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Congenital adrenal hyperplasia (CAH) is a set of defects in cortisol synthesis due to mutations in genes encoding steroidogenic enzymes. Consequently, the loss of glucocorticoid-mediated negative feedback on the HPA axis leads to chronically elevated ACTH (Adrenocorticotropin Hormone) secretion. The sustained ACTH elevation, in turn, stimulates proliferation and hypertrophy of the adrenal cortex and leads to overproduction of androgens. To study the complexity of the ACTH-responsive cell population in the adrenal cortex, we performed single-cell RNA sequencing of the steroidogenic lineage in the adult mouse adrenal. We identified the transcription factor HHEX as a gene with restricted expression in the ACTH-responsive zona fasciculata. Although the role of HHEX in adrenal biology is completely unknown, a meta-analysis identified a germ-line variant of uncertain significance near the gene HHEX associated with increased DHEAS (adrenal-specific androgen) in human serum samples, which led us to hypothesize that HHEX contributes to the unique function of the ACTH-responsive inner cortex. To investigate the mechanisms by which HHEX controls adrenal differentiation and homeostasis, we generated genetically modified mice harboring a deletion of the Hhex gene in the adrenal cortex. Hhex KO mice exhibited progressive adrenomegaly by 15 weeks of age, accompanied by hypertrophy prominent in the inner cortex and disruption of the endothelial organization. Expression of the transcription factor Nr5a1/Sf-1 and steroidogenic enzymes involved in corticosterone production were significantly upregulated at 6 weeks old, prior to adenomegaly, suggesting a precocious increase in cell production of glucocorticoids. For insights into the signaling pathways controlled by HHEX, we analyzed global transcriptional changes during loss of Hhex and found dramatic downregulation of members of the membranous progesterone receptor family (PAQR). PAQR signaling has been implicated in the downregulation of cAMP, a primary mediator of ACTH signaling, and thereby could, in part, drive the increase in steroidogenesis in Hhex KO mice. These findings suggest that the inner cortex contains a progesterone-responsive cell population in which HHEX provides additional fine-tuning of ACTH-driven cAMP signaling by progesterone and derivatives. Since we observed an increase in Hhex expression in a mouse model of CAH, experiments are now ongoing to assess the implication of HHEX and autocrine progesterone signaling in contributing to the hypertrophy and steroidogenic phenotype observed in CAH. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:54 p.m. - 12:59 p.m.

Context Fabry Disease (FD) is a rare X-linked storage disease characterised by a-galactosidase A deficiency and diffuse organ accumulation of glycosphingolipids. Enzyme replacement and chaperone therapies are only partially effective. It remains unclear if FD-related endocrine disorders contribute to the observed morbidity. Objective To investigate the function of the endocrine system in patients with FD. Design We conducted an observational prospective study from 2017 to 2020. Setting and patients We included 77 patients with genetically confirmed FD (27 men, 20/27 Classic, 7/26 Late Onset phenotype, 50 women, 41/50 and 9/50 respectively), who are systematically followed by our reference centre. Results 36/77 (46.8%) patients had VitD deficiency (25(0H)VitD p p = 0.003]. There were no major abnormalities in adrenal, growth and sex-hormone axes. Patients of Classic phenotype had significantly higher High-Density Lipoprotein Cholesterol (HDL-C) levels (p = 0.002) and in men those levels were positively correlated with globotriaosylsphingosin (Lyso-Gb3) values. 10/77 (13%) of the patients were underweight. Conclusions VitD supplementation should be considered for all patients with FD. Thyroid screening should be routinely performed. Malnutrition should be prevented or treated, particularly in Classic phenotype patients. Overall, our data suggest that FD specialists should actively seek and diagnose endocrine disorders in their patients.

The exact risk of type 2 diabetes mellitus (T2DM) in women with polycystic ovary syndrome (PCOS) is unknown. It is also unclear if obesity independently increases T2DM risk in this population. The aim of this study was to systematically review and synthesize the best available evidence regarding the association between PCOS and T2DM, stratified according to obesity status. A comprehensive search was conducted in PubMed, CENTRAL and Scopus databases up to October 31, 2020. Data are expressed as relative risk (RR) with 95% confidence interval (CI). The I2 index was employed for heterogeneity. The eligibility criteria were fulfilled by 23 studies (319,780 participants; 60,336 PCOS and 8847 type 2 diabetes cases). Women with PCOS demonstrated a higher risk of T2DM than those without PCOS (RR 3.45, 95% CI, 2.95–4.05, p

