Formin-mediated nuclear actin at androgen receptors promotes transcription.

Steroid hormone receptors are ligand-binding transcription factors essential for mammalian physiology. The androgen receptor (AR) binds androgens mediating gene expression for sexual, somatic and behavioural functions, and is involved in various conditions including androgen insensitivity syndrome and prostate cancer1. Here we identified functional mutations in the formin and actin nucleator DAAM2 in patients with androgen insensitivity syndrome. DAAM2 was enriched in the nucleus, where its localization correlated with that of the AR to form actin-dependent transcriptional droplets in response to dihydrotestosterone. DAAM2 AR droplets ranged from 0.02 to 0.06 µm3 in size and associated with active RNA polymerase II. DAAM2 polymerized actin directly at the AR to promote droplet coalescence in a highly dynamic manner, and nuclear actin polymerization is required for prostate-specific antigen expression in cancer cells. Our data uncover signal-regulated nuclear actin assembly at a steroid hormone receptor necessary for transcription.

Aberrant phase separation and nucleolar dysfunction in rare genetic diseases.

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1-3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6-8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

Gender-affirming hormonal therapy induces a gender-concordant fecal metagenome transition in transgender individuals.

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 (R2 = 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.

Disruption of the topologically associated domain at Xp21.2 is related to 46,XY gonadal dysgenesis.

BACKGROUND: Duplications at the Xp21.2 locus have previously been linked to 46,XY gonadal dysgenesis (GD), which is thought to result from gene dosage effects of NR0B1 (DAX1), but the exact disease mechanism remains unknown. METHODS: Patients with 46,XY GD were analysed by whole genome sequencing. Identified structural variants were confirmed by array CGH and analysed by high-throughput chromosome conformation capture (Hi-C). RESULTS: We identified two unrelated patients: one showing a complex rearrangement upstream of NR0B1 and a second harbouring a 1.2 Mb triplication, including NR0B1. Whole genome sequencing and Hi-C analysis revealed the rewiring of a topological-associated domain (TAD) boundary close to NR0B1 associated with neo-TAD formation and may cause enhancer hijacking and ectopic NR0B1 expression. Modelling of previous Xp21.2 structural variations associated with isolated GD support our hypothesis and predict similar neo-TAD formation as well as TAD fusion. CONCLUSION: Here we present a general mechanism how deletions, duplications or inversions at the NR0B1 locus can lead to partial or complete GD by disrupting the cognate TAD in the vicinity of NR0B1. This model not only allows better diagnosis of GD with copy number variations (CNVs) at Xp21.2, but also gives deeper insight on how spatiotemporal activation of developmental genes can be disrupted by reorganised TADs causing impairment of gonadal development.

A Prospective Analysis of the Metyrapone Short Test Using Targeted and Untargeted Metabolomics.

INTRODUCTION: The present study aimed to prove the metyrapone short test in a day clinic to be suitable for examining the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected secondary and tertiary adrenal insufficiency and to identify novel effector molecules in acute stress response. METHODS: 44 patients were prospectively enrolled. Based on stimulated 11-deoxycortisol levels, patients were divided into a physiological (11-deoxycortisol ≥70 µg/L) and a pathological (11-deoxycortisol <70 µg/L) response group. Clinical follow-up examination was performed for validation. Ultraperformance liquid chromatography tandem mass spectrometry and a Fourier-transform-ion-cyclotron-resonance-mass-spectrometry were used for targeted and untargeted steroid metabolomics. RESULTS: At baseline, lower levels of cortisone (42 vs. 50 nmol/L, p = 0.048) and 17-OH-progesterone (0.6 vs. 1.2 nmol/L, p = 0.041) were noted in the pathological response group. After metyrapone administration, the pathological response group exhibited significantly lower 11-deoxycortisol (39.0 vs. 94.2 µg/L, p < 0.001) and ACTH (49 vs. 113 pg/mL, p < 0.001) concentrations as well as altered upstream metabolites. Untargeted metabolomics identified a total of 76 metabolites to be significantly up- or downregulated by metyrapone. A significant increase of the bile acid glycochenodeoxycholic acid (GCDC, p < 0.01) was detected in both groups with an even stronger increase in the physiological response group. After a mean follow-up of 17.2 months, an 11-deoxycortisol cut-off of 70 µg/L showed a high diagnostic performance (sensitivity 100%, specificity 96%). CONCLUSION: The metyrapone short test is safe and feasible in a day clinic setting. The alterations of the bile acid GCDC indicate that the liver might be involved in the acute stress response of the HPA axis.

