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Management of patients with congenital adrenal hyperplasia (CAH) poses challenges during pregnancy and prenatal stages, impacting fertility differently in men and women. Women with CAH experience menstrual irregularities due to androgen and glucocorticoid precursor interference with endometrial development and ovulation. Genital surgeries for virilization and urogenital anomalies further impact fertility and sexual function, leading to reduced heterosexual relationships among affected women. Fertility rates vary, with a lower prevalence of motherhood, primarily among those with classic CAH, necessitating optimized hormonal therapy for conception. Monitoring optimal disease control during pregnancy poses challenges due to hormonal fluctuations. Men with CAH often experience hypogonadotrophic hypogonadism and complications like testicular adrenal rest tissue, impacting fertility. Regular monitoring and intensified glucocorticoid therapy may restore spermatogenesis. Genetic counselling is vital to comprehend transmission risks and prenatal implications. Prenatal dexamethasone treatment in affected female fetuses prevents virilization but raises ethical and safety concerns, necessitating careful consideration and further research. The international "PREDICT" study aims to establish safer and more effective prenatal therapy in CAH, evaluating dosage, safety, and long-term effects., (© 2024 John Wiley & Sons Ltd.)

Background: Limited data exists regarding gender-specific microbial alterations during gender-affirming hormonal therapy (GAHT) in transgender individuals. This study aimed to investigate the nuanced impact of sex steroids on gut microbiota taxonomy and function, addressing this gap. We prospectively analyzed gut metagenome changes associated with 12 weeks of GAHT in trans women and trans men, examining both taxonomic and functional shifts., Methods: Thirty-six transgender individuals (17 trans women, 19 trans men) provided pre- and post-GAHT stool samples. Shotgun metagenomic sequencing was used to assess the changes in gut microbiota structure and potential function following GAHT., Results: While alpha and beta diversity remained unchanged during transition, specific species, including Parabacteroides goldsteinii and Escherichia coli, exhibited significant abundance shifts aligned with affirmed gender. Overall functional metagenome analysis showed a statistically significant effect of gender and transition (R 2  = 4.1%, P = 0.0115), emphasizing transitions aligned with affirmed gender, particularly in fatty acid-related metabolism., Conclusions: This study provides compelling evidence of distinct taxonomic and functional profiles in the gut microbiota between trans men and women. GAHT induces androgenization in trans men and feminization in trans women, potentially impacting physiological and health-related outcomes., Trial Registration: Clinicaltrials.gov NCT02185274., (© 2024. The Author(s).)

Background: Subfertility is prevalent in men with classic 21-hydroxylase deficiency (21OHD). We sought to characterize the long-term evolution of their gonadal function., Methods: Retrospective longitudinal single-center study in 27 men (11 with testicular adrenal rest tissue [TART]), median observation period 12 years, testosterone (T), 11-oxygenated androgens, gonadotropins, and inhibin B measurement at each time point., Results: T concentrations were below the normal range (n.s.) in 43.2% (no TART) and 54.6% (TART) per patient. After accounting for body mass index, sex hormone-binding globulin, and age, men with TART exhibited higher T (14.0 ± 0.80 nmol/L) than those without (11.9 ± 0.71 nmol/L). During the observation period, T levels rose in both groups but more in men with TART (from 10.1 ± 1.1 to 17.3 ± 1.9 nmol/L vs 10.3 ± 1.0 to 12.8 ± 1.9 nmol/L); this was accompanied by rising luteinizing hormone and diminishing hydrocortisone equivalent dosages (TART: from 38.1 ± 3.2 to 35.1 ± 1.8 mg/d; vs no TART: 28.8 ± 2.7 to 28.1 ± 1.6 mg/d) without correlation with any markers of adrenal androgen control. Inhibin B declined in men with large TART over time while TART status remained stable., Conclusion: T levels below the normal range are frequent in men with 21OHD, regardless of TART, but change little over time. Besides adrenal androgen control gonadal axis suppression from supraphysiological glucocorticoid dosages needs to be considered. While our results do not endorse regular screening for alterations in TART status among adults, Sertoli cell function should be monitored in men with large TART., Competing Interests: Conflict of interest: All authors declare no conflict of interest. Co-author N.R. is on the editorial board of EJE. She was not involved in the review or editorial process for this paper, on which she is listed as author., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: OpenAI's ChatGPT is a pioneering artificial intelligence (AI) in the field of natural language processing, and it holds significant potential in medicine for providing treatment advice. Additionally, recent studies have demonstrated promising results using ChatGPT for emergency medicine triage. However, its diagnostic accuracy in the emergency department (ED) has not yet been evaluated., Objective: This study compares the diagnostic accuracy of ChatGPT with GPT-3.5 and GPT-4 and primary treating resident physicians in an ED setting., Methods: Among 100 adults admitted to our ED in January 2023 with internal medicine issues, the diagnostic accuracy was assessed by comparing the diagnoses made by ED resident physicians and those made by ChatGPT with GPT-3.5 or GPT-4 against the final hospital discharge diagnosis, using a point system for grading accuracy., Results: The study enrolled 100 patients with a median age of 72 (IQR 58.5-82.0) years who were admitted to our internal medicine ED primarily for cardiovascular, endocrine, gastrointestinal, or infectious diseases. GPT-4 outperformed both GPT-3.5 (P<.001) and ED resident physicians (P=.01) in diagnostic accuracy for internal medicine emergencies. Furthermore, across various disease subgroups, GPT-4 consistently outperformed GPT-3.5 and resident physicians. It demonstrated significant superiority in cardiovascular (GPT-4 vs ED physicians: P=.03) and endocrine or gastrointestinal diseases (GPT-4 vs GPT-3.5: P=.01). However, in other categories, the differences were not statistically significant., Conclusions: In this study, which compared the diagnostic accuracy of GPT-3.5, GPT-4, and ED resident physicians against a discharge diagnosis gold standard, GPT-4 outperformed both the resident physicians and its predecessor, GPT-3.5. Despite the retrospective design of the study and its limited sample size, the results underscore the potential of AI as a supportive diagnostic tool in ED settings., (©John Michael Hoppe, Matthias K Auer, Anna Strüven, Steffen Massberg, Christopher Stremmel. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 08.07.2024.)

