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The most frequent endocrine Carney complex manifestation is a bilateral primary pigmented nodular adrenocortical disease and bilateral adrenalectomy (BA) is therefore its main treatment. In this study, a 40 years follow-up of six members of the same family with heterozygous PRKAR1A germline mutation, is reported over two generations. The first cases, two sisters with severe hyperandrogenism and Cushing syndrome (CS) diagnosed in 1972 at age 14 and 25, were successfully treated with unilateral adrenalectomy (UA). Their two brothers were then diagnosed, one with a CS-related severe osteoporosis treated with BA and the other with CS treated with UA. The second generation was diagnosed with CS signs at 7 and 21 years of age and were treated with BA and UA respectively. Out of the four patients treated with UA, the only event possibly related to CS was spontaneous episode of pulmonary embolism, 30 years after surgery. Hormonal evaluation revealed either eucortisolism in one patient or partial adrenal deficiency in two and mild hypercortisolism in one patient. For the two patients with BA, one of them accidentally died. The second one, surprisingly, recovered progressively normal cortisol secretion and circadian variation. Steroid substitution was stopped 6 years after her surgery and we demonstrated by iodocholesterol scintigraphy the presence of bilateral adrenal remnants. In conclusion, our results of long term evolution of PPNAD patients show that UA in this subset of patients could be considered to treat CS. [ABSTRACT FROM AUTHOR]

We present a patient who had surgically confirmed CD but without the full cushingoid phenotype despite markedly elevated cortisol. Nonpathologic causes of elevated ACTH and cortisol were eliminated as were pathogenic variants in the glucocorticoid receptor gene. Further studies of urine metabolites, cortisol half-life, and the ratios of cortisone to cortisol conversion revealed impaired 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. There have only been 2 prior reports of impaired 11β-HSD1 resulting in lack of classic cushingoid features in the past 2 decades. Our patient's presentation and previous reports demonstrate the key role of 11β-HSD1 in modulating intracellular cortisol concentration, therefore shielding the peripheral tissues from the effects of excess cortisol. When patients present with markedly elevated cortisol but without classic cushingoid features, impaired 11β-HSD1 should be considered in the differential diagnosis. [ABSTRACT FROM AUTHOR]

Non-functioning adrenal incidentalomas (NFAIs) have been placed in relationship with a higher risk of glucose profile anomalies, while the full-blown typical picture of Cushing's syndrome (CS) and associated secondary (glucocorticoid-induced) diabetes mellitus is not explicitly confirmed in this instance. Our objective was to highlight the most recent data concerning the glucose profile, particularly, type 2 diabetes mellitus (T2DM) in NFAIs with/without mild autonomous cortisol secretion (MACS). This was a comprehensive review of the literature; the search was conducted according to various combinations of key terms. We included English-published, original studies across a 5-year window of publication time (from January 2020 until 1 April 2024) on PubMed. We excluded case reports, reviews, studies on T1DM or secondary diabetes, and experimental data. We identified 37 studies of various designs (14 retrospective studies as well 13 cross-sectional, 4 cohorts, 3 prospective, and 2 case–control studies) that analysed 17,391 individuals, with a female-to-male ratio of 1.47 (aged between 14 and 96 years). T2DM prevalence in MACS (affecting 10 to 30% of NFAIs) ranged from 12% to 44%. The highest T2DM prevalence in NFAI was 45.2% in one study. MACS versus (non-MACS) NFAIs (n = 16) showed an increased risk of T2DM and even of prediabetes or higher fasting plasma glucose or HbA1c (no unanimous results). T2DM prevalence was analysed in NFAI (N = 1243, female-to-male ratio of 1.11, mean age of 60.42) versus (non-tumour) controls (N = 1548, female-to-male ratio of 0.91, average age of 60.22) amid four studies, and two of them were confirmatory with respect to a higher rate in NFAIs. Four studies included a sub-group of CS compared to NFAI/MACS, and two of them did not confirm an increased rate of glucose profile anomalies in CS versus NFAIs/ACS. The longest period of follow-up with concern to the glycaemic profile was 10.5 years, and one cohort showed a significant increase in the T2DM rate at 17.9% compared to the baseline value of 0.03%. Additionally, inconsistent data from six studies enrolling 1039 individuals that underwent adrenalectomy (N = 674) and conservative management (N = 365) pinpointed the impact of the surgery in NFAIs. The regulation of the glucose metabolism after adrenalectomy versus baseline versus conservative management (n = 3) was improved. To our knowledge, this comprehensive review included one of the largest recent analyses in the field of glucose profile amid the confirmation of MACS/NFAI. In light of the rising incidence of NFAI/AIs due to easier access to imagery scans and endocrine evaluation across the spectrum of modern medicine, it is critical to assess if these patients have an increased frequency of cardio-metabolic disorders that worsen their overall comorbidity and mortality profile, including via the confirmation of T2DM. [ABSTRACT FROM AUTHOR]

Close social connections are essential for mental and physical health and well-being at any age. A significant proportion of the world's population has experienced lockdown conditions due to the COVID-19 pandemic. There is a growing body of scientific literature on the adverse effects of social isolation on attention, memory, perception, executive function, and other aspects of cognitive processes. This can make people's daily lives more difficult, reducing their quality of life. This review seeks to systematize accumulated scientific data acquired in longitudinal population studies on the relationship between social isolation and the development of cognitive impairment in humans, and also analyzes data on the effects of social isolation of different durations on learning and memory processes obtained in experimental studies in animals. Questions are raised regarding the possible connection of these social isolation-induced disorders with changes in the functioning of one of the stress reactivity systems, i.e., the hypothalamic-pituitary-adrenal axis, and the immunoinflammatory response. [ABSTRACT FROM AUTHOR]

Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11b-hydroxylase, 3b-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD. [ABSTRACT FROM AUTHOR]