Genomic variants reducing expression of two endocytic receptors in 46,XY differences of sex development.

Transporter-dependent steroid hormone uptake into target cells was demonstrated in genetically engineered mice and fruit flies. We hypothesized that mutations in such transporters may cause differences in sex development (DSD) in humans. Exome sequencing was performed in 16 genetically unsolved cases of 46,XY DSD selected from an anonymized collection of 708 lines of genital fibroblasts (GF) that were taken from individuals with incomplete virilization. Selection criteria were based on available biochemical characterization of GF compatible with reduced androgen uptake. Two unrelated individuals were identified with mutations in LDL receptor-related protein 2 (LRP2), a gene previously associated with partial sex steroid insensitivity in mice. Like Lrp2-/- mice, affected individuals had non-descended testes. Western blots on GF confirmed reduced LRP2 expression, and endocytosis of sex hormone-binding globulin was reduced. In three unrelated individuals, two with undescended testes, mutations in another endocytic receptor gene, limb development membrane protein 1 like (LMBR1L), were detected. Two of these individuals had mutations affecting the same codon. In a transfected cell model, mutated LMBR1L showed reduced cell surface expression. Our findings suggest that endocytic androgen uptake in complex with sex hormone-binding globulin is relevant in human. LMBR1L may play a similar role in androgen uptake.

A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development.

We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.

Growth, puberty and testicular function in boys born small for gestational age with a nonspecific disorder of sex development.

OBJECTIVE: Being born small for gestational age (SGA) is frequently associated with unexplained disorders of sex development (nonspecific DSD) in boys. Little is known about their future growth, puberty and testicular function. Our objective is to determine the long-term endocrine outcome of boys born SGA who have a nonspecific DSD. DESIGN: Boys with a nonspecific DSD born SGA and appropriate for GA (AGA) were retrieved through the International Disorders of Sex Development registry and retrospective data collected, based on a spreadsheet containing 102 items. PATIENTS AND MEASUREMENTS: In total, 179 boys were included, of which 115 were born SGA and 64 were born AGA. Their growth and pubertal development were compared. Serum LH, FSH, testosterone, AMH and inhibin B levels in infancy and puberty were analysed to assess testicular function. RESULTS: At 2 years of age, 30% of SGA boys had incomplete or absent catch-up growth. Boys born SGA also had higher LH during minipuberty and lower testosterone in stimulation tests (p = 0.037 and 0.040, respectively), as compared to boys born AGA. No differences were observed in timing or course of puberty or end-pubertal hormone levels. CONCLUSIONS: Almost one out of three SGA boys with a nonspecific DSD experiences insufficient catch-up growth. In addition, our data suggest dysfunction of infantile Leydig cells or altered regulation of the hypothalamic-pituitary-gonadal axis in SGA boys during childhood. Sex steroid production during puberty seems unaffected.

The role of gonadotropins in testicular and adrenal androgen biosynthesis pathways-Insights from males with congenital hypogonadotropic hypogonadism on hCG/rFSH and on testosterone replacement.

