Editorial notice
In the past year, the Federal Project “Fight against Diabetes” 2023–2030 was developed in detail and submitted in detail and submitted to the Government of the Russian Federation, which will significantly improve the practice of working with patients with diabetes, providing them with maximum availability of medical care, including in updated and technologically re -equipped regional endocrinological centers, reviving the active work of “Diabetes schools”, “Diabetic foot” rooms, diagnostic laboratories, introducing new forms of communication with patients, including using personal assistants of a doctor, continuous technologies for monitoring glycemia, etc.
Clinical endocrinology
Cyclic Cushing’s syndrome is a pathological condition characterized by alternating periods of excessive cortisol secretion with corresponding clinical manifestations and periods of spontaneous remission of the disease.
To diagnose Cyclic Cushing’s syndrome it is necessary to record at least three episodes of excessive cortisol secretion alternating with periods of normalization of its production.
In most cases, this pathology is diagnosed in patients with ACTH-secreting pituitary tumor, however, there are rare cases of cyclic hypercorticism with ectopic ACTH secretion by tumors of different localization and without verification of pathological hormonal secretion focus. In addition, cyclic hyperproduction of cortisol can be also observed in ACTH-independent Cushing’s syndrome associated with the presence of corticosteroma or adrenal hyperplasia. The exact causes and mechanisms of the cyclic hypercorticism are currently insufficiently studied.
Due to the atypical course of the disease, the unpredictability of the occurrence of a new «cycle», the variability of its duration and manifestations (not only in different patients, but also in the same patient), verification of the diagnosis and determination of treatment tactics may be difficult in the daily practice of specialists, and the prevalence of this condition can be undervalued.
Oncoendocrinology
Parathyroid cancer (PTC) is usually sporadic; however, it could be presented as a component of hereditary syndromes. The prevalence of PTC among patients with primary hyperparathyroidism (PHPT) is about 1% cases. The lack of reliable preoperative predictors significantly complicates the diagnosis of PTC. The clinical course is non-specific and in most cases is determined by severe hypercalcemia. The final diagnosis can only be made on the basis of invasive histopathologic features, while an analysis immunohistochemical (IHC) one can be used only as an additional method. Given the rarity the diagnosis of MEN1-related PTC a challenge. We present two clinical cases of patients with PTC and a verified heterozygous mutation in the MEN1 gene. The described cases demonstrate the complexity of morphological diagnosis for PTC, the heterogeneity of clinical manifestations in patients with the MEN1 mutation, as well as the need for timely screening to identify other components of MEN1 syndrome and mutations of the MEN1 gene among first-line relatives.
Carbohidrates metabolism disturbancies
BACKGROUND: Myocardial infarction (MI) in patients with diabetes type 2 (T2DM) occurs 1.5–3.0 times higher than in general population. Metformin is contraindicated for patients with T2DM and acute coronary syndrome due to the risk of developing lactic acidosis. Using metformin more than 48 hours of MI is a topical question, which will help to improve patient’s safety.
AIM: To evaluate the safety and quality of glycemic control using metformin in patients with T2DM during inpatient treatment for MI
MATERIALS AND METHODS: The study included 161 patients with T2DM, who were hospitalized consecutively with acute MI with ST-elevation and underwent percutaneous coronary intervention (PCI). Average time of metformin initiation was 5th day from admission. Creatinine was assessed at admission and 48 hours after PCI. The acid-base balance and lactate were assessed at admission and on the 3rd day after the start of using metformin. Criteria for the effectiveness of glycemic control was the proportion of glycemic measurements in target range of 6.1–10.0 mmol/l during hospitalization (“hospital time in range”, hTIR). hTIR >55% was considered to be a critical level. The long-term outcome was estimated at 365 days after hospitalization.
RESULTS: Metformin was prescribed to 99 patients (61%) (“M+”group) during the hospitalization, 62 patients were in “M-”group. Use of metformin was accompanied with better glycemic control in the «M+» group compared to the «M-»: mean glycemia 9.3 ± 1.6 vs 10.3 ± 2.3 mmol/l (p=0,002), SD 2.87 ± 1.1 vs 3.26 ± 1.8 (p=0,049), hTIR 60 ± 18% vs 48 ± 23% (p<0,001). There were clinically insignificant changes in acid-base balance on the 3rd day from the start of metformin use in the “M+” group, the lactate level did not increase. Use of metformin before to hospitalization with MI was not associated with an increased risk of developing acute kidney injury (AKI): RR 0.85 (0.37–1.96), p=0,691.
CONCLUSION: Use of metformin in patients with T2DM and acute MI is associated with better glycemic control. Carrying out angiography in patients, treated with metformin before the hospitalization, is not accompanied by an increased risk of developing AKI. Appointment of metformin in 3–7 days after angiography does not lead to an increase level of lactate and significant deviations in acid-base balance.
BACKGROUND: Numerous studies indicate a high incidence of various disorders of carbohydrate metabolism against the new coronavirus infection. These disorders aggravate the course of infection and increase mortality. Thereby, analysis of risk factors for unfavorable outcomes and assessment of the long-term consequences of COVID-19 in patients with impaired carbohydrate metabolism is of great importance.
