Search

In order to assess the risk of hypertension development, we performed a retrospective analysis of the clinical records of consecutive transgender patients who began gender-affirming hormonal therapy in our Outpatient Gender Identity Clinic with30 years of age and had a follow-up5 years. 149 transgender women treated with estradiol and 153 transgender men treated with testosterone were included; 129 of the transgender women received also androgen blockers (54 spironolactone, 49 cyproterone acetate and 26 LHRH agonists). The annual incidence of hypertension in young transgender men (1.18%) seemed comparable to that of the general population. In young transgender women, it seemed higher (2.14%); we found that the choice of androgen blocker had a remarkable effect, with a highly significant increase in patients treated with cyproterone acetate (4.90%) vs. the rest (0.80%); the adjusted hazard-ratio was 0.227 (p = 0.001). Correlation, logistic regression and mediation analyses were performed for the associations of the available clinical variables with the increase in systolic blood pressure and the onset of hypertension, but besides the use of cyproterone acetate, only the ponderal gain was found significant (Spearman's r: 0.361, p 0.001); with a 36.7% mediation effect (31.2-42.3%). Cyproterone acetate has additional known risks, such as meningioma; although we cannot conclusively prove that it has a role in the development of hypertension, we conclude that the use of cyproterone acetate for this indication should be reconsidered.

Sotos syndrome is characterized by overgrowth, distinctive facial appearance, and learning disability. It is caused by heterozygous mutations, including deletions of NSD1 located at chromosome 5q35. While advanced bone age can occur in some cases, precocious puberty (PP) is reported only in three cases until now. Here, we reported a case of Sotos syndrome diagnosed at the infancy period with central precocious puberty. The discovery of potential factors that trigger puberty is one of the central mysteries of pubertal biology. Depot gonadotropin-releasing hormone (GnRH) analogs constitute the first-line therapy in central precocious puberty (CPP), which has proven to be both effective and safe. In our cases, leuprolide acetate in maximum dose could not be successful for the control of pubertal progression, and cyproterone acetate (CPA) was added to therapy. Then, pubertal progression was controlled. In some specific syndromes with precocious puberty, such as Sotos syndrome, treatment can be challenging. Cyproterone acetate would be an asset for the benefit of treatment.

Objective: Limited data are available on adverse drug reactions (ADRs) of gender-affirming hormone therapy (HT), mainly due to the lack of population-based studies with adequate controls, thus making spontaneous reporting systems a valuable tool to detect potential side reactions. In this nationwide retrospective study, we aimed to analyze ADRs related to gender-affirming HT reported in the French pharmacovigilance database (FPVD). Design: We requested all the individual case safety reports related to gender-affirming HT recorded in the FPVD before the 27th of May 2020. We excluded previously published cases and those for which gender-affirming hormone therapy was not the suspected drug. Results: A total of 28 reports of ADRs were identified. Six concerned transgender men (age range 21-40 years) and 22 transgender women (age range 22-68 years). In transgender men taking testosterone enanthate, all reported adverse effects were cardiovascular events with pulmonary embolism in 50% of cases. In transgender women, antiandrogens, mainly cyproterone acetate, were involved in 68% of cases. Estrogens were involved in 77% of cases, mostly in association with progestin or cyproterone acetate. Meningioma was the principal ADR, followed by cardiovascular events. Conclusions: Our data show a previously unreported and non-negligible proportion of cases indicating cardiovascular ADRs in transgender men younger than 40 years, taking testosterone enanthate. In transgender women, cardiovascular events were the second most frequently reported ADR. Further research is necessary to identify risk factors that might help to the individualization of treatment strategies. There is a necessity to increase awareness and implement preventive and education measures.

PurposeFollistatin is a glycoprotein that represses members of the transforming growth factor-β superfamily including activin. Higher follistatin levels have been associated with an increased risk for type 2 diabetes and with polycystic ovary syndrome (PCOS). In non-obese adolescent girls with PCOS, insulin sensitization results in a healthier endocrine-metabolic outcome than oral contraception (OC); we assessed whether those differences are underscored by changes in serum follistatin concentrations.MethodsCirculating follistatin, endocrine-metabolic markers and hepato-visceral fat were measured longitudinally in 72 girls with PCOS [age, 16 years; body mass index (BMI), 23 Kg/m2] randomized to receive PioFluMet [pioglitazone (7.5 mg/d), metformin (850 mg/d) and flutamide (62.5 mg/d), n=17]; EE-CA [an OC containing 35 µg ethinylestradiol (EE) and 2 mg cyproterone acetate (CA), n=17]; SPIOMET [Spironolactone (50 mg/d), pioglitazone (7.5 mg/d) and metformin (850 mg/d), n=18], or EE-LNG [an OC containing 20 µg EE and 100 mg levonorgestrel (LNG), n=20]. Twenty-eight age- and BMI-matched healthy girls served as controls.ResultsPre-treatment follistatin levels were similar in PCOS and controls. OCs raised serum follistatin after 6 months (6.8-fold vs 2.5-fold for EE-CA and EE-LNG, respectively). Neither SPIOMET nor PioFluMet changed follistatin levels. Follistatin correlated negatively with high-molecular weight adiponectin and positively with mean serum insulin concentrations during an oral glucose tolerance test at baseline, and with liver fat after 6 months.ConclusionIn girls with PCOS, follistatin levels rise significantly after 6 months on OCs and this increase associates to a worsening of markers of insulin resistance and to changes in liver fat.

Objective The aim of this study was to describe progestin-associated meningiomas’ characteristics, outcome and management. Material and methods We included 53 patients operated on and/or followed in the department for meningioma with progestin intake longer than one year and with recent drug discontinuation. Results Cyproterone acetate (CPA), nomegestrol acetate (NomA), and chlormadinone acetate (ChlA) were involved in most cases. Mean duration of progestin drugs intake was 17.5 years. Tumors were multiple in 66% of cases and were located in the anterior and the medial skull base in 71% of cases. Transitional subtype represented 16/25 tumors; 19 meningiomas were WHO grade I and 6 were grade II. The rate of transitional subtype and skull base location was significantly higher compared to matched operated meningioma general population. No difference was observed given WHO classification. But Ki67 proliferation index tends to be lower and 5/6 of the WHO grade II meningiomas were classified as WHO grade II because of brain invasion. Strong progesterone receptors expression was observed in most cases. After progestin discontinuation, a spontaneous visual recovery was observed in 6/10 patients. Under CPA (n = 24) and ChlA/NomA (n = 11), tumor volume decreased in 71% and 18% of patients, was stabilized in 25% and 64% of patients, and increased in 4% and 18% of patients, respectively. Volume outcome was related to meningioma location. Conclusions Outcome at progestins discontinuation is favorable but different comparing CPA versus ChlA-NomA and comparing tumor location. Long-term follow-up is required. In most cases, simple observation is recommended and surgery should be avoided.

Background Spironolactone and cyproterone acetate are commonly used in feminizing hormone therapy to achieve the goal of female range testosterone level; however, the data on the efficacy comparing between these two anti-androgens are scarce. Aim To compare the anti-androgenic effects between spironolactone and cyproterone acetate as the component of feminizing hormone therapy among transgender women population. Methods The study was single-blinded randomized controlled trial involved 52 transgender women from two transgender health clinics. Each participant received oral estradiol valerate 4 mg/day combined with anti-androgen, spironolactone 100 mg/day or cyproterone acetate 25 mg/day, depending on which group they were randomized to. Clinical and biochemical variables were obtained at baseline and at 12 weeks of feminizing hormone therapy. Main Outcome Measures The change of testosterone level from baseline. Other changes including free testosterone, estradiol, prolactin and lipid profile after the therapy. RESULTS After a 12 weeks of feminizing hormone therapy, the change of testosterone level in the cyproterone acetate group [558.0 ng/dL (IQR 352.0 to 783.3)] was significantly higher than the spironolactone group [226.2 ng/dL (IQR,-4.3 to 480.1)](p value Clinical Implications The data on the differences between the two anti-androgen could be benefit for the transgender health-care providers in medication selection and adverse-effects counseling. Strengths & Limitations The study design was randomized controlled trial and controlled the estrogen component by prescribed the same type and dose for each participant. However, the study was suffered from the confound feminizing effects from previous hormone therapy and the high drop-out rate. CONCLUSION For feminizing hormone therapy, cyproterone acetate had a higher testosterone suppression efficacy than spironolactone.

