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Objective Interpreting laboratory results for transgender individuals who started hormone therapy requires careful consideration, specifically for analytes that have sex-specific reference intervals. In literature, conflicting data exist on the effect of hormone therapy on laboratory parameters. By studying a large cohort, we aim to define what reference category (male or female) is most appropriate to use for the transgender population over the course of gender-affirming therapy. Methods A total of 2201 people (1178 transgender women and 1023 transgender men) were included in this study. We analyzed hemoglobin (Hb), hematocrit (Ht), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), creatinine, and prolactin, at 3 different time points: pretreatment, during hormone therapy, and after gonadectomy. Results For transgender women, Hb and Ht levels decrease after initiation of hormone therapy. The concentration of liver enzymes ALT, AST, and ALP decreases whereas the levels of GGT do not change statistically significantly. Creatinine levels decrease whereas prolactin levels rise in transgender women during gender-affirming therapy. For transgender men, Hb and Ht values increase after starting hormone therapy. Liver enzymes and creatinine levels increase statistically significantly as well upon hormone therapy while prolactin concentrations decrease. Overall, reference intervals in transgender people after 1 year on hormone therapy resembled those of their affirmed gender. Conclusions Generating transgender-specific reference intervals is not essential to correctly interpret laboratory results. As a practical approach, we recommend to use the reference intervals of the affirmed gender from 1 year onwards after starting hormone therapy.

Purpose: We examined whether pretreatment levels of angiogenesis- or hypoxia-related proteins and their changes after one cycle of first-line bevacizumab-based therapy were associated with response, PFS, or OS in patients with metastatic breast cancer.Experimental Design: We included 181 patients enrolled in the phase II ATX trial evaluating first-line paclitaxel and bevacizumab without or with capecitabine (NTR1348). Plasma samples were analyzed for VEGF-A, soluble VEGFR2 (sVEGFR2), angiopoietin 2 (ANG2), soluble TIE2 (sTIE2), IL6, IL8, and carbonic anhydrase 9 (CA9). Baseline serum CA15-3 was documented. HR was adjusted for confounding factors. Where appropriate, an optimal cut-off value defining a high and a low group was determined with Martingale residuals.Results: At baseline, multiple proteins were significantly associated with PFS (ANG2, IL6, IL8, CA9, CA15-3) and OS (ANG2, sTIE2, IL6, IL8, CA9, CA15-3). After one cycle, VEGF-A, ANG2, sTIE2, and IL8 significantly decreased, while sVEGFR2 and CA9 significantly increased. The relative change in sVEGFR2 (P = 0.01) and IL8 (P = 0.001) was associated with response. Defining optimal cut-off, patients with a high CA9 rise (>2.9%) had better PFS (HR 0.45) and OS (HR 0.54) than those with low/no rise.Conclusions: Multiple angiogenesis- or hypoxia-related proteins were prognostic for PFS and OS. Molecular agents targeting these proteins might be beneficial in patients with high levels. Changes in IL8 or sVEGFR2 levels at second cycle appear predictive for response. Changes in CA9 levels during bevacizumab-based therapy for prediction of PFS and OS merit further study. Clin Cancer Res; 22(7); 1611–20. ©2016 AACR.

Supplementary Table 1. Clinical outcome of original trial population and biomarker population Supplementary Table 2. Baseline plasma protein levels vs baseline patient and tumor characteristics Supplementary Table 3. Spearman Rho correlation coefficients among protein levels at baseline Supplementary Table 4. Plasma protein changes vs baseline patient and tumor characteristics Supplementary Table 5. Change in levels of proteins per treatment arm Supplementary Table 6. Spearman Rho correlation coefficients among protein changes on C2D1 from baseline Supplementary Figure 1A. A plot of Martingale residual vs log-transformed CA9 change for death Supplementary Figure 1B. Estimation of an optimal cut-off point for CA9 change Supplementary Figure 1C. Changes in CA9 levels in the subgroups of a high rise and a low/no rise