OBJECTIVE: To delineate the role of gonadotropins in male androgen biosynthesis pathways. DESIGN: Case-control study. PATIENTS AND MEASUREMENTS: Twenty five males with congenital hypogonadotropic hypogonadism (CHH) underwent hCG/rFSH and testosterone treatment sequentially. Serum steroid hormone profiles (testosterone precursors and metabolites) on both replacement regimens were analysed, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared to those of healthy controls, matched by age, BMI and serum testosterone. RESULTS: On testosterone replacement, serum concentrations of the classic Δ4 pathway hormones progesterone and 17-hydroxy-progesterone (17-OHP), and the marker steroid of an alternative pathway of testosterone synthesis (androstenediol) were decreased, compared to controls. Androstanediol, a marker of the backdoor pathway of dihydrotestosterone (DHT) synthesis, was increased. 17-OH-pregnenolone, androstenedione and DHEAS (Δ5 pathway), three 11-oxygenated C19 androgens (11-keto-A4, 11-keto-T and 11-keto-DHT) and the testosterone (T) metabolites DHT and 17ß-oestradiol (E2) were similar to controls. On gonadotropin replacement, 17-OHP, 17-OH-pregnenolone, DHEAS and androstenedione, as well as DHT, androstenediol, and all 11-oxygenated C19 androgens were normal. Progesterone (Δ4 pathway) was slightly decreased, and androstanediol (backdoor DHT pathway) and E2 (T metabolite) were increased. CONCLUSIONS: In males with CHH, serum steroid hormone profiles resemble those of healthy men, if hCG/rFSH is used for substitution. Gonadotropins contribute to steroid hormone production along the classic Δ4 pathway and co-activate an alternative pathway of testosterone biosynthesis via androstenediol. Backdoor DHT biosynthesis, Δ5 17-OH-pregnenolone, DHEA(S) and androstenedione synthesis and 11-oxygenated C19 androgen production are activated independently of gonadotropins. The androgen replacement modality used for treatment of hypogonadal males with absent or reduced endogenous LH/FSH secretion may impact on long-term health and quality of life.

Transition from gynaecomastia to lipomastia in pubertal boys.

OBJECTIVE: Gynaecomastia is frequent in pubertal boys and is regarded as a self-limiting abnormality. However, longitudinal studies proving this hypothesis are scarce. DESIGN: Longitudinal follow-up study (median 2.4, range 1.0-4.8 years). METHODS: The regression of breast diameter was analysed in 31 pubertal boys aged 11.7-16.1 (median 13.2) years with gynaecomastia. Furthermore, weight changes (as BMI-SDS) and pubertal stage, oestradiol [E2], oestriol, oestrone, androstenedione, testosterone [T], dihydrotestosterone, gonadotropins, IGF-1, and IGFBP-3 serum concentrations determined at first clinical presentation were related to breast diameter regression determined by palpation and disappearance of breast glandular tissue in ultrasound in follow-up to identify possible predictors of breast regression. RESULTS: During the observation period, the breast diameter decreased (in median -1 (interquartile range [IQR] -5 to +1) cm). At follow-up, 6% of boys had no breast enlargement any more, and 65% developed lipomastia. Gynaecomastia was still present in 29%. None of the analysed hormones was related significantly to breast diameter regression or disappearance of breast glandular tissue. In multiple linear regression analyses adjusted for observational period, as well as age and BMI-SDS at first presentation, changes in BMI-SDS (ß-coefficient 6.0 ± 2.3, p = .015) but not the E2/T ratio or any other hormone determined at baseline was related to changes in breast diameter. CONCLUSIONS: Breast diameter regression seems not to be predictable by a hormone profile in pubertal boys with gynaecomastia. In pubertal boys presenting with gynaecomastia, conversion to lipomastia of smaller volume is common. The reduction of weight status was the best predictor of breast diameter regression.

New Insights Into Extended Steroid Hormone Profiles in Transwomen in a Multi-Center Setting in Germany.