Cytochrome P450 1A1 (CYP1A1) metabolizes estrogens, melatonin, and other key endogenous signaling molecules critical for embryonic/fetal development. The enzyme has increasing expression during pregnancy, and its inhibition or knockout increases embryonic/fetal lethality and/or developmental problems. Here, we present a virtual screening model for CYP1A1 inhibitors based on the orthosteric and predicted allosteric sites of the enzyme. Using 1001 reference compounds with CYP1A1 activity data, we optimized the decision thresholds of our model and classified the training compounds with 68.3% balanced accuracy (91.0% sensitivity and 45.7% specificity). We applied our final model to 11 known CYP1A1 orthosteric binders and related compounds, and found that our ranking of the known orthosteric binders generally agrees with the relative activity of CYP1A1 in metabolizing these compounds. We also applied the model to 22 new test compounds with unknown/unclear CYP1A1 inhibitory activity, and predicted 16 of them are CYP1A1 inhibitors. The CYP1A1 potency and modes of inhibition of these 22 compounds were experimentally determined. We confirmed that most predicted inhibitors, including drugs contraindicated during pregnancy (amiodarone, bicalutamide, cyproterone acetate, ketoconazole, and tamoxifen) and environmental agents suspected to be endocrine disruptors (bisphenol A, diethyl and dibutyl phthalates, and zearalenone), are indeed potent inhibitors of CYP1A1. Our results suggest that virtual screening may be used as a rapid tier-one method to screen for potential CYP1A1 inhibitors, and flag them out for further experimental evaluations. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-021-03111-2.

Background The behavior of meningiomas under influence of progestin therapy remains unclear. Objective To investigate the relationship between growth kinetics of intracranial meningiomas and usage of the progestin cyproterone acetate (PCA). Methods This study prospectively followed 108 women with 262 intracranial meningiomas and documented PCA use. A per-meningioma analysis was conducted. Changes in meningioma volumes over time, and meningioma growth velocities, were measured on magnetic resonance imaging (MRI) after stopping PCA treatment. Results Mean follow-up time was 30 (standard deviation [SD] 29) mo. Ten (4%) meningiomas were treated surgically at presentation. The other 252 meningiomas were followed after stopping PCA treatment. Overall, followed meningiomas decreased their volumes by 33% on average (SD 28%). A total of 188 (72%) meningiomas decreased, 51 (20%) meningiomas remained stable, and 13 (4%) increased in volume of which 3 (1%) were surgically treated because of radiological progression during follow-up after PCA withdrawal. In total, 239 of 262 (91%) meningiomas regressed or stabilized during follow-up. Subgroup analysis in 7 women with 19 meningiomas with follow-up before and after PCA withdrawal demonstrated that meningioma growth velocity changed statistically significantly (P = .02). Meningiomas grew (average velocity of 0.25 mm3/day) while patients were using PCA and shrank (average velocity of -0.54 mm3/day) after discontinuation of PCA. Conclusion Ninety-one percent of intracranial meningiomas in female patients with long-term PCA use decrease or stabilize on MRI after stopping PCA treatment. Meningioma growth kinetics change significantly from growth during PCA usage to shrinkage after PCA withdrawal.

BACKGROUND Anti-Mullerian hormone and inhibin B are produced by Sertoli cells. Anti-Mullerian hormone secretion indicates an immature Sertoli cell state. Inhibin B serves as a marker of male fertility. Identification of markers reflecting the presence of germ cells is of particular relevance in trans persons undergoing gender-affirming hormone therapy in order to offer individualized fertility preservation methods. OBJECTIVES Serum and intratesticular inhibin B and anti-Mullerian hormone values were assessed and related to clinical features, laboratory values, and germ cell numbers. MATERIALS AND METHODS Twenty-two trans women from three clinics were included. As gender-affirming hormone therapy, 10-12.5 mg of cyproterone acetate plus estrogens were administered. Height, weight, age, medication, and treatment duration were inquired by questionnaires. Serum luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol were measured by immuno-assays. Serum and intratesticular inhibin B and anti-Mullerian hormone were measured by commercially available ELISAs. Spermatogonia were quantified as spermatogonia per cubic millimeter testicular tissue applying a morphometric analysis of two independent testicular cross-sections per individual after MAGEA4 immunostaining. RESULTS Patients with high inhibin B levels presented with a higher number of spermatogonia (*p

Context Cyproterone acetate (CPA) is a competitive inhibitor of the androgen receptor and exerts negative hypothalamic feedback. It is often used in combination with estrogens in trans women to achieve feminization. However, CPA has been associated with side effects such as changes in liver enzyme concentrations and increases in prolactin concentrations. The question is whether the testosterone-lowering effect, as well as these side effects, are dose dependent. Objective To assess the lowest effective dose of CPA in trans women to prevent side effects. Methods This longitudinal study, conducted at gender identity centers in Amsterdam, Ghent, and Florence, is part of the European Network for the Investigation of Gender Incongruence (ENIGI), a multicenter prospective cohort study. Participants were trans women (n = 882) using estrogens only or in combination with 10, 25, 50, or 100 mg CPA daily. The primary outcome measure was the concentration of testosterone at 3 and/or 12 months of hormone therapy. Results Using estrogens only (without CPA) led to testosterone concentrations of 5.5 nmol/L (standard error of the mean [SEM] 0.3). All doses of CPA resulted in testosterone concentrations below the predefined threshold of suppression of 2 nmol/L (10 mg, 0.9 nmol/L, SEM 0.7; 25 mg, 0.9 nmol/L, SEM 0.1; 50mg, 1.1 nmol/L, SEM 0.1; 100 mg, 0.9 nmol/L, SEM 0.7). Higher prolactin and lower high-density lipoprotein concentrations were observed with increasing doses of CPA. No differences in liver enzyme concentrations were found between the doses. Conclusion Compared with higher doses of CPA, a daily dose of 10 mg is equally effective in lowering testosterone concentrations in trans women, while showing fewer side effects.

Purpose: To report the results of systematic meningioma screening program implemented by French authorities in patients exposed to progestin therapies (cyproterone (CPA), nomegestrol (NA), and chlormadinone (CMA) acetate).Methods: We conducted a prospective monocentric study on patients who, between September 2018 and April 2021, underwent standardized MRI (injection of gadolinium, then a T2 axial FLAIR and a 3D-T1 gradient-echo sequence) for meningioma screening.Results: Of the 210 included patients, 15 (7.1%) had at least one meningioma; seven (7/15, 47%) had multiple meningiomas. Meningiomas were more frequent in older patients and after exposure to CPA (13/103, 13%) compared to NA (1/22, 4%) or CMA (1/85, 1%; P=0.005). After CPA exposure, meningiomas were associated with longer treatment duration (median=20 vs 7 years, P=0.001) and higher cumulative dose (median=91 g vs. 62 g, P=0.014). Similarly, their multiplicity was associated with higher dose of CPA (median=244 g vs 61 g, P=0.027). Most meningiomas were ≤1 cm3 (44/58, 76%) and were convexity meningiomas (36/58, 62%). At diagnosis, patients were non-symptomatic, and all were managed conservatively. Among 14 patients with meningioma who stopped progestin exposure, meningioma burden decreased in 11 (79%) cases with no case of progression during MR follow-up.Conclusion: Systematic MR screening in progestin-exposed patients uncovers small and multiple meningiomas, which can be managed conservatively, decreasing in size after progestin discontinuation. The high rate of meningiomas after CPA exposure reinforces the need for systematic screening. For NA and CMA, further studies are needed to identify patients most likely to benefit from screening.