AIM: To investigate the association between carbohydrate metabolism disorders in COVID-19 patients and mortality, course of infection, long-term consequences, as well as to identify risk factors for an unfavorable disease course.
MATERIALS AND METHODS: A retrospective analysis of data from the combined multicenter non-interventional real-world AKTIV and AKTIV 2 registries was performed. The sample included 9290 patients who had COVID-19 with varying severity from June 29, 2020, to November 29, 2020 (AKTIV) and from October 01, 2020, to March 30, 2021 (AKTIV 2). The patients were divided into 3 groups: Group 1 — patients with intact carbohydrate metabolism, n=6606; Group 2 — patients with newly diagnosed hyperglycemia (NDH), n=1073; Group 3 — patients with a history of type 2 diabetes mellitus (DM2), n=1611. The groups were assessed for clinical and laboratory parameters, comorbidities, mortality, carbohydrate metabolic status, and well-being during the infection and at 12 months.
RESULTS: The prevalence of carbohydrate metabolism disorders (CMD) was 28,9%, with DM2 patients accounting for 17,3% and patients with newly diagnosed hyperglycemia (NDH) for 11,6%. The mortality rate of patients with hyperglycemia of any origin was 10.6%, which was significantly higher compared to patients without hyperglycemia (3,9%). The probability of lethal outcome increased 2,48-fold in the group of patients with DM2 and 2,04-fold in the group of patients with NDH. At the same time, the probability of a lethal outcome decreased 2,94-fold in patients without CMD. At 12 months, patients with CMD showed a significantly higher frequency and longer persistence of complaints. This trend was more pronounced in patients with DM2 than in those with NDH. Only 1,7% of patients from the NDH group had type 2 diabetes and were receiving oral hypoglycemic medications one year after the infection. A prognostic model was developed to determine the risk of lethal outcome. The model included such known predictors as concomitant ischemic heart disease, history of myocardial infarction or stroke, blood glucose level, and age.
CONCLUSION: Carbohydrate metabolism disorders aggravate the course of COVID-19 and increase mortality. One year after infection, patients with DM2 and NDH were more likely to have symptoms typical for post-COVID syndrome, and NDH resolved in most cases after the infection.
Cell technologies & Genome editing
Glucocorticoid therapy is widely used in the treatment of various pathologies. Sensitivity to glucocorticoids (GC) has a serious impact not only on the effectiveness of their action, but also on the severity of side effects, the formation of risk factors and the development of cardiovascular diseases (CVD). Variability of sensitivity to GC causes different phenotypes and severity of metabolic disorders underlying CVD. Among them, one can distinguish a decrease in muscle mass and strength, obesity, glucose and lipid metabolism impairment, and others. Glucocorticoids carry out their effects by binding to the glucocorticoid receptor (GR), and therefore this is considered a critical point in their action. This review presents data on the significance of the glucocorticoid receptor structure, examines the main single nucleotide polymorphisms (SNP) of the NR3C1 gene associated with hypersensitivity or relative resistance to glucocorticoids in the context of metabolic disorders and the development of CVD. The association of the four most studied SNP of the GR gene with metabolic risks is described in detail: BclI (rs41423247), N363S (rs56149945), ER22/23EK (rs6189/rs6190), GR-9ß (rs6198). Their determination can contribute to clarifying the prognosis of both the effectiveness of GC and the development of metabolic disorders, and subsequent early correction of CVD risk factors.
Pediatric Endocrinology
BACKGROUND: Gonadotropin therapy in boys with congenital isolated hypogonadotropic hypogonadism helps to increase testes volume and induce spermatogenesis in comparison with testosterone therapy. However, difficulties with dose titration, partial therapy success, absence of generally accepted regimen protocols don’t allow to use this therapy in order to induce puberty in adolescents with Kallmann syndrome or normosmic hypogonadotropic hypogonadism.
AIM: To assess the effectiveness of combination hormonal replacement therapy via human chorionic gonadotropin and recombinant follicle stimulation hormone in adolescents with congenital isolated normosmic hypogonadotropic hypogonadism and with Kallmann syndrome
MATERIALS AND METHODS: This is an open single-center prospective non-controlled study. Boys with hypogonadotropic hypogonadism were receiving hormonal replacement therapy for 12 months. Initial dose of human chorionic gonadotropin was 500 IU per week. Initial dose of recombinant follicle stimulation hormone was 37.5 IU per week. Doses were doubled in 6 months. Antropometric data, Tanner stage, testes volumes, inhibin B and anti-Mullerian hormone (AMH) levels were evaluated in all the patients before the treatment, after 6 and 12 months of the therapy.
RESULTS: 8 boys with hypogonadotropic hypogonadism were included into the study. Median age before therapy initiation was 15.7 years [15.33; 16.41]. In 12 months after the therapy initiation puberty development, testosterone increase from 0.44 [0.34;0.62] to 4.39 [0.88;10.51] nmol/l (p=0.012), AMH decrease from 35.70 [18.00;59.00] to 14.41 [11.60;16.65] ng/ml were noted in all the patients (p=0.017). Testes volumes increase and inhibin B level increase were not statistically significant.