Glucocorticoid resistance syndrome is a rare disorder with no genetically proven cases reported from India; in addition, there are no descriptions available regarding its management during pregnancy. A 27-year-old woman, hypertensive since the age of 17 years, presented with hypokalemic paresis. She reported regular menses and acne. On investigation, she had elevated serum cortisol that remained unsuppressed after a low-dose dexamethasone suppression test. Genetic analysis revealed a novel, homozygous missense variant in exon 5 of the NR3C1 gene confirming glucocorticoid resistance syndrome. She was managed with oral dexamethasone followed by tapering of antihypertensive drugs. A year later, she conceived with assisted reproductive techniques when dexamethasone was replaced with prednisolone, necessitating the reintroduction of antihypertensive drugs to maintain normotension and potassium supplements to manage hypokalemia. She presented with acute abdomen at 36 weeks of gestation; evaluation revealed right adrenal hemorrhage, which was managed conservatively. Postpartum, the right adrenal lesion reduced in size and an underlying right adrenal myelolipoma was unveiled. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumors (PanNETs) are rare malignant tumors that occur in the pancreas. They are divided into functioning and non-functioning tumors based on the presence or absence of their specific hormonal hyper-expression symptoms. Adrenocorticotropic hormone (ACTH)-producing PanNETs are rare, functional tumors, and their clinical characteristics and outcomes have not been well reported. Here, we report the cases of two patients with PanNETs who presented with ectopic ACTH syndrome (EAS) during the course of their disease. Case 1 involved a non-functioning PanNET at the time of surgery. During treatment for recurrent liver metastases, the patient presented with EAS and tumor-associated hypercalcemia, probably due to ACTH and parathyroid hormone-related peptide (PTHrP) production from the liver tumor. Case 2 was a gastrinoma, and similar to Case 1, this patient presented with EAS during the treatment of recurrent liver metastases. It is not uncommon for patients with PanNETs to have multiple hormones and develop secondary hormone secretion during their disease course, although tumor phenotypes differ between primary and metastatic sites. In patients with functioning PanNETs, symptom control with anti-hormonal therapy is essential, in addition to anti-tumor therapy, especially for EAS, which is an endocrine emergency disease that requires prompt diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Purpose:This article reviews the relevant literature on paraneoplastic neurological syndromes of small cell lung cancer and discusses the clinical presentation, pathophysiology, and diagnosis of these syndromes. It also includes a summary of the current treatment options for the management of them. Views: Paraneoplastic syndromes are a group of signs and symptoms that develop due to cancer in a remote site, mainly triggered by an autoantibody produced by the tissues involved or lymphocytes during anti-cancer defense. Among the cancers associated with paraneoplastic syndromes, lung cancers are the most common type, with small cell lung cancer being the most common subtype. The most common antibody associated with paraneoplastic syndromes is anti-Hu. Neurological and neuroendocrine syndromes comprise the majority of small cell lung cancer-related paraneoplastic syndromes. Classical paraneoplastic neurological syndromes include inappropriate antidiuretic hormone secretion, Cushing’s syndrome, myasthenia gravis, Lambert-Eaton myasthenic syndrome, limbic encephalitis, paraneoplastic cerebellar degeneration, opsoclonus myoclonus ataxia, sensory neuropathy, and chorea. Conclusions: Antibodies mediate paraneoplastic syndromes, and antibody detection is a crucial part of diagnosing these entities. Managing the underlying tumor is the best treatment approach for most paraneoplastic syndromes. Therefore, early diagnosis of small cell lung cancer may significantly improve the prognosis of paraneoplastic syndromes associated with it. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GC) such as cortisol regulate multiple physiol ogical functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert their e ffects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene in humans). GC signaling follows several consecutive step s leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, and recruitment of functional transcriptional machinery. Generalized glucocorticoid resistance syndrome, due to GR loss-of-function mutations, may be related to the impairment of one of the GC signaling steps. To date, 31 NR3C1 loss-of-function mutations have been reported in patients prese nting with various clinical signs such as hypertension, adrenal hyperplasia, hirsutism or metabolic disorders associated with biological hypercortisolism but without Cushing syndrome signs and no negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Functional characterization of GR loss-of-function mutations often demonstrates GR haploinsufficiency and a decrease of GR target gene induction in relevant cell types. The main signs at presentation are very variable from resistant hypertension, bilateral adrenal hyperplasia likely related to i ncreased ACTH levels but not exclusively, hirsutism to isolated renin-angiotensin-aldosterone system abnormalities in a context of 11ßHSD2 deficiency. Some mutated GR patients are obese or overweight together with a healthier meta bolic profile that remains to be further explored in future studies. Deciphering the molecular mechanisms altered by GR mutations should enhance our knowledge on GR signaling and ultimately facilitate management of GC-resista nt patients. This review also focuses on the criteria facilitating identification of novel NR3C1 mutations in selected patients. Correspondence. [ABSTRACT FROM AUTHOR]

Background: Obesity, a condition associated with the development of widespread cardiovascular disease, metabolic disorders, and other health complications, has emerged as a significant global health issue. Oleanolic acid (OA), a pentacyclic triterpenoid compound that is widely distributed in various natural plants, has demonstrated potential anti-inflammatory and anti-atherosclerotic properties. However, the mechanism by which OA fights obesity has not been well studied. Method: Network pharmacology was utilized to search for potential targets and pathways of OA against obesity. Molecular docking and molecular dynamics simulations were utilized to validate the interaction of OA with core targets, and an animal model of obesity induced by high-fat eating was then employed to confirm the most central of these targets. Results: The network pharmacology study thoroughly examined 42 important OA targets for the treatment of obesity. The key biological processes (BP), cellular components (CC), and molecular functions (MF) of OA for anti-obesity were identified using GO enrichment analysis, including intracellular receptor signaling, intracellular steroid hormone receptor signaling, chromatin, nucleoplasm, receptor complex, endoplasmic reticulum membrane, and RNA polymerase II transcription Factor Activity. The KEGG/DAVID database enrichment study found that metabolic pathways, PPAR signaling pathways, cancer pathways/PPAR signaling pathways, insulin resistance, and ovarian steroidogenesis all play essential roles in the treatment of obesity and OA. The protein-protein interaction (PPI) network was used to screen nine main targets: PPARG, PPARA, MAPK3, NR3C1, PTGS2, CYP19A1, CNR1, HSD11B1, and AGTR1. Using molecular docking technology, the possible binding mechanism and degree of binding between OA and each important target were validated, demonstrating that OA has a good binding potential with each target. The molecular dynamics simulation's Root Mean Square Deviation (RMSD), and Radius of Gyration (Rg) further demonstrated that OA has strong binding stability with each target. Additional animal studies confirmed the significance of the core target PPARG and the core pathway PPAR signaling pathway in OA anti-obesity. Conclusion: Overall, our study utilized a multifaceted approach to investigate the value and mechanisms of OA in treating obesity, thereby providing a novel foundation for the identification and development of natural drug treatments. [ABSTRACT FROM AUTHOR]

Introduction: Diabetes mellitus in pregnancies is associated with adverse outcomes both for the mothers and babies. Postponing pregnancy in unoptimized conditions and stabilisation of glucose should be prioritized. This scoping review is aimed to determine the scope and at the same time map the types of evidence available that is related to family planning behaviours among women with diabetes mellitus, with a particular focus on their factors which influence family planning usage and subsequently enable the identification of knowledge gaps in preventing unintended pregnancies among this high-risk population. Methods: This scoping review is guided by the methodological framework by Arksey and O'Malley's and Prisma-ScR checklist. PubMed, EBSCO and OVID were searched for empirical studies between 2000 and February 2022 using the search terms "family planning", "contraceptive" and "diabetes mellitus". Data were summarized according to the study characteristics and levels of factors influencing family planning behaviours. Results: Thirty-five articles that met the eligibility criteria included 33 quantitative studies, one qualitative study and one mixed-methods study. The prevalence of family planning methods used by women with diabetes mellitus varied ranging from 4.8 to 89.8% among the studied population. Women with diabetes mellitus were reported to be less likely to utilise any family planning methods compared to women without diabetes mellitus. Conclusions: Most of the evidence to date on family planning behaviours among women with diabetes mellitus focuses on the role of individual level sociodemographic factors. Few studies focused on exploring determinants at multiple levels. In this review we found that there is limited evidence on disease control and pregnancy intention in relation to their family planning practices. Future studies with more clinical and contextual factors are needed to guide the strengthening of family planning services for high-risk group women specifically for women with diabetes mellitus. Plain English summary: As the prevalence of diabetes mellitus is increasing globally, more women in reproductive age group are living with diabetes mellitus. Pregnant women with uncontrolled diabetes mellitus have higher risk for complications, both to the mothers and the baby. Therefore, it is very important that family planning needs of women with diabetes mellitus are met. This review is aimed to identify what is known and not known about the factors influencing family planning behaviours among women with diabetes mellitus. We searched three databases for studies published from 2000 to February 2022. Our review included 35 articles and nearly all of the studies were quantitative, with one qualitative and one mixed-methods study. Among the studies that compared between women with diabetes mellitus and without diabetes mellitus, less women with diabetes mellitus were using family planning. Some papers also include the reasons or barriers for using family planning among the studied population. Majority of the articles described sociodemographic were factors related to family planning usage, while only few studies explored beyond individual factors. Little information on the clinical profile of the women with diabetes mellitus were known. Future research should examine clinical and other non-individual factors influencing family planning among this particular group of women as sexual and reproductive health in general is very much influenced by cultural or healthcare system factors. [ABSTRACT FROM AUTHOR]