The study the characteristics of surgical meningiomas in female patients who took CPA and to compare this population to a non-CPA control group. We processed the French Systeme National des Donnees de Sante (SNDS) database to retrieve appropriate cases operated between 2007 and 2017. 1 101 female patients (3.8%) who used to take CPA and underwent a meningioma surgery were extracted from a nationwide population based cohort of 28 924 patients. Median age at CPA prescription was 42 years IQR[36.7–48.9]. The median time between CPA start and surgery was 5.5 years IQR[3.1–7.9]. The median age at surgery was significantly lower in patients who were treated by CPA (47 years, IQR[42–54) compared to the non-CPA population (61 years, IQR[51–70], p

The influence of exposure to hormonal treatments, particularly cyproterone acetate (CPA), has been posited to contribute to the growth of meningiomas. Given the widespread use of CPA, this systematic review and meta-analysis attempted to assess real-world evidence of the association between CPA and the occurrence of intracranial meningiomas. Systematic searches of Ovid MEDLINE, Embase and Cochrane Controlled Register of Controlled Trials, were performed from database inception to 18th December 2021. Four retrospective observational studies reporting 8,132,348 patients were included in the meta-analysis. There was a total of 165,988 subjects with usage of CPA. The age of patients at meningioma diagnosis was generally above 45 years in all studies. The dosage of CPA taken by the exposed group (n = 165,988) was specified in three of the four included studies. All studies that analyzed high versus low dose CPA found a significant association between high dose CPA usage and increased risk of meningioma. When high and low dose patients were grouped together, there was no statistically significant increase in risk of meningioma associated with use of CPA (RR = 3.78 [95% CI 0.31-46.39], p = 0.190). Usage of CPA is associated with increased risk of meningioma at high doses but not when low doses are also included. Routine screening and meningioma surveillance by brain MRI offered to patients prescribed with CPA is likely a reasonable clinical consideration if given at high doses for long periods of time. Our findings highlight the need for further research on this topic.

Background The number of individuals who sexually offended, and who are continued to be treated with pharmacological agents to reduce sex drive after their release from prison or forensic psychiatry, are not known. Furthermore, figures on the number of those who stop their sexdrive supressing antiandrogen treatment in the outpatient setting are unknown as well. This is of central importance though as it might be associated with an increased risk of recidivism. Aim To assess prescription patterns as well as adherence to pharmacological treatment in outpatient clinics in Germany for individuals who have sexually offended and were released from prison or forensic psychiatric hospital. Methods A self-constructed online survey assessing the pharmacological treatment modalities was sent by e-mail to n = 103 forensic outpatient clinics in Germany. Thirty-three (32.0%) completed the questionnaire and reported about 834 patients. Outcomes Prevalence of the use of different pharmacological agents in the treatment of individuals convicted for sexual offenses as well as the number of patients who have discontinued testosterone-lowering medication (TLM). Results Among all institutions, 22.4% (n = 187) of individuals received pharmacological treatment, with 40.1% receiving gonadotropin-releasing-hormone-agonists, 26.2% antipsychotics, 24.6% selective serotonin reuptake inhibitors, 6.4% cyproterone acetate, and 2.7% a combination of gonadotropin-releasing-hormone-agonists and cyproterone acetate. A significant positive correlation was found between the number of patients released from a forensic-psychiatric hospital and the number of patients treated with TLM. Within 1 year 8.6% (n = 16) stopped their TLM during or at the end of the supervision period, most of them against treatment providers advice. Clinical Implications Substantial regional differences indicate uncertainties regarding the prescription of pharmacological agents for outpatients who have committed sexual offences in Germany. The discontinuiation of TLM within the first year of treatment against treatment providers advise in a substantial proportion of patients could be associated with a serious risk for reoffending. Strengths & Limitations The present survey captures prevalences of the pharmacotherapy in forensic aftercare facilities for individuals who have offended sexually, and is the first to record the number of discontinuations. This is a cross-sectional survey covering only 1 country, but includes a large number of individuals. Conclusion Even though the number of treated individuals has increased in prisons, the majority of pharmacological treatment is still provided by forensic hospitals, which then translates into the outpatient setting. The number of those who stop taking such medication is a highly relevant topic for both forensic treatment providers and legal decision makers

Background Self-prescribed gender-affirming hormone therapy (GAHT) is common practice among transgender women, especially in resource-limited countries, yet the effectiveness of each GAHT regimen to achieve female range sex hormone concentrations is not known. Aim To describe the use and sex hormone concentrations of various GAHT regimens among transgender women who self prescribe in Thailand. Methods This was a retrospective study in a community-based setting. Five hundred and 27 records of transgender women taking GAHT who were receiving care at a community health center between January 1, 2018, and December 31, 2020 were included for the analysis. Main Outcome Measures Blood total testosterone and estradiol concentration after at least a 6-month period of GAHT. Results Multiple GAHT regimens were identified including oral estradiol valerate (EV), transdermal 17β-estradiol gel, injectable EV with hydroxyprogesterone caproate, injectable estradiol benzoate with progesterone, oral EV with cyproterone acetate (CPA), and oral contraceptive pills (OCPs). The most common GAHT regimen used by 49.1% of the participants was OCPs that contained 0.035 mg of ethinyl estradiol and 2 mg of CPA. Only 25.2% of this group had female range testosterone concentrations ( Clinical Implications The inadequate sex hormone levels found in these commonly self-prescribed GAHT regimens provide information regarding the efficacy and safety of GAHT regimens for health care providers working with transgender women in a community-based setting. Strengths and Limitations This study reflected a real-world situation and provided hormonal profiles among transgender women taking self-prescribed GAHT. However, issues in recall, medical literacy, and adherence to the medication may limit the results. Conclusion Combined hormonal contraceptive pill was a commonly used GAHT regimen in Thai transgender women who self prescribe GAHT. However, this regimen was not effective to decrease testosterone concentrations to the recommended range of less than 50 ng/dL. Overall, self-prescription of GAHT does not appear to be effective in reaching target sex hormone concentrations. Including health care providers in the prescription and monitoring of GAHT may be a more effective approach in the delivery of GAHT.

Context Cyproterone acetate (CPA) is a competitive inhibitor of the androgen receptor and exerts negative hypothalamic feedback. It is often used in combination with estrogens in trans women to achieve feminization. However, CPA has been associated with side effects such as changes in liver enzyme concentrations and increases in prolactin concentrations. The question is whether the testosterone-lowering effect, as well as these side effects, are dose dependent. Objective To assess the lowest effective dose of CPA in trans women to prevent side effects. Methods This longitudinal study, conducted at gender identity centers in Amsterdam, Ghent, and Florence, is part of the European Network for the Investigation of Gender Incongruence (ENIGI), a multicenter prospective cohort study. Participants were trans women (n = 882) using estrogens only or in combination with 10, 25, 50, or 100 mg CPA daily. The primary outcome measure was the concentration of testosterone at 3 and/or 12 months of hormone therapy. Results Using estrogens only (without CPA) led to testosterone concentrations of 5.5 nmol/L (standard error of the mean [SEM] 0.3). All doses of CPA resulted in testosterone concentrations below the predefined threshold of suppression of 2 nmol/L (10 mg, 0.9 nmol/L, SEM 0.7; 25 mg, 0.9 nmol/L, SEM 0.1; 50mg, 1.1 nmol/L, SEM 0.1; 100 mg, 0.9 nmol/L, SEM 0.7). Higher prolactin and lower high-density lipoprotein concentrations were observed with increasing doses of CPA. No differences in liver enzyme concentrations were found between the doses. Conclusion Compared with higher doses of CPA, a daily dose of 10 mg is equally effective in lowering testosterone concentrations in trans women, while showing fewer side effects.

Normoferritinemic women with functional hyperandrogenism show a mild iron overload. Iron excess, hyperandrogenism, and cardioautonomic dysfunction contribute to blood pressure (BP) abnormalities in these patients. Furthermore, combined oral contraceptives (COC) prescribed for hyperandrogenic symptoms may worse BP recordings. Iron depletion by phlebotomy appears to lower BP in other acquired iron overload conditions. We aimed to determine the effect of iron depletion on the office BP, ambulatory BP monitoring, and frequency of hypertension in patients with functional hyperandrogenism submitted to standard therapy with COC. We conducted a phase 2 randomized, controlled, parallel, open-label clinical trial (NCT02460445) in adult women with functional hyperandrogenism including hyperandrogenic polycystic ovary syndrome and idiopathic hyperandrogenism. After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to three scheduled bloodlettings or observation for another 9 months. Main outcome measures were the changes in office BP, 24-h-ambulatory BP, and frequency of hypertension in both study arms. From June 2015 to June 2019, 33 women were included in the intention-to-treat analyses. We observed an increase in mean office systolic BP [mean of the differences (MD): 2.5 (0.3–4.8) mmHg] and night-time ambulatory systolic BP [MD 4.1 (1.4–6.8) mmHg] after 3 months on COC. The percentage of nocturnal BP non-dippers also increased, from 28.1 to 92.3% (P P