The exact risk of type 2 diabetes mellitus (T2DM) in women with polycystic ovary syndrome (PCOS) is unknown. It is also unclear if obesity independently increases T2DM risk in this population. The aim of this study was to systematically review and synthesize the best available evidence regarding the association between PCOS and T2DM, stratified according to obesity status.A comprehensive search was conducted in PubMed, CENTRAL and Scopus databases up to October 31, 2020. Data are expressed as relative risk (RR) with 95% confidence interval (CI). The IThe eligibility criteria were fulfilled by 23 studies (319,780 participants; 60,336 PCOS and 8847 type 2 diabetes cases). Women with PCOS demonstrated a higher risk of T2DM than those without PCOS (RR 3.45, 95% CI, 2.95-4.05, p 0.001; IWomen with PCOS present an increased risk of T2DM compared with non-PCOS women only if they are obese/overweight.

Background: Levothyroxine (LT4) is one of the most prescribed drugs worldwide. Once started, approximately 90% of patients continue treatment long term. However, accumulating evidence suggests that...

Simple Summary The current clinical gold standard etoposide, doxorubicin, cisplatin, and mitotane (EDP-M) is not satisfying for the treatment of adrenocortical carcinoma (ACC). However, clinical translation of novel, preclinically promising therapies were unfortunately disappointing in recent years, indicating that utilized tumor models inadequately predicted clinical applicability of novel pharmacological approaches. In an attempt to optimize the current preclinical armamentarium, our workgroup initiated a comparative drug screen of clinically relevant chemotherapies and therapies targeting IGF, EGF, and Wnt signaling pathways in the classical NCI-H295R cell line and, for the first time, in the recently developed highly drug-resistant MUC-1 cell line. These testings revealed gemcitabine and cisplatin as a promising combination, but further investigations also indicated developing drug resistance mechanisms on the molecular level. We aimed to decipher underlying resistance mechanisms, identified ribonucleotide reductase as an important player, and successfully targeted the involved DNA damage/repair mechanism. Abstract Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.

BACKGROUND Alopecia areata (AA) is an inflammatory disease with autoimmune, environmental, and inherited components directed at the hair follicle, either limited to patchy hair loss over the scalp (Focalis, AF), total loss of scalp hair (Totalis, AT), or total loss of both scalp and body hair (Universalis, AU). Despite multiple treatment modalities, no therapy exists. Vitamin D deficiency in patients with AA/AT/AF influences disease severity and duration, inversely correlating with inflammation histologically. CASE SUMMARY Three girls presented with AT (P1), AU (P2), and AF (P3) at the ages of 1, 5, and 5 years, respectively. For P1-P2, all available treatments implemented for 2 years had failed. We started an initial 6-mo repletion with oral cholecalciferol 2000/4000 IU/d, with no apparent effect. Then we attempted immunomodulation using oral calcitriol and its analog paricalcitol. On calcitriol, 0.5 mcg/d P1 regrew hair within 6 mo. After 4 years, a relapse with loss of eyebrow hair was resolved after doubling the calcitriol dose to 0.5 mcg × 2/d; the results have been maintained for 6 years to date. On calcitriol, 0.25 mcg × 3/d P2 led to the development of asymptomatic hypercalcemia-hypercalciuria, which was immediately resolved by switching to paricalcitol 2 mcg × 3/d; mild tolerable hypercalciuria was maintained. Hair regrowth was observed at 6 mo, stabilizing only as fur at 12 mo. AF in P3 was resolved completely within 3 mo on a daily high dose (8000 IU) of cholecalciferol. CONCLUSION Vitamin D may have immunomodulating therapeutic impact on AT/AU/AF, which needs to be explored with further pilot clinical trials.

Background/Aims: Polycystic ovary syndrome (PCOS) is associated with disordered carbohydrate metabolism and an increased risk for T2D. However, there are limited data on the magnitude of this risk. Furthermore, 50-80% of women with PCOS are obese and obesity is known to have a synergistic deleterious effect on glucose tolerance in affected women. We systematically reviewed the literature regarding the association between PCOS, obesity and T2D risk. Methods: A comprehensive search was conducted in PubMed, CENTRAL and Scopus databases. Data are expressed as relative risk (RR) with 95% confidence intervals (CI). The I2 index was employed for heterogeneity. The available data, did not allow us to analyze the impact of weight status as normal, overweight and obese and as a consequence the studied subjects were stratified as obese (BMI>30 kg/m2) and non-obese (BMI3-fold increased risk of T2D compared to women without PCOS, but this risk is substantially increased by the presence of obesity. Accordingly, weight reduction should be pursued in these women. References: 1. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38(9):1165-1174.2. Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84(1):165-169.3. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22(1):141-146.4. Rubin KH, Glintborg D, Nybo M, Abrahamsen B, Andersen M. Development and risk factors of type 2 diabetes in a nationwide population of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2017;102(10):3848-3857.

