Endocrinological and ovarian histological investigations in assigned female at birth transgender people undergoing testosterone therapy.

RESEARCH QUESTION: What are the hormonal and ovarian histological effects of a gender affirming hormonal therapy in assigned female at birth (AFAB) transgender people? DESIGN: Prospective observational study of 70 AFAB transgender people taking testosterone therapy before gender-affirming surgery (hystero-oophorectomy). A gynaecological ultrasonographic scan was undertaken and serum hormone concentrations measured, including anti-Müllerian hormone (AMH) and androgenic profile. Histological ovarian evaluation was assessed in both ovaries, including the developmental stages of the follicles. RESULTS: The mean age of the population was 27.7+/-5.14 years. The main biochemical parameters were total testosterone levels 781.5 ± 325.9 ng/dl; AMH levels 3.2 ± 1.4 ng/ml; FSH and LH levels 4.9 ± 2.5 IU/l and 3.9 ± 2.9 IU/l, respectively; and oestradiol values 47.6 ± 13.7 pg/ml. Fifty-five AFAB underwent gynaecological ultrasound before surgery and antral follicles were found in 43 out of 47 ultrasounds (91.5%) (without the presence of a dominant follicle or corpus luteum). Histological follicles were mostly in the primordial stage (88.0) and 3.3% were atretic. The thickness of the tunica albuginea was widely heterogeneous (range 0.15-1.45 mm) and luteinization of the stromal cells was observed in 68.6% of the samples. A negative correlation between testosterone levels and total antral follicles was found (Rs= -0.306, P = 0.029). CONCLUSIONS: AFAB transgender people taking testosterone therapy show cortical follicle distribution in the range previously reported in fertile cisgender women of reproductive age. The follicular population may not be altered as a result of the gender-affirming hormonal therapy, although some cortical and stromal changes have been observed.

Sustained Breast Development and Breast Anthropometric Changes in 3 Years of Gender-Affirming Hormone Treatment.

CONTEXT: Breast development is important for most trans women. An important limitation of current breast development measurement methods is that these do not allow for 3D volume analyses. OBJECTIVES: To examine breast development and change in anthropometry during the first 3 years of gender-affirming hormone treatment using 3D imaging. Associations with clinical or laboratory parameters and satisfaction with the gained breast development were also studied. DESIGN: Prospective cohort study. SETTING: Specialized tertiary gender identity clinic in Amsterdam, the Netherlands. PARTICIPANTS: Participants were 69 adult trans women with a median age of 26 years (interquartile range, 21-38). INTERVENTIONS: Gender-affirming hormone treatment. MAIN OUTCOME MEASURES: Volumetric and anthropometric breast development and satisfaction. RESULTS: Breast volume increased by 72 cc (95% confidence interval [CI], 48-97) to 100 cc (standard deviation 48). This resulted in a cup-size

Approach to Interpreting Common Laboratory Pathology Tests in Transgender Individuals.

CONTEXT: As the number of transgender (trans) people (including those who are binary and/or nonbinary identified) seeking gender-affirming hormone therapy rises, endocrinologists are increasingly asked to assist with interpretation of laboratory tests. Many common laboratory tests such as hemoglobin, iron studies, cardiac troponin, and creatinine are affected by sex steroids or body size. We seek to provide a summary of the impact of feminizing and masculinizing hormone therapy on common laboratory tests and an approach to interpretation. CASES: Case scenarios discussed include 1) hemoglobin and hematocrit in a nonbinary person undergoing masculinizing hormone therapy; 2) estimation of glomerular filtration rate in a trans woman at risk of contrast-induced nephropathy; 3) prostate-specific antigen (PSA) in a trans woman; and 4) chest pain in a trans man with a cardiac troponin concentration between the reported male and female reference ranges. CONCLUSIONS: The influence of exogenous gender-affirming hormone therapy on fat and muscle distribution and other physiological changes determines interpretation of laboratory tests that have sex-specific differences. In addition to affirmative practice to ensure a patient's name, gender, and pronoun are used appropriately, we propose that once individuals have commenced gender-affirming hormone therapy, the reference range of the affirmed gender be reported (and specified by treating clinicians) except for PSA or cardiac troponin, which are dependent on organ size. While suggestions may be challenging to implement, they also represent an opportunity to lead best practice to improve the quality of care and experiences of healthcare for all trans people.