Summary Background Increased mortality in transgender people has been described in earlier studies. Whether this increased mortality is still present over the past decades is unknown. Therefore, we aimed to investigate trends in mortality over five decades in a large cohort of adult transgender people in addition to cause-specific mortality. Methods We did a retrospective cohort study of adult transgender people who visited the gender identity clinic of Amsterdam University Medical Centre in the Netherlands. Data of transgender people who received hormone treatment between 1972 and 2018 were linked to Statistics Netherlands. People were excluded if they used alternating testosterone and oestradiol treatment, if they started treatment younger than age 17 years, or if they had ever used puberty-blockers before gender-affirming hormone treatment. Standardised mortality ratios (SMRs) were calculated using general population mortality rates stratified by age, calendar period, and sex. Cause-specific mortality was also calculated. Findings Between 1972 and 2018, 8831 people visited the gender identity clinic. 4263 were excluded from the study for a variety of reasons, and 2927 transgender women and 1641 transgender men were included in the study, with a total follow-up time of 40 232 person-years for transgender women and 17 285 person-years for transgender men. During follow-up, 317 (10·8%) transgender women died, which was higher than expected compared with general population men (SMR 1·8, 95% CI 1·6–2·0) and general population women (SMR 2·8, 2·5–3·1). Cause-specific mortality in transgender women was high for cardiovascular disease, lung cancer, HIV-related disease, and suicide. In transgender men, 44 people (2·7%) died, which was higher than expected compared with general population women (SMR 1·8, 95% CI 1·3–2·4) but not general population men (SMR 1·2, 95% CI 0·9–1·6). Cause-specific death in transgender men was high for non-natural causes of death. No decreasing trend in mortality risk was observed over the five decades studied. Interpretation This observational study showed an increased mortality risk in transgender people using hormone treatment, regardless of treatment type. This increased mortality risk did not decrease over time. The cause-specific mortality risk because of lung cancer, cardiovascular disease, HIV-related disease, and suicide gives no indication to a specific effect of hormone treatment, but indicates that monitoring, optimising, and, if necessary, treating medical morbidities and lifestyle factors remain important in transgender health care. Funding None.

Context: The impact of gender-affirming hormone therapy (HT) on cardiometabolic parameters is largely unknown. Objective: The effects of 1 year of treatment with oral or transdermal administration of estrogen (plus cyproterone) and transdermal or IM application of testosterone on serum lipid levels and blood pressure (BP) were assessed in transgender persons. Design and Methods: In this prospective, observational substudy of the European Network for the Investigation of Gender Incongruence, measurements were performed before and after 12 months of HT in 242 transwomen and 188 transmen from 2010 to 2017. Results: Mean values are reported. In transmen, HT increased diastolic BP (2.5%; 95% CI, 0.6 to 4.4) and levels of total cholesterol (TC; 4.1%; 95% CI, 1.5 to 6.6), low-density lipoprotein-cholesterol (LDL-C; 13.0%; 95% CI, 9.2 to 16.8), and triglycerides (36.9%; 95% CI, 29.8 to 44.1); high-density lipoprotein-cholesterol levels decreased (HDL-C; 10.8%; 95% CI, 214.0 to 27.6). In transwomen, HT slightly decreased BP (systolic BP, 22.6%, 95% CI, 24.2 to 21.0; diastolic BP, 22.2%, 95% CI, 24.0 to 20.4) and decreased levels of TC (29.7%; 95% CI, 211.3 to 28.1), LDL-C (26.0%; 95% CI, 28.6 to 3.6), HDL-C (29.3%; 95% CI, 211.4 to 27.3), and triglycerides (210.2%; 95% CI, 214.5 to 25.9). Conclusion: Unfavorable changes in lipid profile were observed in transmen; a favorable effect was noted in transwomen. HT effects on BP were negligible. Long-term studies are warranted to assess whether and to what extent HT in trans individuals results in a differential effect on cardiovascular disease outcomes.

Background The transgender population that uses gender‐affirming hormone therapy (GAHT) is rapidly growing. The (side) effects of GAHT are largely unknown. We examined the effect of GAHT on coagulation parameters associated with venous thromboembolism (VTE) risk. Methods Factor (F)II, FIX, FXI, protein (p)C and free pS, fibrinogen, hematocrit, sex hormone‐binding globulin, and normalized activated protein C ratio were measured in 98 transwomen (male sex at birth, female gender identity) and 100 transmen (female sex at birth, male gender identity) before and after 12 months of GAHT (oral or transdermal estradiol and anti‐androgens in transwomen, transdermal or intramuscular testosterone in transmen). Mean paired differences in coagulation measurements were estimated with 95% confidence intervals (95% CI). Differences for route of administration and age were assessed with linear regression. Results After GAHT, transwomen had more procoagulant profiles with a mean increase in FIX: 9.6 IU/dL (95% CI 3.1–16.0) and FXI: 13.5 IU/dL (95% CI 9.5–17.5), and a decrease in pC: −7.7 IU/dL (95% CI −10.1 to −5.2). Changes in measures of coagulation were influenced by route of administration (oral vs. transdermal) and age. A higher sex‐hormone binding globulin level after 12 months was associated with a lower activated protein C resistance. In transmen, changes were not procoagulant overall and were influenced by age. Differences for route of administration (transdermal vs. intramuscular) were small. Conclusions GAHT in transmen was not associated with apparent procoagulant changes, which provides some reassurance regarding VTE risk. In transwomen, GAHT resulted in procoagulant changes, which likely contributes to the observed increased VTE risk.

