of ERα, but not of ERβ, enhanced the OPG induction by 17β-E2. Moreover, estrogen withdrawal after 5-day pretreatment, mimicking the event occurring in vivo at menopause, dramatically diminished the expression of OPG. These findings suggest that down-regulation of OPG after estrogen withdrawal contributes to the enhanced osteoclastic bone resorption and bone loss after menopause by enhancing RANK ligand-RANK system that lies downstream of a large number of bone-resorbing cytokines.
Article
Sexual differentiation in mammals is largely driven by the presence of androgen in males and their absence in females. The presence of androgens induces a number of irreversible changes in males: prenatally, the genital differentiation; during puberty, the development of secondary sex characteristics - the larger facial bones, hand, feet and height in males. A large number of metabolic variables are influenced by sex hormones and consequently show difference between men and women, and this helps to explain differences in pathologies, such as cardiovascular disease, bone fractures and auto immune disease. There is some recent evidence that some sex differences in brain functions are not mediated by sex hormones, but by-products of genes located on the X and Y chromosomes. This communication reviews the results of administration of cross-sex hormone treatment to transsexual persons transitioning to the other sex. Natal males are treated with anti-androgens+oestrogens and natal females with testosterone. This provides a unique opportunity to study which metabolic functions are not irreversibly sex-differentiated but are determined by the prevailing milieu of sex steroids. The insights gained with these studies should lead to a better appreciation of the role of sex steroids in cardiovascular disease and diabetes mellitus which presently do not receive due attention.
Article
Bone mineral density (BMD), bone size and bone turnover are independent determinants of fractures in elderly. Earlier twin studies of these phenotypes have revealed high heritability for BMD and bone area, and more moderate heritability for bone turnover markers. No previous Scandinavian study has evaluated the genetic and environmental contribution to the variance of these phenotypes, despite the fact that Scandinavian countries have the highest incidence of osteoporotic fractures worldwide. Participants were selected from the Swedish Twin Registry. All intact like-sexed twin pairs born in 1965 or earlier and living in the county of Uppsala were invited to participate. A total of 102 twin pairs (45 monozygotic and 57 dizygotic) accepted the invitation to participate. All twins underwent measurement of BMD and bone area using dual-energy X-ray absorptiometry. Hip geometry was also calculated. Markers for bone formation (osteocalcin) and bone resorption (CrossLaps) were measured in serum. We observed a substantial heritability for BMD at the lumbar spine (0.85; 95 % CI 0.54-0.90), the femoral neck (0.75; 95 % CI 0.62-0.83), and the proximal femur (0.84; 95 % CI 0.74-0.90). The values for bone area were approximately similar to those for BMD. Bone turnover markers had a slightly lower genetic influence with a value of 0.69 (0.53-0.80) for osteocalcin and 0.58 (95 % CI 0.33-0.75) for CrossLaps. As a comparison, the heritabilities of body height and weight were 0.95 and 0.82, respectively. The high heritability on bone phenotypes among Swedish middle-aged and older men and women should encourage further work on the identification of specific genetic pathways. Continuing research in this area could reveal the mechanisms behind the strong genetic susceptibility of bone-related phenotypes.