Background Cardiovascular risk is increased in transgender persons using gender-affirming hormone therapy. To gain insight into the mechanism by which sex hormones affect cardiovascular risk in transgender persons, we investigated the effect of hormone therapy on markers of inflammation and hemostasis. Methods In this exploratory study, 48 trans women using estradiol patches plus cyproterone acetate (CPA) and 47 trans men using testosterone gel were included. They were between 18 and 50 years old and did not have a history of cardiovascular events. Measurements were performed before and after 3 and 12 months of hormone therapy. Results After 12 months, in trans women, systemic and endothelial inflammatory markers decreased (hs-CRP -66%, (95% CI -76; -53), VCAM-1–12%, (95% CI -16; -8)), while platelet activation markers increased (PF-4 +17%, (95% CI 4; 32), β-thromboglobulin +13%, (95% CI 2; 24)). The coagulation marker fibrinogen increased transiently, after 3 months (+15%, (95% CI 1; 32)). In trans men, hs-CRP increased (+71%, (95% CI 19; 145)); platelet activation and coagulation markers were not altered. In both trans women and trans men, leptin and adiponectin changed towards reference values of the experienced gender. Conclusions Platelet activation and coagulation marker concentrations increased in trans women using transdermal estradiol plus CPA, but not in trans men using testosterone. Also, concentrations of inflammatory markers decreased in trans women, while hs-CRP increased in trans men. Our results indicate that hormone therapy may affect hemostasis in transgender persons, which could be an underlying mechanism explaining the increased cardiovascular risk in this population.

The relationship between meningioma and progestins has not been elucidated. Meningioma regression after acetate cyproterone (CA) withdrawal has been reported. Our purpose was to evaluate the meningioma evolution after withdrawal of progestins in patients who underwent long-term exposure to CA, nomegestrol acetate (NA), chlormadinone acetate (ChlA)., info:eu-repo/semantics/published

The long-term use of cyproterone acetate (CPA) is associated with an increased risk of developing intracranial meningiomas. CPA discontinuation most often induces a stabilization or regression of the tumor. The underlying biological mechanisms as well as the reasons why some meningiomas still grow after CPA discontinuation remain unknown. We reported a series of patients presenting CPA-induced meningiomatosis with opposed tumor evolutions following CPA discontinuation, highlighting the underlying histological and genetic features.Patients presenting several meningiomas with opposite tumor evolution (coexistence of growing and shrinking tumors) following CPA discontinuation were identified. Clinical and radiological data were reviewed. A retrospective volumetric analysis of the meningiomas was performed. All the growing meningiomas were operated. Each operated tumor was characterized by histological and genetic analyses.Four women with multiple meningiomas and opposite tumor volume evolutions after CPA discontinuation were identified. Histopathological analysis characterized the convexity and tentorial tumors which continued to grow after CPA discontinuation as fibroblastic meningiomas. The decreasing skull base tumor was characterized as a fibroblastic meningioma with increased fibrosis and a widespread collagen formation. The two growing skull base meningiomas were identified as meningothelial and transitional meningiomas. The molecular characterization found two NF2 mutations among the growing meningiomas and a PIK3CA mutation in the skull base tumor which decreased.To our knowledge, this is the first report describing an atypical tumor evolution of CPA-associated meningiomas after CPA discontinuation. The underlying biological mechanisms explaining this observation and especially the close relationship between mutational landscapes and embryologic origins of the meninges in CPA-related meningiomas as well as their clonal origin require further research.

This commentary will explore the important clinical question regarding whether the antiandrogen class of 5α-reductase inhibitors should be considered as an effective and safe treatment option for transfeminine and/or transmasculine individuals. The use of finasteride in transfeminine individuals is based upon the theory that the goal of medical treatment is to reduce the concentrations of androgens, including dihydrotestosterone. Nonetheless, it is unclear that finasteride will have any additive clinical benefit once testosterone levels have already been lowered with standard treatment regimens (i.e. estrogen with spironolactone or cyproterone acetate). For transmasculine individuals, 5α-reductase inhibitors may be a potential treatment option for a subset with androgenetic alopecia but may come at the expense of impairing virilization driven by dihydrotestosterone. In the absence of efficacy and safety data on 5α-reductase inhibitors in gender diverse populations, clinicians should discuss this issue with patients who request or are contemplating their use.

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.

Hidradenitis suppurativa/acne inversa is a disease with deep-seated chronic painful nodules, abscesses, and draining sinus tracts, which manifests on the apocrine gland-rich skin areas of the body. Observational findings demonstrate that the disease usually appears after puberty, exhibits pre-menstrual flares in women, improves in pregnancy, and worsens post-partum, which indicates a role of hormones and particularly of androgens in its pathophysiology. Because increased androgen levels in serum have not been widely reported, an end-organ androgen hypersensitivity has been postulated. The aim of this systematic review was to identify and present evidence for antiandrogen therapeutic options for the treatment of hidradenitis suppurativa/acne inversa. A literature search was conducted in different medical electronic databases using the keywords “hidradenitis”, “suppurativa”, “acne inversa”, and “antiandrogen” on 1 December, 2018. The main therapeutic options were subsequently used as separate keywords with the disease terms in a separate search. The main therapeutic options yielded were cyproterone acetate, spironolactone, finasteride, and metformin. One randomized controlled crossover trial and seven case series were identified following use of a standard extraction form for eligibility. The existing studies do not allow a robust evidence-based recommendation for the use of antiandrogens in the treatment of hidradenitis suppurativa/acne inversa. Further randomized controlled trials are needed to define the role of hormonal treatment as an alternative or concomitant therapy together with antibiotics or biologics.

Objectives A few observational studies have suggested that progesterone and dydrogesterone may have a lower risk of breast cancer than other progestogens. In our earlier xenograft animal experiments, progesterone did not stimulate breast tumors. The aim of this study was to test dydrogesterone for the first time. The study also evaluated the effects of PGRMC1 on proliferation with progestogens. Methods (1) In-vitro study. The proliferative effects of dydrogesterone and of progesterone were assessed in vitro using T47D cells transfected with PGRMC1 or empty vector in the presence or absence of estradiol. Additionally, to find the strongest proliferator for inclusion as a comparator in the xenograft animal study, norethisterone, levonorgestrel, desogestrel, dienogest, drospirenone, nomegestrol, and cyproterone acetate were tested. Methods (2) Xenograft main study. PGRMC1-transfected or empty-vector T47D and MCF7 xenotransplants were each treated with four different hormonal preparations: E2+placebo; E2+dydrogesterone; E2+progesterone; E2+norethisterone. A total of 112 castrated mice were randomly allocated to the 16 groups. This was thus a prospective, randomized, blinded, placebo-controlled four-arm study (45–50 days) with the two T47D and two MCF7 xenografts. Tumor volumes were monitored twice weekly. Results (1) In-vitro study. The strongest proliferation was with norethisterone, but only with PGRMC1-transfected cells. There was significant proliferation with dydrogesterone, but not with progesterone in the absence of estradiol. However, no increase in proliferation was achieved by adding dydrogesterone to estradiol compared with the proliferation induced with estradiol alone, in contrast to norethisterone. Results (2) Xenograft main study. There was significantly faster tumor growth with norethisterone + E2 than with E2+placebo in T47D and MCF7 PGRMC1 xenografts, but not with dydrogesterone + E2 or progesterone + E2. There was less tumor growth in empty-vector xenografts, without between-group differences. Conclusion PGRMC1 increases the breast-cell proliferation effects of certain progestogens, including dydrogesterone, in contrast to progesterone, but not during estradiol-induced proliferation, either in vitro or in a xenograft animal model, in contrast to norethisterone. Thus the proliferative potency of dydrogesterone may be similar to that of progesterone. Clinical studies in women overexpressing PGRMC1 are recommended.