Background: In trans women receiving hormone therapy, body fat and insulin resistance increases, with opposite effects in trans men. These metabolic alterations may increase or decrease the risk of developing type 2 diabetes in trans women and trans men, respectively. Currently, there is no data on the incidence of type 2 diabetes in transgender individuals. Methods: Retrospective data from the Amsterdam Cohort of Gender Dysphoria with transgender individuals on hormone therapy between 1972 and 2018 were linked to a nationwide health data registry. Because no central registry of diabetes was available, the occurrence of diabetes was deferred from the first dispense of a glucose-lowering agent. Standardized incidence ratios (SIR) were computed for trans women and trans men in comparison with respectively men and women from the general population. Findings: Compared to their birth sex in the general population, no difference in the incidence of type 2 diabetes mellitus was observed in trans women (N = 2585, 90 cases, SIR 0.94 95%CI 0.76–1.14) or trans men (N = 1514, 32 cases, SIR 1.40 95%CI 0.96–1.92). Interpretation: Despite studies reporting an increase in insulin resistance in feminizing hormone therapy and an increase in insulin sensitivity in masculinizing hormone therapy, the incidence of type 2 diabetes in transgender individuals after initiation of hormone therapy was not different compared to the general population. Earlier studies on the effect of hormone therapy on insulin sensitivity in transgender individuals might have revealed specific effects of cyproterone acetate rather than effects of estradiol. Funding: None to declare. Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Medical Ethics Committee of the Amsterdam University Medical Centre

Objective Transgender individuals sometimes report a lack of physical change during hormone treatment, such as alterations in muscle tone or fat distribution. Identifying characteristics of this subgroup could be a step toward individualizing hormone therapy in transgender individuals. Therefore, we study the variation of changes in body composition and characteristics associated with a lack of change. Design and methods: Body composition measures were recorded in 323 transmen and 288 transwomen at every visit from the start of hormone therapy to a maximum of 24 months follow-up. Absence of change was defined as transmen with a decrease in lean body mass or transwomen with a decrease in fat percentage. Results A lack of change at 24 months was observed in 19 of 94 (20.2%) transmen and in 9 of 96 (9.4%) transwomen. The risk of not achieving change in body composition was related to lower testosterone levels and less suppression of LH in transmen (OR: 0.67, 95% CI: 0.48–0.94 per SD increase in testosterone and OR: 1.36, 95% CI: 1.01–1.83 per SD increase in LH). Conclusions: There is a large variation in body composition changes during hormone therapy, with a substantial proportion of individuals with no measurable effects. In transmen, serum testosterone and LH were associated with a lack of change, but serum hormone levels were not associated with body composition changes in transwomen. The results provide a rationale for individualizing hormone therapy in transmen, by considering individual effects rather than solely relying on a standardized dosage of hormone therapy.

Context Trans women (male sex assigned at birth, female gender identity) mostly use antiandrogens combined with estrogens and can subsequently undergo vaginoplasty including orchiectomy. Because the prostate remains in situ after this procedure, trans women are still at risk for prostate cancer. Objective To assess the incidence of prostate cancer in trans women using hormone treatment. Design In this nationwide retrospective cohort study, data of participants were linked to the Dutch national pathology database and to Statistics Netherlands to obtain data on prostate cancer diagnosis and mortality. Setting Gender identity clinic. Participants Trans women who visited our clinic between 1972 and 2016 and received hormone treatment were included. Main Outcome Measures Standardized incidence ratios (SIRs) were calculated using the number of observed prostate cancer cases in our cohort and the number of expected cases based on age-specific incidence numbers from the Netherlands Comprehensive Cancer Organization. Results The study population consisted of 2281 trans women with a median follow-up time of 14 years (interquartile range 7-24), and a total follow-up time of 37 117 years. Six prostate cancer cases were identified after a median 17 years of hormone treatment. This resulted in a lower prostate cancer risk in trans women than in Dutch reference males (SIR 0.20, 95% confidence interval 0.08-0.42). Conclusions Trans women receiving androgen deprivation therapy and estrogens have a substantially lower risk for prostate cancer than the general male population. Our results support the hypothesis that androgen deprivation has a preventive effect on the initiation and development of prostate cancer.

•Transgender people experience incongruence between the sex assigned at birth and the gender with which they identify. •Transgender people can be treated with sex hormones and gender-affirming surgery to induce desired physical changes of the gender they identify with. •Treatment with sex hormones is effective; it induces the desired physical characteristics and improves self-image. •Transgender women have a higher risk of venous thromboembolism, stroke and meningioma compared to cisgender men and cisgender women. Compared to cisgender men, transgender women have a higher risk of breast cancer and transgender women50 years old have a higher risk of fractures. •Transgender men have a higher risk of myocardial infarction than cisgender women. Their risk of fracture is just as high as that of cisgender women and their risk of breast cancer is lower. •Although hormone treatment is generally considered safe for transgender people, the risk of cardiovascular disease should definitely be carefully monitored. Transgender people should also be advised to participate in population screening programmes based on the organs they have.