Context Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with obesity, insulin resistance, and dyslipidemia. Hyperandrogenism is a major characteristic of PCOS. Increased androgen exposure is believed to deregulate metabolic processes in various tissues as part of the PCOS pathogenesis, predominantly through the androgen receptor (AR). Notably, various metabolic features in PCOS are similar to those observed after excess glucocorticoid exposure. Objective We hypothesized that glucocorticoid receptor (GR) signaling is involved in the metabolic symptoms of PCOS. Methods In a PCOS model of chronic dihydrotestosterone (DHT) exposure in female mice, we investigated whether GR signaling machinery was (de)regulated, and if treatment with a selective GR antagonist alleviated the metabolic symptoms. Results We observed an upregulation of GR messenger RNA expression in the liver after DHT exposure. In white adipose tissues and liver we found that DHT upregulated Hsd11b1 , which encodes for the enzyme that converts inactive into active glucocorticoids. We found that preventive but not therapeutic administration of a GR antagonist alleviated DHT-induced hyperglycemia and restored glucose tolerance. We did not observe strong effects of GR antagonism in DHT-exposed mice on other features like total fat mass and lipid accumulation in various tissues. Conclusion We conclude that GR activation may play a role in glucose metabolism in DHT-exposed mice. [ABSTRACT FROM AUTHOR]

Background: Unwanted pregnancies in diabetic women can endanger the mother and the fetus. The present study was conducted to determine contraceptive methods for diabetic women referred to government diabetes clinics in the north of Iran. Methods: A total of 153 diabetic women referred to government clinics in Guilan were included in this cross-sectional study. A questionnaire made by the researcher regarding personal and social information and information related to contraceptive methods was administered. Data were analyzed analytically using SPSS version 19. Results: The findings of the present study revealed that 87.6% of diabetic women used contraceptive methods, of which 44.4% utilized low-effective contraceptive methods (withdrawal method and condoms), and 43.2% opted for highly effective contraceptive methods (tubal ligation, oral contraceptive pill, intrauterine device, and vasectomy). Decision regarding the choice of contraceptive methods was mainly made by couples, followed by consultation with a doctor. Conclusions: A relatively high percentage of diabetic women use less effective contraceptive methods, and the decision to use contraceptive methods is made mainly by couples. Therefore, targeted reproductive health interventions and providing counseling services as part of medical care for diabetic women seem necessary. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent metabolic disease, although prevalence could change according to region, nowadays is considered a public health problem whose real impact on the health system is unknown. NAFLD has a multifactorial and complex pathophysiology, due to this, developing a unique and effective pharmacological treatment has not been successful in reverting or avoiding the progression of this liver disease. Even though NAFLD pathophysiology is known, all actual treatments are focused on modifying or regulating the metabolic pathways, some of which interplay with obesity. It has been known that impairments in hunger and satiety signals are associated with obesity, however, abnormalities in these signals in patients with NAFLD and obesity are not fully elucidated. To describe these mechanisms opens an additional option as a therapeutic target sharing metabolic pathways with NAFLD, therefore, this review aims to describe the hormones and peptides implicated in both hunger-satiety in NAFLD. It has been established that NAFLD pharmacological treatment cannot be focused on a single purpose; hence, identifying interplays that lead to adding or modifying current treatment options could also have an impact on another related outcome such as hunger or satiety signals. [ABSTRACT FROM AUTHOR]

Patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) usually present bilateral benign adrenocortical macronodules at imaging and variable levels of cortisol excess. PBMAH is a rare cause of primary overt Cushing's syndrome but may represent up to one-third of bilateral adrenal incidentalomas with evidence of cortisol excess. The increased steroidogenesis in PBMAH is often regulated by various G protein–coupled receptors (GPCRs) aberrantly expressed in PBMAH tissues; some receptor ligands are ectopically produced in PBMAH tissues, creating aberrant autocrine/paracrine regulation of steroidogenesis. The bilateral nature of PBMAH and familial aggregation led to the identification of germline heterozygous inactivating mutations of the ARMC5 gene, in 20% to 25% of the apparent sporadic cases and more frequently in familial cases; ARMC5 mutations/pathogenic variants can be associated with meningiomas. More recently, combined germline mutations/pathogenic variants and somatic events inactivating the KDM1A gene were specifically identified in patients affected by glucose-dependent insulinotropic peptide (GIP)-dependent PBMAH. Functional studies demonstrated that inactivation of KDM1A leads to GIP-receptor (GIPR) overexpression and over- or downregulation of other GPCRs. Genetic analysis is now available for early detection of family members of index cases with PBMAH carrying identified germline pathogenic variants. Detailed biochemical, imaging, and comorbidity assessment of the nature and severity of PBMAH is essential for its management. Treatment is reserved for patients with overt or mild cortisol/aldosterone or other steroid excesses, taking in account comorbidities. It previously relied on bilateral adrenalectomy; however, recent studies tend to favor unilateral adrenalectomy or, less frequently, medical treatment with cortisol synthesis inhibitors or specific blockers of aberrant GPCR. [ABSTRACT FROM AUTHOR]

We examined the effectiveness of a 26-week culture-inclusive intervention on reducing salivary stress biomarker levels, and perceived stress, depressive, and post-traumatic stress disorder (PTSD) symptoms measured using scales in 53 Indigenous women in Ontario, Canada. Statistical analyses compared the average biomarker levels, and the area under the curve (AUC) of biomarkers. Differences in biomarkers and mental health scale scores pre- and post-intervention were compared using mixed models with a random intercept. Interaction terms were included between the intervention and age, education, disability, and HIV status, individually, to test for sub-group differences. Cortisol AUC post-intervention was decreased compared to pre-intervention (β -1.29 µg/dL; 95%CI -2.35, -0.23). There was a slight decrease in perceived stress levels (aOR: -2.80; 95%CI -5.09, -0.50). The associations were stronger among women of younger age, higher education, and no disabilities. These interventions can be effective, but future interventions should target Indigenous population sub-groups to address individual needs. [ABSTRACT FROM AUTHOR]