Context Germ cell tumours (GCTs) secreting β-human chorionic gonadotropin (β-HCG) are a rare cause of gonadotropin-independent precocious puberty (GIPP). Case description A 5.7-year-old boy presented with GIPP. Investigations to elucidate the underlying cause revealed elevated serum β-HCG. Ultrasound of the abdomen and testes, urine steroid profile, bone isotope scan, and sequencing of the luteinizing hormone receptor gene (LHCGR) were normal. Despite paired serum and cerebrospinal fluid β-HCG measurement suggesting local (brain) β-HCG production, repeated magnetic resonance imaging (MRI) of the brain as well as MRI of the mediastinum did not identify a tumour source of persistently elevated serum β-HCG. Treatment with cyproterone acetate and spironolactone was unsuccessful. Increase in testicular volumes prompted the addition of a gonadotropin releasing hormone (GnRH) analogue. Due to progressing virilisation and skeletal maturation, treatment was changed to a combination of anastrozole and bicalutamide at the age of 7 years. One year later, serum β-HCG and testosterone concentrations spontaneously normalised followed by reductions in the height velocity, skeletal maturation and virilisation. The proband achieved his genetic height potential. No medication side effects were observed. The patient subsequently presented with non-secreting pineal GCT at 14 years, 8½ years after his initial presentation with GIPP. Conclusions Our case highlights that GIPP with no definite underlying aetiology at diagnosis should be considered as a prodrome for GCTs, and regular radiological surveillance for earlier tumour identification is warranted. To the best of our knowledge, our case is the first reported case of the use of anastrozole and bicalutamide in the setting of idiopathic GIPP. The good height outcome in our case warrants the trial of anastrozole and bicalutamide in similar cases.

Multiple idiopathic cervical root resorption is an aggressive form of external root resorption that occurs at the cementoenamel junction and can affect multiple teeth (a minimum of 3) throughout the entire dentition. Most of the individuals affected are healthy with noncontributory medical histories. The resorption is usually detected as an incidental finding on radiographs or during dental examination. This case report describes an adult female with multiple cervical root resorptions who had been treated with chemotherapy for ovarian cancer at 16 years old. Nine years later, a total of 12 teeth were diagnosed with cervical root resorption. All of the known causative factors for external cervical resorption were discarded. To our knowledge, this is the first case reported of multiple cervical root resorption related to chemotherapy.

Cyproterone acetate (CPA) is an antiandrogenic drug which has recently been recognized to promote the occurrence and growth of intracranial meningiomas. Nomegestrol acetate (NOMAC) is a widely used progestin-like drug that could be suggested as an alternative for patients taking CPA. We report a case of CPA-related meningioma for which relay from CPA to NOMAC led to further tumor growth and cessation of NOMAC-induced tumor shrinkage. We suggest NOMAC can have a similar effect than CPA on meningiomas. The use of NOMAC as replacement for CPA in the presence of a meningioma should be discouraged until further evidence becomes available on the role of NOMAC in such instances.

Background/Aims: Mutations in the DAX1 gene cause X-linked adrenal hypoplasia congenita (AHC) classically associated with hypogonadotropic hypogonadism. Unexpectedly, precocious puberty (PP) has been reported in some cases, its mechanism remaining unclear. Methods: We longitudinally studied a boy with AHC due to DAX1 gene mutation who developed peripheral PP at age 4.5 years. Initially he presented pubic hair, penile enlargement, advanced bone age and elevated testosterone levels. PP progressed with acne, body odour and ejaculations. In addition, we summarized reported findings of patients with DAX1 mutations and PP in the literature in a structured manner providing a basis to discuss possible pathomechanisms of PP in DAX1 patients. Results: In our patient, hydrocortisone treatment was increased to 20 mg/m2/day as suggested in similar published cases. However, despite the suppression of adrenocorticotropic hormone (ACTH), this remained without clinical effect or change in laboratory results. The progression of symptoms of pubertal development was well suppressed under cyproterone acetate treatment. Twenty-four-hour steroid urine excretion rate measurements excluded an effect of adrenal androgens and showed a prepubertal rise of excreted testosterone. Testes size remained small. GnRH testing showed peripheral PP. Conclusion: We hypothesize that an intrinsic, gonadotropin- and ACTH-independent activation of steroidogenesis in the DAX1 deficient testes leads to PP in AHC patients with DAX1 mutations.

Introduction Meningiomas are the most common tumors of the central nervous system. Most meningiomas are benign and occur mainly in middle aged women. Risk factors include female sex, exposure to ionizing radiation, and age. The relationship between meningiomas and sex hormones is supported by their higher expression of specific receptors. Only few cases of meningiomas in identical twins have been reported. Cyproterone acetate (CPA) is an antiandrogenic progestin used to treat hirsutism in some countries. We report the case of identical twin sisters with multiple CPA-induced meningiomas and their spontaneous decrease after drug discontinuation, permitting surgical abstention. Method This study is an original case report with 18 month follow up, at University Hospital Reims, France. Study population are two 48-year-old identical twin sisters under CPA treatment against hirsutism with 50 mg daily during 30 years (total dose of approximately 547.5 g per person). Results We described four biggest lesions (two per patient) as markers of evolution with the average decrease of volume of the four described lesions (combined results patient one and two) after eighteen month of CPA stopping was 58.6 %. Conclusions These two identical twin patients illustrate the risk of development of multiple meningiomas with long-term use of CPA. Eighteen-month follow-up showed decrease of meningiomas after treatment interruption. The history of these two patients suggests the presence of genetic abnormalities that would favor the development of progestin-associated meningiomas. In our case influence of both factors seems strongly possible. The stopping of CPA permitted surgical abstention and significant reduction of tumor volume.

Cortisol, a stress hormone, plays key roles in mediating stress and anti-inflammatory responses. As abnormal cortisol levels can induce various adverse effects, screening cortisol and cortisol analogues is important for monitoring stress levels and for identifying drug candidates. A novel cell-based sensing system was adopted for rapid screening of cortisol and its functional analogues under complex cellular regulation. We used glucocorticoid receptor (GR) fused to a split intein which reconstituted with the counterpart to trigger conditional protein splicing (CPS) in the presence of targets. CPS generates functional signal peptides which promptly translocate the fluorescent cargo. The sensor cells exhibited exceptional performance in discriminating between the functional and structural analogues of cortisol with improved sensitivity. Essential oil extracts with stress relief activity were screened using the sensor cells to identify GR effectors. The sensor cells responded to peppermint oil, and L-limonene and L-menthol were identified as potential GR effectors from the major components of peppermint oil. Further analysis indicated L-limonene as a selective GR agonist (SEGRA) which is a potential anti-inflammatory agent as it attenuates proinflammatory responses without causing notable adverse effects of GR agonists.

Prostate cancer is a major cause of death in males. Cyproterone acetate (CPA), the steroidal anti-androgen for part of androgen deprivation therapy, may block the androgen-receptor interaction and then reduce serum testosterone through its weak anti-gonadotropic action. In addition to CPA inducing hepatitis, CPA is known to cause liver tumors in rats also. Aryl hydrocarbon receptor (AhR) is a cytoplasmic receptor and regulates multiple physiological functions. CYP1A1 is an AhR-targeted gene. We found that CPA induced CYP1A1 expression, transcriptional activity of the aryl hydrocarbon response element (AHRE), and the nuclear localization of AhR in mouse Hepa-1c1c7 cells. However, CPA suppressed CYP1A1 mRNA expression and the transcriptional activity of AHRE in human HepG2 and MCF7 cells, and also decreased AhR ligand-induced CYP1A1 protein expression and transcriptional activity of AHRE in HepG2 cells. In summary, CPA is an AhR agonist in mouse cells, but an AhR antagonist in human cells. Accordingly, CPA potentially plays a role as an endocrine disruptor of the AhR. This study helps us to understand why CPA induces acute hepatitis, gene mutation, and many other side effects. In addition, it may trigger further studies investigating the relationships between CPA, glucocorticoid receptor and castration-resistant prostate cancer in the future.