Objective: Patients with congenital adrenal hyperplasia (CAH) require life-long glucocorticoid replacement, including stress dosing (SD). This study prospectively assessed adrenal crisis (AC) incidence, frequency, and details of SD and disease knowledge in adult and paediatric patients and their parents., Design: Prospective, observational study., Methods: Data on AC and SD were collected via a patient diary. In case of AC, medical records were reviewed and patient interviews conducted. Adherence to sick day rules of the German Society of Endocrinology (DGE) and disease knowledge using the German version of the CAH knowledge assessment questionnaire (CAHKAQ) were assessed., Results: In 187 adult patients, the AC incidence was 8.4 per 100 patient years (py) and 5.1 in 100 py in 38 children. In adults, 195.4 SD episodes per 100 py were recorded, in children 169.7 per 100 py. In children 72.3% and in adults 34.8%, SD was performed according to the recommendations. Children scored higher on the CAHKAQ than adults (18.0 [1.0] vs 16.0 [4.0]; P = .001). In adults, there was a positive correlation of the frequency of SD and the incidence of AC (r = .235, P = .011) and CAHKAQ score (r = .233, P = .014), and between the incidence of AC and CAHKAQ (r = .193, P = .026)., Conclusion: The AC incidence and frequency of SD in children and adults with CAH are high. In contrast to the paediatric cohort, the majority of SD in adults was not in accordance with the DGE recommendations, underlining the need for structured and repeated education of patients with particular focus on transition., Competing Interests: Conflict of interest: All authors declare no conflict of interest. Co-author N.R. is on the editorial board of EJE. She was not involved in the review or editorial process for this paper, on which she is listed as author., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Estradiol (E2) has been implicated in sexual functioning in both sexes. E2 levels change distinctively over the menstrual cycle, peaking around ovulation. Data on short-term effects of fluctuating E2 levels on sexual desire are however sparse and mostly based on observational studies. To fill this gap, we ran a double-blind, randomized, placebo-controlled study (N = 126) to investigate the effects of a short-term increase in E2 on sexual desire and orgasm frequency in healthy, young men and women. Circulating E2 levels were elevated through estradiol valerate (E2V) administered over two consecutive days to simulate the rise in E2 levels around ovulation. E2V had no effect on orgasm frequency and only minor effects on sexual desire. On average, the administered E2V dampened change in sexual desire compared to untreated participants with comparable baseline sexual desire in such a way that sexual desire was slightly reduced even in those with higher baseline sexual desire. These findings suggest that short-term increases in E2 have little effect on sexual function and are unlikely to explain the increase in sexual desire around ovulation., Competing Interests: Declaration of Competing Interest The authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: E47 has been identified as a modulating transcription factor of glucocorticoid receptor target genes, its loss protecting mice from metabolic adverse effects of glucocorticoids. We aimed to analyze the role of E47 in patients with endogenous glucocorticoid excess [Cushing's syndrome (CS)] and its association with disorders of lipid and glucose metabolism., Methods: This is a prospective cohort study including 120 female patients with CS (ACTH-dependent = 79; ACTH-independent = 41) and 26 healthy female controls. Morning whole blood samples after an overnight fast were used to determine E47 mRNA expression levels in patients with overt CS before and 6-12 months after curative surgery. Expression levels were correlated with the clinical phenotype of the patients. Control subjects underwent ACTH stimulation tests and dexamethasone suppression tests to analyze short-term regulation of E47., Results: E47 gene expression showed significant differences in patient cohorts with overt CS vs. patients in remission ( p = 0.0474) and in direct intraindividual comparisons pre- vs. post-surgery ( p = 0.0353). ACTH stimulation of controls resulted in a significant decrease of E47 mRNA expression 30 min after i.v. injection compared to baseline measurements. Administration of 1 mg of dexamethasone overnight in controls did not change E47 mRNA expression. E47 gene expression showed a positive correlation with total serum cholesterol ( p = 0.0036), low-density lipoprotein cholesterol ( p = 0.0157), and waist-arm ratio ( p = 0.0138) in patients with CS in remission., Conclusion: E47 is a GC-dependent gene that is upregulated in GC excess potentially aiming at reducing metabolic glucocorticoid side effects such as dyslipidemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Nowotny, Theodoropoulou, Simon, Hemmer, Bidlingmaier, Auer, Reincke, Uhlenhaut and Reisch.)

Introduction: Patients with primary adrenal insufficiency (PAI) suffer from increased risk of infection, adrenal crises and have a higher mortality rate. Such dismal outcomes have been inferred to immune cell dysregulation because of unphysiological cortisol replacement. As the immune landscape of patients with different types of PAI has not been systematically explored, we set out to immunophenotype PAI patients with different causes of glucocorticoid (GC) deficiency., Methods: This cross-sectional single center study includes 28 patients with congenital adrenal hyperplasia (CAH), 27 after bilateral adrenalectomy due to Cushing's syndrome (BADx), 21 with Addison's disease (AD) and 52 healthy controls. All patients with PAI were on a stable GC replacement regimen with a median dose of 25 mg hydrocortisone per day. Peripheral blood mononuclear cells were isolated from heparinized blood samples. Immune cell subsets were analyzed using multicolor flow cytometry after four-hour stimulation with phorbol myristate acetate and ionomycin. Natural killer (NK-) cell cytotoxicity and clock gene expression were investigated., Results: The percentage of T helper cell subsets was downregulated in AD patients (Th1 p = 0.0024, Th2 p = 0.0157, Th17 p < 0.0001) compared to controls. Cytotoxic T cell subsets were reduced in AD (Tc1 p = 0.0075, Tc2 p = 0.0154) and CAH patients (Tc1 p = 0.0055, Tc2 p = 0.0012) compared to controls. NKCC was reduced in all subsets of PAI patients, with smallest changes in CAH. Degranulation marker CD107a expression was upregulated in BADx and AD, not in CAH patients compared to controls (BADx p < 0.0001; AD p = 0.0002). In contrast to NK cell activating receptors, NK cell inhibiting receptor CD94 was upregulated in BADx and AD, but not in CAH patients (p < 0.0001). Although modulation in clock gene expression could be confirmed in our patient subgroups, major interindividual-intergroup dissimilarities were not detected., Discussion: In patients with different etiologies of PAI, distinct differences in T and NK cell-phenotypes became apparent despite the use of same GC preparation and dose. Our results highlight unsuspected differences in immune cell composition and function in PAI patients of different causes and suggest disease-specific alterations that might necessitate disease-specific treatment., Competing Interests: SK has received honoraria from TCR2 Inc, Novartis, BMS and GSK. SK is inventor of several patents in the field of immuno-oncology. SK received license fees from TCR2 Inc and Carina Biotech. A.G. received research support from Tabby Therapeutics for work unrelated to the manuscript. SK received research support from TCR2 Inc., Plectonic GmbH and Arcus Bioscience for work unrelated to the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Nowotny, Marchant Seiter, Ju, Gottschlich, Schneider, Zopp, Vogel, Tschaidse, Auer, Lottspeich, Kobold, Rothenfusser, Beuschlein, Reincke, Braun and Reisch.)

It has been postulated that in patients with congenital adrenal hyperplasia (CAH) with salt wasting (SW), fludrocortisone needs might be higher in those on synthetic glucocorticoid replacement therapy in comparison to conventional hydrocortisone due to the lower mineralocorticoid activity. Here we report the results of a cross-sectional single center study comparing mineralocorticoid needs between patients taking synthetic glucocorticoids (S-GC) (N = 24) and those on conventional hydrocortisone (HC) (N = 16). We could show that while both groups took comparable HC-equivalent dosages, there was no significant difference in FC dosage (GC: 0.075 mg; IQR 0.05-0.1; HC: 0.1 mg; IQR 0.05-0.1; p = 0.713). Although there was a trend for higher renin levels in the S-GC group (67.1 µU/ml; IQR 40.5-113.9 vs. 40.4 IQR 14.2-73.1; p = 0.066), this failed to reach significance. With regard to blood pressure, those taking S-GC had even significantly elevated mean systolic (125.0 mmHg, IQR 117.5-130.0 vs 116.5 mmHg IQR 111.8-124.8; p = 0.036) and diastolic (78.0 mmHg, IQR 74.3-83.8 vs 74.5mmHG, IQR 69.3-76.0; p = 0.044) during the day. Systolic dipping was however more pronounced in those on GC in comparison to those taking HC (11.3%; IQR 8.7-14.6 vs. 6.4 IQR 3.4-12.7; p = 0.031). In conclusion, we could show in this small, albeit well-balanced cohort that mineralocorticoid dosage does not significantly differ between patients receiving synthetic glucocorticoids or conventional hydrocortisone. Higher blood pressure values despite the tendency for higher renin levels in those on S-GC support the notion that the assessment of MR adequacy should be guided by the clinical picture and blood pressure on a regular basis., Competing Interests: Declaration of Competing Interest All authors have declared that no conflict of interest exists., (Copyright © 2023. Published by Elsevier Ltd.)

First-trimester prenatal treatment with glucocorticoid (GC) dexamethasone (DEX) in pregnancies at risk for classic congenital adrenal hyperplasia (CAH) is associated with ethical dilemmas. Though effective in reducing virilisation in girls with CAH, it entails exposure to high doses of GC in fetuses that do not benefit from the treatment. The current paper provides an update on the literature on outcomes of prenatal DEX treatment in CAH cases and unaffected subjects. Long-term follow-up research is still needed to determine treatment safety. In addition, advances in early prenatal diagnostics for CAH and sex-typing as well as studies assessing dosing effects of DEX may avoid unnecessary treatment and improve treatment safety.