Glucocorticoid resistance syndrome is a rare genetic condition characterized by generalized or partial target-tissue insensitivity to glucocorticoids and a consequent hyperactivation of the hypothalamic-pituitary-adrenal axis. Clinical manifestations may include mineralocorticoid and/or androgen excess without manifestations of Cushing syndrome. At a cellular level, glucocorticoid actions are mediated by the nuclear glucocorticoid receptor encoded by the NR3C1 gene. To date, only 33 glucocorticoid receptor loss-of-function pathogenic variants have been associated with glucocorticoid resistance syndrome. The NR3C1 gene has 2 known disease-causing mechanisms: haploinsufficiency and negative dominance. We describe a mother and her son with a mild hyperandrogenic phenotype and a novel genetic variant of the NR3C1 gene predicting a truncated protein and causing glucocorticoid resistance syndrome. To date, no accurate genotype-phenotype correlation has been found. [ABSTRACT FROM AUTHOR]

A man in his 20s was referred by his general practitioner because of the finding of adrenocorticotropic hormone (ACTH)-dependent hypercortisolaemia, discovered as part of investigation of fatigue and alopecia. The man had no other clinical findings suggestive of Cushing syndrome. Further investigation revealed intact diurnal rhythm in cortisol production, normal bone density and excluded assay interference. Further investigation revealed the man’s sibling had been labelled as having Cushing syndrome because of similar biochemical abnormalities. A diagnosis of familial primary generalised glucocorticoid resistance syndrome was made. Testing for mutations in the NR3C1 gene is awaited. [ABSTRACT FROM AUTHOR]

Global Coronavir us disease 2019 (COVID-19) vaccination efforts are being intensified to combat the pandemic. As the frequency of immunization against COVID-19 has increased, some adverse effects related to vaccination have emerged. Within this context, this article reviewed 62 Graves' disease (GD) cases following COVID-19 vaccination, to probe the potential association between the vaccination and the onset of GD. A comprehensive search of the PubMed, Web of Science, and Scopus databases was conducted to collect GD cases following COVID-19 vaccination up to June 7, 2023. Among the 62 GD cases included in this review, there were 33 (53.2%) new-onset GD and 10 (16.1%) relapsed GD patients following mRNA vaccination, 14 (22.6%) new-onset GD and 4 (6.5%) relapsed GD patients following viral vector vaccination, and 1 (1.6%) relapsed GD patients following inactivated vaccination. Median durations to symptoms onset for new-onset and relapsed GD were 12 (range: 1–60) and 21 (range: 5–30) days following mRNA vaccination, while 7 (range: 1–28) and 14 (range: 10–14) days following viral vector vaccination, respectively. While the definitive pathogenesis of GD following COVID-19 vaccination remains unclear, it might be associated with cross-immune responses triggered by molecular mimicry, and an adjuvant-induced autoimmune/inflammatory syndrome. However, due to the limited number of observed GD cases following COVID-19 vaccination and the lack of systematic experimental studies, a causal relationship between COVID-19 vaccination and the onset of GD has not been definitively confirmed. It should be highlighted that most of GD patients following COVID-19 vaccination experienced positive outcomes after treatment. In the broader context of ending the COVID-19 pandemic and reducing mortality rates, the benefits of COVID-19 vaccination significantly outweigh mild risks such as treatable GD. Adherence to the COVID-19 vaccination schedule is therefore imperative in effectively managing the pandemic. [ABSTRACT FROM AUTHOR]

A previously healthy 11-year-old male was found to have a mass in the pancreatic head after several months of abdominal pain and jaundice. Pathology was consistent with a World Health Organization grade 2 pancreatic neuroendocrine tumor. He developed refractory hypertension and was found to have Cushing syndrome from ectopic ACTH secretion, with oligometastatic liver disease. He underwent surgical resection of the pancreatic tumor and metastases. Postoperatively, his Cushing syndrome resolved, but it reemerged 1 year later in the setting of disease recurrence. He was not a candidate for bilateral adrenalectomy. Ketoconazole therapy was inadequate and he was started on metyrapone, lanreotide, cabergoline, and spironolactone. Although this regimen was well-tolerated, his Cushing syndrome recurred 4 months later as his metastatic disease burden increased. Osilodrostat was begun and the dose was gradually increased in response to his uncontrolled Cushing syndrome. Osilodrostat resulted in rapid improvement and eventual normalization of his urinary free cortisol at a dose of 18 mg twice daily. He had no adverse effects. This rare case highlights the successful off-label use of osilodrostat, a medication intended for refractory Cushing disease in adult patients, in a pediatric patient with Cushing syndrome caused by ectopic ACTH secretion. [ABSTRACT FROM AUTHOR]

Background: Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is characterized by immune system dysregulation after exposure to adjuvants, such as aluminum. Although cases of autoimmune thyroid diseases caused by ASIA have been reported, Graves' disease is one of the rarer diseases. There are some reports that vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause ASIA. Here, we describe a case of Graves' disease following SARS-CoV-2 vaccination and a review of the literature. Case presentation: A 41-year-old woman was admitted to our hospital because of palpitations and fatigue. Two weeks after receiving the second SARS-CoV-2 vaccine (BNT162b2, Coronavirus Modified Uridine messenger RNA (mRNA) Vaccine, Pfizer), she developed fatigue and gradually worsened. On admission, she exhibited thyrotoxicosis (thyroid-stimulating hormone (TSH) < 0.01 mIU/L (0.08–0.54), free triiodothyronine (FT3) 33.2 pmol/L (3.8–6.3), and free thyroxine (FT4) 72.1 pmol/L (11.6–19.3)) and palpitations associated with atrial fibrillation. TSH receptor antibody (TRAb) was positive (TRAb 5.0 IU/L (< 2.0)), and 99mTc scintigraphy showed diffuse uptake in the thyroid gland, suggesting that the thyrotoxicosis in this case was caused by Graves' disease. Thiamazole was prescribed to correct her condition, and soon after this treatment was initiated, her symptoms and thyroid hormone levels were significantly reduced. Conclusions: This case report reinforces the potential correlation between ASIA affecting the thyroid and SARS-CoV-2 mRNA vaccines. The clinical course suggests that it is essential to consider the possibility of developing ASIA, such as Graves' disease, after exposure to the SARS-CoV-2 vaccine. [ABSTRACT FROM AUTHOR]

