[Dynamics of NT-proBNP and ST2 levels as markers of heart failure in patients with endogenous Cushing syndrome (hypercortisolism)].

AIM: To evaluate frequency of heart failure syndrome in patients with endogenous hypercortisolism and to establish relationship between effective treatment for hypercortisolism and regression of heart failure with particular emphasis on the observation of NT-proBNP and ST2 levels. MATERIALS AND METHODS: 56 patients with endogenous hypercortisolism (45 female, mean age 47 years [36; 55] hospitalized with endogenous hypercortisolism to National Medical Research Center for Endocrinology were enrolled in the study. All patients underwent comprehensive clinical investigation including expert echocardiography with speckle tracking and evaluation of NT-proBNP and ST2 cardiac biomarkers at baseline and 6 months after surgical treatment. RESULTS: According to clinical data and elevated biomarkers of cardiac stress 28 out of 56 patients (50%) at baseline met the criteria for heart failure. 20 patients were included in the final analysis. Follow-up investigation with focus on changes in NT-proBNP and ST2 levels demonstrated that surgical correction of endogenous hypercortisolism resulted in resolution of heart failure syndrome in 11 patients (55%). CONCLUSION: These preliminary data suggest that signs and symptoms of heart failure are observed in patients with endogenous hypercortisolism in about half the cases. Surgical correction results in resolution of heart failure in approximately two thirds of the cases. Prospective evaluation NT-proBNP and ST2 levels may provide important diagnostic and prognostic information in patients with endogenous hypercortisolism.

[Endocrine late-effects and bone mineral density after combined treatment of malignant brain tumors in childhood and adolescence].

BACKGROUND: The implementation of standardized protocols for combined treatment of cancer into clinical practice inevitably leads to a long-term consequence. AIMS: To study the prevalence of endocrine disorders, to assess the prevalence and degree of decline of bone mineral density (BMD) in individuals who have undergone combined treatment of malignant brain tumors in childhood and adolescence. MATERIALS AND METHODS: A retrospective study was conducted with 59 young adults (31 men; 28 women) who have undergone surgical treatment of malignant brain tumour followed by radiation treatment (craniospinal radiation in combination with or without polychemotherapy). Group I consisted of 37 patients, who were treated between the ages of 3 and 16 years. Group II included 22 patients who received treatment between the ages of 16 and 38 years. RESULTS: GH deficiency according to the results of the insulin hypoglycemia test was diagnosed in 48 patients (81%), 22 -patients had secondary adrenal insufficiency (37%). The majority of those examined (33 patients (56%)) did not achieve the target growth. Only 5 people from I group was treated with recombinant GH. Correlation analysis demonstrates that age of treatment is the main factor affecting final growth (r=0,619, p<0,001). Many cases of hypothyroidism (n=39 (66%)) and hypogonadism (19 women; 17 men) were detected. According to the DXA, a decrease of BMD ≤-2.0 SD (Z-score) in L1-L4 was found in 35 of 59 patients (59%). The BMD in the I group was significantly lower than in patients treated at an older age (p<0.001). A moderate correlation was discovered between BMD in L1-L4 at the time of examination and the level of estradiol in women (r=0.596, p<0.05) and testosterone in men (r=0.472, p<0.05). Direct correlation between BMD and age of diagnosis was revealed (r=0.781, p<0.01). CONCLUSIONS: The results show that patients need to be monitored annually and for life after the combined treatment of malignant brain tumors in order to detect the long-term effects of the treatment. The high incidence of osteopenic conditions determines the relevance and need for early diagnosis to prevent further bone loss, reduced bone strength and the risk of fractures.

[Differences in plasma miRNA levels in inferior petrosal sinus samples of patients with ACTH-dependent Cushing's syndrome].