Congenital adrenal hyperplasia is a group of autosomal recessive disorders leading to multiple complex hormonal imbalances caused by various enzyme deficiencies in the adrenal steroidogenic pathway. The most common type of congenital adrenal hyperplasia is due to steroid 21-hydroxylase (21-OHase, henceforth 21OH) deficiency. The rare, classic (severe) form caused by 21OH deficiency is characterised by life-threatening adrenal crises and is the most common cause of atypical genitalia in neonates with 46,XX karyotype. After the introduction of life-saving hormone replacement therapy in the 1950s and neonatal screening programmes in many countries, nowadays neonatal survival rates in patients with congenital adrenal hyperplasia are high. However, disease-related mortality is increased and therapeutic management remains challenging, with multiple long-term complications related to treatment and disease affecting growth and development, metabolic and cardiovascular health, and fertility. Non-classic (mild) forms of congenital adrenal hyperplasia caused by 21OH deficiency are more common than the classic ones; they are detected clinically and primarily identified in female patients with hirsutism or impaired fertility. Novel treatment approaches are emerging with the aim of mimicking physiological circadian cortisol rhythm or to reduce adrenal hyperandrogenism independent of the suppressive effect of glucocorticoids., Competing Interests: Declaration of interests NR is a Principal Investigator of clinical trials sponsored by Diurnal, Spruce Biosciences, and Neurocrine Biosciences at the Medizinische Klinik IV, Klinikum der Universität München, Munich, Germany, and reports scientific consultancy fees from Diurnal, Spruce Biosciences, and Neurocrine Biosciences. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Central Diabetes Insipidus (CDI) is mainly associated with structural pathologies of the hypothalamic-pituitary area. Etiologies underlying CDI are identified in most patients, however idiopathic CDI is reported in 13-17% of cases after excluding other etiologies. The Hypopituitarism ENEA Rare Observational Study (HEROS study) retrospectively collected data of patients with idiopathic CDI from 14 pituitary centers in 9 countries. The cohort included 92 patients (59 females 64%), mean age at diagnosis was 35.4 ± 20.7 years, and a mean follow up of 19.1 ± 13.5 years following CDI diagnosis. In 6 women, diagnosis was related to pregnancy. Of 83 patients with available data on pituitary imaging, 40(48%) had normal sellar imaging, and 43(52%) had pathology of the posterior pituitary or the stalk, including loss of the bright spot, posterior pituitary atrophy or stalk enlargement. Anterior pituitary hormone deficiencies at presentation included hypogonadism in 6 (6.5%) patients (5 females), and hypocortisolism in one; during follow-up new anterior pituitary deficiencies developed in 6 patients. Replacement treatment with desmopressin was given to all patients except one, usually with an oral preparation. During follow up, no underlying disease causing CDI was identified in any patient. Patients with idiopathic CDI following investigation at baseline are stable with no specific etiology depicted during long-term follow-up., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: In this study we evaluate sleep patterns of patients treated for non-secreting intra- and parasellar tumors and age- and sex-matched healthy controls., Methods: We conducted a self-report cross-sectional case-control study with 104 patients treated for non-secreting intra- and parasellar tumors and 1800 healthy controls in an 1:8 matching. All subjects answered the Munich ChronoType Questionnaire, whereas patients were provided the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale, the Short-Form 36 Health survey, the Beck Depression Inventory and the State-Trait Anxiety Inventory additionally., Results: Patients treated for non-secreting intra- and parasellar tumors go to bed earlier, fall asleep earlier, need less time to prepare to sleep but also to get up. Additionally, they lie and sleep longer. The subgroup analysis showed that patients with secondary adrenal insufficiency compared to controls experienced shorter daily light exposure and longer sleep latency. Higher hydrocortisone dose (>20mg) was associated with worse score in global, physical and mental health, shorter time to prepare to sleep, earlier sleep onset and longer sleep duration., Conclusion: Our study shows that patients treated for non-secreting intra- and parasellar tumors, even if successfully treated, experience altered sleep patterns compared to controls. We suggest that managing clinicians should enlighten these possible sleep alterations to their patients and use specific questionnaires to document sleep disturbances. Additionally, when treating patients surgically, especially by transcranial approach, damaging the suprachiasmatic nucleus should be avoided. Furthermore, circadian hydrocortisone replacement therapy ideally with dual-release hydrocortisone - if possible, in a dose not more than 20mg daily - that resembles physiological cortisol levels more closely may be beneficial and could improve sleep patterns and sleep-related quality of life., Competing Interests: CW, MA, CJ-S declare no conflict of interest. MS received speakers’ fees by Novartis, Ipsen, Pfizer, consultancy fees by Novartis and research funding by Novartis, Pfizer. AA-K and GS received consultancy fees and/or reimbursements of delegate fees for conferences/educational events and/or travel expenses and/or funding for research projects from Pfizer, Ipsen, Lilly, Shire, Novartis, Sandoz, NovoNordisk, HRA and Recordati., (Copyright © 2022 Wild, Stieg, Stalla, Jung-Sievers, Auer and Athanasoulia-Kaspar.)

Objective: Differentiation of an adrenal from an ovarian source of hyperandrogenemia can be challenging. Recent studies have highlighted the importance of 11-oxygenated C19 steroids to the androgen pool in humans. The aim of this study was to confirm the origin of 11-oxygenated androgens in females and to explore their potential use in the diagnostics of hyperandrogenic disorders., Methods: We measured testosterone and its precursors (dehydroepiandrosterone-sulfate and androstenedione) and 11-oxygenated androgens (11β-hydroxyandrostenedione (11-OHA4) and 11-ketotestosterone (11-KT)) in the periphery, adrenal and ovarian veins in four different cases of hyperandrogenism in females (polycystic ovary syndrome (PCOS), primary bilateral macronodular adrenal hyperplasia, Sertoli-Leydig cell tumor and ovarian steroid cell tumor)., Results: Two patients demonstrate excessive testosterone secretion in neoplastic ovarian tumors which was not paralleled by a significant secretion of 11-oxygenated androgens as determined by adrenal and ovarian vein sampling. In androgen-secreting bilateral adrenal macronodular hyperplasia, steroid profiles were characterized by elevated 11-KT and 11-OHA4 concentrations in adrenal veins and the periphery. In the patient with PCOS, peripheral 11-KT concentrations were slightly elevated in comparison to the other patients, but the 11-KT and 11-OHA4 concentrations were comparable in ovarian veins and in the periphery., Conclusion: This study confirms that 11-OHA4 and 11-KT are not biosynthesized by the ovary. We propose that the testosterone/11-KT ratio as well as 11-OHA4 could help identify predominant adrenal androgen excess and distinguish neoplastic and non-neoplastic ovarian androgen source., Significance Statement: This study confirms that 11β-hydroxyandrostenedione (11-OHA4) and 11-ketotestosterone (11-KT) are not biosynthesized by the human ovary. We propose that the testosterone/11-KT ratio as well as 11-OHA4 could help to identify predominant adrenal androgen excess and distinguish neoplastic and non-neoplastic ovarian androgen source.

Background: Symptoms of hyperandrogenism are common in patients with Cushing's disease (CD), yet they are not sufficiently explained by androgen concentrations. In this study, we analyzed the contribution of 11-oxygenated C19 steroids (11oxC19) to hyperandrogenemia in female patients with CD., Methods: We assessed saliva day profiles in females with CD pre (n = 23) and post (n = 13) successful transsphenoidal surgery, 26 female controls, 5 females with CD treated with metyrapone and 5 treated with osilodrostat for cortisol, cortisone, androstenedione (A4), 11-hydroxyandrostenedione (11OHA4), testosterone (TS), 11-ketotestosterone (11KT), as well as metabolites of classic and 11-oxygenated androgens in 24-h urine. In addition, morning baseline levels of gonadotropins and estradiol, sex hormone-binding globulin, cortisol and dehydroepiandrosterone sulfate (DHEAS) in serum and adrenocorticotrophic hormone in plasma in patients and controls were investigated., Results: Treatment-naïve females with CD showed a significantly elevated area under the curve of 11OHA4 and 11KT in saliva throughout the day compared to controls (11OHA4 mean rank difference (mrd) 18.13, P = 0.0002; 11KT mrd 17.42; P = 0.0005), whereas A4, TS and DHEAS were comparable to controls. Gonadotropin concentrations were normal in all patients with CD. After transsphenoidal surgery, 11oxC19 and their metabolites dropped significantly in saliva (11OHA4 P < 0.0001; 11KT P = 0.0010) and urine (11-oxo-androsterone P = 0.0011; 11-hydroxy-androsterone P < 0.0001), treatment with osilodrostat and metyrapone efficaciously blocked 11oxC19 synthesis., Conclusion: Hyperandrogenemia in CD is predominantly caused by excess of 11oxC19 steroids.