Background: While systemic inflammation is recognized as playing a central role in the pathogenesis of organ failures in patients with liver cirrhosis, less is known about its relevance in the development of classical hepatic decompensation. Aim: To characterize the relationship between systemic inflammation, hemodynamics, and anemia with decompensation of liver cirrhosis. Methods: This is a post-hoc analysis of a cohort study of outpatients with advanced liver fibrosis or cirrhosis. Results: Analysis included 338 patients of whom 51 patients (15%) were hospitalized due to decompensation of liver cirrhosis during a median follow-up time of six months. In univariate analysis, active alcoholism (p = 0.002), model of end-stage liver disease (MELD) score (p = 0.00002), serum IL-6 concentration (p = 0.006), heart rate (p = 0.03), low arterial blood pressure (p &lt, 0.05), maximal portal venous flow (p = 0.008), and low hemoglobin concentration (p &lt, 0.00001) were associated with hospitalization during follow-up. Multivariate analysis revealed an independent association of low hemoglobin (OR = 0.62, 95% CI = 0.51&ndash, 0.78, p = 0.001) and serum IL-6 concentration (OR = 1.02, 95% CI = 1.01&ndash, 1.04, p = 0.03)&mdash, but not of hemodynamic parameters&mdash, with hepatic decompensation. An inverse correlation between hemoglobin concentration and portal venous flow (R = &minus, 0.362, p &lt, 0.0001) was detected for the non-hospitalized patients. Accuracy of baseline hemoglobin levels for predicting hospitalization (AUC = 0.84, p &lt, 0.000001) was high. Conclusion: Anemia and systemic inflammation, rather than arterial circulatory dysfunction, are strong and independent predictors of hepatic decompensation in outpatients with liver cirrhosis.

If circulating adrenal androgens levels rise before the age of 8 years in girls, this phenomenon is termed premature adrenarche (PA), while the concomitant appearance of pubic hair is called premature pubarche (PP). Girls with PA-PP display an unfavorable hormonal profile compared to their normal peers and have an increased risk of developing polycystic ovary syndrome (PCOS) features peripubertally. However, the sequelae of premature adrenarche remains unclear. We assessed metabolic, hormonal, psychologic profiles, and ovarian morphology in 21 women of mean age (±SD) 21.3±3.3 years, BMI: 23.6±4.4 kg/m2 with PA-PP, 45 women with PCOS and 26 controls, matched for age and BMI. PA-PP women displayed a favorable lipid profile compared to PCOS and controls. Insulin resistance index (HOMA-IR), however, were similar in PA-PP and PCOS women (2.09±1.42, 2.08±0.83) and higher than controls (1.13±0.49, p

Polycystic ovary syndrome (PCOS), considered a lifelong condition, manifests mainly as a cluster of hyperandrogenic symptoms during the early reproductive years, with the affected woman gradually developing an adverse cardiometabolic profile over the years. However, some data point to the possibility of differences in the evolution of PCOS according to a woman’s weight. The aim of the present study was to evaluate the metabolic and hormonal profiles of women with PCOS over time. A total of 763 lean women with PCOS (BMI 20–25 kg/m2) and 376 controls were included. The study group was further divided into three age groups representing women post-adolescence, of reproductive age, and of late reproductive age. All subjects were assessed clinically, biochemically, and hormonally. Waist circumference, lipids, androgens, and insulin resistance index (homeostasis model assessment of IR index (HOMA-IR)) were significantly higher in the PCOS group compared with controls. Age subgroup analysis showed a progressive decrease of HOMA-IR and waist circumference, and lipid levels were comparable between PCOS and controls in all age groups. Androgens remained significantly higher in PCOS, but they gradually decreased through time. A significant negative association of age with waist circumference, androgens, insulin, and HOMA-IR was revealed. Univariate and multivariate regression analysis disclosed a strong correlation of HOMA-IR with age (p = 0.014, β − 0.19, SE coefficient 0.008) as a single parameter or in combination with total cholesterol (TC) (p

Context Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. Objective Multicenter survey on current clinical approaches in managing AI during pregnancy. Design Retrospective anonymized data collection from 19 international centers from 2013 to 2019. Setting and Patients 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). Results Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. Conclusions This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.

