Endocrinology Research Center

Introduction. Despite favorable prognosis for differentiated thyroid cancer, 5–10 % of the cases are radioiodine-refractory form of this pathology characterized by aggressive course. Molecular and genetic causes of the resistance are genetic mutations, primarily in the BRAF (V600E mutations), TP53, TERT, RAS, NTRK and RET genes, oligoclonality, and somatic tumor heterogeneity. These cell events can affect response to targeted therapy, promote the «evasion» effect, development of radioiodine resistance, and underlie the possibility of tumor re-differentiation when treatment affects these targets. Clinical case. The article describes a clinical case of combination treatment of differentiated thyroid cancer with lung metastases. In 2016–2022, the female patient received 3 courses of radioiodine therapy which did not achieve any significant effect. Due to this, targeted therapy with sorafenib at the place of residence was initiated. Considering development of medication intolerance and disease progression (local metastasis of BRAF-positive tumor and laryngeal stenosis), targeted therapy was switched to BRAF / MEK-specific with subsequent course of radioiodine therapy and achievement of stable disease for 1 year. Genetic examination of the primary tumor and metastasis showed presence of the BRAFV600E mutation. Variant allele frequencies (VAF) in metastasis and recurrent tumor were 12 and 6 %, respectively. In the recurrent tumor, H1047L mutation in the PIK3CA gene was found (VAF 8 %). Previous examinations in two other laboratories did not show BRAF gene mutation in this tumor which did not correspond to primary partial response to targeted therapy with BRAF / MEK inhibitors. That said, our analysis identified this mutation. Conclusion. The obtained data highlight significant diagnostic difficulties of analysis of formalin-fixed and paraffin-embedded samples: preanalytical degradation of nucleic acids, fixation artefacts, low VAF, non-representative biopsy sampling increase the risk of false negative results. The presented clinical case demonstrates the necessity of routing of patients with aggressive tumors into specialized centers, and that treatment and diagnostic tactics should be determined by a qualified multidisciplinary team.

Aim: to present clinical guidelines describing the clinical, laboratory, endoscopic and histological characteristics of autoimmune gastritis (AIG) and to provide information support for decision-making on diagnosis, prognosis assessment and choice of management tactics for patients with AIG. Key points. AIG is an organ-specific autoimmune disease characterized by the presence of antibodies to parietal cells and/or intrinsic factor, in which inflammation and atrophy are limited to the gastric mucosa, functionally manifesting as hypo- and achlorhydria. There is evidence of an increase in the incidence of AIG worldwide. AIG is often associated with autoimmune thyroiditis (up to 40 % of cases), type 1 diabetes mellitus, and autoimmune polyglandular syndrome. Data on laboratory diagnostic methods, esophagogastroduodenoscopy, and histological examination of biopsies are presented, with an analysis of the endoscopic and histological picture typical of AIG. When AIG is combined with H. pylori infection, eradication therapy is recommended. In addition to symptomatic treatment and treatment of anemia, long-term rebamipide therapy is recommended to potentiate the protective properties of the gastric mucosa. Endoscopic monitoring of patients with AIG is recommended at intervals of once every 3 years.

BACKGROUND : Male hypogonadism is associated with obesity; therefore, it is of interest to evaluate the impact of bariatric surgery – one of the most effective methods for reducing adipose tissue mass on testosterone production. AIM : Evaluation of the effect of bariatric surgery on testosterone production in men. MATERIALS AND METHODS : A solid prospective observational single-center interventional study included men with obesity who underwent bariatric surgery at the National Medical Research Center for Endocrinology of the Ministry of Health of the Russian Federation between January 2022 and August 2024. Dynamic assessment of body weight, body mass index, and total testosterone levels was performed. Group comparisons were made using nonparametric methods. Differences were considered statistically significant at p < 0.05. The Bonferroni correction was applied for multiple comparisons. RESULTS : A statistically significant reduction in body weight, amounting to -30.7 [-32.8; -27.2]% from baseline, was accompanied by a statistically significant increase in testosterone levels of 6.7 [4.2; 11.4] nmol/L. Hypogonadism was resolved in 56% (95% CI 31; 79) of men. Patients who achieved eugonadism had a statistically significantly higher baseline total testosterone level of 8.2 [7.3; 8.7] nmol/L compared to men with persistent hypogonadism — 5.5 [3.7; 6.5] nmol/L, p=0.005. There were no complications from bariatric surgery. CONCLUSION : The use of bariatric surgery leads to increased testosterone production and reduced frequency of hypogonadism in men.

Thyroid eye disease (TED) is an autoimmune pathology of the orbital tissues associated with autoimmune thyroid disease, most commonly occurring with Graves' disease. The clinical presentation of TED is extremely diverse, ranging from mild orbital involvement to potentially vision-threatening optical neuropathy. Early diagnosis of the active phase of TED is crucial, as immunosuppressive therapy is effective only during this phase, while treatment for patients in the inactive phase consists only of rehabilitative surgery. High-dose intravenous glucocorticoids are the first-line treatment for patients with moderate to severe active TED. Glucocorticoids are widely used due to their anti-inflammatory and immunosuppressive properties, but about 20-30% of patients remain resistant to glucocorticoid treatment. One promising direction in the treatment of glucocorticoid-resistant TED is the use of monoclonal antibodies targeting specific antigen epitopes. We present a clinical case of tocilizumab treatment in severe glucocorticoid-resistant TED complicated by optic neuropathy.