Objective : Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) may have poor quality of life (QoL) and low satisfaction with body appearance. We investigated the influence of the patients' satisfaction with their support on their QoL and body image. Design : Retrospective, comparative, Europe-wide study as part of the multicenter dsd-LIFE study. Methods : 203 women with CAH were included in this study. We investigated the patients' QoL and body image compared to a healthy control group. The patients' satisfaction with their treatment and support in childhood and adolescence as well as in adulthood was assessed by questionnaire and its influence on the patients' body image and QoL was analyzed by multiple regression models. Results : Women with CAH showed worse body image and poorer physical, psychological and social QoL compared to a healthy reference population. The patients' satisfaction with professional care in the last 12 months was a significant positive predictor for all four domains of QoL (psychological, physical, social, environmental). Dissatisfaction with care in childhood and adolescence and with general support through different stages of life was a significant negative predictor for QoL and body image. Conclusions : These results show that women with CAH have poor QoL and body image compared to a healthy reference population. Psychosocial factors such as general and family support, and social interactions with professionals have a substantial impact on QoL and body image in adult females with CAH. This should be taken into account regarding patient care and multimodal therapy.

Anxiety-related behaviours as well as the prevalence of anxiety disorders show a large sex difference in humans. Clinical studies in humans as well as behavioural studies in rodents suggest that estradiol may have anxiolytic properties. In line with this, anxiety symptoms fluctuate with estradiol levels along the menstrual cycle. However, the influence of estradiol on subjective, behavioural, as well as physiological correlates of anxiety has never been systematically addressed in humans. We ran a double-blind, randomized, placebo-controlled study (N = 126) to investigate the effects of estradiol on anxiety in men and women. In healthy volunteers, circulating estradiol levels were elevated through estradiol administration over two consecutive days to simulate the rise in estradiol levels around ovulation. Subjective, behavioral, as well as, physiological correlates of anxiety were assessed using a virtual reality elevated plus-maze (EPM). Estradiol treatment reduced the physiological stress response with blunted heart rate response and lower cortisol levels compared to placebo treatment in both sexes. In contrast, respiration frequency was only reduced in women after estradiol treatment. Behavioural measures of anxiety as well as subjective anxiety on the EPM were not affected by estradiol treatment. In general, women showed more avoidance and less approach behavior and reported higher subjective anxiety levels on the EPM than men. These results highlight the limited anxiolytic properties of circulating levels of estradiol in humans, which influence physiological markers of anxiety but not approach and avoidance behaviour or subjective anxiety levels., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Context: Several studies have highlighted the importance of the 11-oxygenated 19-carbon (11oxC19) adrenal-derived steroids as potential biomarkers for monitoring patients with 21-hydroxylase deficiency (21OHD)., Objective: To analyze circadian rhythmicity of 11oxC19 steroids in saliva profiles and evaluate their relevance as potential monitoring parameters in 21OHD., Design, Setting, and Participants: Cross-sectional single-center study including 59 patients with classic 21OHD (men = 30; women = 29) and 49 body mass index- and age-matched controls (men = 19; women = 30)., Outcome Measures: Salivary concentrations of the following steroids were analyzed by liquid chromatography-tandem mass spectrometry: 17-hydroxyprogesterone (17OHP), androstenedione (A4), testosterone (T), 11β-hydroxyandrostenedione (11OHA4), and 11-ketotestosterone (11KT)., Results: Similar to the previously described rhythmicity of 17OHP, 11OHA4 and 11KT concentrations followed a distinct diurnal rhythm in both patients and controls with highest concentrations in the early morning and declining throughout the day (11-OHA4: mean reduction of hormone concentrations between timepoint 1 and 5 (Δ mean) in male patients = 66%; male controls Δ mean = 83%; female patients Δ mean = 47%; female controls Δ mean = 86%; 11KT: male patients Δ mean = 57%; male controls Δ mean = 63%; female patients Δ mean = 50%; female controls Δ mean = 76%). Significant correlations between the area under the curve for 17OHP and 11KT (rpmale = 0.773<0.0001; rpfemale = 0.737<0.0001), and 11OHA4 (rpmale = 0.6330.0002; rpfemale = 0.5640.0014) were observed in patients but not present or reduced in controls., Conclusions: Adrenal 11oxC19 androgens are secreted following a diurnal pattern. This should be considered when evaluating their utility for monitoring treatment control., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Trans people suffer from increased rates of depression and suicidality even after gender-affirming medical interventions. The present study aims to examine the prevalence of childhood adversities in patients with gender dysphoria and to analyze its impact on adult depression and suicidality. Participants meeting diagnostic criteria of Gender Dysphoria were recruited in a cross-sectional multicenter study at four German health-care centers. Childhood adversities were assessed with the Childhood Trauma Questionnaire (CTQ) and additional single items for other childhood adversities. Associations between childhood adversities and adult depression and suicidality were calculated using regression analyses. A large majority of participants reported childhood adversities, and only 7% endorsed no adversities in the CTQ. Over 30% reported severe to extreme childhood adversities. One-fourth reported parents exhibiting violent behavior while bullying by peers was experienced by 70%. These adversities were associated with an increased risk for adult depression and suicidality. Time since beginning of hormonal therapy did not show a significant influence neither on depression nor on suicidality. Childhood adversities are common and associated with adult depression and suicidality in trans people. Adequately addressing these childhood adversities and providing trauma-informed mental health care might ameliorate the mental health burden in trans people., (Copyright © 2021. Published by Elsevier Ltd.)