CONCLUSION: Gonadotropin therapy is effective in order to puberty initiation in adolescents with congenital hypogonadotropic hypogonadism. In helps to achieve not only androgenization, but also to Sertoli cells maturation.
BACKGROUND: Congenital hyperinsulinism (CHI) is a rare life-threatening disease characterised by persistent hypoglycaemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants.
AIM: To evaluate neurophysiological characteristics of central nervous system in children with congenital hyperinsulinism treated according to the international protocol in Russian Federation.
MATERIALS AND METHODS: Our retrospective, prospective cohort study included 73 patients who received treatment for CHI according to the current international protocol at different departments of the Almazov National Medical Research Centre from 2017 to 2022. All patients underwent a comprehensive examination, including electroencephalography (EEG).
RESULTS: Among 73 patients with CHI, 35% (23) had focal form of the disease, 65% had non-focal form (49% (39) — diffuse form, 16% (11) — atypical form). All patients with focal form of CHI had a recovery as an outcome.
Analysing the EEG data we found that paroxysmal activity was recorded in 23 patients (32%), 50 patients did not have paroxysmal activity (68%). Diffuse changes were observed in 47 patients (64%), whereas 26 patients (36%) were absent of it. By constructing Kaplan-Meier curves we found that the alpha rhythm is formed significantly (p=0.026) earlier in patients with a focal form of CHI.
CONCLUSION: CHI patients treated according to the international guidelines in Russian Federation show rather positive neurological outcome. We established that alpha rhythm earliest formation is associated with focal form of CHI.
BACKGROUND: Loss-of-function mutations in the TSH receptor gene (TSHR) (NP_000360.2) are the potential causes of thyroid dysgenesis in patients with congenital hypothyroidism. Heterozygous variants of the TSHR gene lead to partial resistance to TSH, homozygous and compound heterozygous variants have been shown to cause CH due to thyroid hypoplasia or TSH resistance. Recently more and more articles in this field have appeared in the international literature sources, while local publications are limited. The studies are necessary to understand the etiology, pathogenesis of the disease, to improve the management of these patients.
AIM: To assess the frequency of incidence of pathogenic variants of the TSHR gene in children with CH due to thyroid dysgenesis. To study inheritance and phenotypic patterns of CH in families.
MATERIALS AND METHODS: In this single-center interventional one-stage non-comparative study a group of CH patients was examined. The patients underwent neck ultrasound and radionuclide imaging. The examination was performed 14 days after hormone replacement therapy suspension or prior to its initiation. The structure of thyroid dysgenesis was estimated, genetic testing for mutations in the TSHR gene was performed using the NGS method.
RESULTS: The study included 95 children with primary CH (75 girls; 20 boys). The patients’ median age at the time of examination was 6.2 years [4.5; 8.9], the median level of neonatal TSH was 157.5 mU/l [60.9; 257.2]. Ectopic thyroid was found in 52% of children, aplasia in 36%, hypoplasia and hemiagenesis in 10% and 2%, respectively. In 5.4% of cases (in 5 out of 95 patients), different variants of the TSH gene were detected. Two children had heterozygous p.R450H and p.D487N variants in TSHR gene, two patients was homozygous for the p.S49Afs * 9 variant, one child had compound heterozygous variants (p.A485D and p.R450H). According to ultrasound imaging, all patients had thyroid hypoplasia of varying severity. Three children underwent thyroid scintigraphy, which revealed decreased 99mТc pertechnetate uptake (0.3–0.9%).
CONCLUSION: In our study, the incidence of different variants in the TSHR gene in children with CH was 5.3%. Our analysis uncovered two previously undescribed variants. Genetic testing may be able to help with making the diagnosis, patient’s management, and genetic counseling.
Reproductive Endocrinology
The increasing of older age group in the population determines studying of age related diseases and emergence of new investigations in this area. In Female body, entering the menopausal transition is the start of «aging» of reproductive function and linked with decreasing of sex hormons levels. A direct connection between changes of estrogen, progesterone, androgen ratios and cognitive function of women was revealed. The anatomical localization of sex hormone receptors, the mechanisms of interaction of hormones with these receptors determine the ways of implementing biological effects of steroids on the CNS. Modern theories of «healthy nerve cells» and «eu-estrogenemia» explains the role of additional criteria, such as the absence of neurological diseases history and the duration of hypoestrogenia, to the outcome of menopausal hormone therapy. Additional factors that can affect to MHT action include: the composition of hormone therapy, administration methods, regimens (cyclic, continuous), duration of treatment, history of endocrine diseases, diabetes mellitus, gynecological history (parity, menarche age, COC use), heredity. The sections present the effect of menopausal transition on the development of depression, mood changes, sleep disturbances and mental disabilities. The explanation of negative effects of menopausal hormone therapy to cognitive health is also described by modern point of view. The ambivalent opinions of researchers, the potential of new reading of the results of earlier studies, confirms the necessity of continuing study of this topic.

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ISSN 2308-1430 (Online)