© 2018 American Society of Andrology and European Academy of Andrology. In trans persons on gender-affirming hormonal treatment, a decrease (in trans women) or increase (in trans men) in hematocrit is often observed. Reference ranges for evaluation of hematocrit levels in trans persons have not been established. This prospective cohort study is part of the European Network for the Investigation of Gender Incongruence (ENIGI). At the Ghent and Amsterdam sites, we included 625 hormone-naive trans persons. Gender-affirming hormonal treatment was initiated at the first visit. In trans men, serum hematocrit (Hct) levels increased during the first year (+4.9 Hct %, 95% CI 3.82-5.25), with the most pronounced increase during the first 3 months (+2.7 Hct %, 95% CI 1.94-3.29). Trans men receiving testosterone esters had a larger increase in serum hematocrit levels compared to trans men receiving testosterone undecanoate (Δ 0.8 Hct %). Of 192 trans men, 22 (11.5%) developed serum hematocrit levels ≥50.0%. Trans men on testosterone undecanoate were less likely to develop hematocrit levels ≥50% or ≥52%, compared to trans men on testosterone esters, and were less likely to develop hematocrit levels ≥50%, compared to trans men on testosterone gel. In trans women, serum hematocrit had dropped by 4.1 Hct % (95% CI 3.50-4.37) after 3 months, after which only small decreases were observed. In conclusion, serum hematocrit levels can be found in the reference range of the perceived gender as from 3 months after the initiation of gender-affirming hormonal treatment.

Objective Cross-sex hormonal therapy (CHT) in trans persons affects their total body fat and total lean body mass. However, it is unknown how separate body regions are affected and whether these changes alter body shape. Therefore, the aim of this study was to determine the effects on body fat and lean body mass in separate body regions and on body shape after one year of CHT. Design and methods In a multicenter prospective study at university hospitals, 179 male-to-female gender dysphoric persons, referred to as transwomen, and 162 female-to-male gender dysphoric persons, referred to as transmen, were included. All underwent whole-body dual-energy X-ray absorptiometry and anthropometric measurements before and after one year of CHT. Results In transwomen, increases in body fat ranged from +18% (95% CI: 13%;23%) in the android region to +42% (95% CI: 37%;46%) in the leg region and +34% (95% CI: 29%;38%) in the gynoid region. In transmen, changes in body fat ranged from −16% (95% CI: −19;−14%) in the leg region and −14% in the gynoid region (95% CI: −16%;−12) to no change in the android region (+1%, 95% CI: −3%;5%). Waist-to-hip ratio (WHR) decreased in transwomen (−0.03, 95% CI: −0.04;−0.02) mainly due to an increase in hip circumference (+3.2 cm, 95% CI: 2.3;4.0). Transmen have a decrease in hip circumference (−1.9 cm, 95% CI: −3.1;−0.7) resulting in an increase in WHR (+0.01, 95% CI: 0.00;0.02). Conclusions CHT causes a more feminine body fat distribution and a lower WHR in transwomen and a more masculine body fat distribution with a lower hip circumference in transmen.

Context: Breast development is a key feature of feminization and therefore important to transwomen (male-to-female transgender persons). However, it is not exactly known when breast development starts after initiating cross-sex hormone therapy (CHT) and how much growth may be expected of CHT alone. Objective: To investigate breast development in centimeters and bra cup-sizes in transwomen during their first year of CHT, and whether clinical or laboratory parameters predict the breast development. Design: This study was performed as part of the European Network for the Investigation of Gender Incongruence (ENIGI), which is a prospective multicenter cohort study. Setting: Specialized gender clinics in Amsterdam, Ghent, and Florence. Participants: All transwomen who completed the first year of CHT (n=229) were eligible for analyses. Intervention: Cross-sex hormone therapy. Main outcome measures: Breast development in centimeter and cup-size. Results: The median age of the included transwomen was 28 years (range 18;69 years). Mean breast - chest difference increased from 4.1±2.9cm at baseline to 7.9±3.1cm after one year of CHT, mainly resulting in less than an AAA cup-size (48.7%). Main breast development occurred in the first six months of therapy. Serum estradiol levels did not predict breast development after one year CHT (first quartile: +3.6cm(95% CI +2.7;+4.5cm), second quartile: +3.2cm(95% CI +2.3;+4.2cm), third quartile: +4.4(95% CI +3.5;+5.3cm), fourth quartile: +3.6cm(95% CI +2.7;+4.5cm)). Conclusion: This study shows that after one year of CHT breast development is modest and occurs primarily in the first six months. No clinical or laboratory parameters were found that predict breast development.