Context: Hypothalamus-pituitary-gonadal (HPG)-axis disturbances are a common phenomenon in patients with classic congenital adrenal hyperplasia (CAH). 11-oxygenated androgens have been suggested to play a role in this context., Design: Cross-sectional single center study including 89 patients (N = 42 men, N = 55 women) with classic CAH., Main Outcome Measures: Differences in steroid markers in men with hypogonadism and women with secondary amenorrhea with a special focus on 11-ketotestosterone (11KT) and 11β-hydroxyandrostenedione (11OHA4)., Results: Hypogonadotropic hypogonadism was present in 23 % of men and 61 % of those women currently not on contraceptives suffered from irregular menstrual cycles or amenorrhea. Testicular adrenal rest tumor (TART) was documented in 28 % of men. 11KT (3.5x) and 11OHA4 (5.7x) among other adrenal steroids were significantly elevated in men with hypogonadism and in women with amenorrhea in comparison to those with a regular cycle (11KT: 5.2x; 11OHA4: 3.7x). 11-oxygenated androgens were not higher in men with TART than in those without. There was a negative association of 11KT and 11OHA4 with FSH but not with LH in men. As expected, all steroids were strongly correlated with each other and cases of disproportionally elevated 11-oxygenated androgens that could explain for HPG-disturbances or TART in otherwise controlled patients were rare and also found in eugonadal individuals., Conclusions: In CAH, 11-oxygenated androgens are elevated in women with menstrual disturbances and in men with hypogonadotropic hypogonadism. Due to the close correlation of 11-oxygenated androgens with other adrenal steroids it remains to be shown if their measurement is superior to conventional markers of androgen control., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Patients with craniopharyngioma (CP) frequently suffer from morbid obesity. Endocannabinoids (ECs) are involved in weight gain and rewarding behavior but have not been investigated in this context., Design: Cross-sectional single-center study., Methods: Eighteen patients with CP and 16 age- and sex-matched controls were included. Differences in endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and endocannabinoid-like molecules (oleoyl ethanolamide (OEA), palmitoylethanolamide (PEA), and arachidonic acid (AA) were measured at baseline and following endurance exercise. We further explored ECs-dynamics in relation to markers of HPA-axis activity (ACTH, cortisol, copeptin) and hypothalamic damage., Results: Under resting conditions, independent of differences in BMI, 2-AG levels were more than twice as high in CP patients compared to controls. In contrast, 2-AG and OEA level increased in response to exercise in controls but not in CP patients, while AEA levels decreased in controls. As expected, exercise increased ACTH and copeptin levels in controls only. In a mixed model analysis across time and group, HPA measures did not provide additional information for explaining differences in 2-AG levels. However, AEA levels were negatively influenced by ACTH and copeptin levels, while OEA levels were negatively predicted by copeptin levels only. There were no significant differences in endocannabinoids depending on hypothalamic involvement., Conclusion: Patients with CP show signs of a dysregulated endocannabinoid system under resting conditions as well as following exercise in comparison to healthy controls. Increased 2-AG levels under resting conditions and the missing response to physical activity could contribute to the metabolic phenotype of CP patients.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, whose core symptoms consist of deficits in social interaction and communication as well as restricted and repetitive behavior. Brain oxytocin (OXT) has been associated with various prosocial behaviors, and might, therefore, be involved in the pathogenesis of disorders associated with socio-emotional dysfunctions such as ASD. However, significant associations between central and peripheral OXT levels may only be present in response to physiological or stressful stimuli but were not shown under baseline conditions. In this study, we, therefore, investigated salivary and plasma OXT in response to physical exercise in adults with ASD ( n  ​= ​33, mean age: 36.8 ​± ​10.7 years) without intellectual impairment (IQ ​> ​70) and neurotypical controls ( n  ​= ​31, mean age: 31.0 ​± ​11.7 years). To stimulate the OXT system, we used rapid cycling and measured cortisol (CORT) concentrations to monitor the physiological stress response. When controlling for age, neither salivary OXT ( p  ​= ​.469), plasma OXT ( p  ​= ​.297) nor CORT ( p ​= ​.667) concentrations significantly differed between groups at baseline. In addition, neither OXT nor CORT concentrations significantly differed between groups after physical exercise. Social anxiety traits were negatively correlated with plasma, but not saliva OXT concentrations in neurotypicals at baseline, while empathetic traits were positively correlated with saliva, but not plasma concentrations in autistic patients at baseline. No significant correlations between salivary and plasma OXT concentrations were found at any time point. Future studies including adult participants should investigate the effect of age on CORT and OXT concentrations in response to stress., Competing Interests: None., (© 2021 The Author(s).)

Purpose: Patients with non-functioning pituitary adenomas (NFPA) suffer from pronounced impairments in physical and mental measures that result in an impairment of health-related quality of life (HRQOL). The role of secondary adrenal insufficiency (SAI) and especially the one of the hydrocortisone (HC) replacement dose on the HRQOL seems to be conflicting. The primary aim of this study is to assess the HRQOL in patients with NFPA in terms of presence of SAI and in patients without SAI and the secondary to explore the impact of treatment parameters such as daily HC dose., Design/methods: In a cross-sectional study we evaluated parameters of HRQOL in 95 patients with NFPA of the Endocrine Outpatient Unit of the Max Planck Institute of Psychiatry in Munich using standardized questionnaires like Short Form (SF-36), Beck's Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI) and a self-constructed questionnaire about medical history., Results: We could not find any significant difference between patients with and without SAI in the standardized questionnaires in terms of HRQOL. We could show that higher doses of HC were negatively correlated with HRQOL measured by SF-36 global health score regardless of using BDI or STAI in the block (β =  - 0.397; p = 0.021, β =  - 0.390; p = 0.016, respectively)., Conclusions: NFPA patients with SAI do not have a worse HRQOL than patients with NFPA and intact corticotropic axis. We could show that higher doses of HC are associated with an impaired HRQOL measured by SF-36 global and physical health score, whereas mental health score is not significantly influenced by the HC dose.

Context: This study aimed to determine the role of modifiable predictors on bone health in congenital adrenal hyperplasia (CAH)., Design: Cross-sectional, single center study, including 97 patients (N = 42 men) with classic CAH due to 21-hydroxylase deficiency (N = 65 salt wasting, N = 32 simple virilizing)., Main Outcome Measures: Treatment-related predictors of bone health., Results: Average T scores (-0.9 ± 1.4 vs. -0.4 ± 1.4; p = 0.036) as well as Z scores (-1.0 ± 1.3 vs. -0.1 ± 1.4; p = 0.012) at the spine in patients with CAH were significantly lower in men than women. While osteoporosis was rare in women, it was documented in 9.1% of men with CAH. There was a significant positive correlation of Z scores at the spine with advancing age in women with CAH (R² = 0.178; p = 0.003). In multivariate analysis, the intake of conventional hydrocortisone (HC) instead of synthetic glucocorticoids was independently associated with a higher bone mineral density (BMD) at the hip region in both sexes. In women, there was a positive association with vitamin D concentrations. Interestingly, higher sodium levels were associated with a lower BMD independent of renin levels and fludrocortisone dosage. Neither in men nor in women, markers of androgen control were predictive for BMD at any site. Markers of bone turnover indicated low bone turnover. No pathological fractures were documented., Conclusions: Men with CAH are particularly prone to low bone density, while women seem to be relatively protected by androgen excess compared to the general female population. The use of HC instead of synthetic GCs for hormone replacement may translate into better bone health., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: One of the most prominent etiological theories of gender incongruence in trans women proposes a paraphilic erotic target location error (ie, autogynephilia) as a causal factor in gynephilic (ie, exclusively gynephilic and bisexual) trans women. We hypothesized that a paraphilic erotic target location should manifest itself in various aspects of sexual behavior, solitary and dyadic sexual desire, and psychosexual experience., Aim: To compare sexual behavior, sexual desire, and psychosexual experience of exclusively gynephilic and bisexual trans women with that of androphilic trans women to explore whether their sexuality differs substantially., Methods: Trans women diagnosed with gender dysphoria (Diagnostic and Statistical Manual of Mental Disorders-5) were recruited at 4 transgender healthcare centers in Germany. The present study analyzed items on sexual behavior, desire, and experience of a self-report questionnaire, collected as part of a cross-sectional multicenter study., Main Outcomes: Multiple aspects of sexuality were examined using self-constructed items. Sexual desire was measured using the Sexual Desire Inventory and psychosexual experience using the Multidimensional Sexuality Questionnaire., Results: Significantly more exclusively gynephilic than androphilic trans women reported a history of sexual arousal in relation to cross-dressing. However, little evidence was found that gynephilic and androphilic sexual desire, behavior, and psychosexual experience differ profoundly. Interestingly, a statistically non-significant trend indicated that gynephilic trans women who had not yet undergone gender affirming surgery showed the highest levels of sexual desire (solitary and dyadic), whereas the opposite was the case for androphilic trans women., Clinical Translation: Data of this study indicate that sexual orientation does not appear to be a good predicator for sexual behavior, desire, and psychosexual experience in trans women., Strengths and Limitations: We investigated sexual desire and experience using standardized and evaluated measures such as the Sexual Desire Inventory and Multidimensional Sexuality Questionnaire. Future studies with a larger sample size should investigate how different gender affirming medical intervention might have diverging influences on sexual behavior, desire, and experience., Conclusion: Ultimately, this study found little evidence for the hypothesis that sexual behavior, sexual desire, and psychosexual experience differ substantially in gynephilic (exclusively gynephilic and bisexual) and androphilic trans women. Laube JS, Auer M, Biedermann SV, et al. Sexual Behavior, Desire, and Psychosexual Experience in Gynephilic and Androphilic Trans Women: A Cross-Sectional Multicenter Study. J Sex Med 2020;17:1182-1194., (Copyright © 2020 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Oxytocin is a neuropeptide known to affect social behaviour and cognition. Craniopharyngioma patients are considered to have an oxytocin-release-deficit caused by a rare tumour affecting the pituitary and/or the hypothalamus relevant for oxytocin production and release. To assess social behaviour and socio-cognitive abilities in this patient group, we tested 13 patients and 23 healthy controls on self-report questionnaires and an eye-tracking paradigm including fast facial emotion recognition. Additionally, saliva oxytocin levels acquired before and after a physical stress induction were available from a previous study, representing the reactivity of the oxytocin system. The data revealed three major results. First, patients with an oxytocin-release-deficit scored higher on self-reported autistic traits and reduced levels of hedonia for social encounters, although they showed no impairments in attributing mental states. Second, patients showed more difficulties in the fast emotion recognition task. Third, although automatic gaze behaviour during emotion recognition did not differ between groups, gaze behaviour was related to the reactivity of the oxytocin system across all participants. Taken together, these findings demonstrate the importance of investigating the reactivity of the oxytocin system and its relationship with social cognition. Our findings suggest that reduced emotional processing abilities may represent a pathological feature in a group of craniopharyngioma patients, indicating that this patient group might benefit from specific treatments within the social domain., (© 2020 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Data on cardiovascular morbidity in adults with congenital adrenal hyperplasia (CAH) is sparse. We therefore aimed to determine the role of androgen control and glucocorticoid therapy on metabolic health. For that purpose, we included 90 patients (N = 39 men, N = 51 women) with classic CAH due to 21-hydroxylase deficiency (N = 61 salt wasting, N = 29 simple virilizing) and an equal number of controls matched for age, sex, BMI and smoking-habits. We could show that there was no difference in intima-media-thickness between patients and controls and only one patient fulfilled all criteria of the metabolic syndrome. CAH men presented with an increased relative body fat mass in comparison to controls (25.6 % vs. 22.1 %; p = 0.011) while this was not true for CAH women. Body fat was lower in those taking hydrocortisone instead of synthetic glucocorticoids (B = -3.27; p = 0.048). While arterial hypertension was rare, 54 % of patients had an impaired systolic drop at night or were classified as non-dippers (17 %). Impaired dipping was not associated with evening glucocorticoid and fludrocortisone intake but mediated by sodium levels. Insulin resistance was more common in CAH women (B = 1.689; p = 0.036) and in those with poor androgen control (B = 0.823; p = 0.046). In summary, we could show that good cardiovascular health outcome in adult CAH patients can be achieved. Hydrocortisone is superior in terms of body composition. It is yet unclear how non-dipping will translate into cardiovascular morbidity in the long-term., Competing Interests: Declaration of Competing Interest All authors have declared that no conflict of interest exists., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: To evaluate scalp hair steroid concentrations as a monitoring tool for androgen control and metabolic outcomes in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency., Methods: 17-hydroxyprogesterone (17-OHP), androstenedione, testosterone, cortisol, cortisone, progesterone, prednisolone, and prednisone concentrations were measured in scalp hair by means of LC-MS/MS in 27 women and 15 men with CAH and controls (37 women, 42 men)., Results: In CAH men and women, 17-OHP levels in hair showed a significant positive correlation with corresponding levels in serum (ρ = 0.654; p = 0.01; ρ = 0.553, p = 0.003 respectively), while total testosterone levels were only significantly correlated in CAH men (ρ = 0.543; p = 0.036). Androstenedione levels did not show a significant correlation. Receiver-operating characteristic (ROC) curve analysis indicated that a cutoff value of 21.7 pg/mg for 17-OHP in hair provided a sensitivity of 100% and a specificity of 88.9% for identifying men with elevated serum androstenedione. Hair 17-OHP in women showed a poorer performance in terms of identifying those with elevated androstenedione serum levels. However, when applying a cutoff value of 5.5 for the free androgen index as a marker of significant hyperandrogenism in CAH women, 17-OHP >27.6 pg/mg in hair provided a sensitivity of 100% and a specificity of 95.8% (AUC 0.986, 95% CI 0.945-1.000; p < 0.001). Neither hair cortisol nor markers of adrenal androgen control in hair showed significant associations with cardiometabolic outcome or bone health., Conclusion: This study shows that scalp hair 17-OHP concentrations may be a promising noninvasive long-term parameter for treatment monitoring in adult patients with CAH., (© 2019 S. Karger AG, Basel.)