BACKGROUND: For the last decades microRNAs (miR) have proven themselves as novel biomarkers for various types of diseases. Identification of specific circulating microRNA panel that differ patient with Cushing's disease (CD) and ectopic ACTH syndrome (EAS) could improve the diagnostic procedure. AIM: to evaluate the differences in miR levels in plasma samples drained from inferior petrosal sinuses in patients with CD and EAS. MATERIALS AND METHODS: single-center, case-control study: we enrolled 24 patients with ACTH-dependent Cushing's syndrome (CS) requiring bilateral inferior petrosal sinus sampling (BIPSS).  Among them 12 subjects were confirmed as CD (males=2, females=10; median age 46,5 [IR 33,8;53,5]) and 12 as EAS (males=4, females=8, median age 54 [IR 38,75;60,75]). BIPSS was performed through a percutaneous bilateral approach. Once catheters were properly placed, blood samples were withdrawn simultaneously from each petrosal sinus and a peripheral vein. Plasma samples from both sinuses were centrifuged and then stored at -80 C. MiRNA isolation from plasma was carried out by an miRneasy Plasma/Serum Kit (Qiagen, Germany) on the automatic QIAcube station according to the manufacturer protocol. To prevent degradation, we added 1 unit of RiboLock Rnase Inhibitor (Thermo Fisher Scientific, USA) per 1 µL of RNA solution. The concentration of total RNA in the aqueous solution was evaluated on a NanoVue Plus spectrophotometer (GE Healthcare, USA). The libraries were prepared by the QIAseq miRNA Library Kit following the manufacturer standard protocols. MiR expression was then analyzed by sequencing on Illumina NextSeq 500 (Illumina, USA). RESULTS: 108 miRNAs were differently expressed (p <0,05) in inferior petrosal sinus samples of patients with CD vs EAS. We divided these miRNAs into 3 groups based on the significance of the results. The first group consisted of samples with the highest levels of detected miR in both groups. Four miRNAs were included: miR-1203 was downregulated in CD vs EAS - 36.74 (p=0,013), and three other were upregulated in CD vs EAS: miR-383-3p 46.36 (p=0,01), miR-4290 6.84 (p=0,036), miR-6717-5p 4.49 (p=0,031). This miRs will be validated in larger cohorts using RT-qPCR. CONCLUSION: Plasma miR levels differ in inferior petrosal samples taken from patients with CD vs EAS. These miRs need to be validated by different methods and in peripheral plasma samples in order to be used as potentially non-invasive biomarkers to differentiate ACTH-dependent CS.

[Clinical and laboratory characteristics and results of treatment of patients with ACTH-producing neuroendocrine tumors of various localization].

AIM: To study the clinical, biochemical characteristics, treatment results and follow-up of patients with ectopic ACTH syndrome EAS (ACTH adrenocorticotropic hormone ). MATERIALS AND METHODS: A retrospective, observational, single-center study of 130 patients with EAS. Demographic information of patients, medical history, results of laboratory and instrumental investigations at the pre- and postoperative stages and follow-up of EAS were analyzed. RESULTS: The mean age at the diagnosis ranged from 12 to 74 years (Me 40 years [28; 54]). The duration of the disease from the onset of symptoms to the verification of the diagnosis varied from 2 to 168 months (Me 17.5 months [7; 46]). Eighty-one (62,3%) patients had bronchopulmonary NET, 9 thymic carcinoid, 7 pancreatic NET, 5 pheochromocytoma, 1 cecum NET, 1 appendix carcinoid tumor, 1 medullary thyroid cancer and 25 (19.2%) had an occult source of ACTH. The median follow-up period of patients was 27 months [9.75; 61.0] with a maximum follow-up of 372 months. Currently, primary tumor was removed in 82 (63.1%) patients, bilateral adrenalectomy was performed in 23 (18%) patients, in 16 of them there was an occult source of ACTH-producing NET and in 7 patients in order to control hypercortisolism after non-successful surgical treatment. Regional and distant metastases were revealed in 25 (19.2%) patients. At the time of the last observation 59 (72%) patients were exhibited a full recovery, 12 (14.6%) had relapse of the disease and 26 (20%) died from multiple organ failure (n=18), pulmonary embolism (n=4), surgical complications (n=2), disseminated intravascular coagulation syndrome (n=1) or COVID-19 (n=1). CONCLUSION: In our cohort of patients bronchopulmonary NET are the most frequent cause of EAS (62.3%). Surgical treatment leads to remission of hypercortisolism in 72% cases; the proportion of relapse (14.6%) and fatal outcome (20%) remains frequent in EAS.