Context: Prospective studies have demonstrated the efficacy of osilodrostat in Cushing disease. No study has evaluated osilodrostat in a series of patients with paraneoplastic Cushing syndrome/ectopic adrenocorticotropin syndrome (PNCS/EAS). Objective: This work aimed to evaluate in France the real-world efficacy and safety of osilodrostat in patients with PNCS/EAS. Methods: A total of 33 patients with PNCS/EAS with intense/severe hypercortisolism were involved in this retrospective, multicenter, real-world study. Patients received osilodrostat between May 2019 and March 2022 at a median initial dose (range) of 4 mg/day (1-60) and maximum dose, 20 mg/day (4-100), first under patient then cohort temporary authorizations and after marketing authorization. Regimens used titration (n=6), block and replace (n =16), or titration followed by block and replace (n =11). Results: In 11 patients receiving osilodrostat as first-line monotherapy, median 24-hour urinary free cortisol (24h-UFC) decreased dramatically (from 26 x upper limit of normal [ULN; 2.9-659] to 0.11 x ULN [0.08-14.9]; P< .001). In 9 of them, 24h-UFC normalization was achieved in 2 weeks (median). Thirteen additional patients were previously treated with classic steroidogenesis inhibitors but 10 of these 13 were not controlled. In these patients, osilodrostat monotherapy, used as second line, induced a significantly decreased of 24h-UFC (from 2.6 x ULN [1.1-144] to 0.22 x ULN [0.12-0.66]; P<.01). Nine additional patients received osilodrostat in combination with another anticortisolic drug, decreasing 24h- UFC from 11.8 x ULN (0.3-247) to 0.43 x ULN (0.33-2.4) (P<.01). In parallel, major clinical symptoms/comorbidities improved dramatically with improvement in blood pressure, hyperglycemia, and hypokalemia, allowing the discontinuation or dose reduction of patient treatments. Adrenal insufficiency (grade 3-4) was reported in 8 of 33 patients. Conclusion: Osilodrostat is a rapidly efficient therapy for PNCS/EAS with severe/intense hypercortisolism. Osilodrostat was generally well tolerated; adrenal insufficiency was the main side effect. [ABSTRACT FROM AUTHOR]

Over several decades, excess glucocorticoids (GCs) of endogenous or exogenous origin have been recognized to significantly inhibit collagen synthesis and accelerate skin aging. However, little is known regarding their molecular mechanisms. We hypothesized that the action of GCs on collagen production is at least partially through the glucocorticoid receptor (GR) and its target genes, and therefore aimed to identify GR target genes that potentially inhibit collagen synthesis in Hs68 human dermal fibroblasts. We first confirmed that dexamethasone, a synthetic GC, induced canonical GR signaling in dermal fibroblasts. We then collected 108 candidates for GR target genes reported in previous studies on GR target genes and verified that 17 genes were transcriptionally upregulated in dexamethasone-treated dermal fibroblasts. Subsequently, by individual knockdown of the 17 genes, we identified that six genes, AT-rich interaction domain 5B, FK506 binding protein 5, lysyl oxidase, methylenetetrahydrofolate dehydrogenase (NADP + dependent) 2, zinc finger protein 36, and zinc fingers and homeoboxes 3, are potentially involved in GC-mediated inhibition of collagen synthesis. The present study sheds light on the molecular mechanisms of GC-mediated skin aging and provides a basis for further research on the biological characteristics of individual GR target genes. [ABSTRACT FROM AUTHOR]

Indigenous women encounter increased stressful life experiences such as socioeconomic insecurities as well as inequities in health services and outcomes. These stress inequities, which stem from the historical and ongoing effects of settler colonialism, also worsen health outcomes for those women living with HIV. As a part of a broader research project on the impacts of stress-reducing interventions for indigenous women, this study examines the experiences of the women who facilitated the intervention. This research was conducted to evaluate the impacts of a biweekly stress-reducing intervention conducted in Thunder Bay, Ontario. The facilitators of the intervention participated in a focus group in 2019 where they detailed the reach, effectiveness, adoption, and implementation of the intervention. The results suggest that effective stress-reducing interventions should strive to be accessible and inclusive and that doing so can increase program engagement with the service organization hosting the intervention. Further, the results highlight the strengths and challenges of the intervention, including how it helped foster leadership skills and increased indigenous cultural learning among facilitators. These findings demonstrate the strength of community-led interventions and subsequent opportunities for facilitators to grow as leaders. Further, the study highlights how this style of intervention can also encourage participants to engage in other health and wellbeing programs offered by the community partner hosting the intervention. These findings suggest that interventions aimed at reducing stress among indigenous women facing socioeconomic insecurities, including those living with HIV, are both feasible and beneficial for participants, facilitators, and the nonprofit service organizations delivering them. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is the leading cause of death from gynecological malignancies worldwide. Fortunately, recent advances in OC biology and the discovery of novel therapeutic targets have led to the development of novel therapeutic agents that may improve the outcome of OC patients. The glucocorticoid receptor (GR) is a ligand-dependent transcriptional factor known for its role in body stress reactions, energy homeostasis and immune regulation. Notably, evidence suggests that GR may play a relevant role in tumor progression and may affect treatment response. In cell culture models, administration of low levels of glucocorticoids (GCs) suppresses OC growth and metastasis. Conversely, high GR expression has been associated with poor prognostic features and long-term outcomes in patients with OC. Moreover, both preclinical and clinical data have shown that GR activation impairs the effectiveness of chemotherapy by inducing the apoptotic pathways and cell differentiation. In this narrative review, we summarize data related to the function and role of GR in OC. To this aim, we reorganized the controversial and fragmented data regarding GR activity in OC and herein describe its potential use as a prognostic and predictive biomarker. Moreover, we explored the interplay between GR and BRCA expression and reviewed the latest therapeutic strategies such as non-selective GR antagonists and selective GR modulators to enhance chemotherapy sensitivity, and to finally provide new treatment options in OC patients. [ABSTRACT FROM AUTHOR]

Background: The anti-osteosarcoma effects of hydrocortisone and thiram, an inhibitor of type 2 11ß-hydroxysteroid dehydrogenase (11HSD2), have not been reported. The purpose of this study was to investigate the effects of hydrocortisone alone or the combination of hydrocortisone with thiram on osteosarcoma and the molecular mechanism, and determine whether they can be as new therapeutic agents for osteosarcoma. Methods: Normal bone cells and osteosarcoma cells were treated with hydrocortisone or thiram alone or in combination. The cell proliferation, migration, cell cycle and apoptosis were detected by using CCK8 assay, wound healing assay, and flow cytometry, respectively. An osteosarcoma mouse model was established. The effect of drugs on osteosarcoma in vivo was assessed by measuring tumor volume. Transcriptome sequencing, bioinformatics analysis, RT–qPCR, Western blotting (WB), enzymelinked immunosorbent assay (ELISA) and siRNA transfection were performed to determine the molecular mechanisms. Results: Hydrocortisone inhibited the proliferation and migration, and induced apoptosis and cell cycle arrest of osteosarcoma cells in vitro. Hydrocortisone also reduced the volume of osteosarcoma in mice in vivo. Mechanistically, hydrocortisone decreased the levels of Wnt/β-catenin pathway-associated proteins, and induced the expression of glucocorticoid receptor α (GCR), CCAAT enhancer-binding protein β (C/EBP-beta) and 11HSD2, resulting in a hydrocortisone resistance loop. Thiram inhibited the activity of the 11HSD2 enzyme, the combination of thiram and hydrocortisone further enhanced the inhibition of osteosarcoma through Wnt/β-catenin pathway. Conclusions: Hydrocortisone inhibits osteosarcoma through the Wnt/β-catenin pathway. Thiram inhibits 11HSD2 enzyme activity, reducing hydrocortisone inactivation and promoting the effect of hydrocortisone through the same pathway. [ABSTRACT FROM AUTHOR]