Background: Studies in mammals indicate a role for sex hormones in the regulation of hypothalamic-pituitary-adrenal (HPA)-axis reactivity. However, in humans, experimental paradigms investigating long-term exposure to sex hormones are sparse, limiting the understanding of the influence of sex hormones on HPA-axis activity. Gender-affirming hormone therapy (GAHT) in transgender persons enables to study the physiological role of sex steroids partially uncoupled from the distinct genetic background of men and women., Methods: Ten transwomen (male genotype and female gender identity) and 15 transmen (female genotype and male gender identity) were investigated at baseline and following three months of GAHT by means of the combined dexamethasone (dex)/CRH-test. Linear mixed-effects model analysis was used to assess changes over time and to identify determinants of HPA-axis reactivity., Results: In response to CRH, overall ACTH (+18%) as well as cortisol (+15%) output were increased in transwomen after 3-months of estrogen and antiandrogen treatment, while the opposite was the case for transmen after testosterone treatment (-15% and -58%, respectively). The ACTH/Cortisol-ratio indicated that testosterone attenuated sensitivity for ACTH at the adrenal level in transmen. Interestingly, copeptin levels before CRH administration were a strong predictor of overall cortisol secretion., Conclusions: This is the first study demonstrating long-term effects of a complete reversal of the sex-hormonal milieu on HPA-axis activity in humans. Our findings hereby expand the current knowledge of the physiology of HPA-axis regulation. and may be particularly relevant for transgender and cisgender people undergoing hormonal suppression or substitution therapies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To develop a multidimensional and integrated clinical scoring instrument, that encompasses, summarizes and weights appropriately the desired clinical benefits of a treatment for Cushing's disease (CD)., Methods: A panel of 42 variables potentially relevant to the clinical course of CD was predefined by endocrinology experts taking into account relevant literature. Variables as well as biochemical disease activity assessed as urinary free cortisol (UFC) levels were evaluated at baseline and at least after 12 months in patients treated between 2012 and 2016 in two Munich-based academic centres of the German Cushing's Registry. The primary endpoint was the identification of variables whose changes from baseline to follow-up visit(s) could characterize well biochemical cured from not cured patients after 12 months., Results: Ninety nine patients with at least two consecutive visits were enrolled. Biochemical data were available for 138 visit-pairs among which UFC was not controlled in 48 (34.8%) and controlled in 90 (65.2%) first visits. In 41 (29.7%) consecutive visits (visit-pairs) changes in biochemical activity categories was observed between visits; concretely: in 17 (12.3%) consecutive visits changing from previously controlled to not controlled, and in 24 (17.4%) from uncontrolled to controlled biochemical activity. Multivariate statistical analyses (especially analyses of variance) based on data of the 138 visit-pairs were performed in order to proof possible effects of biochemical activity on clinical benefits. However, in none of the considered 42 variables corresponding to quality of life-dimensions, laboratory, anthropometric, musculo-skeletal or other clinical areas any statistically significant differences between different categories of biochemical activity were observed., Conclusion: It was not possible to provide clinical key parameters in our population of patients with CD discriminating biochemical cured from non-cured patients and to construct a clinical scoring system reflecting clinical treatment benefits.