[Heart arrhythmias and conduction disorders in patients with acromegaly: the role of cardiac magnetic resonance imaging].

Cardiovascular complications including arrhythmias and cardiac conduction disorders are one of the main reasons of high mortality rate in acromegaly, while they have not been well explored. AIM: To estimate arrhythmias frequency in acromegaly, identify risk factors leading to the development of arrhythmia and cardiac conduction disorder, to determine the role of cardiac MRI in detecting structural and functional changes. MATERIALS AND METHODS: A single-center prospective cohort study, which included 461 patients (151 men and 310 women) with acromegaly, was conducted. All the patients underwent a standard medical examination, including hormonal blood test, electrocardiogram, echocardiography, electrocardiogram daily monitoring. 18 patients with arrhythmias (11 men and 7 women) had cardiac MRI with gadolinium-based contrast. RESULTS: The results of our research show high frequency of arrhythmias and cardiac conduction disorders in patients with acromegaly 42%. Most frequent kinds of arrhythmias and cardiac conduction disorders were sinus bradycardia 19.1% of the cases and conduction disorders of bundle branch blocks 14.5%. Men were more likely to suffer from arrhythmias and cardiac conduction disorders than women (54.2% and 37.4%, respectively,p=0.0005). Not acromegaly activity but duration of the disease was a main risk factor of arrhythmias and cardiac conduction disorders. Patients with arrhythmias had a long anamnesis of acromegaly (10 and 7 years, respectively, p=0.04). Meanwhile, cardiac conduction disorders were commonly observed in the patients who were treated with somatostatin analogs comparing to the patients who didnt undergo this therapy (50% and 38.6% respectively,p=0.004). We showed that 61% of patients with acromegaly and cardiac conduction disorders who underwent magnetic resonance imaging (MRI) had the signs of myocardial fibrosis. The value of the ejection fraction of the left ventricle according to MRI was higher than with echocardiography (p=0.04). CONCLUSION: Arrhythmias and cardiac conduction disorders are often observed in patients with acromegaly even with remission of the disease. High risk group need careful diagnostic and monitoring approaches. Cardiac MRI is the gold standard for visualization of structural and morphological changes in the heart. Use of cardiac MRI in acromegalic patients expands our understanding of arrhythmias and cardiac conduction disorders in this disease. There are no specific laboratory markers of diffuse myocardial fibrosis, and the role of myocardial fibrosis in the occurrence of cardiac arrhythmias and conduction disorders needs further studying.

[Hereditary Cushing's syndrome caused by primary bilateral macronodular adrenal hyperplasia due to ARMC5 mutation with concomitant primary hyperparathyroidism: the first known case in Russia].

Primary bilateral macronodular adrenal hyperplasia (PBMAH), a genetically heterogeneous disease, is a rare cause of Cushing's syndrome. Until recently, few cases were attributed to mutations in known genes. However, in 2013, ARMC5, a newly discovered tumor suppressor gene, was identified. Further studies have shown that mutations in the ARMC5 gene are found in 25-55% of all PBMAH cases. This article describes a clinical case of hereditary Cushing's syndrome caused by PBMAH in a 37-year old patient. The patient's family history is remarkable for the presence of Cushing's syndrome and PBMAH in the patient's mother. Bilateral adrenalectomy was performed as the treatment of choice. Genetic analysis using whole-exome sequencing confirmed the hereditary cause of the disease, revealing a germline heterozygous mutation in the ARMC5 gene. The patient also had concomitant mild primary hyperparathyroidism, which had not been observed before in genetic carriers with the ARMC5 mutation.