Background Transgender women with intact gonads receive lifelong hormonal treatment to suppress physiologic androgen production, the optimal efficacious and safe cyproterone acetate (CPA) dose has not been established. Aim To assess the effectiveness and safety of low-dose (10–20 mg/day) compared with high-dose (50–100 mg/day) CPA treatment. Methods We conducted a historical cohort study of transgender women treated at a tertiary center for transgender health. Outcome Measures Serum levels of testosterone, estradiol, prolactin, gonadotrophins, liver enzymes, and lipids. RESULTS There were 38 transgender women in the low-dose group and 26 in the high-dose group. Age (median 24.9 years, interquartile range [IQR] 21–30 vs 25 years, IQR 19–35) and follow-up time (median 12 months, IQR 6–23 vs 15 months, IQR 12–36) were similar in the low- and high-dose groups, respectively. Serum gonadotropins and testosterone were suppressed to a similar level at all time points in both groups. Prolactin levels increased significantly in both groups, however, with a more substantial increase in the high- vs the low-dose group (804 ± 121 vs 398 ± 69 mIU/ml at 12 months, respectively, P = .004). Total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels were not significantly affected by the dose. Clinical Implications We suggest an adjustment of current clinical practice guidelines to recommend lower doses of CPA for the treatment of transgender women. Strengths & Limitations This is the first demonstration that low-dose CPA treatment of transgender women is effective. Limitations include a relatively small sample and retrospective study design. CONCLUSION Low-dose CPA treatment of transgender women is as effective as high-dose treatment and possibly safer.

Objective To assess the risk of meningioma associated with use of high dose cyproterone acetate, a progestogen indicated for clinical hyperandrogenism. Design Observational cohort study. Setting Data from SNDS, the French administrative healthcare database, between 2007 and 2015. Participants 253 777 girls and women aged 7-70 years living in France who started cyproterone acetate between 2007 and 2014. Participants had at least one reimbursement for high dose cyproterone acetate and no history of meningioma or benign brain tumour, or long term disease status. Participants were considered to be exposed when they had received a cumulative dose of at least 3 g during the first six months (139 222 participants) and very slightly exposed (control group) when they had received a cumulative dose of less than 3 g (114 555 participants). 10 876 transgender participants (male to female) were included in an additional analysis. Main outcome measure Surgery (resection or decompression) or radiotherapy for one or more intracranial meningiomas. Results Overall, 69 meningiomas in the exposed group (during 289 544 person years of follow-up) and 20 meningiomas in the control group (during 439 949 person years of follow-up) were treated by surgery or radiotherapy. The incidence of meningioma in the two groups was 23.8 and 4.5 per 100 000 person years, respectively (crude relative risk 5.2, 95% confidence interval 3.2 to 8.6; adjusted hazard ratio 6.6, 95% confidence interval 4.0 to 11.1). The adjusted hazard ratio for a cumulative dose of cyproterone acetate of more than 60 g was 21.7 (10.8 to 43.5). After discontinuation of cyproterone acetate for one year, the risk of meningioma in the exposed group was 1.8-fold higher (1.0 to 3.2) than in the control group. In a complementary analysis, 463 women with meningioma were observed among 123 997 already using cyproterone acetate in 2006 (risk of 383 per 100 000 person years in the group with the highest exposure in terms of cumulative dose). Meningiomas located in the anterior skull base and middle skull base, particularly the medial third of the middle skull base, involving the spheno-orbital region, appeared to be specific to cyproterone acetate. An additional analysis of transgender participants showed a high risk of meningioma (three per 14 460 person years; 20.7 per 100 000 person years). Conclusions A strong dose-effect relation was observed between use of cyproterone acetate and risk of intracranial meningiomas. A noticeable reduction in risk was observed after discontinuation of treatment.

Transgender women are assigned male at birth but identified as women. The incidence of gender dysphoria is estimated to be around 1% of the population. Gender dysphoria may be associated with depression and low quality of life, which in most cases improves during gender-affirming hormonal treatment (GAHT). Feminizing hormonal treatment for transgender women or gender non-binary people typically includes natural estrogen (estradiol). Additional testosterone-blocking treatment is often needed to ensure the suppression of the pituitary-gonadal axis and may include cyproterone acetate, a gonadotropin-releasing hormone agonist (GnRH-a), or spironolactone. The health risks of cyproterone acetate as anti-androgen treatment are debated and randomized protocols with other anti-androgen treatments are requested. Orchiectomy is performed in some transgender women after various duration of GAHT. Currently, natural progesterone is not recommended as part of GAHT due to limited knowledge on the balance between risks and benefits. In the present article, we discuss evidence regarding established and upcoming feminizing treatment for adult transgender women or gender non-binary people seeking feminization. Data on study populations with transgender women are put into a wider context of literature regarding the effects of sex steroid hormones in cisgender study populations. Relevant follow-up and monitoring during feminizing treatment is debated. The review has a special focus on the pharmacotherapy of feminizing hormonal therapy.

Cyproterone acetate (CPA) has in preliminary studies been linked to the development of meningiomas. Possibly, CPA may induce or increase meningioma growth due to antiandrogen and proprogestin properties, as two-thirds of meningiomas express progesterone and androgen receptors.1 Among individuals assigned male sex at birth, CPA is used to treat prostate cancer, hypersexuality disorder, and as feminising hormone therapy. In individuals assigned female sex at birth, it is used in the treatment of acne, hirsutism, seborrhoea, hair loss and in a low-dose variant in combination with ethinylestradiol in birth control pills.2 A recent cohort study comparing females exposed to high cumulative doses versus low cumulative doses of CPA, found a 6–20 fold increased risk of meningioma.3 Subsequently, the European Medicines Agency’s (EMA) issued a recommendation to restrict CPA to less than 10 milligrams per day.4 In this nationwide study, we assessed national trends in use of CPA and the risk of meningioma according to cumulative exposure to CPA, as compared with non-users. ### Study population In this prospective register-based cohort study, we used nationwide Danish registers to identify all individuals born between 1930 and 2000. Individuals were included in the study at age 15, date of immigration to Denmark or 1 January 1995, whichever came last. Study participants were then followed until a diagnosis of meningioma, neurofibromatosis type 2, death, emigration or 31 December 2017, whichever came first. We excluded individuals with prior meningioma, intracranial surgery, neurofibromatosis type 2 or who died before inclusion. Spinal or cerebral meningioma was the event of interest, defined using diagnosis codes in the National Patient Register or the Cancer Register (details in online supplemental file, …

Background Polycystic ovary syndrome (PCOS) affects up to 18% of reproductive-age females. The prevalence of obesity in PCOS patients reaches up to 80%, which is 2-fold higher than the general population. Objective The present study aimed to compare the effectiveness of 55 pharmacological interventions across 17 different outcomes in overweight/obese PCOS patients with hyperandrogenism manifestations for both short- and long-term follow-ups. A comprehensive literature search was performed on PubMed, Scopus, Embase, Science Direct, Web of Science, and Cochrane CENTRAL for randomized controlled trials comparing any conventional pharmacological intervention as a monotherapy or a combination in overweight/obese patients with polycystic ovary syndrome and hyperandrogenism manifestations. Extracted data included three main parameters; I. Anthropometric parameters (BMI, Waist and Hip circumferences, and Waist/HIP ratio), II. Hormonal parameters (FSH, LH, FSG, SHBG, Estradiol, Total Testosterone, Free testosterone, DHEAS, Androstenedione), and III. Metabolic parameters (Total Cholesterol, LDL-C, HDL-C, Triglycerides, Fasting glucose, Fasting glucose, HOMA-IR). Critical appraisal and risk of bias assessments were performed using the modified Jadad scale, and the overall quality of this network meta-analysis was evaluated according to the CINeMA framework. We performed both a pairwise meta-analysis and a network meta-analysis to evaluate the effect sizes with 95% CI, and we calculated the surface under the cumulative ranking curve (SUCRA) for each intervention. Results Our final search on May 15th 2021 retrieved 23,305 unique citations from searching six electronic databases. Eventually, 101 RCTs of 108 reports with a total of 8,765 patients were included in our systematic review and multi-treatments meta-analysis. 55 different interventions were included: 22 monotherapies, and 33 combinations. The two-dimensional cluster ranking of the average SUCRA values for metabolic and hormonal parameters with significant estimates revealed flutamide (77.5%, 70%; respectively) as the highest and rosiglitazone (38.2%, 26.3%; respectively) as the lowest, in terms of the overall efficacy in reducing weight and hyperandrogenism. However, cyproterone-acetate+ethinylestradiol exhibited a higher ranking in improving hormonal parameters (71.1%), but even a lower-ranking regarding metabolic parameters (34.5%). Conclusions and relevance Current evidence demonstrated the superiority of flutamide in improving both metabolic and hormonal parameters, and the higher efficacy of cyproterone-acetate+ethinylestradiol only in improving hormonal parameters. Nearly all interventions were comparable in female hormones, FGS, HDL, glucose, and insulin levels improvements.