Secondary amenorrhea is a pathological condition that may develop as a result of either functional hypothalamic amenorrhea (FHA) or primary ovarian insufficiency (POI). In recent years, metabolomic studies in gynecology have gained importance for improving diagnostics, optimizing pharmacological treatment, and monitoring therapeutic outcomes. It is well established that cortisol production increases in response to chronic stress and relative energy deficiency syndrome. Therefore, it is reasonable to expect elevated cortisol levels in patients with functional amenorrhea associated with weight loss, which may adversely affect menstrual function. To investigate and compare the parameters of the multicomponent blood steroid profile (multisteroid analysis), including androstenedione, corticosterone, testosterone, cortisol, cortisone, and dehydroepiandrosterone (DHEA), in patients with secondary amenorrhea of different origins (FHA, POI), and to identify alterations in target markers using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). A single-center cross-sectional comparative study was conducted involving two populations of women aged 18-39 years: (1) patients with secondary amenorrhea of various origins (FHA, POI) (n=120), and (2) healthy women (n=34). Blood steroid profile parameters were assessed using HPLC-MS/MS. A total of 154 women were examined. The lowest corticosterone levels were observed in the POI group - 3.95 nmol/L [2.4; 5.7] (p<0.0001). No statistically significant differences were found between other groups. Hypercortisolemia was not detected in any of the study participants, nor were there significant differences in cortisol, cortisone, or DHEA levels between groups. In this study, based on a targeted quantitative analysis of steroid hormones, their precursors, and metabolites using HPLC-MS/MS technology, we characterized the features of the blood steroid profile in patients with secondary amenorrhea. The profile demonstrated similar characteristics across all amenorrhea types, regardless of etiology, suggesting a common underlying mechanism. However, the observed decrease in corticosterone levels in POI patients and the absence of hypercortisolemia in FHA women are of particular interest and warrant further investigation.

Background: Male infertility is a common reproductive disorder, affecting about 7% of men in the general population. Despite its prevalence, the cause of infertility is often unknown. This case report presents the results of a comprehensive evaluation of a patient with severe oligoasthenoteratozoospermia and primary infertility. Methods: The patient underwent clinical, andrological, and genetic examinations, including semen analysis, transmission electron microscopy, cytogenetic examination, molecular analysis of the AZF locus and the CFTR gene, whole-exome sequencing, and Sanger sequencing. Results: Semen analysis revealed severe oligoasthenoteratozoospermia. Transmission electron microscopy showed acrosome detachment from the nucleus in 49% of the spermatozoa. A high percentage (54%) of spermatozoa with insufficiently condensed (“immature”) chromatin was also observed. No chromosomal abnormalities, Y chromosome microdeletions, or pathogenic CFTR gene variants were identified. Whole-exome sequencing revealed a novel c.821G>C variant (chrX:127185365G>C; NM_138289.4) in the ACTRT1 gene (Xq25). This variant was hemizygous in the patient and heterozygous in his mother, as determined by Sanger sequencing. According to the ACMG guidelines (PM2, PP3), this missense variant in the ACTRT1 gene was classified as a variant of uncertain clinical significance (VUS). Amino acid conservation and 3D protein modeling predict that the identified variant has a deleterious effect on the protein. Conclusions: This study suggests a potential link between a novel ACTRT1 variant and a specific teratozoospermia phenotype. Further functional studies are needed to confirm this association and determine the role of the gene in X-linked male infertility.

This study assessed sarilumab in treating patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). This phase 2b, open-label study (NCT02776735) consisted of three sequential parts (each with a core-treatment and extension phase). During part 1, three doses were assessed in two weight groups (group A/B: ≥30-60 kg/≥10 to <30 kg) to select the optimal dose with regard to pharmacokinetics, safety and efficacy were evaluated in latter parts. During the extension phase of part 1, patients initially assigned to the selected optimal dose continued on this dose; the remaining patients were switched to this selected dose. Patients in parts 2 and 3 received the selected dose from baseline. The primary endpoint was pharmacokinetic exposure (area under the serum concentration versus time curve during a dose interval Շ of 2 weeks [AUC0-Շ], maximum serum concentration observed [Cmax], and concentrations observed before treatment administration during repeated dosing [Ctrough]). Safety and efficacy were assessed. The mean age of treated patients (N = 101; 76.2% female) was 9.4 years. Of the evaluated doses in part 1, dose 2 (group A/B: 3.0/4.0 mg/kg every 2 weeks [q2w]) was selected. In patients receiving the selected dose from baseline (n = 73), Cmax, AUC0-14 days and Ctrough at steady state in group A/B were 27.1/40.4 mg/L, 276/395-day*mg/L, and 9.57/14.4 mg/L, respectively. At week 48, the JIA-American College of Rheumatology 30%, 50%, 70%, and 90% improvement criteria rates were 100%, 100%, 93.8%, and 76.6%, respectively. Adverse events were reported in 70 of 73 patients (95.9%). Twenty-seven patients (37%) experienced grade 3/4 neutropenia; there were no associated infections. No deaths occurred. In patients with pcJIA receiving the selected dose from baseline, pharmacokinetic exposure was comparable to a dose of 200 mg q2w for adults with rheumatoid arthritis. Clinically relevant improvements were observed in disease activity, with safety being consistent with the known profile of sarilumab.

The parathyroid glands (PG) and diseases associated with changes in their functional activity have been studied since the 19th century. In the last few decades, the basic principles of calcium-phosphorus metabolism, diagnostic methods, and treatment options for mineral disorders has changed significantly. The knowledge and experience of previous investigators in the anatomical, physiological, morphological, molecular, and genetic aspects of normal and abnormal PG, along with the introduction of innovative laboratory and instrumental methods, has been instrumental in the development of the field. Recent advances have opened new possibilities for personalized patient care. In our historical review, we describe the approaches to mineral and bone pathology, starting with the discovery of the PG and ending with modern achievements using the single endocrinology center as an example.