The liver is the central metabolic organ of the body. The plethora of anabolic and catabolic pathways in the liver is tightly regulated by physiological signaling but may become imbalanced as a consequence of malnutrition or exposure to certain chemicals, so-called metabolic endocrine disrupters, or metabolism-disrupting chemicals (MDCs). Among different metabolism-related diseases, obesity and non-alcoholic fatty liver disease (NAFLD) constitute a growing health problem, which has been associated with a western lifestyle combining excessive caloric intake and reduced physical activity. In the past years, awareness of chemical exposure as an underlying cause of metabolic endocrine effects has continuously increased. Within this review, we have collected and summarized evidence that certain environmental MDCs are capable of contributing to metabolic diseases such as liver steatosis and cholestasis by different molecular mechanisms, thereby contributing to the metabolic syndrome. Despite the high relevance of metabolism-related diseases, standardized mechanistic assays for the identification and characterization of MDCs are missing. Therefore, the current state of candidate test systems to identify MDCs is presented, and their possible implementation into a testing strategy for MDCs is discussed. [ABSTRACT FROM AUTHOR]

Background: As a powerful anti‐inflammatory, immunosuppressive, and antiproliferative drug, glucocorticoid (GC) plays an important role in the treatment of various diseases. However, some patients may experience glucocorticoid resistance (GCR) in clinical, and its molecular mechanism have not been determined. Methods: The authors performed a review of the literature on GCR focusing on mutations in the NR3C1 gene and impaired glucocorticoid receptor (GR) signalling, using METSTR (2000 through May 2022) to identify original articles and reviews on this topic. The search terms included 'glucocorticoid resistance/insensitive', 'steroid resistance/insensitive', 'NR3C1', and 'glucocorticoid receptor'. Results: Primary GCR is mainly caused by NR3C1 gene mutation, and 31 NR3C1 gene mutations have been reported so far. Secondary GCR is caused by impaired GC signalling pathways, including decreased expression of GR, impaired nuclear translocation of GR, and impaired binding of GR to GC and GR to target genes. However, the current research is more on the expression level of GR, and there are relatively few studies on other mechanisms. In addition, methods for improving GC sensitivity are rarely reported. Conclusion: The molecular mechanisms of GCR are complex and may differ in different diseases or different patients. In future studies, when exploring the mechanism of GCR, methods to improve GC sensitivity should also be investigated. [ABSTRACT FROM AUTHOR]

The pharmacological treatment of systemic lupus erythematosus (SLE) aims to decrease disease activity, progression, systemic compromise, and mortality. Among the pharmacological alternatives, there are chemically synthesized drugs whose efficacy has been evaluated, but which have the potential to generate adverse events that may compromise adherence and response to treatment. Therapy selection and monitoring will depend on patient characteristics and the safety profile of each drug. The aim of this review is to provide a comprehensive understanding of the most important synthetic drugs used in the treatment of SLE, including the current treatment options (mycophenolate mofetil, azathioprine, and cyclophosphamide), review their mechanism of action, efficacy, safety, and, most importantly, provide monitoring parameters that should be considered while the patient is receiving the pharmacotherapy. [ABSTRACT FROM AUTHOR]

A clinical quiz on a case of a child patient with growth retardation and late-onset hypertension is presented.

(1) Background: Autoimmune diseases, including autoimmune endocrine diseases (AIED), are thought to develop following environmental exposure in patients with genetic predisposition. The vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could represent a new environmental trigger for AIED, including Graves' disease (GD). (2) Methods: We performed a literature search of MEDLINE/PubMed databases regarding thyroid dysfunction after SARS-CoV-2 vaccination since 1 January 2020 to 31 July 2022, considering only cases of thyrotoxicosis that meet the 2016 American Thyroid Association guidelines criteria for the diagnosis of GD and arising after administration of the anti-SARS-CoV-2 vaccine, regardless of the number of doses. (3) Results: A total of 27 articles were identified, consisting of case reports or case series, of which 24 describe the appearance of 48 new diagnoses of GD and 12 GD recurrences arising after the administration of the anti-SARS-CoV-2 vaccine, and 3 papers that instead report only 3 cases of GD relapse following vaccination. (4) Conclusions: physicians should be aware of the possibility of developing GD and other autoimmune sequelae following SARS-CoV-2 vaccination. Regardless of the underlying pathogenetic mechanisms (autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome), cytokines induction, molecular mimicry, and cross-reactivity), an individual predisposition seems to be decisive for their development. [ABSTRACT FROM AUTHOR]

Hypertension is one of the leading causes of premature death in humans and exhibits a complex aetiology including environmental and genetic factors. Mutations within the glucocorticoid receptor (GR) can cause glucocorticoid resistance, which is characterized by several clinical features like hypercortisolism, hypokalaemia, adrenal hyperplasia and hypertension. Altered glucocorticoid receptor signalling further affects sodium and potassium homeostasis as well as blood pressure regulation and cell proliferation and differentiation that influence organ development and function. In salt-sensitive hypertension, excessive renal salt transport and sympathetic nervous system stimulation may occur simultaneously, and, thus, both the mineralocorticoid receptor (MR) and the GR-signalling may be implicated or even act interdependently. This review focuses on identified GR mutations in human primary generalized glucocorticoid resistance (PGGR) patients and their related clinical phenotype with specific emphasis on adrenal gland hyperplasia and hypertension. We compare these findings to mouse and rat mutants harbouring genetically engineered mutations to further dissect the cause and/or the consequence of clinical features which are common or different. [ABSTRACT FROM AUTHOR]

In the present study, we investigated the antioxidant effect of grape seed extract (GSE) against chronic immobilization stress‐induced zona fasciculata injury in Wistar male rats. Thirty male rats were divided into three groups: Non‐stress group: rats were not subjected to stress protocol and received distilled water orally for 30 days. Stress group: rats received distilled water orally for 15 consecutive days before the induction of chronic immobilization stress experiment (repeated stress for 15 consecutive days), distilled water was continued along with the constant stress experiment. GSE‐stress group: rats treated with oral GSE (300 mg/kg), administered orally for 15 consecutive days before the induction of chronic immobilization stress experiment (repeated stress for 15 consecutive days), GSE was continued along with the stress exposure. Chronic stress was induced by placing each animal in a restrainer for 2 h daily for 15 consecutive days in both Stress and GSE‐stress groups. The serum corticosterone and adrenal cortex malondialdehyde (MDA) levels were measured as indices of stress. Immunohistochemistry of the inducible nitric oxide synthase (iNOS) as a nitrosative stress marker beside the adrenal cortex's ultrastructure, particularly zona fasciculata, was assessed. Chronic restraint stress significantly elevated the serum corticosterone and adrenal cortex MDA levels, while oral administration of GSE reduced the serum corticosterone level, adrenal cortex MDA levels, and iNOS immunoreactivity in zona fasciculata. Besides, adrenocortical ultrastructure significantly improved. These results suggested that GSE enhanced the antioxidant defense against reactive oxygen species produced under chronic stress conditions, protecting the adrenal cortex. Research Highlights: This research highlighted the significant protective effects of grape seed extract administration on the histological findings, both in light and electron microscopic studies, as well as the biochemical and functional parameters in cases of stress‐induced adrenal cortex injury in rats. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Early diagnosis and elimination of risk factors are crucial for better managing CVDs. Atherosclerosis, whose development might be associated with glucocorticoids (GCs), is a critical factor in the development of carotid artery (CA) stenosis and most other CVDs. Aim: To investigate the association of Tth111I, N363S, and ER22/23EK-NR3C1 polymorphisms and the incidence of CA stenosis. Methods: The study group consisted of 117 patients diagnosed with coronary artery disease (CAD) and CA stenosis and 88 patients with CAD and ruled out CA stenosis. Genomic DNA was extracted from blood, and genotyping was carried out using Tth111I, N363S, and ER22/23EK-NR3C1 polymorphism sequencing. Results: No significant association between studied polymorphisms and the incidence or the severity of CA stenosis in the Polish population with CAD was found. Conclusion: This is the first study that proves that common NR3C1 gene variants do not influence CA stenosis and probably are not associated with atherosclerosis. The search for genes that can act as prognostic markers in predicting CA stenosis is still ongoing. [ABSTRACT FROM AUTHOR]