Case Presentation A 30-year-old transgender woman who was HIV positive presented to the ED with progressive severe dyspnea and hemoptysis that started 1 day earlier. The patient was undergoing antiretroviral therapy with emtricitabine-rilpivirine-tenofovir with good compliance and feminizing hormone therapy with cyproterone acetate. She was otherwise healthy and was not taking any other medications.

Prostate cancer is one of the most common cancer in males. Both the incidence and the mortality rates of prostate cancer show an increasing trend. Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer. The aim of our study was to show the epidemiology of prostate cancer and the proportion of patients utilizing ADT. This study used Taiwan's National Health Insurance Research Database (NHIRD) and identified the patients who had been diagnosed with prostate cancer (International Classification of Disease (ICD)-10: C61) and followed up between Jan 1, 2008 and Dec 31, 2015. The ADT drugs used by prostate cancer patients were recorded: Gonadotropin-releasing hormone (GnRH) agonists; GnRH antagonist; estrogen analogs and androgen receptor antagonist. A total of 25,233 patients with newly diagnosed prostate cancer in 2008–2014 were enrolled. The utilization of ADT increased from more than 7,000 person-time in 2008 to more than 50,000 person-time in 2014. Cyproterone acetate was the most commonly used drug in 2008–2015, but its proportion of utilization, which was the highest in stage 2 cancer, dropped from 43% in 2008 to 15% in 2015. Bicalutamide was the second most used drug from 2008 to 2015, but its utilization was not different for different stages. The incidence rate of prostate cancer increased in the study period and medical expenditure also increased in ADT treatment. Health insurance benefits for various ADT drugs should be further evaluated.

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.

Hormone-associated meningiomas tend to stop growing or decrease in size after cessation of certain progestins, mainly cyproterone acetate. We report three observations on the natural history of hormone-associated intraosseous meningiomas, showing in a first patient that those tumors may grow rapidly under nomegestrol. We then demonstrate the sustained growth of intraosseous hormone-associated meningiomas after cessation of promesgestone and nomegestrol, independently of the intracranial portion, which concurrently decreased in size in the second case or was resected at the time of nomegestrol withdrawal in the third case, thus giving new insights into the tumorigenesis mechanisms of hormone-associated intraosseous meningiomas.

Antiandrogens are frequently used with estradiol in transgender women seeking feminization. Antiandrogens act by various mechanisms to decrease the production or effects of testosterone, but it is unclear which antiandrogen is most effective at feminization. A systematic review was performed using PRISMA guidelines. We searched online databases (Medline, Embase and PsycINFO) and references of relevant articles for studies of antiandrogens in transgender women aged 16+ years to achieve feminization (namely changes in breast size, body composition, facial or body hair) or changes in serum total testosterone concentration when compared to placebo, estradiol alone or an alternative antiandrogen. Four studies fulfilled eligibility criteria and were included in a narrative review. The addition of cyproterone acetate, leuprolide and medroxyprogesterone acetate may be more effective than spironolactone or estradiol alone at suppressing the serum total testosterone concentration. Body composition changes appear similar in transgender women treated with estradiol and additional cyproterone acetate or leuprolide. No eligible studies adequately evaluated the effects of antiandrogens on breast development or facial and body hair reduction. It remains unclear which antiandrogen is most effective at achieving feminization. Cyproterone acetate, medroxyprogesterone acetate and leuprolide may be more effective than spironolactone at suppressing the serum total testosterone concentration. However, due to spironolactone's antagonism of the androgen receptor, it is unclear whether this results in clinically meaningful differences in feminization. Further research with clinically meaningful endpoints is needed to optimize the use of antiandrogens in transgender women.

Introduction: Postmenopausal osteoporosis (PMOP), which is a common and frequently occurring age-related metabolic bone disease in perimenopausal women, severely affects patients living quality. Modern medicine therapies for PMOP have several problems such as side reactions, low compliance, and high costs. Thus, nonpharmacological modality is urgently needed. Although acupoint thread embedding treatment is widely used in clinical practice, there is no persuasive evidence of its effect on increasing bone mass for PMOP. This experiment aims to investigate the efficacy and safety of acupoint thread embedding on PMOP and elucidate the correlations among brain neural activation, bone mineral density (BMD), and clinical outcomes with magnetic resonance evidence, thus to explore its neural mechanism. Methods: This parallel designed, exploratory randomized, controlled, assessor-statistician-blinded, positive medicine clinical trial will include 70 participants with PMOP recruited from 2 traditional Chinese Medicine hospitals. These participants will be randomly allocated to a treatment group (Group Embedding) and a control group (Group Medication) in a 1:1 ratio. Participants in the treatment group will receive acupoint thread embedding treatment once 2 weeks in the following predefined acupoints: Shenshu (BL23), Sanyinjiao (SP6), Guanyuan (RN4), Ganshu (BL18), Dazhu (BL11), Xuanzhong (GB39), Zusanli (ST36), and Pishu (BL20). Meanwhile, the participants in the control group will take 0.3 mg Climen tablet orally, 1 tablet/day; every month has a schedule of the 21-day-continuous-taking-medicine period, and 7-day tablet-free period. There is a study period of 3 months and a follow-up period of 1 month for each group. The primary outcomes will be the following therapeutic indexed: Short-Form of McGill Pain Questionnaire (SF-MPQ), Osteoporosis Symptom Score during the observation period and follow-up period. The secondary outcomes will be Osteoporosis Quality of Life Scale (OQOLS), 16-item Assessment of Health-Related Quality of Life in Osteoporosis. In addition, functional magnetic resonance imaging (fMRI) scans and bone density test will be done before and after the observation period to show cranial neuroimaging changes. All the outcomes will be evaluated before and after treatment. The safety of interventions will be assessed at every visit. Discussion: We present study design and rationale to explore the effectiveness and neural mechanism of acupoint thread embedding for PMOP through these outcomes. Trial registration: Chinese Clinical Trial Registry, ChiCTR-INR-17011491.

A decrease in high-density lipoprotein (HDL)-cholesterol concentrations during transgender hormone therapy has been shown. However, the ability of HDL to remove cholesterol from arterial wall macrophages, termed cholesterol efflux capacity (CEC), has proven to be a better predictor of cardiovascular disease (CVD) largely independently of HDL-concentrations. In addition, the serum capacity to load macrophages with cholesterol (cholesterol loading capacity, CLC) represents an index of pro-atherogenic potential. As transgender individuals are exposed to lifelong exogenous hormone therapy (HT), it becomes of interest to study whether HDL-CEC and serum CLC are affected by HT. HDL-CEC and serum CLC have been evaluated in 15 trans men treated with testosterone and in 15 trans women treated with estradiol and cyproterone acetate at baseline and after 12 months of HT.Total HDL-CEC from macrophages and its major contributors, the ATP-binding cassette transporters (ABC) A1 and ABCG1 HDL-CEC and HDL-CEC by aqueous diffusion were determined by a radioisotopic assay. CLC was evaluated in human THP-1 macrophages.In trans women, total HDL-CEC decreased by 10.8% (95%CI: -14.3;-7.3; p 0.001), ABCA1 HDL-CEC by 23.8% (-34.7; -12.9; p 0.001) and aqueous diffusion HDL-CEC by 4.8% (-8.4;-1.1; p 0.01). In trans men, only aqueous diffusion HDL-CEC decreased significantly, -9.8% (-15.7;-3.9; p 0.01). ABCG1 HDL-CEC did not change in either group. Serum CLC and HDL subclass distribution were not modified by HT in both groups.Total HDL-CEC decreased during HT in trans women, with a specific reduction in ABCA1 CEC. This finding might contribute to a higher CVD risk.

Objective Meningiomas have a female predilection, which is even stronger for spinal than for intracranial meningiomas. The relationship between meningiomas and endogenous or exogenous sex hormones such as cyproterone acetate (CPA) is well documented, yet their underlying mechanism remains unknown. Clarification of the expression profile of hormonal receptors by meningiomas would help us to better understand their hormonal susceptibility. Methods We used tissue microarray and immunohistochemistry to determine the receptor status of the 3 main sex hormones: androgen (AR), estrogen, and progesterone (PR) in 30 intracranial meningiomas, 30 spinal meningiomas, and 30 meningiomas developed on CPA. Results AR status was positive in 73% of meningiomas in the intracranial group, 87% of meningiomas in the CPA group, and in all meningiomas in the spinal group. Estrogen status was positive in only 7% of meningiomas in the intracranial group and in only 3% of meningiomas in the CPA group but in 30% of meningiomas in the spinal group. PR status was positive in 90% of meningiomas in the intracranial group, in 97% of meningiomas in the CPA group, and in 87% of meningiomas in the spinal group. These specific hormonal receptor statuses based on immunoreactive score were reflected on staining intensities. Furthermore, AR and PR expression was correlated in each group. Conclusions Our study shows that intracranial meningiomas, spinal meningiomas, and meningiomas developed on CPA express specific hormonal receptor patterns. This result invites the scientific community to review the potential role of AR in the unbalanced sex ratio of meningiomas.