Article
Background: We examined the association between 799 single-nucleotide polymorphisms in 39 sex hormone genes and blood pressure (BP) responses to a dietary-sodium intervention. Methods: A 7-day low-sodium feeding study (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding study (307.8 mmol sodium/day) was conducted among 1,906 Han Chinese participants. Nine BP measurements were obtained at baseline and the end of each intervention period using a random-zero sphygmomanometer. Results: Among men, absolute BP responses to sodium interventions decreased with the number of minor alleles of estrogen receptor 1 (ESR1) markers rs9340844, rs9397453, rs9371562, rs9397459, and rs9383951. For example, mean diastolic blood pressure (DBP) responses to low-sodium intervention (95% confidence interval) were -2.67 (-3.13, -2.22) mm Hg among those with the rs9397453 C/C genotype, -1.23 (-1.98, -0.48) mm Hg among those with the C/T genotype, and 0.08 (-2.31, 2.47) mm Hg among those with the T/T genotype (P = 1×10(-4); false discovery rate (FDR)-q = 0.04). Mean DBP responses to high sodium according to the rs9397453 genotypes were 1.46 (1.03, 1.89) mm Hg among those with C/C, 0.19 (-0.54, 0.91) mm Hg among those with C/T, and -1.10 (-2.82, 0.61) mm Hg among those with T/T (P = 2×10(-4); FDR-q = 0.04). Similar trends were noted for the association between these ESR1 variants and SBP responses to the dietary intervention. There were no significant associations between sex hormone gene variants and salt sensitivity in women, with genotype-gender interactions noted for the ESR1 markers that achieved significance in men. Conclusions: We identified strong, consistent associations between ESR1 gene variants and salt sensitivity in men. Our results support a gender-specific role for ESR1 in the etiology of this complex trait.
Article
Objective: Cross-sex hormonal therapy and sex reassignment surgery (including gonadectomy) in transsexual persons has an impact on body composition and bone mass and size. However, it is not clear whether baseline differences in bone and body composition between transsexual persons and controls before cross-sex hormonal therapy play a role. Design: A cross-sectional study with 25 male-to-female transsexual persons (transsexual women) before cross-gender sex steroid exposure (median age 30 years) in comparison with 25 age-matched control men and a male reference population of 941 men. Main outcome measures: Areal and volumetric bone parameters using respectively dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT), body composition (DXA), grip strength (hand dynamometer), Baecke physical activity questionnaire, serum testosterone and 25-OH vitamin D. Results: Transsexual women before cross-sex hormonal therapy presented with less muscle mass (p≤0.001) and strength (p≤0.05) and a higher prevalence of osteoporosis (16%) with a lower aBMD at the hip, femoral neck, total body (all p<0.001) and lumbar spine (p=0.064) compared with control men. A thinner radial cortex (p≤0.01) and lower cortical area at the radius and tibia (both p<0.05) was found in transsexual women vs. control men. Serum testosterone was comparable in all 3 groups, but 25-OH vitamin D was lower in transsexual women (p≤0.001). Conclusions: Transsexual women before the start of hormonal therapy appear to have lower muscle mass and strength and lower bone mass compared with control men. These baseline differences in bone mass might be related to a less active lifestyle.
Article
Background: Estrogen receptors (ER) belong to the super-family of the nuclear hormone receptors which act as ligand-regulated transcription factor to control a diverse set of essentials functions, such as growth development, metabolism, and reproduction. Though, the involvement of these receptors in several diseases including cancer was shown in numerous studies. Aim: Here, we reviewed the literature to report genetic polymorphisms and mutations investigated in the ESR genes (α and β) and to explore their relationship and their potential role to develop some diseases as well as the ER expression status especially in cancer. Methods: We searched the MEDLINE database with the keywords of estrogens receptors gene polymorphisms, short tandem repeat (STR) sequences, single-nucleotide polymorphisms (SNPs), cancer risk and diseases susceptibility. Results: The functional effects of some mutations, short nucleotide polymorphisms and STR polymorphisms of ESR gene on susceptibility of multiple diseases, especially on cancer risk, are well approved. Conclusions: The involvement of genetic variations of the ERs in the risk of multiples diseases is frequently established, which incite to more elucidate the functional role of these markers in cell. Therefore, further investigations are needed to see the impact of these variations in drug response which makes them suitable therapeutic.