Background: Women with complete androgen insensitivity syndrome (CAIS) after gonadectomy have complained about reduced psychological wellbeing and sexual satisfaction. The aim of this study was to compare the effectiveness of hormone-replacement therapy with either androgen or oestrogen in women with 46,XY karyotype and CAIS after gonadectomy., Methods: This national, multicentre, double-blind, randomised crossover trial was performed at three university medical centres and three specialised treatment institutions in Germany. Eligible participants were women aged 18-54 years with 46,XY karyotype, genetically diagnosed CAIS, and removed gonads. Participants were randomly assigned (14:12) by a central computer-based minimisation method to either oestradiol 1·5 mg/day for 6 months followed by crossover to testosterone 50 mg/day for 6 months (sequence A) or to testosterone 50 mg/day for 6 months followed by crossover to oestradiol 1·5 mg/day for 6 months (sequence B). Participants also received oestradiol or testosterone dummy to avoid identification of the active substance. All participants received oestradiol 1·5 mg/day during a 2 months' run-in phase. The primary outcome was mental health-related quality of life, as measured with the standardised German version of the SF-36 questionnaire. Secondary outcomes were psychological wellbeing, as measured with the Brief Symptom Inventory (BSI), sexual function, as measured with the Female Sexual Function Index (FSFI), and somatic effects, such as signs of virilisation and effects on metabolic blood values. The primary analysis included all patients who were available at least until visit 5, even if protocol violations occurred. The safety analysis included all patients who received at least oestradiol during the run-in phase. This trial is registered with the German Clinical Trials Register, number DRKS00003136, and with the European Clinical Trials Database, number 2010-021790-37., Findings: We enrolled 26 patients into the study, with the first patient enrolled on Nov 7, 2011, and the last patient leaving the study on Jan 23, 2016. 14 patients were assigned to sequence A and 12 were assigned to sequence B. Ten participants were withdrawn from the study, two of whom attended at least five visits and so could be included in the primary analysis. Mental health-related quality of life did not differ between treatment groups (linear mixed model, p=0·794), nor did BSI scores for psychological wellbeing (global severity index, p=0·638; positive symptom distress index, p=0·378; positive symptom total, p=0·570). For the FSFI, testosterone was superior to oestradiol only in improving sexual desire (linear mixed model, p=0·018). No virilisation was observed, and gonadotrophin concentrations remained stable in both treatment groups. Oestradiol and testosterone concentrations changed substantially during the study in both treatment groups. 28 adverse events were reported for patients receiving oestradiol (23 grade 1 and five grade 2), and 38 adverse events were reported for patients receiving testosterone (34 grade 1, three grade 2, and one grade 3). One serious adverse event (fibrous mastopathy) and 20 adverse events (16 grade 1 and four grade 2) were reported during the run-in phase, and 12 adverse events during follow-up (nine grade 1 and three grade 2)., Interpretation: Testosterone was well tolerated and as safe as oestrogen for hormone-replacement therapy. Testosterone can be an alternative hormone substitution in CAIS, especially for woment with reduced sexual functioning., Funding: German Federal Ministry of Education and Research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: Patients with non-functioning pituitary adenomas exhibit high morbidity and mortality rates. Growth hormone deficiency and high doses of glucocorticoid substitution therapy have been identified as corresponding risk factors. Interestingly, high levels of endogenous cortisol in, e.g., patients with post-traumatic stress disorder or patients with Cushing's disease have been linked to shorter telomere length. Telomeres are noncoding DNA regions located at the end of chromosomes consisting of repetitive DNA sequences which shorten with ageing and hereby determine cell survival. Therefore, telomere length can serve as a predictor for the onset of disease and mortality in some endocrine disorders (e.g., Cushing's disease)., Design/methods: We examine telomere length from blood in patients (n = 115) with non-functioning pituitary adenomas (NFPA) in a cross-sectional case control (n = 106, age-, gender- matched) study using qPCR. Linear regression models were used to identify independent predictors of telomere length., Results: We show that patients with NFPA exhibited shorter telomeres than controls. No significant association of indices of growth hormone deficiency (IGF-1-level-SDS, years of unsubstituted growth hormone deficiency etc.) with telomere length was detected. Interestingly, linear regression analysis showed that hydrocortisone replacement dosage in patients with adrenal insufficiency (n = 52) was a significant predictor for shorter telomere length (β = 0.377; p = 0.018) independent of potential confounders. Median split analysis revealed that higher hydrocortisone intake (> 20 mg) was associated with significantly shorter telomeres., Conclusion: These observations strengthen the importance of adjusted glucocorticoid treatment in NFPA patients with respect to morbidity and mortality rates.

Background: Many trans individuals undergo medical interventions that result in irreversible loss of fertility. Little is known about their desire to have children and attitudes toward fertility preservation options., Aim: To study how the desire for children and the use of fertility preservation options varies among trans women and trans men in different transitioning stages in Germany., Methods: In this cross-sectional multi-center study, N = 99 trans women and N = 90 trans men were included. Of these, 26 of each sex were just about to start medical treatment., Outcomes: Outcome parameter were the prevalence and determinants of a desire to have children in trans persons., Results: Before treatment, a desire for children was significantly higher in trans men compared to trans women (P = .016). In contrast, in those who had already started treatment, a current desire to have children was equally present in about one fourth of participants of both genders while the interest in having children in the future was significantly higher in trans women (69.9%) than in trans men (46.9%; P = .034). Although 76.1% of trans women and 76.6% of trans men indicated that they had at least thought about preserving germ cells before starting medical transition, only 9.6% of trans women and 3.1% of trans men had put this idea into practice. Most trans men in both groups indicated that insemination of a female partner with sperm from an unrelated donor was a suitable option to fulfill their child wish, potentially explaining their low interest in preserving their own germ cells. Finally, a logistic regression analysis accounting for potential confounders revealed that overall trans women were more than twice as likely to have a current desire to have children (odds ratio 2.58), and this wish was on average 5.3% lower with each year of increasing age., Clinical Translation: A low level of fertility preservation among trans persons is contrasted by a high level of desire for children. This highlights the importance of counseling trans individuals regarding fertility preservation options., Conclusions: To our knowledge, this is the first study that addresses desire to have children in a clinical sample of trans women. It is also the first that investigates this issue among trans men who have not started medical treatment, and the first comparison of both genders. A limitation for the generalization of our results is the special legal context in Germany that forbids oocyte donation for reciprocal in vitro fertilization. Reproductive desire is high among trans individuals, but the use of reproductive options is surprisingly low. Auer MK, Fuss J, Nieder TO, et al. Desire to Have Children Among Transgender People in Germany: A Cross-Sectional Multi-Center Study. J Sex Med 2018;15:757-767., (Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Empty sella is the neuroradiological or pathological finding of an apparently empty sella turcica containing no pituitary tissue. The prevalence of primary empty sella, i.e., empty sella without any discernible cause, is not precisely known; estimates range from 2% to 20%. Technical advances in neuroradiology have made empty sella an increasingly common incidental finding. It remains unclear whether, and to what extent, asymptomatic adult patients with an incidentally discovered empty sella should undergo diagnostic testing for hormonal disturbances., Methods: To answer this question, the authors carried out a systematic search in the PubMed and Web of Science databases for publications that appeared in the period 1995-2016 and that contained the search term "empty sella" (registration: PROSPERO 2015: CRD42015024550)., Results: The search yielded 1282 hits. After the exclusion of duplicates, pediatric reports, case reports, and veterinary studies, 120 publications on primary empty sella syndrome (PES) were identified. 4 of these dealt with the prevalence of pituitary insufficiency in patients with PES as an incidental finding. Among patients with PES, the relative frequency of pituitary insufficiency in the pooled analysis was 52% (95% confidence interval [38; 65])., Conclusion: The data on PES as an incidental finding are too sparse to enable any evidence-based recommendation on the potential indications for hormone testing or its nature and extent. We advise basic neuroendocrinological testing (fasting cortisol, free thyroxine [fT4], estradiol or testosterone, insulin-like growth factor 1 [IGF-1], and prolactin). There is an unexplained discrepancy between the reported high prevalence of pituitary insufficiency among persons with PES and its low prevalence in epidemiologic studies. We suspect that the former may be high because of selection bias in the publications that we reviewed, or else the latter may be erroneously low.