Sex steroids are important determinants of bone acquisition and bone homeostasis. Cross-sex hormonal treatment (CHT) in transgender persons can affect bone mineral density (BMD). The aim of this study was to investigate in a prospective observational multicenter study the first-year effects of CHT on BMD in transgender persons. A total of 231 transwomen and 199 transmen were included who completed the first year of CHT. Transwomen were treated with cyproterone acetate and oral or transdermal estradiol; transmen received transdermal or intramuscular testosterone. A dual-energy X-ray absorptiometry (DXA) was performed to measure lumbar spine (LS), total hip (TH), and femoral neck (FN) BMD before and after 1 year of CHT. In transwomen, an increase in LS (+3.67%, 95% confidence interval [CI] 3.20 to 4.13%, p < 0.001), TH (+0.97%, 95% CI 0.62 to 1.31%, p < 0.001), and FN (+1.86%, 95% CI 1.41 to 2.31%, p < 0.001) BMD was found. In transmen, TH BMD increased after 1 year of CHT (+1.04%, 95% CI 0.64 to 1.44%, p < 0.001). No changes were observed in FN BMD (-0.46%, 95% CI -1.07 to 0.16%, p = 0.144). The increase in LS BMD was larger in transmen aged ≥50 years (+4.32%, 95% CI 2.28 to 6.36%, p = 0.001) compared with transmen aged

Objective: This study explored the overall suicide death rate, the incidence over time, and the stage in transition where suicide deaths were observed in transgender people. Methods: A chart study, including all 8263 referrals to our clinic since 1972. Information on death occurrence, time, and cause of death was obtained from multiple sources. Results: Out of 5107 trans women (median age at first visit 28 years, median follow-up time 10 years) and 3156 trans men (median age at first visit 20 years, median follow-up time 5 years), 41 trans women and 8 trans men died by suicide. In trans women, suicide deaths decreased over time, while it did not change in trans men. Of all suicide deaths, 14 people were no longer in treatment, 35 were in treatment in the previous two years. The mean number of suicides in the years 2013–2017 was higher in the trans population compared with the Dutch population. Conclusions: We observed no increase in suicide death risk over time and even a decrease in suicide death risk in trans women. However, the suicide risk in transgender people is higher than in the general population and seems to occur during every stage of transitioning. It is important to have specific attention for suicide risk in the counseling of this population and in providing suicide prevention programs.

Concerns about bone health in transgender people using gender‐affirming hormonal treatment (HT) exist, but the fracture risk is not known. In this nationwide cohort study, we aimed to compare the fracture incidence in transgender people using long‐term HT with an age‐matched reference population. All adult transgender people who started HT before 2016 at our gender‐identity clinic were included and were linked to a random population‐based sample of 5 age‐matched reference men and 5 age‐matched reference women per person. Fracture incidence was determined using diagnoses from visits to hospital emergency rooms nationwide between 2013 and 2015. A total of 1089 trans women aged

Background Gender-affirming hormonal treatment (HT) in adult transgender people influences bone mineral density (BMD). Besides BMD, bone geometry and trabecular bone score are associated with fracture risk. However, it is not known whether bone geometry and TBS changes during HT. Purpose To investigate the bone geometry and TBS in adult transgender people at different time points, up to 25 years, of HT. Methods A total of 535 trans women and 473 trans men were included, who were divided into three groups at time of their DXA: 20–29 years, 30–39 years, and 40–59 years. Subsequently, each group was divided into different HT durations: baseline, or after 5, 15, or 25 years of HT. Hip structure analysis was performed to measure subperiosteal width, endocortical diameter, average cortical thickness, and section modulus. TBS was calculated based on lumbar spine DXA images. Results In trans women in all age groups and in young trans men, no differences were observed in periosteal width, endocortical diameter, average cortical thickness, and section modulus for different durations of HT. In trans men aged 40–59 years, subperiosteal width, endocortical diameter, and section modulus were slightly higher in the groups who were using HT compared to the (peri- or postmenopausal) baseline group. In younger trans women, TBS tended to be higher in those using HT compared to the baseline groups, and in older trans women TBS was higher in those using HT for 25 years versus baseline (+0.04, 95%CI +0.00; +0.08). In younger trans men, TBS tended to be lower in those who used HT compared to the baseline groups, and in older trans men TBS was lower in those using 5 years HT versus baseline (−0.05, 95%CI −0.08; −0.01). Conclusion No differences in cortical bone geometry parameters were found during different HT-durations. TBS increased in trans women and decreased in trans men, indicating that estrogens have positive effects on TBS. These data may be helpful in determining what sex reference values for calculating T-scores and Z-scores in adult transgender people should be used.