Effects of adult male rat feminization treatments on brain morphology and metabolomic profile.

Body feminization, as part of gender affirmation process of transgender women, decreases the volume of their cortical and subcortical brain structures. In this work, we implement a rat model of adult male feminization which reproduces the results in the human brain and allows for the longitudinal investigation of the underlying structural and metabolic determinants in the brain of adult male rats undergoing feminization treatments. Structural MRI and Diffusion Tensor Imaging (DTI) were used to non-invasively monitor in vivo cortical brain volume and white matter microstructure over 30 days in adult male rats receiving estradiol (E2), estradiol plus cyproterone acetate (CA), an androgen receptor blocker and antigonadotropic agent (E2 + CA), or vehicle (control). Ex vivo cerebral metabolic profiles were assessed by 1H High Resolution Magic Angle Spinning NMR (1H HRMAS) at the end of the treatments in samples from brain regions dissected after focused microwave fixation (5 kW). We found that; a) Groups receiving E2 and E2 + CA showed a generalized bilateral decrease in cortical volume; b) the E2 + CA and, to a lesser extent, the E2 groups maintained fractional anisotropy values over the experiment while these values decreased in the control group; c) E2 treatment produced increases in the relative concentration of brain metabolites, including glutamate and glutamine and d) the glutamine relative concentration and fractional anisotropy were negatively correlated with total cortical volume. These results reveal, for the first time to our knowledge, that the volumetric decreases observed in trans women under cross-sex hormone treatment can be reproduced in a rat model. Estrogens are more potent drivers of brain changes in male rats than anti-androgen treatment.

Pathologic Evaluation of Breast Tissue From Transmasculine Individuals Undergoing Gender-Affirming Chest Masculinization.

CONTEXT.­: Bilateral mastectomy for chest masculinization is one of the gender-affirming procedures for transmasculine individuals. OBJECTIVE.­: To optimize gross handling protocols and assess histopathologic findings in transmasculine breast tissue specimens. DESIGN.­: We identified all gender-affirming mastectomies from 2015 to 2018. We sequentially identified reduction mammoplasty (RM) cases for macromastia from the same period as control. Significant findings were defined as atypical ductal or lobular hyperplasia (ADH, ALH), ductal or lobular carcinoma in situ (DCIS, LCIS), or invasive carcinoma. RESULTS.­: Significant findings were present in 6 of 211 gender-affirming mastectomies (2.8%) as follows: ADH (n = 5) and LCIS together with ALH (n = 1). By comparison, 19 of 273 RM specimens (7%) yielded significant findings as follows: ALH (n = 11), ADH (n = 4), LCIS (n = 2), DCIS (n = 1), and invasive lobular carcinoma (n = 1). In the gender-affirming group, 142 transmen underwent androgen therapy before surgery, of whom 2 had significant pathologic findings. Thirty and 41 individuals had a family history of breast cancer in the gender-affirming and RM group, of whom 1 and 3 individuals had significant pathologic findings, respectively. CONCLUSIONS.­: Our study demonstrates that we handle transmasculine mastectomy specimens by examining 2.8 times more slides on average than for RMs, with a 2.5 times lower rate of significant pathologic findings. Prior family history of breast cancer or the use of androgen therapy before surgery in gender-affirming individuals did not increase the risk of identifying significant breast lesions. We recommend submitting 4 tissue blocks per mastectomy for individuals undergoing gender-affirming breast surgery.

A Retrospective Review of Medical Records of Laboratory-Tested Sexually Transmitted Infections of Transsexual Men from Southern Brazil.