Despite the high prevalence of panhypopituitarism and diabetes insipidus in patients with craniopharyngioma (CP), little is known about the functioning of the neuropeptide oxytocin in these patients. This is of special interest as tumor-associated lesions often impair sites critical for oxytocin production and release, and affective dysfunction in CP links with elsewhere reported prosocial, antidepressant and anxiolytic oxytocin effects. Using a prospective study-design, we tested whether oxytocin is reduced in CP-patients, and whether altered oxytocin levels account for affective and emotional dysfunction. 26 adult CP-patients and 26 healthy controls matched in sex and age underwent physical exercise, a stimulus previously shown to induce oxytocin release. Baseline and stimulated salivary oxytocin levels, as well as empathy, depression and anxiety scores were measured. Results showed that patients overall did not present with lower baseline oxytocin levels than controls (F[1,30]=0.21, p=0.649), but baseline oxytocin levels were indeed reduced in patients with hypothalamic damage, as assessed by MRI-based grading (F[2,9.79]=4.54, p=0.040). In response to exercise-induced stimulation, all CP-patients showed a blunted oxytocin-release compared to controls (F[1,30]=9.36, p=0.005). DI was not associated with oxytocin levels. Regarding affective function, unexpectedly, higher baseline oxytocin was related to higher trait anxiety (b=2.885, t(43)=2.421, p=0.020, CI[.478; 5.292]); the positive link with higher depression failed to reach statistical significance (b=1.928, t(43)=1.949, p=0.058, CI[-0.070; 3.927]). A blunted oxytocin-release was linked with higher state anxiety (b=-0.133, t(43)=-2.797, p=0.008, CI[-0.230; -0.037]). Empathy was not associated with oxytocin measures. In conclusion, we observed reduced baseline oxytocin levels only in CP-patients with hypothalamic damage. Exercise-induced stimulation de-masked an oxytocin-deficiency in all CP-patients. Baseline oxytocin levels and stimulated OT-responses might have different effects on affective function, which should be considered in future substitution paradigms., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Context: Hormonal treatment in transgender persons affects many components of the metabolic syndrome (MS)., Objective: To determine the role of direct hormonal effects, changes in metabolic cytokines, and body composition on metabolic outcomes., Design, Setting, and Participants: 24 transwomen and 45 transmen from the European Network for the Investigation of Gender Incongruence were investigated at baseline and after 12 months of hormonal therapy., Outcome Measures: Best predictors for changes in components of MS, applying least absolute shrinkage and selection operator regression., Results: In transwomen, a decrease in triglyceride levels was best explained by a decrease in fat mass and an increase in fibroblast growth factor 21 (FGF-21); the decrease in total and low-density lipoprotein cholesterol levels was principally due to a decrease in resistin. A decrease in high-density lipoprotein cholesterol depended on an inverse association with fat mass. In contrast, in transmen, an increase in low-density lipoprotein cholesterol was predicted by a decrease in FGF-21 and an increase in the waist/hip ratio; a decrease in the high-density lipoprotein/total cholesterol ratio depended on a decline in adiponectin levels. In transwomen, worsened insulin resistance and increased early insulin response seemed to be due to a direct treatment effect; however, improvements in hepatic insulin sensitivity in transmen were best predicted by a positive association with chemerin, resistin, and FGF-21 and were inversely related to changes in the waist/hip ratio and leptin and adipocyte fatty acid-binding protein levels., Conclusions: The effects of hormonal therapy on different components of the MS are sex-specific and involve a complex interplay of direct hormonal effects, changes in body composition, and metabolic cytokine secretion., (Copyright © 2017 Endocrine Society)

Background: A dearth of laboratory tests to study actual human approach-avoidance behavior has complicated translational research on anxiety. The elevated plus-maze (EPM) is the gold standard to assess approach-avoidance behavior in rodents., Methods: Here, we translated the EPM to humans using mixed reality through a combination of virtual and real-world elements. In two validation studies, we observed participants' anxiety on a behavioral, physiological, and subjective level., Results: Participants reported higher anxiety on open arms, avoided open arms, and showed an activation of endogenous stress systems. Participants' with high anxiety exhibited higher avoidance. Moreover, open arm avoidance was moderately predicted by participants' acrophobia and sensation seeking, with opposing influences. In a randomized, double blind, placebo controlled experiment, GABAergic stimulation decreased avoidance of open arms while alpha-2-adrenergic antagonism increased avoidance., Conclusion: These findings demonstrate cross-species validity of open arm avoidance as a translational measure of anxiety. We thus introduce the first ecologically valid assay to track actual human approach-avoidance behavior under laboratory conditions.

Autobiographical memory deficits are known in depression. The temporal distribution thereof across periods of life has rarely been considered yet. Autobiographical memories for 5 life periods were investigated in 27 depressed in-patients and compared to 31 matched healthy controls using the Bielefelder Autobiographisches Gedächtnis Inventar. Depressed patients reported significantly less details in memories dating from childhood to 30 years, correlating with severity of depression. Memories from childhood and recent periods were less positive in depressed patients. Thus, we found a distinct pattern of autobiographical memory deficits in depressed patients. Possible etiological factors, however, need further investigations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Endocannabinoids are critical for rewarding behaviors such as eating, physical exercise, and social interaction. The role of endocannabinoids in mammalian sexual behavior has been suggested because of the influence of cannabinoid receptor agonists and antagonists on rodent sexual activity. However, the involvement of endocannabinoids in human sexual behavior has not been studied., Aim: To investigate plasma endocannabinoid levels before and after masturbation in healthy male and female volunteers., Outcomes: Plasma levels of the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide, the endocannabinoid-like lipids oleoyl ethanolamide and palmitoyl ethanolamide, arachidonic acid, and cortisol before and after masturbation to orgasm., Methods: In study 1, endocannabinoid and cortisol levels were measured before and after masturbation to orgasm. In study 2, masturbation to orgasm was compared with a control condition using a single-blinded, randomized, 2-session crossover design., Results: In study 1, masturbation to orgasm significantly increased plasma levels of the endocannabinoid 2-AG, whereas anandamide, oleoyl ethanolamide, palmitoyl ethanolamide, arachidonic acid, and cortisol levels were not altered. In study 2, only masturbation to orgasm, not the control condition, led to a significant increase in 2-AG levels. Interestingly, we also found a significant increase of oleoyl ethanolamide after masturbation to orgasm in study 2., Clinical Translation: Endocannabinoids might play an important role in the sexual response cycle, leading to possible implications for the understanding and treatment of sexual dysfunctions., Strengths and Limitations: We found an increase of 2-AG through masturbation to orgasm in 2 studies including a single-blinded randomized design. The exact role of endocannabinoid release as part of the sexual response cycle and the biological significance of the finding should be studied further. Cannabis and other drug use and the attainment of orgasm were self-reported in the present study., Conclusion: Our data indicate that the endocannabinoid 2-AG is involved in the human sexual response cycle and we hypothesize that 2-AG release plays a role in the rewarding consequences of sexual arousal and orgasm. Fuss J, Bindila L, Wiedemann K, et al. Masturbation to Orgasm Stimulates the Release of the Endocannabinoid 2-Arachidonoylglycerol in Humans. J Sex Med 2017;14:1372-1379., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Excessive intake of high-caloric diets as well as subsequent development of obesity and diabetes mellitus may exert a wide range of unfavorable effects on the central nervous system (CNS) in the long-term. The potentially harmful effects of such diets were suggested to be mitigated by physical exercise. Here, we conducted a study investigating early effects of a cafeteria-diet on gray and white brain matter volume by means of voxel-based morphometry (VBM) and region-of-interest (ROI) analysis. Half of the mice performed voluntary wheel running to study if regular physical exercise prevents unfavorable effects of a cafeteria-diet. In addition, histological analyses for myelination and neurogenesis were performed. As expected, wheel running resulted in a significant increase of gray matter volume in the CA1-3 areas, the dentate gyrus and stratum granulosum of the hippocampus in the VBM analysis, while a positive effect of the cafeteria-diet was shown for the whole hippocampal CA1-3 area only in the ROI analysis, indicating a regional volume effect. It was earlier found that hippocampal neurogenesis may be related to volume increases after exercise. Interestingly, while running resulted in a significant increase in neurogenesis assessed by doublecortin (DCX)-labeling, this was not true for cafeteria diet. This indicates different underlying mechanisms for gray matter increase. Moreover, animals receiving cafeteria diet only showed mild deficits in long-term memory assessed by the puzzle-box paradigm, while executive functioning and short term memory were not affected. Our data therefore highlight that high caloric diet impacts on the brain and behavior. Physical exercise seems not to interact with these mechanisms.