© The Author(s) (2018). Benign brain tumours may be hormone sensitive. To induce physical characteristics of the desired gender, transgender individuals often receive cross-sex hormone treatment, sometimes in higher doses than hypogonadal individuals. To date, long-term (side) effects of cross-sex hormone treatment are largely unknown. In the present retrospective chart study we aimed to compare the incidence of common benign brain tumours: meningiomas, pituitary adenomas (non-secretive and secretive), and vestibular schwannomas in transgender individuals receiving cross-sex hormone treatment, with those reported in general Dutch or European populations. This study was performed at the VU University Medical Centre in the Netherlands and consisted of 2555 transwomen (median age at start of cross-sex hormone treatment: 31 years, interquartile range 23-41) and 1373 transmen (median age 23 years, interquartile range 18-31) who were followed for 23 935 and 11 212 person-years, respectively. For each separate brain tumour, standardized incidence ratios with 95% confidence intervals were calculated. In transwomen (male sex assigned at birth, female gender identity), eight meningiomas, one non-secretive pituitary adenoma, nine prolactinomas, and two vestibular schwannomas occurred. The incidence of meningiomas was higher in transwomen than in a general European female population (standardized incidence ratio 4.1, 95% confidence interval 1.9-7.7) and male population (11.9, 5.5-22.7). Similar to meningiomas, prolactinomas occurred more often in transwomen compared to general Dutch females (4.3, 2.1-7.9) and males (26.5, 12.9-48.6). Noteworthy, most transwomen had received orchiectomy but still used the progestogenic anti-androgen cyproterone acetate at time of diagnosis. In transmen (female sex assigned at birth, male gender identity), two cases of somatotrophinomas were observed, which was higher than expected based on the reported incidence rate in a general European population (incidence rate females = incidence rate males; standardized incidence ratio 22.2, 3.7-73.4). Based on our results we conclude that cross-sex hormone treatment is associated with a higher risk of meningiomas and prolactinomas in transwomen, which may be linked to cyproterone acetate usage, and somatotrophinomas in transmen. Because these conditions are quite rare, performing regular screenings for such tumours (e.g. regular prolactin measurements for identifying prolactinomas) seems not necessary.

In hypogonadal/postmenopausal individuals, hormone therapy has been associated with an increased risk for cardiovascular events (CVEs). A steeply growing population that often receives exogenous hormones is transgender individuals. Although transgender individuals hypothetically have an increased risk of CVEs, there is little known about the occurrence of CVEs in this population.1 Therefore, we determined the incidences of acute/spontaneous strokes (ischemic/hemorrhagic, transient ischemic attack, or subarachnoid hemorrhage), myocardial infarctions (MIs), and venous thromboembolic events (VTEs) in transwomen and transmen receiving transgender hormone therapy (THT). Subsequently, we compared these incidences with those reported in women and men from the general population.

Background The phase II ATX trial aimed at evaluating safety and efficacy of first-line AT or ATX for HER2-negative LR/MBC (NTR1348; BOOG 2006-06). Plasma samples were collected for investigation of circulating proteins involved in angiogenesis and their possible association with therapy outcome. We here report the prognostic value of plasma VEGF-A, soluble (s)VEGFR-2, ANG2, sTIE2, IL6, IL8 and CA9 at baseline (C1D1) and their changes after cycle 1 (C2D1). Methods 312 patients were randomized 1:1 to AT (T 90 mg/m2 d1, 8, 15 & A 10 mg/kg d1, 15 q4w x 6 cycles → A 15 mg/kg d1 q3w for next cycles) or ATX (T 90 mg/m2 d1, 8, A 15 mg/kg d1 & X 825 mg/m2 bid d1–14 q3w x 8 cycles → A & X at same dose q3w for next cycles). Plasma proteins were measured by immunoassays (R&D Systems and MSD). The association of (continuous) protein levels on C1D1 and their changes on C2D1 with response, PFS and OS were evaluated by Mann-Whitney U test and univariate Cox regression analysis. Results The biomarker cohort (n=181) and trial cohort had similar baseline characteristics and clinical outcome. After a median follow-up of 46 months, there were 178 (98%) PFS events and 152 (84%) deaths. On C1D1, levels of ANG2 and sTIE2 were significantly higher in patients with hormone-receptor positive disease compared to those with triple-negative disease (p=.025 and p=.001, respectively). A high level of VEGF-A was noted in patients with visceral metastases (p=.028) and those with an increasing number of metastatic sites (p=.017). High levels of ANG2, IL6, IL8 and CA9 were significantly associated with poor PFS and OS (Table 1). Protein levels were not associated with response. Table 1. Association of circulating proteins at baseline with PFS and OSPFS HR (95%CI)PFS p-valueOS HR (95%CI)OS p-valueANG22.3 (1.0-4.9).043.1 (1.4-7.0).007IL61.6 (1.1-2.3).021.9 (1.3-2.8).001IL81.9 (1.3-2.8).0012.8 (1.8-4.3) On C2D1, levels of all proteins, except for IL6, had significantly changed. Whereas VEGF-A, ANG2, sTIE2 and IL8 decreased significantly, sVEGFR2 and CA9 showed a significant increase. The median relative change of both IL8 and sVEGFR2 was significantly different between patients having CR/PR vs. SD/PD (for IL8: -19.4% vs. 22.3%, p=.001 and for sVEGFR2: 6.5 vs. 2.1%, p=.01). A large relative increase in CA9 level was associated with better PFS (HR = 0.36, 95% CI, 0.19 – 0.68, p=.002) and OS (HR = 0.50, 95% CI, 0.27 – 0.94, p=.03). All patients had very low levels of free VEGF-A on C2D1 (median 8 pg/ml). Conclusions In patients with HER2-negative LR/MBC receiving first-line bevacizumab-containing chemotherapy, high baseline plasma levels of ANG2, IL6, IL8 and CA9 indicate a high risk for poor PFS and OS. These proteins might be useful for stratification according to prognosis. Moreover, relative decrease in IL8 and increase in sVEGFR2 on C2D1 are associated with response, whereas a large relative increase in CA9 is associated with better PFS and OS. Changes in these proteins after one cycle might be early indicators of efficacy of bevacizumab combined with chemotherapy. Financial support from Roche Netherlands. Citation Format: Siu W Lam, Nienke M Nota, Steffen M de Groot, Agnes Jager, Monique MEM Bos, Sabine C Linn, Joan van den Bosch, Hans J Braun, Ankie MT van der Velden, Maartje Los, Johanneke EA Portielje, Judith R Kroep, Aafke H Honkoop, Carolien H Smorenburg, Bea Tanis, Johanna MGH van Riel, Jetske M Meerum Terwogt, Marien O den Boer, Joep Douma, Frank Jeurissen, Johan Berends, Harm van Tinteren, Epie Boven. Plasma biomarker analysis in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC) treated with first-line bevacizumab (A) and paclitaxel (T) without or with capecitabine (X) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-09.

