No 3 (2021)

Based on the data of foreign and Russian articles, this review comparatively analyzes the pathogenesis of endometriosis and cancer. It has been established that endometriosis, especially its infiltrative forms, has many properties in common with cancer: uncontrolled growth and multifocal localizations of endometrioid implants, reduced apoptosis, metastasis to the lymph nodes and spread inside and outside the abdominal cavity, penetration into the surrounding tissues, stimulation of non-angiogenesis, as well as chronic inflammation and oxidative stress. The endometrioid implants show genetic and epigenetic mutations involved in oncogenic transformation. Enhanced angiogenesis required for cell growth is the most important sign of a malignant tumor. The same increased level of angiogenic factors is also found in the tissues of deep infiltrative endometriosis. Antiangiogenic therapy effectively suppresses endometrioid tissue growth and reduces pain. Women with endometriosis have an increased incidence of malignant neoplasms, which indicates the similarity of their pathogenesis and common environmental molecular and genetic risk factors. Conclusion. When aggregating these data, it becomes possible to consider endometriosis in the context of oncogenesis, wh ich opens up new possibilities of drug therapy.

The given review analyzes the data available in the literature on the main etiological factors and pathogenetic mechanisms of endometrial susceptibility disorders in patients with recurrent implantation failures in assisted reproductive technology programs. The paper includes the publications available in the Pubmed database (https://pubmed.ncbi.nlm.nih.gov/) on this topic. It gives information on modern molecular genetic methods for determining the personalized window of implantation and for correcting the timing of embryo transfer, for identifying the pathogenic microorganisms that cause chronic endometritis, and for analyzing the species and quantitative composition of the endometrial microbiota. It summarizes the results of the most effective methods of immunotherapy, which are aimed at improving the receptive properties of the endometrium, by using platelet-rich plasma, mononuclear cells, granulocyte-stimulating factor, growth hormone, and the drugs dexamethasone and letrozole. The paper reflects the expediency of etiotropic antibacterial therapy in patients with chronic endometritis and recurrent implantation failures at the stage of preparation for assisted reproductive technology programs. It shows an association between endometrial scratching and improved reproductive outcomes in patients with recurrent implantation failures. Special attention in overcoming infertility is paid to the possibilities of cell therapy using mesenchymal stem cells in women with Asherman’s syndrome and endometrial hypoplasia. Conclusion. Patients with multiple implantation failures in assisted reproductive technology programs require the in-depth diagnosis of the endometrial receptor apparatus and the application of personalized approach to preparing the endometrium.

The paper analyzes the data available in the literature on the results of investigating the sequences and relationships of genetic disorders in endometriosis. Hereditary predisposition to this disease is characteristic for women with clinical manifestations of endometriosis. This category of patients is noted to have epigenetic disorders in the progenitor cells and stem cells of the coelomic epithelium, endometrium, endometrial vasculature, and in other tissues of the reproductive system. Critical disorders of genome-wide DNA methylation and changes in the signaling pathways of gene expression regulation are shown to be characteristic for endometrioid stromal cells. Most of these disorders develop in the stromal cells that have the properties of stem cells and partially the characteristics of ovarian cell granules and immune cells, such as the production of estradiol, prostaglandin, and cytokines. These cells originating from the ectopic endometrium show the abnormal expression of a number of transcription factors that regulate key genes necessary for progesterone-regulated differentiation of normal endometrial stromal cells. It has been shown that the endometrial cells exhibit mutations, including driver mutations in ovarian cancer. Intense paracrine inflammatory signals, together with estrogens from epigenomically improperly programmed endometrioid cells, can lead to increased epithelial mutagenesis and activation of carcinogenesis. Conclusion. It is necessary to further study the genetic aspects of endometriosis in order to deepen our understanding of the pathogenesis of the disease and to develop promising treatment methods.