Article
Humoral immune responses are sexually dimorphic. Female individuals generally exhibit more-robust antibody responses to vaccines and, in the clinical setting as well as in experimental models, are more likely than male individuals to produce autoreactive antibodies of pathogenic potential. A number of differences between the sexes might account for these observations, including differences in the dosage of specific X-chromosome and Y-chromosomal genes, increased exposure of female individuals to antigenic stimulation in childbearing, and differences in circulating concentrations of gonadal steroid hormones. The role of gonadal steroids in modulating such humoral immune responses has been studied for nearly a century, but advances in our knowledge of B-lymphocyte development and function, the mechanisms of immune tolerance, and the molecular basis of gonadal steroid hormone action are now yielding new understanding of the influence of gonadal steroid hormones on the humoral immune system. This Review examines how oestrogens and androgens modulate B-lymphocyte development and function, focusing on the areas of B-cell production in the bone marrow, the maintenance of immune tolerance for self antigens, and the processes of immunoglobulin heavy chain gene somatic hypermutation and class switch recombination during maturation of cells involved in humoral immune responses.
Article
Different pathways involved in the complex machinery implicated in determining cell fate have been investigated in the recent years. Different forms of cell death have been described: apart from the "classical" form of death known as necrosis, a well characterized traumatic injury of the cell, several additional forms of cell death have been identified. Among these, apoptosis has been characterized in detail. These studies stem from the implication that the apoptotic process plays a key role in a plethora of human pathologies, including cardiovascular diseases. In fact, defects in the mechanisms of cell death, i.e., both an increase or a decrease of apoptosis, have been associated with the pathogenesis of vessel and myocardial diseases. Some new insights also derived from the study of autophagy, a less characterized form of cell damage mainly associated with cell survival strategies but that also leads, as final event, to the death of the cell. Interestingly, very recently, a gender difference has been found in this respect: cells from males and females can behave differently. In fact, they seem to display several different features, including those determining their fate. These gender cytology differences are briefly described here. The study of this gender disparity is of great relevance in cardiovascular disease pathogenesis and pharmacology. The comprehension of the gender-related mechanisms of cell demise can in fact disclose new scenarios in preclinical and clinical management of cardiovascular diseases.
Article
While there has been increasing support for the existence of cerebral sex differences, the mechanisms underlying these differences are unclear. Based on animal data, it has long been believed that sexual differentiation of the brain is primarily linked to organizational effects of fetal testosterone. This view is, however, in question as more recent data show the presence of sex differences before the onset of testosterone production. The present study focuses on the impact that sex chromosomes might have on these differences. Utilizing the inherent differences in sex and X-chromosome dosage among XXY males, XY males, and XX females, comparative voxel-based morphometry was conducted using sex hormones and sex chromosomes as covariates. Sex differences in the cerebellar and precentral gray matter volumes (GMV) were found to be related to X-chromosome dosage, whereas sex differences in the amygdala, the parahippocamus, and the occipital cortex were linked to testosterone levels. An increased number of sex chromosomes was associated with reduced GMV in the amygdala, caudate, and the temporal and insular cortices, with increased parietal GMV and reduced frontotemporal white matter volume. No selective, testosterone independent, effect of the Y-chromosome was detected. Based on these observations, it was hypothesized that programming of the motor cortex and parts of cerebellum is mediated by processes linked to X-escapee genes, which do not have Y-chromosome homologs, and that programming of certain limbic structures involves testosterone and X-chromosome escapee genes with Y-homologs.
Article
It is unknown whether long term cross-sex hormone treatment affects the human skeleton. We monitored bone mineral density and biochemical markers of bone turnover for 28–63 months in 20 male-to-female transsexuals (M → F) treated with anti-androgens and oestrogens, and 19 female-to-male transsexuals (F → M) treated with androgens. They underwent gonadectomy 13–35 months after the start of cross-sex hormone administration. Bone mineral density (BMD) and the markers of bone turnover osteocalcin, alkaline phosphatase, fasting urinary calcium/creatinine and hydroxyproline/creatinine, were measured at baseline, after 1 year and after 28–63 months of cross-sex hormone administration. In oestrogen-treated M → F, variables of bone turnover decreased significantly with consecutive measurements. BMD had increased significantly after 1 year, but decreased again to baseline levels after 28–63 months of cross-sex hormones. In F → M, alkaline phosphatase levels increased during the first year. BMD did not change during the first year but had decreased significantly after 28–63 months following ovariectomy. In both M → F and F → M, the change of BMD correlated inversely with serum LH and FSH levels. Of all biochemical variables LH levels appeared to be the best predictor of loss of BMD; in the long-term LH levels were more elevated in testosterone-treated F → M than in oestrogen-treated M → F transsexuals. In M → F, oestrogen treatment prevented bone loss after testosterone deprivation. In F → M the testosterone dosage used, associated with a decline in serum oestradiol levels, was unable to maintain bone mass fully in all subjects in the longer term. The inverse relationship between BMD and serum LH levels suggests that the dose of hormone replacement has been too low in subjects with a decline in their BMD. Its cause might be underdosing or non-compliance in some patients. We propose that serum LH levels may be used as a measure of the adequacy of replacement with sex steroids.