The cause of prolactin alterations in transgender persons is often assigned to oestrogens, but the precise cause and time course during different phases of cross-sex hormone treatment (CHT) remain unclear. In this study, we prospectively examined prolactin levels in 55 female-to-males (FtMs) and 61 male-to-females (MtFs) during the first year of CHT. Because long-term prolactin data were not available in this population, we studied these levels in a retrospective population of 25 FtMs and 38 MtFs who underwent gonadectomy. FtMs were treated with testosterone and MtFs with estradiol, with or without the anti-androgen cyproterone acetate (CPA) (after gonadectomy CPA is cessated). During the first year of CHT, prolactin decreased with 25% (95CI: −33%, −12%) in FtMs and increased with 193% (95CI: 156%, 219%) in MtFs. Eighteen MtFs developed hyperprolactinemia (≥0.6 IU L−1). In the retrospective population, post-gonadectomy levels in FtMs were lower than baseline levels (−39%; 95CI: −51%, −20%) while in MtFs post-gonadectomy levels and baseline levels were comparable (−6%; 95CI: −24%, 15%). No hyperprolactinemia was found after gonadectomy. In conclusion, in FtMs, prolactin decreased consistently during CHT and in MtFs, prolactin increased during pre-surgical CHT but normalised after gonadectomy. It is likely that CPA induces increasing prolactin levels in MtFs.

Various previous studies have reported that brains of people diagnosed with gender dysphoria (GD) show sex-atypical features. In addition, recent functional magnetic resonance imaging studies found that several brain resting-state networks (RSNs) in adults with GD show functional connectivity (FC) patterns that are not sex-atypical, but specific for GD. In the current study we examined whether FC patterns are also altered in prepubertal children and adolescents with GD in comparison with non-gender dysphoric peers. We investigated FC patterns within RSNs that were previously examined in adults: visual networks (VNs), sensorimotor networks (SMNs), default mode network (DMN) and salience network. Thirty-one children (18 birth assigned males; 13 birth assigned females) and 40 adolescents with GD (19 birth assigned males or transgirls; 21 birth assigned females or transboys), and 39 cisgender children (21 boys; 18 girls) and 41 cisgender adolescents (20 boys; 21 girls) participated. We used independent component analysis to obtain the network maps of interest and compared these across groups. Within one of the three VNs (VN-I), adolescent transgirls showed stronger FC in the right cerebellum compared with all other adolescent groups. Sex differences in FC between the cisgender adolescent groups were observed in the right supplementary motor area within one of the two SMNs (SMN-II; girls > boys) and the right posterior cingulate gyrus within the posterior DMN (boys > girls). Within these networks adolescent transgirls showed FC patterns similar to their experienced gender (female). Also adolescent transboys showed a FC pattern similar to their experienced gender (male), but within the SMN-II only. The prepubertal children did not show any group differences in FC, suggesting that these emerge with aging and during puberty. Our findings provide evidence for the existence of both GD-specific and sex-atypical FC patterns in adolescents with GD.