Objective. To study the prognostic role of determining the content of mitochondrial DNA in the blood and voltage-dependent anion channel 1 (VDAC1) in the placenta during preterm birth. Materials and methods. The study included 142 pregnant women. They were divided into three groups: group 1 consisted of 43 patients who had a spontaneous preterm birth; group 2 included 47 women who had a preterm birth and premature rupture of membranes (PROM) and group 3 consisted of 52 women who had threatened preterm labor followed by term birth. The quantitative assessment of mtDNA copy number in peripheral blood plasma (reverse transcription quantitative real-time PCR (RT-qPCR)) as well as determining the level of VDAC1 in the placenta were carried out using western blotting. Results. The study of the VDAC1 protein content in the placenta showed its statistically significantly high content in patients who had a preterm birth and PROM at 22-27 6/7 and 28-33 6/7 weeks’ gestation compared to the patients who had a term birth and a spontaneous preterm birth at 22-27 6/7 weeks’ gestation (p<0.05). Patients with normal pregnancy showed an increase in the level of mtDNA in the peripheral blood plasma with the gestational age, reaching the maximum values by 37-40 weeks. Patients who had preterm labor with PROM showed significantly higher mtDNA levels at 22-27 6/7 and 28-33 6/7 weeks than those who had a normal pregnancy, but it was lower than in patients with term birth. In case of spontaneous preterm birth, the level of mtDNA at 22-27 6/7 and 34-36 6/7 weeks’ gestation was statistically significantly higher, compared with one in normal pregnancy and term birth. Determining the level of mtDNA copy number using ROC analysis with high sensitivity (77%) and specificity (93%) makes it possible to predict the risk of preterm birth. Conclusion. Statistically significant differences in the content of VDAC1 protein in the placenta and the level of mtDNA copy number in the peripheral blood plasma in spontaneous preterm birth and in preterm birth with PROM in contrast to the normal course of pregnancy suggest that they contribute to the development of these complications of pregnancy. The identification of these markers can facilitate timely diagnosis and initiation of personalized complex therapy aimed at prolonging pregnancy.

Aim. To investigate the causes of and therapeutic approaches for different types of fetal bradyarrhythmia. Materials and methods. We examined 15 women with fetal bradycardia at 18-36 weeks of gestation. Group I included nine pregnant women with moderate bradycardia (fetal heart rate 86-110 bpm). Six women with severe bradycardia (fetal heart rate 45-78 bpm) made up group II. The study methods included special laboratory examination and statistical analysis. Therapeutic approaches were based on indications and comprised hydroxychloroquine, therapeutic plasmapheresis, immunoglobulin therapy, and pulse corticosteroid therapy. Results. Group II patients were statistically significantly more likely to have autoimmune diseases and higher titers of autoantibodies to SSA (Ro) and antinuclear antibodies. In the setting of specific therapy, 33.3% of patients showed regression of bradyarrhythmia to grade 1-2 AVblock. In 66.7% of patients, there was no heart failure progression or the development of non-immune fetal hydrops. In group I, 88.8% of patients required no specific therapy. The gestational age at delivery in both groups was 38.4 (1.1) weeks. Thirty-three percent of the neonates in group I had multiple cardiovascular and pulmonary malformations. Transient cardiac arrhythmias were observed in 44% of group I neonates. Four out of 6 newborns in group II required pacemaker implantation. Conclusion. Early diagnosis (up to 19-20 weeks of gestation) of fetal heart rate abnormalities, timely and comprehensive examination of the pregnant woman contributes to the early initiation of therapy and the prevention of irreversible damage to the fetal cardiac conduction system.

Introduction. Investigating pathological changes in endogenous steroidogenesis associated with advanced extragenital endometriosis (AEGE) requires high-precision and sensitive methods. Aim. To investigate blood steroidome changes in AEGE. Materials and methods. Patients with AEGE and control subjects were tested for serum hormones using high-performance liquid chromatography-mass spectrometry (HPLC-MS). Results. Patients with AEGE had significant changes in the concentration of 9 steroids. Blood hormone concentrations in patients with and without AEGE were as follows: estradiol 0.18 vs. 0.12 ng/ml (p=0.05), 17-OH-progesterone0.55vs. 0.44ng/ml(p=0.05), testosterone0.81 vs. 0.43ng/ml(p<0.01), dihydrotestosterone- 0.16 vs. 0.37 ng/ml (p<0.1), dehydroepiandrosterone 3.56 vs. 5.98 ng/ml (p<0.01), DHEA sulfate 2533.00 vs. 4425.00 ng/ml (p<0.01), androstenedione 1.35 vs. 1.31 ng/ml (p=0.29), cortisol 164.00 vs. 90.50 ng/ml (p<0.01), corticosterone 4.87 vs. 1.20 ng/ml (p<0.01), 11-deoxycorticosterone 0.87 vs. 0.37 ng/ml (p<0.01). Progesterone concentrations were below the detection limit in both groups. Four logistic regression models allowed differentiation of blood steroidome of AEGE patients from that in controls. Conclusion. Endometriotic cysts in stage III - IVAEGE have no significant effect on changes in the steroidome. HPLC-MS differences in blood steroidome allow differentiation of patients with AEGE from control subjects.