Article
This study investigates determinants of peak bone mass (PBM) in healthy men, focusing on effects and interactions of parameters reflecting mechanical loading and sex steroids. Healthy male siblings (n = 677; 25–45 yr) were recruited in a cross-sectional, population-based study. Physical activity score was assessed by a self-reported questionnaire. Cross-sectional muscle area (CSMA) and bone parameters of radius (4% and 66% site) and tibia (66% site) were assessed using pQCT. Peak torque of biceps and quadriceps muscles was assessed by isokinetic dynamometry. Serum testosterone (T) and estradiol (E2) levels were measured using immunoassays; free hormone fractions were calculated. Relations between indices of bone strength, CSMA, muscle strength, and sex steroids were studied using linear mixed-effects modeling. Physical activity, CSMA, and muscle strength were positively associated with indices of bone strength, except for volumetric BMD (vBMD). After controlling for age, weight, and height, free E2 levels were positively associated with trabecular and cortical vBMD, negatively associated with endosteal circumference at the radius, and positively associated with cortical vBMD at the tibia. In addition, positive interactions between physical activity and serum E2 concentrations were observed for bone size at the tibia. No associations between free T levels and pQCT bone parameters were found. In this population of healthy men at the age of PBM, parameters reflecting mechanical loading are confirmed as important determinants of bone size. E2, but not T, levels are positively associated with vBMD and modulate the impact of physical activity on bone size at the tibia.
Article
Female-to-male transsexual persons (transsexual men) undergo extreme hormonal changes due to ovariectomy and testosterone substitution, allowing studies on sex steroid effects on bone geometry and physiology in the adult. The objective of the study was to examine the effects of cross-gender sex steroid exposure on volumetric bone parameters in transsexual men. This was a cross-sectional study. Participants were recruited from the Center for Sexology and Gender Problems at the Ghent University Hospital (Ghent, Belgium). Fifty transsexual men after sex reassignment surgery with 50 age-matched control women and an additional 16 transsexual men before testosterone substitution and sex reassignment surgery with 16 control women participated in the study. The main outcome measures were areal and volumetric bone parameters using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography, body composition (dual-energy X-ray absorptiometry), sex steroids, markers of bone turnover and grip strength. Before hormonal treatment, transsexual men had similar body composition and bone geometry as female controls. The transsexual men on long-term testosterone therapy, however, demonstrated a higher lean body mass and muscle mass and a greater grip strength as well as a lower body and subcutaneous fat mass and a larger waist and smaller hip circumference compared with female controls (all P < 0.001). We observed a larger radial cortical bone size (P < 0.001) and lower cortical volumetric bone mineral density at the radius and tibia (P < 0.05) in transsexual men on testosterone therapy. Transsexual men on testosterone substitution therapy present with a different body composition with more muscle mass and strength and less fat mass as well as an altered bone geometry with larger bones compared with female controls.