Background: Difficult-to-treat rhinosinusitis (DTRS) seriously affects the quality of work and life of patients, and the cause is still unclear. We aimed to explore the association between the glucocorticoid receptor (NR3C1) gene polymorphisms and DTRS. Methods: A nested case–control study was conducted. The exons of NR3C1 gene were sequenced by an ABI 9700 DNA analyzer in 30 DTRS patients and 70 matched chronic rhinosinusitis (CRS) patient with good outcome (non-DTRS). The genotypic and allele frequencies were calculated and linkage disequilibrium was analyzed. Results: The three SNPs showed a significant difference between the DTRS and non-DTRS groups. In allelic model analysis, we found that the allele "C" of rs6196, the allele "A" of rs258751, and the allele "T" of rs6194 were associated with increased the risk of DTRS (all p < 0.05). In addition, the haplotype CAT of the 3 SNPs was detected to be significantly associated with DTRS risk (p = 0.001), while the haplotype TGC was associated with the decreased risk of DTRS (p = 0.008). Conclusion: NR3C1 gene polymorphisms are significantly associated with the DTRS. [ABSTRACT FROM AUTHOR]

Monogenic disorders of hypertension are a distinct group of diseases causing dysregulation of the renin–angiotensin–aldosterone system and are characterized by low plasma renin activity. These can chiefly be classified as causing (i) excessive aldosterone synthesis (familial hyperaldosteronism), (ii) dysregulated adrenal steroid metabolism and action (apparent mineralocorticoid excess, congenital adrenal hyperplasia, activating mineralocorticoid receptor mutation, primary glucocorticoid resistance), and (iii) hyperactivity of sodium and chloride transporters in the distal tubule (Liddle syndrome and pseudohypoaldosteronism type 2). The final common pathway is plasma volume expansion and catecholamine/sympathetic excess that causes urinary potassium wasting; hypokalemia and early-onset refractory hypertension are characteristic. However, several single gene defects may show phenotypic heterogeneity, presenting with mild hypertension with normal electrolytes. Evaluation is based on careful attention to family history, physical examination, and measurement of blood levels of potassium, renin, and aldosterone. Genetic sequencing is essential for precise diagnosis and individualized therapy. Early recognition and specific management improves prognosis and prevents long-term sequelae of severe hypertension. [ABSTRACT FROM AUTHOR]

Adrenocorticotropic Hormone (ACTH)-secreting pituitary adenomas are rare tumors characterized by autonomous ACTH secretion with a consequent increase in circulating cortisol levels. The resulting clinical picture is called Cushing's disease (CD), a severe condition burdened with high morbidity and mortality. Apart from increased cortisol levels, CD patients exhibit a partial resistance to the negative glucocorticoid (GC) feedback, which is of paramount clinical utility, as the lack of suppression after dexamethasone administration is one of the mainstays for the differential diagnosis of CD. Since the glucocorticoid receptor (GR) is the main regulator of negative feedback of the hypothalamic–pituitary–adrenal axis in normal conditions, its implication in the pathophysiology of ACTH-secreting pituitary tumors is highly plausible. In this paper, we review GR function and structure and the mechanisms of GC resistance in ACTH-secreting pituitary tumors and assess the effects of the available medical therapies targeting GR on tumor growth. [ABSTRACT FROM AUTHOR]

PTIP-associated protein 1 (PA1) is a unique component of MLL3/4 complexes, which are important mammalian histone 3 lysine 4 (H3K4) methyltransferases. PA1 has generated research interest due to its involvement in many essential biological processes such as adipogenesis, B cell class switch recombination, spermatogenesis, and embryonic development. In addition to the classical role of PA1 in H3K4 methylation, non-classical functions have also been discovered in recent studies. In this review, we systematically summarize the expression pattern of PA1 protein in humans and sort the specific molecular mechanism of PA1 in various biological processes. Meanwhile, we provide some new perspectives on the role of PA1 for future studies. A comprehensive understanding of the biological functions and molecular mechanisms of PA1 will facilitate the investigation of its complicated roles in transcriptional regulation. [ABSTRACT FROM AUTHOR]

An association between endometriosis and luteinized unruptured follicle syndrome (LUFs) has long been identified. Although inactivating mutation of luteinizing hormone/choriogonadotropin receptor (LHGCR) results in LUFs, whether LHCGR contributes to promoting LUFs in endometriosis remains elusive. To investigate the effect of LHCGR signaling in the development of endometriosis-associated LUFs and dissect the underlying mechanism in vivo mouse endometriosis model was established to measure the effect on ovarian folliculogenesis. In vitro cultures of primary human GCs collected from patients undergoing in vitro fertilization were performed and treated with human chorionic gonadotropin (hCG), dibutyryl cyclic-AMP (db-cAMP), LHCGR or CCAAT/enhancer binding protein-α (C/EBPα) small interfering RNA to identify the potential mechanisms. KGN cell line was used to investigate the mechanistic features of transcriptional regulation. Results showed an increased incidence of LUFs was observed in mice with endometriosis. The expression of LHCGR was decreased in the GCs of endometriosis mice. In in vitro cell models, LHCGR signaling increased the expression of C/EBPα and cyclooxygenase-2(COX-2), while inhibiting C/EBPα mitigated the induced COX-2 expression. Mechanically, C/EBPα bounded to the promoter region of COX-2 and increased the transcriptional activity under the stimulation of hCG or db-cAMP. Taken together, this study demonstrated that the LHCGR signaling was reduced in GCs of endometriosis and resulted in a decrease in gonadotropin-induced COX-2 expression. Our study might provide new insights into the dysfunction of GCs in endometriosis. [ABSTRACT FROM AUTHOR]