Aim. To analyze the content of heparan sulfate proteoglycans (HSPGs) in eutopic and heterotopic endometrium in women with ovarian endometriosis (OE). Materials and methods. Surgical samples of endometrioid ovarian cysts and endometrial biopsy specimens obtained from 11 women of reproductive-age in the proliferative phase of the ovarian cycle with stage III OE (according to the American Fertility Society classification) were analyzed using real-time semi-quantitative PCR and immunohistochemistry (IHC). The expression patterns of core proteins of three HSPGs and the enzyme heparanase (HPSE) were assessed. Nonparametric statistical methods were used for data processing. Results. Real-time PCR analysis of the relative expression of core proteins of HSPGs in endometrial heterotopias revealed a 2-fold increase in total transcriptional activity of the gene encoding perlecan (HSPG2) and HPSE compared to eutopic endometrium (p<0,05). IHC analysis of these molecules in surgical samples confirmed these data. The relative expression of HPSE in heterotopias positively correlated with concentration of the tumor marker CA125 in blood serum. Conclusion. HSPG2 and HPSE participate in the pathomorphogenesis of OE, leading to extracellular matrix modification and impairment of intercellular communications. They can be used as markers of stage III OE.

Aim. To study IL-8 production and IL-8 (251T>A) gene polymorphism in patients of reproductive age with external genital endometriosis (EGE). Materials and methods. The study included 71 patients with different stages of external genital endometriosis and 24 patients without endometriosis in the control group. The levels of IL-8 in serum and peritoneal fluid were determined by enzyme immunoassay using the kits produced by MedSystems (Austria). The distribution of alleles and genotypes of the 251T>A polymorphism of the gene IL-8 was carried out by the method of polymerase chain reaction followed by restriction analysis (GosNIIgenetika, Moscow). Results. The increased IL-8 concentrations in the peritoneal fluid were found in patients with stages I-IIEGE. The distribution of IL-8 gene allelic variants among patients with various stages of ЕGE was characterized by a predominance of the T/T genotypes of the 251T> A polymorphism. Conclusion. Increased IL-8 concentrations in the peritoneal fluid and the presence of the polymorphic marker 251T>A in IL-8 gene were associated with a risk of development of EGE in patients of reproductive age.

Aim. To investigate fetal adaptation profile during antenatal cardiotocography (CTG) with subsequent analysis of neonatal outcomes. Materials and methods. The retrospective study included 1927 observations at 33 to 40 weeks of gestation. Consecutive RR intervals were recorded using a UNICOS fetal computerized cardiac monitor. Heart rate variability (HRV) was assessed during the first 30 measurements. Based on cluster analysis, observations were divided into two groups categorized by fetal adaptation profiles as 1 [habituation, n=1702 (88.3%)] and 2 [dishabituation, n=225 (11.7%)]. The relationship between adaptation profiles and data on the early neonatal complications was analyzed. Results. Fetal HRV analysis showed that in most cases, fetuses quickly adapted to the CTG and maintained parameters throughout the procedure. In the first group, the profile showed a decrease in RR interval variance with relatively low basal heart rate and fetal condition indicator (FCI). In the second group (newborns with complicated neonatal course), the profile was characterized by a high basal heart rate, high RR interval variance, and higher mean FCI. HRV changes during adaptation to the CTG were associated with complications identified in newborns. Conclusion. Fetal HRV assessment during adaptation to CTG is essential for assessing the fetal condition and predicting the complicated neonatal course.