[An ovarian hyperstimulation syndrome caused by gonadotropinoma in a young woman].

From 14 to 54% of all pituitary adenomas are nonfunctioning pituitary adenomas (NPAs), their prevalence is estimated as 7.041.3 cases per 100 000 population. The most common type of NPAs (73% of cases) are gonadotropinomas. In most cases, gonadotropinoma is characterized by secretion of biologically inactive hormones, so the release of gonadotropins does not lead to the development of any clinical symptoms. For this reason the diagnosis of gonadotropinomas is most often performed on the basis of immunohistochemical analysis. However, in rare cases, gonadotropinomas secrete biologically active hormones, most often follicle-stimulating (FSH). Ovarian hyperstimulation syndrome due to gonadotropin-secreting pituitary tumors occurs in about 3% of women with hormonally inactive pituitary adenomas at reproductive age and in 8% of patients with verified gonadotropinomas. This clinical case describes a young patient with a rare pathology: FSH/LH-secreting macroadenoma of the pituitary, which led to the development of ovary hyperstymulation symdrome. The diagnosis of pituitary adenoma was performed due to the identified hyperprolactinemia one month before the development of visual impairment, which can be considered a late diagnosis. Surgical treatment of gonadotropinomy was carried out successfully and without complications, remission of the disease was achieved, visual function was restored, the patient successfully became pregnant.

[Expression of plasma microRNA in patients with acromegaly].

BACKGROUND: microRNA is a class of small non-coding RNA molecules involved in posttranscriptional regulation of gene expression. MicroRNAs are detectable in blood in stable concentrations, which makes them promising biomarkers for various diseases. AIM: to assess plasma microRNA expression in patients with active acromegaly compared with healthy controls. MATERIAL AND METHODS: single-center, case-control study: assessment of plasma microRNA in patients with acromegaly compared with healthy controls. Fasting blood samples were drawn and centrifuged at +5С temperature and 3000 rpm for 20 minutes, then aliquoted and frozen at 80C until further analysis. MicroRNA extraction and library preparation was done according to manufacturers instructions. Expression analysis was performed on NextSeq sequencer. Bioinformatic analysis using atropos (adapted deletion), STAR (aligning), FastQC (quality control), seqbuster/seqcluster/miRge2 (microRNA annotation, isomiR and new microRNA search, expression analysis). Primary endpoint of the study differential expression of plasma microRNA in patients with acromegaly compared with healthy controls. RESULTS: we included 12 patients with acromegaly age 33.1 [20; 47], BMI 29.3 kg/m2 [24.0; 39.6], IGF-1 686.1 ng/mL [405.9; 1186.0] and 12 healthy subjects age 36.2 [26; 44], BMI 26.7 kg/m2 [19.5; 42.5], IGF-1 210.4 ng/mL [89.76; 281.90]; gender ratio for both groups 4 males, 8 females. The groups did not differ in gender (p=0.666), age (p=0.551) and BMI (p=0.378). We found decreased expression of four microRNAs in patients with acromegaly: miR-4446-3p 1.317 (p=0.001), miR-215-5p 3.040 (p=0.005), miR-342-5p 1.875 (p=0.013) and miR-191-5p 0.549 (p=0.039). However, none of these changes were statistically significant after adjustment for multiple comparisons (q 0.1). CONCLUSION: we found four microRNAs, which could potentially be downregulated in plasma of patients with acromegaly. The result need to be validated using different measurement method with larger sample size.

[Current aspects of diagnosis and treatment of adult GH-deficiency].