Article
The “four core genotypes” (FCG) model comprises mice in which sex chromosome complement (XX vs. XY) is unrelated to the animal’s gonadal sex. The four genotypes are XX gonadal males or females, and XY gonadal males or females. The model allows one to measure (1) the differences in phenotypes caused by sex chromosome complement (XX vs. XY), (2) the differential effects of ovarian and testicular secretions, and (3) the interactive effects of (1) and (2). Thus, the FCG model provides new information regarding the origins of sex differences in phenotype that has not been available from studies that manipulate gonadal hormone levels in normal XY males and XX females. Studies of the FCG model have uncovered XX vs. XY differences in behaviors (aggression, parenting, habit formation, nociception, social interactions), gene expression (septal vasopressin), and susceptibility to disease (neural tube closure and autoimmune disease) not mediated by gonadal hormones. Some sex chromosome effects are mediated by sex differences in dose of X genes or their parental imprint. Future studies will identify the genes involved and their mechanisms of action.
Article
The relationship between pretreatment levels of plasma homovanillic acid (pHVA) and the outcome of clozapine treatment was studied in 18 male patients with schizophrenia who were resistant to treatment with conventional neuroleptics. After 6 months of clozapine treatment, 7 patients demonstrated ⩾ 20% decrease in the Brief Psychiatric Rating Scale (BPRS) (responders), while 11 patients did not (non-responders). Responders and non-responders did not differ with respect to the baseline pHVA level. The BPRS Positive Symptom scores at 6 weeks and 3 months, but not those at baseline and 6 months, following initiation of clozapine treatment negatively correlated with pHVA levels for all patients. The correlations became stronger when only responders were included. No significant correlation between Positive Symptom scores and pHVA levels was observed for non-responders. The BPRS Total and Negative Symptom scores did not correlate with pHVA for all patients, responders or non-responders at any time. The percent decrease in the BPRS Positive Symptom scores from baseline at 6 weeks following clozapine treatment correlated significantly with pHVA levels in responders. These results suggest that pretreatment levels of pHVA can be used to predict relatively short-term changes in the positive symptoms of patients with schizophrenia receiving clozapine treatment, particularly for clozapine responders.
Article
Introduction: It has been hypothesized that cognitive and memory-related brain function in transsexuals during cross-sex hormonal treatment might be activated towards that of the subjective gender. However, research on this topic has produced inconsistent results, and to the best of our knowledge no studies have investigated memory changes in androgen-treated female-to-male (FM) transsexuals. Methods: A total of 33 FM transsexuals underwent neuropsychological testing in order to examine the effects of androgen on memory. We used a longitudinal design in which 14 FM transsexuals were tested twice, before and after receiving 6 months of testosterone treatment. In addition, a cross-sectional design was used to compare 10 individuals off treatment versus 9 individuals on testosterone treatment for at least 6 months. Results: Participants tested before and after 6 months of androgen treatment improved significantly their performance on a visual memory task (visual paired associates, immediate recall, WMS-R). The cross-sectional design confirmed that patients on androgen treatment for at least 6 months performed better than subjects off treatment on the same task and also on another visual memory task (Rey-Osterrieth complex figure test, ROCF; copy and delayed recall). No differences were found in any verbal memory test for either design. Conclusions: The results indicate that androgen has an influence on visual memory, but not on verbal memory. Therefore, for FM transsexuals the data support an activating effect for androgens on visual memory, a domain that generally tends to favour males.
Article
Diffusion tensor imaging (DTI) can sensitively detect white matter sex differences and the effects of pharmacological treatments. Before cross-sex hormone treatment, the white matter microstructure of several brain bundles in female-to-male transsexuals (FtMs) differs from those in females but not from that in males. The purpose of this study was to investigate whether cross-sex hormone treatment (androgenization) affects the brain white matter microstructure. Using a Siemens 3 T Trio Tim Magneton, DTI was performed twice, before and during cross-sex hormonal treatment with testosterone in 15 FtMs scanned. Fractional anisotropy (FA) was analyzed on white matter of the whole brain, and the latter was spatially analyzed using Tract-Based Spatial Statistics. Before each scan the subjects were assessed for serum testosterone, sex hormone binding globulin level (SHBG), and their free testosterone index. After at least seven months of cross-gender hormonal treatment, FA values increased in the right superior longitudinal fasciculus (SLF) and the right corticospinal tract (CST) in FtMs compared to their pre-treatment values. Hierarchical regression analyses showed that the increments in the FA values in the SLF and CST are predicted by the free testosterone index before hormonal treatment. All these observations suggest that testosterone treatment changes white matter microstructure in FtMs.