BACKGROUND: Little information is available on steroid hormone profiles in transwomen on the day of gender affirming surgery (GAS) after gender affirming hormone therapy (GAHT). AIM: We compared extended serum steroid hormone profiles of 77 transwomen with 3 different treatment regimens in order to get more insight on how GAHT changes the hormone system. METHODS: Samples were obtained from 3 independent clinics. Individuals in clinic A (n = 13) and B (n = 51) discontinued GAHT 4-6 weeks and 2 weeks before GAS, individuals in clinic C (n = 13) continued treatment. Testicular tissue, blood samples and questionnaires on age, weight, height, and medication use were received from each patient. Steroid hormones were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), 6 sex hormones were determined by immunofluorometric assays, and ELISA. Spermatogenesis was scored using the Bergman/Kliesch score. OUTCOMES: Participants were not different with regard to age, BMI, treatment duration, and dosage. Feminized blood serum levels with low LH, low FSH and low testosterone, however, were achieved in persons taking GAHT until GAS. Significantly reduced cortisone levels were seen after stopping GAHT before GAS. RESULTS: GAHT had marked effects on the sex-steroid profile in each person. Factor analysis provided a model explaining 78% of the variance and interdependency of sex steroid levels. Stopping treatment was inversely associated with intactness of the corticosteroid-axis with adrenal steroidogenesis as well as it was inversely associated with pituitary-gonadal hormone production. CLINICAL IMPLICATIONS: Transwomen generally did not have elevated cortisone levels but differed significantly depending on and when GAHT was stopped. STRENGTHS & LIMITATIONS: This is the first study examining the steroid hormone profiles of transgender persons on the day of GAS in a multi-center setting. Additional studies (including follow ups before and after GAS and stress questionnaires) will be necessary to assess these conflicting results about the possible psychological impact on persons undergoing GAS to improve care. CONCLUSION: Concerning feminized blood serum levels, continued GAHT seems the better alternative, however stopping treatment 4-6 weeks prior to surgery was associated with reduced cortisone levels. Schneider F, Wistuba J, Holterhus P-M, et al. New Insights Into Extended Steroid Hormone Profiles in Transwomen in a Multi-Center Setting in Germany. J Sex Med 2021;18:1807-1817.

Type 1 diabetes and epilepsy in childhood and adolescence: Do glutamic acid decarboxylase autoantibodies play a role? Data from the German/Austrian/Swiss/Luxembourgian DPV Registry.

AIMS: We aimed to analyze the relationship between epilepsy and glutamic acid decarboxylase autoantibodies (GADA) in patients with type 1 diabetes mellitus (T1DM) and the impact of GADA on demographic, clinical, and metabolic data in T1DM patients with epilepsy. METHODS: We searched for patients with T1DM ≤20 years and GADA measurements, and within this group for patients with epilepsy. We formed groups: T1DM + Epilepsy + GADA positive; T1DM + Epilepsy + GADA negative; T1DM + GADA positive; T1DM + GADA negative. We used logistic regression to analyze the relationship between epilepsy and GADA with odds ratio adjusted for sex, duration of diabetes (DOD), and age at diabetes onset (ADO). We used logistic regression with odds ratio adjusted for DOD and ADO onset using epilepsy as a dependent variable and GADA, HbA1c, ketoacidosis, severe hypoglycemia (SH), sex, celiac disease, and autoimmune thyroiditis as independent variables. We conducted regression analyses adjusted for sex, DOD, and ADO to analyze differences in clinical/metabolic parameters between the groups. RESULTS: Epilepsy was not more frequent in GADA-positive patients (GPP). Logistic regression including all patients with GADA measurements showed that hypoglycemia with coma (HC) correlated with epilepsy when compared to no SH. We found no differences in clinical and metabolic data between GPP and GADA-negative patients (GNP) with epilepsy. SH occurred more often in GPP with epilepsy in comparison to GPP without epilepsy. GNP with epilepsy had a higher rate of HC than GPP without epilepsy. CONCLUSION: We found no relationship between epilepsy and GADA. A relationship between T1DM and epilepsy might be explainable by SH.

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11ß-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11ß-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11ß-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11ß-hydroxylase deficiency CAH.

A novel mutation of the StAR gene with congenital adrenal hyperplasia and its association with heterochromia iridis: a case report.