The present study assessed the prevalence of sexually transmitted infections (STIs) in 90 transsexual men (female-to-male transsexual persons) from southern Brazil. A retrospective review of the medical records of all transsexual men who visited an outpatient clinic in Rio Grande do Sul from 1998 to 2017 was performed. Although the sample had a high prevalence of risk factors for contracting STIs, such as drug use, one-third of the participants had never been tested for STIs and, when screened, it was mostly for HIV, but not for syphilis or other STIs. Based only on laboratory-tested transsexual men, the prevalence of syphilis and hepatitis C was 3.4% and 1.6%, respectively, which is higher than the general population. It is clear that health professionals need to broaden their understanding of transsexual men, acknowledging STIs as a possible diagnosis.

Routine histopathological examination after female-to-male gender-confirming mastectomy.

BACKGROUND: The number of transmen seeking gender-confirming surgery has risen steadily throughout the last decade. Pathologists are increasingly confronted with transmale mastectomy specimens. It is not clear whether routine histopathological examination is useful. This study explored the possible benefit of routine investigation through detailed description of lesions encountered in mastectomy specimens after female-to-male gender-confirming surgery. METHODS: Breast tissue from a cohort of transmen was reviewed. The presence of benign and malignant breast lesions was recorded. The number of terminal duct-lobule units (TDLUs) per ten low-power fields (LPFs) was quantified. Information on hormone therapy and morphometry was retrieved for selected patients. RESULTS: The cohort included 344 subjects with a mean age of 25·8 (range 16-61) years at the time of surgery; the age at surgery decreased significantly over time. Older individuals presented with a significantly higher number of breast lesions. The number of TDLUs per LPF was lower in heavier breasts, but did not correlate with age. Breast lesions, either benign or malignant, were present in 166 individuals (48·3 per cent). Invasive breast cancer was found in two (0·6 per cent); one tumour was an unexpected finding. The number of breast lesions encountered on histopathological examination increased significantly when more tissue blocks were taken. CONCLUSION: The discovery of an unexpected breast cancer in a 31-year-old transman emphasizes the importance of thorough routine histopathological examination of mastectomy specimens. The number of tissue blocks taken should be based on age and breast weight.

Effects of testosterone treatment on hypothalamic neuroplasticity in female-to-male transgender individuals.

Diffusion-weighted imaging (DWI) is used to measure gray matter tissue density and white matter fiber organization/directionality. Recent studies show that DWI also allows for assessing neuroplastic adaptations in the human hypothalamus. To this end, we investigated a potential influence of testosterone replacement therapy on hypothalamic microstructure in female-to-male (FtM) transgender individuals. 25 FtMs were measured at baseline, 4 weeks, and 4 months past treatment start and compared to 25 female and male controls. Our results show androgenization-related reductions in mean diffusivity in the lateral hypothalamus. Significant reductions were observed unilaterally after 1 month and bilaterally after 4 months of testosterone treatment. Moreover, treatment induced increases in free androgen index and bioavailable testosterone were significantly associated with the magnitude of reductions in mean diffusivity. These findings imply microstructural plasticity and potentially related changes in neural activity by testosterone in the adult human hypothalamus and suggest that testosterone replacement therapy in FtMs changes hypothalamic microstructure towards male proportions.

Transsexual Mastectomy: Selection of Appropriate Technique According to Breast Characteristics.

BACKGROUND: Subcutaneous mastectomy for female- to-male transsexuals is usually the first surgical pro- cedure in sexual reassignment. The main objective of subcutaneous mastectomy is to create an aesthetically pleasing male chest contour by removing all glandular tissue while minimizing chest wall scars. AIMS: In this paper, we present our experience with subcutaneous mastectomy performed in female-to- male transsexual patients. The authors recommend their point of view to aid in selecting the most suitable subcutaneous mastectomy technique depending on breast characteristics. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Between March 2011 and December 2014, 52 patients underwent bilateral subcutaneous mastec- tomies (total of 104 mastectomies), performed using the following four techniques: Webster semicircular, concentric circular, vertical, and apron flap. The tech- nique decision depended on the breast size, degree of skin excess, skin elasticity, chest width, nipple areolar complex size and position. RESULTS: Seventeen patients (32.7%) were operated with Webster semicircular, 7 patients (13.5%) with con- centric periareolar, 12 patients with vertical (23%); and 16 patients (30.8%) with the apron flap technique. The overall postoperative complication rate was 13.4%. All patients were satisfied with the aesthetic results of their subcutaneous mastectomies within the follow-up period. CONCLUSION: To obtain higher patient satisfaction with aesthetic results and lower postoperative complication rates, breast characteristics are evaluated in a detailed fashion, while choosing the ideal technique of Female-to-Male (FtM) subcutaneous mastectomy. The presented surgical new algorithm facilitates the selection of the most reliable surgical technique.