Adult growth hormone (GH) deficiency (AGHD) is a condition characterized by alterations in body composition, lipid and carbohydrate metabolism, bone mineral density and poor quality of life; however, clinical presentations of AGHD are mostly non-specific. Untreated AGHD is associated with increased cardiovascular morbidity and mortality. Stimulation tests are used for the diagnosis: insulin tolerance test, glucagon stimulation test, growth-hormone releasing hormone and arginine stimulation test. Moreover, in 2017 FDA approved the use of macimorelin (oral GH secretagogue) for the diagnosis of AGHD. In childhood GH-deficiency, apolipoprotein A-IV, CFHR4 (complement factor H-related protein 4) and PBP (platelet basic protein) were identified as potential biomarkers of the disease, however, this was not investigated in AGHD. GH treatment starts from the minimal dose, which allows minimizing the adverse effects. According to published meta-analyses, AGHD treatment generally does not lead to increased risk of malignancy and recurrence of sellar neoplasms in adult patients. Published data on GH receptor polymorphism associations with treatment efficacy remains controversial. Development of long-acting GH formulations is a currect perspective for the increase of treatment compliance.

Effects of endogenous hypercortisolism on bone mRNA and microRNA expression in humans.

Hypercortisolism in humans suppresses osteoblastogenesis and osteoblast function through the upregulation of Wnt-signaling antagonists (sclerostin, Dkk1) and changes in microRNAs levels (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) which are associated with mesenchymal stem-cell commitment to adipocytes or cartilage cells over the osteoblasts. INTRODUCTION: The purpose of this study was to evaluate the responses of bone to chronic glucocorticoid (GC) excess by measuring the levels of selected mRNA and microRNA (miR) in bone samples of patients with Cushing's disease (CD). METHODS: Bone samples were obtained during transsphenoidal adenomectomy from the sphenoid bone (sella turcica) from 16 patients with clinically and biochemically evident CD and 10 patients with clinically non-functioning pituitary adenomas (NFPA) matched by sex, age, and body mass index. Quantitative polymerase chain reactions (qPCR) were used to examine the expression of genes (mRNA and miRs) known to be involved in bone remodeling regulation based on studies in animals and cell culture. RESULTS: Hypercortisolism was associated with the downregulation of genes involved in osteoblast function and maturation (ACP5, ALPL, BGLAP, COL1A1, COL1A2, BMP2, RUNX2, TWIST1). An excess of GC caused increased expression of Wnt-signaling antagonists (Dkk1, SOST) and changes in the levels of miRs that are known to suppress osteoblastogenesis (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) p < 0.05, q < 0.1. Interestingly, compensatory mechanisms were found in long-term hypercortisolism: upregulation of Wnt10b, LRP5, and LRP6; downregulation of SFRP4; changes in miRs involved in osteoblastogenesis (miR-210-5p, miR-135a-5p, miR-211, miR-23a-3p, miR-204-5p); and downregulation of genes associated with osteoclastogenesis. None of these changes prevented the suppression of bone formation. CONCLUSIONS: An excess of endogenous GC in humans suppresses bone formation through the upregulation of Wnt-signaling antagonists and dysregulation of miRs involved in mesenchymal stem-cell commitment. Both Wnt-signaling antagonists and miRs seem to be promising targets for further research in therapeutic intervention in glucocorticoid-induced osteoporosis.

Serum extracellular secreted antagonists of the canonical Wnt/ß-catenin signaling pathway in patients with Cushing's syndrome.