BACKGROUND: We report a novel mutation within the StAR gene, causing congenital adrenal hyperplasia, with the so far unreported association with heterochromia iridis. CASE PRESENTATION: In a now 15-year-old girl (born at 41 + 6 weeks of gestation) adrenal failure was diagnosed in the neonatal period based on the clinical picture with spontaneous hypoglycaemia, hyponatremia and an extremely elevated concentration of ACTH (3381 pmol/l; ref. level 1,1-10,1 pmol/l), elevated renin (836 ng/l; ref. level 5-308 ng/l), and a decreased concentration of aldosterone (410 pmol/l; ref. level 886-3540 pmol/l). In addition to hyperpigmented skin the patient exhibited sectorial heterochromia iridis. Sequence analysis of the steroidogenic acute regulatory protein (StAR) gene showed a novel homozygous mutation (c.652G > A (p.Ala218Thr), which was predicted in-silico to be possibly damaging. Under daily steroid substitution her electrolyte levels are balanced while she became obese. Puberty occurred spontaneously. CONCLUSION: A novel mutation in the StAR gene was identified in a patient with severe adrenal hypoplasia and sectorial heterochromia iridis. We discuss a causal relationship between these two rare phenotypes, i.e. whether very high levels of ACTH and alpha-MSH during early development might have disturbed early differentiation and distribution of uveal melanocytes. If confirmed in additional cases, discolorization of the iris might be considered as an additional phenotypical feature in the differential diagnosis of congenital adrenal insufficiency.

Weight loss in obese girls with polycystic ovarian syndrome is associated with a decrease in Anti-Muellerian Hormone concentrations.

OBJECTIVE: The Anti-Muellerian Hormone (AMH) has been reported as surrogate marker of antral follicles, which are the origins of hyperandrogenism in polycystic ovarian syndrome (PCOS). Therefore, AMH may be useful for the diagnosis of PCOS. The objective was to study the longitudinal changes in AMH concentrations in girls with and without PCOS. DESIGN: This is a longitudinal study of obese girls participating in a 1-year lifestyle intervention. PATIENTS: Forty obese girls aged 13-16 years (50% with PCOS) were included in the study. Girls with and without PCOS were matched to age, BMI and change in weight status. MEASUREMENTS: AMH, gonadotropins, androstenedione, testosterone, oestradiol and sex hormone-binding globulin (SHBG) were determined. RESULTS: Obese girls with PCOS demonstrated significantly (P<.001) higher AMH concentrations (5.8±3.1 ng/mL) compared to obese girls without PCOS (2.4±1.4 ng/mL). None of the girls without PCOS had AMH concentrations ≥6 ng/mL and none of the PCOS girls showed AMH concentrations ≤3 ng/mL. Weight loss in girls with PCOS was associated with a significant drop in AMH concentrations (-1.4±1.8 ng/mL, P=.045). AMH was significantly related to testosterone (cross-sectional: b-coefficient 3.7±1.7, P=.001, longitudinal: b-coefficient 0.54±0.47, P=.026) and luteinizing hormone (LH) (cross-sectional: b-coefficient 0.05±0.04, P=.039, longitudinal: b-coefficient 0.005±0.004, P=.039), but not to any other analysed parameter in multiple linear regression analyses adjusted to multiple confounders. CONCLUSIONS: AMH was increased in adolescent girls with PCOS and normalized with weight loss. AMH was cross-sectionally and longitudinally related to hyperandrogenism.

Prenatal maternal distress seems to be associated with the infant's temperament and motor development: an explorative study.

According to the concept of fetal programming, prenatal distress has long-lasting consequences on the offspring's health later in life. The hypothalamic-pituitary-adrenal axis is considered a mediating system by which maternal distress is transferred to the fetus in intrauterine environment. In this longitudinal explorative study on 30 mother-child-dyads, reported maternal distress and salivary cortisol were collected during pregnancy. Infant temperament, motor and cognitive development were assessed at 16 months. Additionally, infant cortisol levels throughout the day and in reaction to a psycho-social stressor where measured. As expected, infants whose mothers had experienced higher prenatal distress expressed a more difficult temperament and lower fine motor development at 16 months. No association could be shown between prenatal maternal distress and infant salivary cortisol.