Background: Polycystic ovary syndrome (PCOS) constitutes one of the most common endocrine diseases that should be considered as a continuum. This life span disease is originating in foetal life and through long reproductive period falling into long-term consequences extending beyond menopause. Hence, it is considered to increase diabetes risk as well cardiovascular risk and outcomes. However, the natural course of the disorder is not completely understood, and recent data suggest differences in the evolution of the disease between normal-weight and obese patients, indicating that the cardiometabolic effects may be an epiphenomenon of the obesity and not of PCOS per se. We aimed to define the evolution of normal-weight Caucasian women with PCOS through the years. Materials and Methods: In this multicenter cross-sectional case control study 763 normal-weight women with PCOS according to Rotterdam criteria and 376 age and BMI-matched controls were included. The study group was further divided into three age groups, representing women post-adolescence, of reproductive age, and of late reproductive age to menopause. All the subjects were assessed clinically, biochemically, hormonally, and with the means of pelvic ultrasound. Results: Waist circumference, WHR, FG score, glucose, lipids, gonadotropin, androgen levels as well as HOMA-IR and ovarian volume were significantly higher in the PCOS group in comparison to controls. No statistical difference was noted among PCOS women diagnosed with the Rotterdam criteria vs. those who met the NIH criteria. Age subgroup analysis showed that androgens remained significantly higher among PCOS and controls, whereas insulin and lipid levels, as well as HOMA-IR, were comparable between PCOS and controls in all age groups. Pearson correlations of studied parameters with age revealed a significant negative association of age with waist circumference, FG score, androgens (testosterone, FAI, DHEAS, D4), insulin, FSH, and HOMA-IR. Finally, multiple regression analysis of factors affecting HOMA-IR disclosed a negative association with age (r:-0.123, p: 0.001) and a positive association with BMI (r: 0.105, p: 0.004) and DHEAS (r: 0.175, p: 0.001). Conclusions: Lipids, androgens, insulin resistance, and menstrual cyclicity are gradually improved in an age-dependent manner in PCOS lean patients and age and BMI matched controls. Normal-weight PCOS women exhibit a higher degree of IR and dyslipidaemia compared to their healthy peers, but these aberrations improve gradually. If PCOS women retain their normal weight over the years, they may develop a metabolic and hormonal profile comparable to that of their peers without PCOS later in life.

The first and rate-limited step of steroidogenesis in all steroidogenic tissues is the conversion of cholesterol to pregnenolone, catalysed by P450scc side-chain cleavage enzyme (CYP11A1 gene—SCC). SCC deficiency has been characterised as an autosomal recessive disorder, although it may also be inherited as an autosomal dominant trait in humans. Here, we describe a family of three members carrying the same novel heterozygous CYP11A1 mutation, a c.235G > A missense variant in exon 1: pVal79Ile. A 46 XY boy (P1) was presented at the age of 3 months with early onset adrenal insufficiency and life-threatening failure to thrive, with low adrenal androgens but normal external genitalia. Five years later, the parents had twin girls, one of whom (P2) presented acute adrenal crisis a few hours after birth. The father (P3), born at term, was reported as having suffered from failure to thrive during the neonatal period, though not his only male sibling. This report of severe early adrenal insufficiency caused by a heterozygous mutation of the CYP11A1 gene clearly demonstrates that SCC deficiency may be inherited as an autosomal dominant trait in humans.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since jeudi 19 mai 2016

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since lundi 27 avril 2015

Atopic dermatitis (AD) is a chronic inflammatory disease affecting children and adolescence. The traditional therapeutic options for AD, including emollients topically and immune modulatory agents systemically focusing on reducing skin inflammation and restoring the function of the epidermal barrier, are proven ineffective in many cases. Several studies have linked vitamin D supplementation with either a decreased risk to develop AD or a clinical improvement of the symptoms of AD patients. In this report, we present a girl with severe AD who under adequate supplementation with cholecalciferol was treated with calcitriol and subsequently with paricalcitol. She had significant improvement—almost healing of her skin lesions within 2 months, a result sustained for more than 3 years now. Because of hypercalciuria as a side effect from calcitriol therapy, treatment was continued with paricalcitol, a vitamin D analogue used in secondary hyperparathyroidism in chronic kidney disease. Calcitriol therapy may be considered as a safe and efficacious treatment option for patients with severe AD, particularly for those with refractory AD, under monitoring for possible side effects. Treatment with paricalcitol resolves hypercalciuria, is safe, and should be further investigated as an alternative treatment of atopic dermatitis and possibly other diseases of autoimmune origin.