Effects of Elevated ß-Estradiol Levels on the Functional Morphology of the Testis - New Insights.

Elevated estradiol levels are correlated with male infertility. Causes of hyperestrogenism include diseases of the adrenal cortex, testis or medications affecting the hypothalamus-pituitary-gonadal axis. The aim of our study was to elucidate the effects of estradiol treatment on testicular cellular morphology and function, with reference to the treatment regimen received. Testes samples (n = 9) were obtained post-orchiectomy from male-to-female transsexuals within the age range of 26-52 years. Each patient had a minimum of 1-6 years estradiol treatment. For comparison, additional samples were obtained from microscopically unaltered testicular tissue surrounding tumors (n = 7). The tissues obtained were investigated by stereomicroscopy, histochemistry, scanning electron microscopy (SEM) and immunohistochemistry. Our studies revealed that estradiol treatment significantly decreased the diameter of the seminiferous tubules (p < 0.05) and induced fatty degeneration in the surrounding connective tissue. An increase in collagen fiber synthesis in the extracellular matrix (ECM) surrounding the seminiferous tubules was also induced. Spermatogenesis was impaired resulting in mainly spermatogonia being present. Sertoli cells revealed diminished expression of estrogen receptor alpha (ERα). Both Sertoli and Leydig cells showed morphological alterations and glycoprotein accumulations. These results demonstrate that increased estradiol levels drastically impact the human testis.

Neuroimaging studies in people with gender incongruence.

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.

Oestrogens are Not Related to Emotional Processing: a Study of Regional Brain Activity in Female-to-Male Transsexuals Under Gonadal Suppression.

Although the prevailing opinion is that emotional processes are influenced by sex hormones, the literature is still inconclusive. The aim of the current study was to examine the effects of gonadal suppression on brain activity during affective picture processing. Twenty-one female-to-male (FtM) transsexuals and 19 control women were recruited and underwent functional magnetic resonance imaging scanning while rating emotional pictures adapted from the International Affective Picture System. The gonadal hormone production of the FtMs was suppressed for 8 weeks, the control group did not receive any treatment before scanning. Under gonadal suppression, FtMs showed less brain activation in the superior temporal lobe compared with female controls during perception of positive affective pictures. Regression analysis showed that during processing of positive affective images, brain activity within the right superior temporal lobe was not correlated with levels of estradiol, luteinizing hormone, and follicle-stimulating hormone. In the absence of associations with hormonal levels, the difference in activation in the superior temporal lobe during positive emotional stimuli between FtMs and control women may be attributed to a priori differences between the 2 groups. Future studies should clarify if these differences are a result of atypical sexual differentiation of the brain in FtMs.

Cerebral gray matter volume variation in female-to-male transsexuals: a voxel-based morphometric study.

Several studies seem to support the hypothesis that brain anatomy is associated with transsexualism. However, these studies were still limited because few neuroanatomical findings have been obtained from female-to-male (FtM) transsexuals. This study compared the cerebral regional volumes of gray matter (GM) between FtM transsexuals and female controls using a voxel-based morphometry. Twelve FtM transsexuals who had undergone sex-reassignment surgery and 15 female controls participated in this study. Both groups were age matched and right-handed, with no history of neurological illness. Fifteen female controls were recruited to determine whether GM volumes in FtM transsexuals more closely resembled individuals who shared their biological sex. MRI data were processed using SPM 8 with the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL). FtM transsexuals showed significantly larger volumes of the thalamus, hypothalamus, midbrain, gyrus rectus, head of caudate nucleus, precentral gyrus, and subcallosal area compared with the female controls. However, the female controls showed a significantly larger volume in the superior temporal gyrus including Heschl's gyrus and Rolandic operculum. These findings confirm that the volume difference in brain substructures in FtM transsexuals is likely to be associated with transsexualism and that transsexualism is probably associated with distinct cerebral structures, determining gender identity.