Summary Objectives It is hypothesized that transpeople show sex-atypical differentiation of the brain. Various structural neuroimaging studies provide support for this notion, but little is known about the sexual differentiation of functional resting-state networks in transpeople. In this study we therefore aimed to determine whether brain functional connectivity (FC) patterns in transpeople are sex-typical or sex-atypical, before and after the start of cross-sex hormone therapy (CHT). Methods We acquired resting-state functional magnetic resonance data in 36 transpeople (22 with female sex assigned at birth), first during gonadal suppression, and again four months after start of CHT, and in 37 cisgender people (20 females), both sessions without any hormonal intervention. We used independent component analysis to identify the default mode network (DMN), salience network (SN), and left and right working memory network (WMN). These spatial maps were used for group comparisons. Results Within the DMN, SN, and left WMN similar FC patterns were found across groups. However, within the right WMN, cisgender males showed significantly greater FC in the right caudate nucleus than cisgender females. There was no such sex difference in FC among the transgender groups and they did not differ significantly from either of the cisgender groups. CHT (in transgender participants) and circulating sex steroids (in cisgender participants) did not affect FC. Conclusion Our findings may suggest that cisgender males and females experience a dissimilar (early) differentiation of the right WMN and that such differentiation is less pronounced in transpeople.

ObjectiveTo investigate the incidence and characteristics of breast cancer in transgender people in the Netherlands compared with the general Dutch population.DesignRetrospective, nationwide cohort study.SettingSpecialised tertiary gender clinic in Amsterdam, the Netherlands.Participants2260 adult trans women (male sex assigned at birth, female gender identity) and 1229 adult trans men (female sex assigned at birth, male gender identity) who received gender affirming hormone treatment.Main outcome measuresIncidence and characteristics (eg, histology, hormone receptor status) of breast cancer in transgender people.ResultsThe total person time in this cohort was 33 991 years for trans women and 14 883 years for trans men. In the 2260 trans women in the cohort, 15 cases of invasive breast cancer were identified (median duration of hormone treatment 18 years, range 7-37 years). This was 46-fold higher than in cisgender men (standardised incidence ratio 46.7, 95% confidence interval 27.2 to 75.4) but lower than in cisgender women (0.3, 0.2 to 0.4). Most tumours were of ductal origin and oestrogen and progesterone receptor positive, and 8.3% were human epidermal growth factor 2 (HER2) positive. In 1229 trans men, four cases of invasive breast cancer were identified (median duration of hormone treatment 15 years, range 2-17 years). This was lower than expected compared with cisgender women (standardised incidence ratio 0.2, 95% confidence interval 0.1 to 0.5).ConclusionsThis study showed an increased risk of breast cancer in trans women compared with cisgender men, and a lower risk in trans men compared with cisgender women. In trans women, the risk of breast cancer increased during a relatively short duration of hormone treatment and the characteristics of the breast cancer resembled a more female pattern. These results suggest that breast cancer screening guidelines for cisgender people are sufficient for transgender people using hormone treatment.

Sex steroids are important determinants of bone acquisition and bone homeostasis. Cross-sex hormonal treatment (CHT) in transgender persons can affect bone mineral density (BMD). The aim of this study was to investigate in a prospective observational multicenter study the first-year effects of CHT on BMD in transgender persons. A total of 231 transwomen and 199 transmen were included who completed the first year of CHT. Transwomen were treated with cyproterone acetate and oral or transdermal estradiol; transmen received transdermal or intramuscular testosterone. A dual-energy X-ray absorptiometry (DXA) was performed to measure lumbar spine (LS), total hip (TH), and femoral neck (FN) BMD before and after 1 year of CHT. In transwomen, an increase in LS (+3.67%, 95% confidence interval [CI] 3.20 to 4.13%, p 0.001), TH (+0.97%, 95% CI 0.62 to 1.31%, p 0.001), and FN (+1.86%, 95% CI 1.41 to 2.31%, p 0.001) BMD was found. In transmen, TH BMD increased after 1 year of CHT (+1.04%, 95% CI 0.64 to 1.44%, p 0.001). No changes were observed in FN BMD (-0.46%, 95% CI -1.07 to 0.16%, p = 0.144). The increase in LS BMD was larger in transmen aged ≥50 years (+4.32%, 95% CI 2.28 to 6.36%, p = 0.001) compared with transmen aged50 years (+0.68%, 95% CI 0.19 to 1.17%, p = 0.007). In conclusion, BMD increased in transgender persons after 1 year of CHT. In transmen of postmenopausal age, the LS BMD increased more than in younger transmen, which may lead to the hypothesis that the increase in BMD in transmen is the result of the aromatization of testosterone to estradiol. © 2017 American Society for Bone and Mineral Research.