Copeptin in obese children and adolescents: relationships to body mass index, cortisol and gender.

OBJECTIVE: Copeptin has been reported to be associated with stress, obesity and the metabolic syndrome (MetS) in adults. However, data in childhood are scarce. Therefore, we studied the relationships between copeptin, cortisol, puberty and parameters of the MetS in children. DESIGN: Cross-sectional study. PATIENTS: A total of 51 obese children (10·8 ± 3·2 years, 39% male, 45% prepubertal, body mass index standard deviation score (BMI-SDS) 2·77 ± 0·56) and 24 lean children of similar age, gender and pubertal stage. MEASUREMENTS: Copeptin, serum cortisol, 24-h urinary free cortisol, BMI-SDS and, as parameters of the MetS, insulin resistance index (HOMA), HbA1c, uric acids, blood pressure and lipids. RESULTS: Copeptin levels were significantly (P = 0·047) higher in obese children (5·8 ± 2·8pmol/l) compared to lean children (4·6 ± 2·2pmol/l). BMI-SDS (ß-coefficient 0·38 ± 0·35, P =0·033), but not any parameter of the MetS, was significantly related to copeptin in multiple linear regression analyses adjusted for age, gender and pubertal stage. A 24-h urinary free cortisol (ß-coefficient 0·13 ± 0·06, P < 0·001), but not serum cortisol, was significantly related to copeptin in multiple linear regression analyses adjusted for age, gender, pubertal stage and BMI-SDS. Pubertal boys (6·6 ± 2·8pmol/l) demonstrated significantly (P = 0·042) higher copeptin levels compared to pubertal girls (4·8 ± 2·6pmol/l), while copeptin concentrations did not differ between prepubertal girls and boys. CONCLUSIONS: Copeptin levels are related to 24-h urinary free cortisol in obese children. Pubertal boys, but not prepubertal boys, demonstrated higher copeptin levels than girls, suggesting that sex hormones are involved in the regulation of copeptin levels. Further studies are necessary to understand the relationship between obesity, cortisol, gender, pubertal stage and copeptin levels.

Low prevalence of patients with mitochondrial disease in the German/Austrian DPV diabetes registry.

UNLABELLED: The aim of this study was to characterize the phenotype and treatment of young patients (manifestation <30 years) with diabetes of mitochondrial origin (DMO), based on the German/Austrian DPV (Diabetes Patienten Verlaufsdokumentation) registry. Only 13 (0.02 %) of all patients with diabetes in this cohort were identified with DMO, mainly due to the Kearns-Sayre (n = 5), Pearson (n = 3), or mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome (n = 2). The onset of DMO (14.2, interquartile range (IQR) 7.1-16 years) was later than diabetes onset in individuals with T1D but earlier than in T2D. At manifestation, patients exhibited a mild elevation of blood glucose concentrations (251, IQR 178-299 mg/dl) without ketoacidosis. They had lower body mass index (BMI) values (-1.39 ± 0.28 kg/m(2)) than peers with T1D or T2D (p < 0.0001) and higher triglycerides (211, IQR 134-574 mg/dl) than in T1D (p = 0.04) while there was a high rate of dyslipidemia (86 %). Insulin requirements (0.58, IQR 0.37-0.90 U/kg/d) were between T1D and T2D while glucometabolic control (glycated hemoglobin A1c (HbA1c) 7.4 ± 0.52 %) in DMO was comparable to age-matched T2D and stable over a 5-year follow-up. CONCLUSION: Primary mitochondrial disorders are a rare cause of juvenile diabetes and likely to be underdiagnosed. As there is clinical overlap with T1D and T2D, dyslipidemia and low body weight may help to identify further DMO cases. WHAT IS KNOWN: • In adults diabetes of mitochondrial origin (DMO) is a rare cause of non-autoimmune diabetes, affecting about 0.8 % of diabetes cases. • Common features are a maternal family history of diabetes, hearing loss and neurological abnormalities. What is New: • In our juvenile cohort 0.02 % of diabetes patients (age < 30 years) were affected by DMO, while Kearns Sayre, MELAS and Pearson syndrome were the most frequent entities. • Juvenile DMO patients exhibited dyslipidemia, higher triglycerides and a lower BMI than peers with T1D or T2D, while some patients also showed retinal changes.