Regional volumes and spatial volumetric distribution of gray matter in the gender dysphoric brain.

The sexual differentiation of the brain is primarily driven by gonadal hormones during fetal development. Leading theories on the etiology of gender dysphoria (GD) involve deviations herein. To examine whether there are signs of a sex-atypical brain development in GD, we quantified regional neural gray matter (GM) volumes in 55 female-to-male and 38 male-to-female adolescents, 44 boys and 52 girls without GD and applied both univariate and multivariate analyses. In girls, more GM volume was observed in the left superior medial frontal cortex, while boys had more volume in the bilateral superior posterior hemispheres of the cerebellum and the hypothalamus. Regarding the GD groups, at whole-brain level they differed only from individuals sharing their gender identity but not from their natal sex. Accordingly, using multivariate pattern recognition analyses, the GD groups could more accurately be automatically discriminated from individuals sharing their gender identity than those sharing their natal sex based on spatially distributed GM patterns. However, region of interest analyses indicated less GM volume in the right cerebellum and more volume in the medial frontal cortex in female-to-males in comparison to girls without GD, while male-to-females had less volume in the bilateral cerebellum and hypothalamus than natal boys. Deviations from the natal sex within sexually dimorphic structures were also observed in the untreated subsamples. Our findings thus indicate that GM distribution and regional volumes in GD adolescents are largely in accordance with their respective natal sex. However, there are subtle deviations from the natal sex in sexually dimorphic structures, which can represent signs of a partial sex-atypical differentiation of the brain.

Neovaginal perforation following sexual intercourse in a transsexual patient.

BACKGROUND: Neovaginal perforation can develop following sexual intercourse in patients that have undergone male to female gender reassignment surgery. In such cases urinary tract symptoms may mimic acute cystitis and acute pyelonephritis. CASE PRESENTATION: A 33-year old white transsexual patient presented to the emergency department with dysuria, hematuria, difficulty urinating, widespread groin pain, bilateral side pain, clear vaginal discharge, abdominal pain, and nausea 2-3 h after sexual intercourse. Abdominal tomography showed fluid around the vaginal cuff and air throughout the abdomen. Vaginography showed contrast leaking to the abdomen from the vaginal cuff. The patient was considered as vaginal perforation and admitted to clinic. CONCLUSION: Vaginal perforation should be considered in transsexual patients that develop urinary system symptoms following sexual intercourse. Such cases were treated medically without the need surgery.

Cerebral serotonin transporter asymmetry in females, males and male-to-female transsexuals measured by PET in vivo.

The serotonergic system modulates brain functions that are considered to underlie affective states, emotion and cognition. Several lines of evidence point towards a strong lateralization of these mental processes, which indicates similar asymmetries in associated neurotransmitter systems. Here, our aim was to investigate a potential asymmetry of the serotonin transporter distribution using positron emission tomography and the radioligand [(11)C]DASB in vivo. As brain asymmetries may differ between sexes, we further aimed to compare serotonin transporter asymmetry between females, males and male-to-female (MtF) transsexuals whose brains are considered to be partly feminized. Voxel-wise analysis of serotonin transporter binding in all groups showed both strong left and rightward asymmetries in several cortical and subcortical structures including temporal and frontal cortices, anterior cingulate, hippocampus, caudate and thalamus. Further, male controls showed a rightward asymmetry in the midcingulate cortex, which was absent in females and MtF transsexuals. The present data support the notion of a lateralized serotonergic system, which is in line with previous findings of asymmetric serotonin-1A receptor distributions, extracellular serotonin concentrations, serotonin turnover and uptake. The absence of serotonin transporter asymmetry in the midcingulate in MtF transsexuals may be attributed to an absence of brain masculinization in this region.

Testosterone replacement elevates the serum uric acid levels in patients with female to male gender identity disorder.