Background: ACTH-independent macronodular hyperplasia (AIMAH) is an uncommon disorder characterized by massive enlargement of both adrenal glands and hypersecretion of cortisol. Concomitant AIMAH and multiple endocrine neoplasia type1 (MEN1) is rare to our knowledge. Case presentation: Herein, we describe a 32 year old woman with long history of prolactinoma and secondary ammonhrea presented with not-severe manifestation of hypoglycemia due to concomitant presence of insulinoma with AIMAH leading to 12 years delay of MEN1 diagnosis. Laboratory tests showed severe hypoglycemia associated with hyper insulinemia (non-fasting blood sugar = 43 mg/dl, insulin = 80.6 μIU /ml, C-peptide = 9.3 ng/ml) hyperparathyroidism (calcium = 10.3 mg/dl, phosphor = 3.1 mg/dl, PTH = 280 pg/ml) and chemical evidence of an ACTH-independent hypercortisolism (serum cortisol value of 3.5, after 1 mg dexamethasone suppression test serum ACTH value of 17 pg/ml, and high urinary cortisol level). Abdominal CT scan demonstrated two enhancing well-defined masses 27*20 mm and 37*30 mm in the tail and body of the pancreas, respectively, and a 36*15 mm mass in left adrenal gland (seven Hounsfield units). Dynamic pituitary MRI revealed a partial empty sella. The physical examination of the patient was unremarkable. Distal pancreatectomy and a left adrenalectomy were performed. After the surgery, we observed clinical and biochemical remission of hyper insulinemia and gradual decrease in urinary cortisol. The histological features of the removed left adrenal gland were consistent with AIMAH. Histological examination of the pancreatic lesions revealed well differentiated neuroendocrine tumors. Genetic abnormalities in the MEN1, heterozygote for pathogenic variant chr11; 645,773,330-64577333AGAC, c.249-252delGTCT, p. (11e85Serfs Ter33) in exon 2 were found. It was recommended the patient undergoes parathyroidectomy as soon as possible. Conclusion: Given the history and presentation of our case, we recommend that the clinicians consider the possibility of autonomous cortisol production in MEN1 patients who do not show severe symptoms of hypoglycemia in the presence of insulinoma. [ABSTRACT FROM AUTHOR]

Summary: Increasing evidence points to a relation between increased glucocorticoid (GC) exposure and weight gain. In support, long‐term cortisol measurements using hair analysis revealed that many individuals with obesity appear to have cortisol values in the high physiological range. The mechanisms behind this relationship need to be determined in order to develop targeted therapy to reach sustainable weight loss in these subgroups. The effect of GCs is not only determined by the plasma concentration of GCs but also by individual differences in GC sensitivity and the target tissue, which can be analyzed by functional GC assays. GC sensitivity is influenced by multiple genetic and acquired (e.g., disease‐related) factors, including intracellular GC availability, hormone binding affinity, and expression levels of the GC receptors and their isoforms, as well as factors involved in the modulation of gene transcription. Interindividual differences in GC sensitivity also play a role in the response to exogenous GCs, with respect to both therapeutic and adverse effects. Accordingly, in this review, we summarize current knowledge on mechanisms that influence GC sensitivity and their relationships with obesity and discuss personalized treatment options targeting the GC receptor. [ABSTRACT FROM AUTHOR]

Hypoxia, a common stressor with preterm birth, increases morbidity and mortality associated with prematurity. Glucocorticoids (GCs) are administered to the preterm infant to improve oxygenation; prolonged use of GCs remains controversial. We evaluated a selective glucocorticoid receptor (GR) antagonist (CORT113176) in our neonatal rat model of human prematurity to assess how fasting and hypoxia-induced increases in neonatal corticosterone affects endogenous hormones and endocrine pancreas function. Neonatal rat pups at postnatal day (PD) 2, PD8, and PD15 were pretreated with CORT113176 and, after 60 minutes of separation and fasting, exposed to hypoxia (8% O2) or control (normoxia) for 30 or 60 minutes while fasting was continued. Plasma corticosterone, ACTH, glucose, and insulin were measured and fasting Homeostatic Model Assessment of Insulin Resistance was calculated. Glucocorticoid and insulin receptor-sensitive gene mRNAs were analyzed in liver, muscle, and adipose to evaluate target tissue biomarkers. CORT113176 pretreatment augmented baseline and hypoxia-induced increases in corticosterone and attenuated hypoxia-induced increases in insulin resistance at PD2. Normoxic and hypoxic stress increased the hepatic GR-sensitive gene mRNAs, Gilz and Per1 ; this was eliminated by pretreatment with CORT113176. CORT113176 pretreatment decreased baseline insulin receptor-sensitive gene mRNAs Akt2 , Irs1 , Pik3r1 , and Srebp1c at PD2. We show that CORT113176 variably augments the stress-induced increases in corticosterone concentrations (attenuation of negative feedback) and that GR is critical for hepatic responses to stress in the hypoxic neonate. We also propose that measurement of Gilz and Per1 mRNA expression may be useful to evaluate the effectiveness of GR antagonism. [ABSTRACT FROM AUTHOR]

Adrenal tumors are commonly discovered incidentally on cross-sectional abdominal imaging performed for reasons other than adrenal mass. Incidence of adrenal tumors increased 10-fold in the past 2 decades, with most diagnosed in older adults. In any patient with a newly discovered adrenal mass, determining whether the adrenal mass is malignant and whether it is hormonally active is equally important to guide the best management. Malignancy is diagnosed in 5% to 8% of patients with adrenal tumors, with a higher risk in young patients, if history of extra-adrenal malignancy, in those with large adrenal tumors with indeterminate imaging characteristics, and in bilateral adrenal tumors. Although overt hormone excess is uncommon in adrenal incidentalomas, mild autonomous cortisol secretion can be diagnosed in up to 30% to 50% of patients. Because autonomous cortisol secretion is associated with increased cardiovascular morbidity and metabolic abnormalities, all patients with adrenal incidentalomas require work up with dexamethasone suppression test. Management of adrenal tumors varies based on etiology, associated comorbidities, and patient's preference. This article reviews the current evidence on the diagnosis and evaluation of patients with adrenal mass and focuses on management of the most common etiologies of adrenal incidentalomas. [ABSTRACT FROM AUTHOR]

Context Glucocorticoids act through the glucocorticoid receptor (GR) encoded by the nuclear receptor subfamily 3 group C member 1 (NR3C1) gene. Objective This study aimed to examine the function of NR3C1 variants and their possible pathogenic role in Cushing disease (CD). Methods Next-generation sequencing was conducted in 49 CD patients. Corticotroph tumor GR protein expression was examined by immunohistochemistry (IHC). Constructs harboring the 3 NR3C1 -mutant and wild-type (WT) GR were transfected into the murine corticotropic adenoma cell line (AtT-20), and GR protein expression was quantified by Western blot. Translocation activity was assessed by immunofluorescence and effects of the GR mutants on corticotroph tumor proliferation, pro-opiomelanocortin (POMC) transcription, and ACTH secretion were tested. Results Clinical features were similar in patients harboring the NR3C1 mutations and WT GR. Recurrent adenomas showed higher GR IHC scores than nonrecurrent tumors. In vitro studies demonstrated that the p.R469X mutant generated a truncated GR protein, and the p.D590G and p.Y693D GR mutants resulted in lower GR expression. Dexamethasone (DEX) treatment of AtT-20 cells demonstrated decreased DEX-induced nuclear translocation, increased cell proliferation, and attenuated suppression of POMC transcription of 3 GR mutants. Interestingly, the p.R469X GR mutant resulted in increased murine corticotroph tumor ACTH secretion compared to WT GR. Conclusion Our findings identify 3/49 (6.1%) consecutive human corticotroph tumors harboring GR mutations. Further findings demonstrate the role NR3C1 plays in CD pathogenesis and offer insights into a novel treatment approach in this patient subset. [ABSTRACT FROM AUTHOR]