Objective. To evaluate the effectiveness of treatment of girls aged 15-18 years with different phenotypes of polycystic ovary syndrome (PCOS) using combined oral contraceptives (COCs) and inositols depending on overweight and insulin resistance in girls. Materials and methods. The study included 153 patients aged 15-18years with PCOS and 32 healthy controls; girls of the study group had oligo/amenorrhea, hyperandrogenism, and polycystic ovarian morphology revealed by the ultrasound assessment. The comparative analysis of clinical and anamnestic data of patients with PCOS (n=153) and the control group (n=32) was performed at the first stage of the study. Depending on the PCOS phenotype, overweight, and insulin resistance, there were groups of hormonal and non-hormonal management; the results of the clinical examination were compared before the administration of therapy and 6 months after it. The groups were compared with each other and with the control group; the results obtained after receiving the treatment were compared with the baseline values and with the group of healthy girls. Results. Before the therapy, the patients with PCOS showed a significant increase in the level of luteinizing hormone (LH), testosterone (T), androstenedione, anti-Mullerian hormone (AMH), and free androgen index (FIA) accompanied by low levels of sex hormone-binding globulin (SHBG) (p<0.0001for all indicators) as well as significantly higher levels of 17-OHP, DHEA-S, and cortisol (p<0.005). Phenotypes B and D differed from phenotype A having higher levels of LH, T, androstenedione, and FIA (p<0.005for all indicators). After the therapy with combined oral contraceptives, patients with phenotype A showed a significant decrease in LH, T, FIA, DHEA-S, androstenedione (p<0.005for all indicators) and ovarian volume (p<0.005), but it was necessary to continue administering therapy, as the main hormonal and ultrasound characteristics were not normalized. A half of the patients with phenotypes B and D who received non-hormonal treatment with inositols showed a clinical effect after 6 months; their menstrual cycle restored and the main hormonal parameters were normalized according to the levels of LH, T, FIA, and SHBG. As the result did not demonstrate statistical signif icance and normative values, it was necessary to continue administering the non-hormonal therapy. There was no clinical effect of non-hormonal therapy in 13.6% of patients with PCOS, therefore, the therapy was changed. Conclusion. The administration of microdosed COCs with drospirenone for 6 months demonstrated its clinical effectiveness in the treatment of teenagers with classic PCOS, however, this period of administration was not sufficient for the clinical effect. It is recommended to continue the treatment of PCOS with COCs in teenagers for more than 6 months, and assess the hormonal parameters and the degree of hyperandrogenism before withdrawal of the drugs. The clinical effect was also observed in patients with non-classical PCOS after receiving non-hormonal combined therapy, namely the 5:1 ratio of myoinositol and D-chiroinositol. There was a tendency for normalization of hormonal and ultrasound parameters, which did not reach the standard values, so the therapy should be continued. However, the treatment had to be changed in 13% of the patients as they did not respond to the therapy.

Objective. To assess the effect of preimplantation genetic testing for aneuploidy (PGT-A) on the outcomes of assisted reproductive technologies (ART) cycles with vitrified embryo transfer in different protocols. Material and methods. This study analyzed 313 ART cycles with vitrified embryo and use of dydrogesterone for luteal phase support. These cycles were differentiated depending on the type of cryotransfer protocol and performance of PGT-A. The association of PGT-A and the outcome of the ART program with the vitrified embryo was evaluated depending on the type of protocol. Results. The protocols with the ovulatory cycle revealed a higher frequency of implantation in the cycles with PGT-A. The protocols with estrogens in the subgroup with PGT-A showed an increase in the frequency of implantation and a decrease in the proportion of pregnancy losses at the stage from biochemical to clinical pregnancy. GnRH agonist protocols demonstrated that the use of PGT-A was associated with a significant increase in the frequency of positive outcomes of the ART program (p=0.036). Conclusion. PGT-A positively affects the outcomes of ART programs with vitrified embryo and use of dydrogesterone for luteal phase support, improving their clinical outcomes.

Vitamin D deficiency is recorded in various populations in 80-83% of people, more often in women than in men. There is a significant influence of vitamin D deficiency on the risk of gynecological diseases, reproductive disorders, pregnancy complications and negative outcomes. Vitamin D def iciency has been proved to be associated with spermatogenesis disorders, hypogonadism, andfertility disorders in men. Women have shown the relationship between low levels of vitamin D in the blood serum and irregular menstruation, reduced ovarian reserve, and incidence of such diseases as endometriosis, fibroids, polycystic ovary syndrome, breast cancer. D-status significantly affects female fertility and live birth rates in assisted reproduction. Hypovitaminosis D in pregnant women is associated with a high incidence of miscarriages, preeclampsia, gestational diabetes, bacterial vaginosis, as well as disorders of fetal growth and neurodevelopmental disorders in the newborn. The experimental model showed the anti-inflammatory, antiproliferative, antifibrotic and pro-apoptotic effects of vitamin D. Conclusion. The review of the modern literature suggests that it is necessary to maintain the optimal level of vitamin D3 in the blood serum in women at all stages of life. Further studies are needed to assess the effects of vitamin D supplements during pregnancy, especially in terms of the risk of maternal adverse events.

Background. Basal cell carcinoma (BCC) is the most common human malignant tumor that accounts for as high as 75% of all malignant skin neoplasms. In all cases, BCC is associated with excessive ultraviolet insolation and is more often located on the open skin areas exposed to sunlight. Vulvar BCC is an extremely rare tumor with unknown etiology, which is asymptomatic and frequently diagnosed late. Case report. The paper describes a clinical case of vulvar BCC in an 87-year-old patient. The neoplasm in the perineal region appeared two months before her visit to a physician and was rounded in shape with clear boundaries of 1.5x1.0 cm. The diagnosis was confirmed by morphopathological examination. Conclusion. The clinical case is presented for the formation of caution in dermatologists and physicians of other specialists in relation to cancers, including their rare localizations.