Gender identity disorder (GID) results from a disagreement between a person's biological sex and the gender to which he or she identifies. With respect to the treatment of female to male GID, testosterone replacement therapy (TRT) is available. The uric acid (UA) level can be influenced by testosterone; however, the early effects and dose-dependency of TRT on the serum UA concentration have not been evaluated in this population. We herein conducted a dose-response analysis of TRT in 160 patients with female to male GID. The TRT consisted of three treatment groups who received intramuscular injections of testosterone enanthate: 125 mg every two weeks, 250 mg every three weeks and 250 mg every two weeks. Consequently, serum UA elevation was observed after three months of TRT and there was a tendency toward testosterone dose-dependency. The onset of hyperuricemia was more prevalent in the group who received the higher dose. We also demonstrated a positive correlation between increased levels of serum UA and serum creatinine. Since the level of serum creatinine represents an individual's muscle volume and the muscle is a major source of purine, which induces UA upregulation, the serum UA elevation observed during TRT is at least partially attributed to an increase in muscle mass. This is the first study showing an association between serum UA elevation and a TRT-induced increase in muscle mass. The current study provides important information regarding TRT for the follow-up and management of the serum UA levels in GID patients.

Reflexões sobre a possibilidade da despatologização da transexualidade e a necessidade da assistência integral à saúde de transexuais no Brasil / Reflexiones sobre la posibilidad de despatologización de la transexualidad y la necesidad de asistencia integral a la salud de transexuales en Brasil / Reflections on the possibility of depatologizing transsexuality and the need for comprehensive health care for transsexuals in Brazil

O presente artigo tem como objetivo problematizar algumas questões acerca da patologização da transexualidade a fim de provocar a reflexão sobre a possibilidade da sua despatologização no Brasil, mantendo em perspectiva a necessidade de atenção integral à saúde de transexuais. Neste panorama, se para a medicina e as ciências psi (psiquiatria, psicologia e psicanálise) a transexualidade constitui uma desordem mental, para alguns autores que discutem as experiências trans, em especial nas ciências sociais e humanas e na saúde coletiva, estas são vivências que colocam em questão as normas de gênero que regem nossos conceitos de sexo, gênero e, no limite, de humano. Todavia, a despeito das críticas acadêmicas e do movimento mundial em prol da despatologização das identidades trans, no contexto brasileiro ainda vigora uma interpretação patologizada destas vivências que não apenas sustenta sua definição como um transtorno psiquiátrico como orienta as políticas públicas destinadas a este segmento.

El presente artículo problematiza determinadas cuestiones en torno de la patologización de la transexualidad. Teniendo en vista la necesidad de atención integral a la salud de transexuales, busca provocar una reflexión sobre la posibilidad de su despatoligización en Brasil. Si para la medicina y las ciencias 'psi' (psiquiatría, psicología y psicoanálisis) la transexualidad constituye un desorden mental, para algunos autores -que discuten las experiencias trans, en especial desde las ciencias sociales, humanas y desde la salud colectiva-estas son vivencias cuestionadoras de las normas de género que rigen nuestros conceptos de sexo, género y, en último término, nuestra concepción de lo humano. A pesar de las críticas académicas y del movimiento mundial en pos de la despatologización de las identidades trans, en el contexto brasileño rige todavía una interpretación patologizada de estas vivencias que no sólo da sustento a su definición como trastorno psíquico sino que orienta las políticas públicas destinadas a este segmento de la población.

This article discusses issues regarding the pathologization of transsexuality in order to provoke a reflection on the possibility of its depathologization in Brazil, keeping in view the need for comprehensive health care for transsexuals. If to medicine and the psy sciences (psychiatry, psychology, psychoanalysis) transsexuality is a mental disorder, for some authors who think about trans experiences, particularly in the social sciences, humanities, and community health, the living experiences of trans persons question the gender norms that govern our concepts of sex, gender and, ultimately, humanity. However, despite scholarly criticisms and the global movement in support of the depathologization of trans identities, in Brazil a pathological interpretation of trans not only sustains its definition as a psychiatric disorder, but also guides public policy towards this segment.