UNLABELLED: Patients with endogenous hypercortisolism have higher sclerostin, but do not differ in Dickkopf 1 (Dkk1) or secreted frizzled-related protein 1 (SFRP1) levels as compared to healthy control. INTRODUCTION: Endogenous Cushing's syndrome (CS), usually affecting young and otherwise healthy patients, is a good model to validate the effects of supraphysiological levels of glucocorticoids in humans. This study evaluates circulating levels of extracellular antagonists of the Wnt/ß-catenin signaling pathway (sclerostin, Dkk1, SFRP1) in patients with CS versus healthy individuals. METHODS: Forty patients with clinically and biochemically evident CS and 40 sex-, age-, and body mass index-matched healthy subjects provided fasting serum samples for sclerostin, SFRP1 and Dkk1, along with bone turnover markers. RESULTS: Patients with CS had higher sclerostin levels (34.5 (30.3-37.1) pmol/L) versus healthy individuals (29.9 (24.3-36.8) pmol/L) (p = 0.032). Differences in sclerostin were due to the lack of lower sclerostin values rather than an increase in protein levels above the upper limits of the healthy control. The odds of sclerostin levels being higher than 30 pmol/L were greater in patients with CS as compared with the odds in healthy subjects (odds ratio = 3.81 95 % confidence interval 1.45-10.02) (p = 0.01). It coexisted with suppressed bone formation and unchanged bone resorption markers. Dkk1, SFRP1 did not differ from the control group. CONCLUSIONS: Of all the tested proteins (sclerostin, Dkk1, SFRP1), only sclerostin showed a significant difference when contrasting CS with healthy subjects. Hypercortisolism might prevent the down-regulation of sclerostin. Targeting sclerostin seems to be a promising therapeutic approach to treating osteoporosis in patients with CS.

[The first experience with selective blood collection from the inferior petrosal sinuses in Russia (case reports)].

This paper reports two clinical cases of ACTH-dependent hypercorticism. Difficulties encountered in differential diagnosis of this condition were due to poor informative value of routine diagnostic methods. The use of selective blood collection from the inferior petrosal sinuses (for the first time in Russia) greatly facilitated the choice of the adequate treatment strategy. A detailed description of clinical features of ACTH-dependent hypercorticism in two young women is presented along with the results of laboratory and instrumental studies. Technical aspects of selective blood collection from the inferior petrosal sinuses in conjunction with the desmopressin stimulation protocol are considered. Indications for the use of this diagnostic method under real clinical conditions are proposed. Results of the study are discussed with reference to the treatment strategy chosen for the management of ACTH-dependent hypercorticism and the outcome of surgical intervention.

[Significance of the method of selective blood collection from the inferior petrosal sinuses for differential diagnosis of ACTH-dependent hypercorticism].

This review paper was designed to discuss the accumulated worldwide experience with selective collection of blood from the inferior petrose sinuses for the purpose of differential diagnostics of ACTH-dependent hypercorticism. The history of the development of the method is described, principal indications and contraindications to its clinical application are considered with reference to the informative value of this diagnostic tool. Possible causes of false positive and false negative results as well as complications ever reported as associated with the diagnostic procedure are discussed. Much attention is given to the comparative analysis of advantages and disadvantages of alternative techniques for blood collection and to the use of pharmaceutical agents that may increase efficiency of the method under consideration.

[Role of exercises in health and in diabetes mellitus].

Exercise has been seen as beneficial in the treatment of diabetes. This therapy was recognized as useful and was widely used by physicians of the 19th and early 20th centuries. Following the discovery of insulin, many researchers recommended physical activity as one of the main principles for diabetes management.Currently, due to the development of new opportunities in the treatment of diabetes mellitus, physical activity is not considered as the only necessary part of the impact on each patient with diabetes, as it was in the past. Over the past 2 decades, many studies using new technologies have explored the relationship between physical fitness and metabolic control of diabetes. With the publication of new clinical reviews, it has become increasingly apparent that exercise can be a therapeutic tool in different patients with diabetes or the risk of developing diabetes, but their effect, like any other therapy, should be understandable. From a practical point of view, this means that doctors must understand and analyze both the risk and the gain from physical activity for each individual patient. On the other hand, it is generally accepted that physical exercise is associated with an improvement in the quality of life and has a beneficial effect on the cardiovascular system; therefore, metabolic control should not be just one criterion in assessing the beneficial effects of training programs for patients with diabetes. It is important to recommend optimal training for patients to improve glycemic control and the state of the cardiovascular system, or to help select appropriate therapy if the patient independently chooses the type of exercise.