The sperm-specific K+ channel Slo3 is inhibited by albumin and steroids contained in reproductive fluids.

To locate and fertilize the egg, sperm probe the varying microenvironment prevailing at different stages during their journey across the female genital tract. To this end, they are equipped with a unique repertoire of mostly sperm-specific proteins. In particular, the flagellar Ca2+ channel CatSper has come into focus as a polymodal sensor used by human sperm to register ligands released into the female genital tract. Here, we provide the first comprehensive study on the pharmacology of the sperm-specific human Slo3 channel, shedding light on its modulation by reproductive fluids and their constituents. We show that seminal fluid and contained prostaglandins and Zn2+ do not affect the channel, whereas human Slo3 is inhibited in a non-genomic fashion by diverse steroids as well as by albumin, which are released into the oviduct along with the egg. This indicates that not only CatSper but also Slo3 harbours promiscuous ligand-binding sites that can accommodate structurally diverse molecules, suggesting that Slo3 is involved in chemosensory signalling in human sperm.

Behavior and circadian glucocorticoids in prepubertal monozygotic twins with birthweight differences: A prospective longitudinal cohort study on twin-to-twin transfusion syndrome patients.

BACKGROUND/OBJECTIVE: Low birthweight may have adverse sequelae in later life. Therefore, we analyzed behavioral difficulties and salivary glucocorticoid profiles in monozygotic twins with intra-twin birthweight differences due to twin-to-twin transfusion syndrome (TTTS). METHODS: 46 monozygotic TTTS twin pairs with birthweight differences of <1SDS (concordant; n=29) and ≥1SDS (discordant; n=17) were recruited at a mean age of 6.9 years for a prospective longitudinal cohort study. For glucocorticoid analysis, saliva samples were collected (at 7 h, 13 h, 18 h and 21 h) and analyzed with liquid chromatography-tandem mass spectrometry. Parents completed the Strengths and Difficulties Questionnaire. RESULTS: From the parents' perspective, the formerly smaller twins had statistically higher scores regarding hyperactivity (mean 4.63 vs 3.48, p=0.003) and emotional problems (mean 2.67 vs 2.02, p=0.042). Less catch-up growth (Δintra-twin height SDS 4 years of age - Δintra-twin birth length SDS) of the smaller twins was associated with higher scores for hyperactivity (Adj. R²=0.261, p<0.001, ß=-1.88, F(1.44)=16.86, n=46, f²=0.35), while smaller birthweight (Adj. R²=0.135, p=0.007, ß=-0,87, F(1.44)=8.03, n=46, f²=0.16) and birth length (Adj. R²=0.085, p=0.028, ß=-0,78, F(1.44)=5.19, n=46, f²=0.09) were associated with higher scores for peer problems. Greater Δintra-twin for cortisol (7 h: rho=0.337, p=0.029; cumulative: rho=0.458; p=0.024) and cortisone (7 h: rho=0.329, p=0.029; 13 h: rho=0.436, p=0.005) correlated with a greater Δintra-twin for conduct problems. In the discordant group, circa 1 SDS in head circumference persisted from birth (mean SDS: smaller twin -1.18, larger twin -0.08, p<0.001) to present (mean SDS: smaller twin -1.16, larger twin -0.14, p<0.001). CONCLUSION: Higher cortisol and cortisone concentrations in smaller twins were associated with higher scores for conduct problems. Lower birthweight and absent catch-up growth affected the parents' perspective on the smaller twins' behavior. They saw those children as more hyperactive, with more peer problems and emotional problems. Thus, it seems important to introduce regular check-ups where behavioral difficulties can be assessed, and assistance and advice can be given to the families. Due to the persisting smaller head circumference in the smaller discordant twins, this should be measured regularly.