Article
Sex based differences in immune responses, affecting both the innate and adaptive immune responses, contribute to differences in the pathogenesis of infectious diseases in males and females, the response to viral vaccines and the prevalence of autoimmune diseases. Indeed, females have a lower burden of bacterial, viral and parasitic infections, most evident during their reproductive years. Conversely, females have a higher prevalence of a number of autoimmune diseases, including Sjogren's syndrome, systemic lupus erythematosus (SLE), scleroderma, rheumatoid arthritis (RA) and multiple sclerosis (MS). These observations suggest that gonadal hormones may have a role in this sex differential. The fundamental differences in the immune systems of males and females are attributed not only to differences in sex hormones, but are related to X chromosome gene contributions and the effects of environmental factors. A comprehensive understanding of the role that sex plays in the immune response is required for therapeutic intervention strategies against infections and the development of appropriate and effective therapies for autoimmune diseases for both males and females. This review will focus on the differences between male and female immune responses in terms of innate and adaptive immunity, and the effects of sex hormones in SLE, MS and RA.
Article
Sex specific development in the human comprises irreversible sexual differentiation of the external genitalia during embryogenesis, sexual maturation of secondary sex characteristics during puberty (e.g., sex specific body proportions, pubertal voice change) and eventually sex specific development of extragenital tissues and organs, including the brain. The presence or absence of androgens acting via the androgen receptor plays a key role therein. At the single cell level, androgens cause reversible short term changes of gene transcription by activating the androgen receptor. From a developmental perspective, this often leads to irreversible long-term changes of anatomy (e.g., sex-specific differentiation of the external genitalia) and function (e.g., sex-specific play behavior in children). These observations are discussed in the context of recent genome-wide gene expression studies and first published experimental data at the epigenome level. In essence, there is evidence for a molecular androgen memory at both the transcriptome and the epigenome level.
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After sequencing the human genome, it has become clear that genetic information alone is not sufficient to understand phenotypic manifestations. The way the DNA code is translated into function depends not only on its sequence but also on the interaction with environmental factors. It is in this intersection where the science of epigenetics plays a crucial role. Epigenetic mechanisms like DNA methylation and histone modifications are essential for multiple physiological processes like development, establishment of tissue identity, imprinting, X-chromosome inactivation, chromosomal stability and gene transcription regulation. Additionally, environmental factors like nutrition or maternal behavior in early childhood are able to induce epigenetic changes. This short review aims at summarizing the role of epigenetics in multiple aspects of biology and medicine, including development, cancer, non-tumoral diseases, environmentally induced phenotypic changes, and also in inheritance and evolution.
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Autoimmunity is influenced by multiple factors including gender and sex hormones. A definite female predominance is found in many autoimmune diseases. Gender is also associated with differences in clinical presentation, onset, progression and outcome of autoimmune diseases. Sex hormones might influence the target organ's vulnerability to an autoimmune response. Gender differences also exist in organ specific autoimmune diseases such as multiple sclerosis, Guillain-Barré syndrome, Crohn's disease and celiac disease. Nevertheless, other organ specific autoimmune diseases (i.e. ulcerative colitis) are seemingly characterized with similar prevalence in both males and females. The reason for gender differences in certain autoimmune diseases remains unknown, but may be attributed to sex hormone influence, fetal microchimerism, X chromosome inactivation, and X chromosome abnormalities. Sex hormones have been found to have immune modulating properties, as well as providing cellular protection following tissue damage in certain circumstances. Sex hormones also influence innate and adaptive immune cells, number of B and T cells, antigen presentation and cytokine secretion. Herein, we review the influence of gender on organ-specific autoimmune diseases affecting the heart, blood vessels, central nervous system and gastrointestinal tract. It appears that sex hormones may have a therapeutic potential in several autoimmune conditions, although further research is required before therapeutic recommendations can be made.