International audience; ObjectiveThe great heterogeneity of meningiomas is challenging and we need to distinguish relevant subgroups. Spheno-orbital osteomeningiomas (SOOM) constitute a clinically specific entity, with slow-growing benign osteo-meningiomatous tumors, which recur after surgery in one fourth of cases. Neurosurgical daily practice, supported by the literature, shows that the vast majority of patients with SOOM are women, and we explored whether their epidemiological and hormonal profiles suggest a progesterone influence.MethodsWe retrospectively documented all radiologically and histologically confirmed cases of SOOM operated in 2005–2019 in our institution. We completed the clinical and hormone history by systematic telephone interviews.ResultsIn the literature, SOOM occur significantly more often in women than other meningiomas (749/847, 86.4% versus 73.8%, p = 0.002). Among 175 cases, we included 124 patients, 93.5% were women, younger than men (51 ± 5 versus 63 ± 8, p = 0.02). Women’ meningiomas showed more progesterone receptors (96.4% versus 50%, p

Background: This study aims to assess the therapeutic effects of a well-known component (puerarin) obtained from a Chinese herb root in patients with polycystic ovary syndrome (PCOS). Methods: Women with premature ovarian failure (POF) were assigned to the obese group (body mass index [BMI] ≥24 kg/m2 and waist hip ratio [WHR] >0.85) or non-obese group (group 3, n = 21). Obese patients were further randomly assigned to the obese treatment group (group 1, n = 15) and obese control group (group 1, n = 15). All patients received standard treatment (Diane-35, 1 tablet/d, orally, plus metformin, 1.5 g/d, orally). In addition to the standard modality, patients in group 1 and group 3 also orally received 150 mg/d of puerarin tablets for 3 months. Venous blood was drawn before and after treatment. Then, the metabolic and antioxidant biomarkers were measured. The normality of distribution of the data was tested using the Kolmogorov–Smirnov method. The baseline characteristics were analyzed using one-factor analysis of variance (ANOVA), and post-hoc was performed using the least significance difference (LSD)-t test. Results: Significantly improved blood levels of sex hormone binding globulin (SHBG) and superoxide dismutase (SOD) were observed in patients who received the additional treatment of puerarin, regardless of their lean or obese status, while these were not observed in patients who did not receive puerarin. Furthermore, obese patients with PCOS had significantly lower systolic blood pressure, total cholesterol, and testosterone blood levels, when compared with before treatment. Conclusion: The addition of puerarin to the present treatment protocol can be considered for the management of metabolic disorders and hyperandrogenism in PCOS patients.

Background Long-term use of high-dose progestin is known to promote the development of meningioma. Atypical meningioma in a patient under progestin has not previously been reported. Case report A 53-year-old right-handed woman presented with focal onset seizures, without impaired consciousness. Medical history featured endometriosis, treated successively by cyproterone acetate 25 mg/day for 2 months then 50 mg/day for 101 months, and chlormadinone acetate 5 mg/day for 68 months then 10 mg/day for 83 months. Brain MRI revealed multiple extra-axial lesions suggestive of left central meningioma associated with anterior skull base meningiomatosis. Surgical resection of the left central meningioma was achieved and progestin was withdrawn. Neuropathology diagnosed grade II atypical meningioma. Close clinical and imaging monitoring was implemented without adjuvant oncological treatment. At 25 months, imaging follow-up showed no recurrence of the left central meningioma and a significant regression of all other lesions, except for the right frontal lesion. Conclusions Neurosurgeons should be aware of the possible aggressiveness of meningioma in patients under progestin, and particularly those treated by different types of progestin over a long period of time without interruption. This may require systematic close monitoring, to adapt neurosurgical management.

Intermittent androgen deprivation therapy with gonadotropin-releasing-hormone (GnRH) agonists can prevent or delay disease progression and development of castration resistant prostate cancer for subpopulations of prostate cancer patients. It may also reduce risk and severity of side effects associated with chemical castration in prostate cancer (PCa) patients. One of the earliest comprehensively documented clinical trials on this was reported in a Canadian patient population treated with leuprorelin preceded by a lead-in with cyproterone acetate. A systems-based mixed effect analysis of testosterone response in active and recovery phases allows inference of new information from this patient population. Efficacy of androgen deprivation therapy is presumed to depend on a treshold value for testosterone at the nadir, below which no additional beneficial effects on PSA reponse can be expected, and occurance of testosterone breakthroughs during active therapy. The present analysis results in a mixed effect model, incorporating GnRH receptor activation, testosterone turnover and feedback mechanisms, describing and predicting testosterone inhibition under intermittent androgen deprivation therapy on the individual and population level, during multiple years of therapy. Testosterone levels in these patients decline over time with an estimated first order rate constant of 0.083 year−1(T1/2 = 8.4 y), with a substantial distribution among this patient population, compared to the general population. PCa patients leaving the trial due to unmanageble PSA relapse appear to have slightly higher testosterone levels at the nadir than sustained responders. These findings are expected to contribute to an increased understanding of the role of testosterone in long term disease progression of prostate cancer.

STUDY QUESTION Does gender-affirming treatment prevent full spermatogenesis in transgender women (TW)? SUMMARY ANSWER Adequate hormonal therapy (HT) leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. WHAT IS KNOWN ALREADY Gender-affirming treatment in transgender individuals may involve gender-affirming HT. The effects on spermatogenesis in TW remain unclear. In order to add information from a referral centre for transgender care, we wish to compare results of earlier studies with our population of TW who received a standard hormone treatment. STUDY DESIGN, SIZE, DURATION This was a prospective cohort study part of the European Network for the Investigation of Gender Incongruence (ENIGI), conducted between 15 February 2010 and 30 September 2015. There were 162 TW were included in the ENIGI study at the Ghent University Hospital in Belgium. Participants are included in ENIGI when they first start HT, and follow-up visits occur over the next 3 years. PARTICIPANTS/MATERIALS, SETTING METHODS The study included 97 TW who initiated HT with cyproterone acetate (CPA) plus oestrogens and proceeded with gonadectomy at the Ghent University Hospital. Testicular tissue retrieved during gonadectomy was processed and stained for four different germ cell markers by the Biology of the Testis lab at the Vrije Universiteit Brussel. Subsequent immunohistochemical staining was performed for melanoma-associated antigen A4 (MAGE-A4, marker for spermatogonia and early spermatocytes), boule homologue, RNA-binding protein (BOLL, marker for secondary spermatocytes and round spermatids), cAMP-responsive element modulator (CREM, marker for round spermatids) and acrosin (marker for acrosome visualization). Serum levels of sex steroids were measured prior to surgery. MAIN RESULTS AND THE ROLE OF CHANCE Suppressed testosterone levels ( LIMITATIONS, REASONS FOR CAUTION Testicular function of the participants prior to initiation of HT was not assessed, although all participants presented with cisgender male serum testosterone values before initiation of HT. The current study only reports on people using CPA at a fixed dose and may therefore not be applicable to all TW. WIDER IMPLICATIONS OF THE FINDINGS HT leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. Serum testosterone levels are associated with the sperm maturation rate. It is important to discuss sperm preservation before the start of hormone therapy. If serum testosterone levels remain higher, spermatogenesis may still occur. STUDY FUNDING/COMPETING INTEREST(S) D.V.S. is a post-doctoral fellow of the Fonds Wetenschappelijk Onderzoek (FWO; 12M2819N). Processing of the testis specimens was funded by the Biology of The Testes (BITE) research group (Department of Reproduction, Genetics and Regenerative medicine at Vrije Universiteit Brussel (VUB)). There are no competing interests. TRIAL REGISTRATION NUMBER N/A.