卷 73, 编号 6 (2024)

Background: Chronic hyperglycemia and abnormal glucose variability are established risk factors for perinatal complications. Abnormal fetal growth and diabetic fetopathy can be associated not only with carbohydrate metabolism disorders, but also with impaired production of cytokines, chemokines, and growth factors that regulate intercellular interactions.

Aim: The aim of this study was to evaluate cytokine and growth factor levels in the blood serum of pregnant women with type 1 diabetes mellitus and in umbilical cord blood of their neonates, as well as assessing the associations of these levels with the development of fetal macrosomia and diabetic fetopathy.

Materials and methods: This prospective study included 88 women with a singleton pregnancy and cesarean delivery. All the patients provided informed consent for participation. The study groups comprised individuals with type 1 diabetes mellitus (n = 32) and non-impaired glucose tolerance (n = 56). The levels of interferons alfa 2 and gamma, monokine induced by interferon-gamma, interleukin-1α, -1β, -2, -3, -4, -5, -6, -7, -8, -9, -10, -13, -15, -16, -17, -18, interleukin-1 receptor antagonist, interleukin-2 receptor alpha subunits, p40 and p70 subunits of interleukin-12, monocyte chemotactic protein-1, -3, macrophage inflammatory protein-1α, -1β, leukemia inhibitory factor, macrophage ingibitory factor, nerve growth factor beta, stem cell factor, cutaneous T-cell-attracting chemokine, growth-regulated oncogene alpha, hepatocyte growth factor, stem cell growth factor beta, stromal cell-derived factor-1 alfa, interferon gamma inducible protein 10, platelet-derived growth factor-bb, vascular endothelial growth factor, basic fibroblast growth factor, eotaxin, chemokine ligand 5, and macrophage, granulocyte, and granulocyte/macrophage colony-stimulating factors, tumor necrosis factor alfa and beta, and tumor necrosis factor-related apoptosis-inducing ligand were measured with multiplex immunoassay in the blood serum of women at 36–40 weeks of gestation and in the umbilical cord blood serum of their neonates.

Results: Cytokine levels varied widely in the both study groups. Women with type 1 diabetes mellitus had higher levels of interleukin-1β, -6, -17, basic fibroblast growth factor, macrophage inflammatory protein-1α, -1β, and lower levels of interleukin-1ra compared to the control group. Their neonates had higher levels of interleukin-6, -8, granulocyte colony-stimulating factor, macrophage inflammatory protein-1α, -1β. Higher levels of interleukin-1β, -6, -17, and basic fibroblast growth factor in the blood serum of the women were associated with time in range less than 70% and the development of diabetic fetopathy. Time in range was inversely associated with the interferon gamma / interleukin-5 (ρ = −0.531; p = 0.013), interferon gamma / interleukin-10 (ρ = −0.441; p = 0.045), interleukin-2 / -10 (ρ = −0.473; p = 0.030), interleukin-1β / -10 (ρ = −0.561; p = 0.008), interleukin-1β / -1ra (ρ = −0.635; p = 0.002), and interleukin-6 / -10 (ρ = −0.540; p = 0.012) ratios.

Conclusions: Cytokine profile alterations were the most pronounced in pregnant women with non-target time in range values and in those with diabetic fetopathy development. Serum cytokine levels correlate with glycemic profile parameters but are considered non-specific markers of pregnancy complications.

Background: The role of the microbial factor in the genesis of early miscarriages (up to 10 weeks of pregnancy) has not been established. However, disruption of the vaginal microbiota may be associated with the occurrence of late miscarriage.

Aim: The aim of this study was to evaluate the frequency of early and late miscarriages and to determine the prognostic significance of the microbial factor in early pregnancy registration.

Materials and methods: This study involved 113 pregnant women registered before 10 weeks of gestation, who were divided into two study groups. Group I consisted of 22 women whose pregnancy ended in miscarriage before 22 weeks (subgroup IA of 19 patients with early miscarriage and subgroup IB of three patients with late miscarriage). Group II comprised 91 women whose pregnancy ended in term delivery. Vaginal microflora was investigated using microscopic and molecular biological methods.

Results: The frequency of miscarriages among the examined women was 20.4%. The proportion of early miscarriages was 86.4% and late miscarriages 13.6%. In Group I, the number of births in the anamnesis was higher than in Group II. The average rate of births per woman was 2.0 in Group I and 0.9 in Group II (p = 0.037); the number of previous pregnancy loss per woman was 1.2 in Group I and 0.5 in Group II (p = 0.019). Lactobacilli were detected in the vaginal biotope of all pregnant women. Lactobacillus iners and Lactobacillus crispatus were the most frequently occurring species. In subgroup IA and Group II, opportunistic pathogenic microorganisms were detected with equal frequency at first pregnancy examination and did not alter the existing vaginal microbiocenosis. In subgroup IB, Gardnerella vaginalis, Atopobium vaginae, Enterobacteriaceae, Staphylococcus spp., Streptococcus spp., Mycoplasma hominis or Ureaplasma spp. were detected simultaneously in early pregnancy, with Lactobacillus cristatus predominating.

Conclusions: The proportion of early miscarriages was six times higher than that of late miscarriages. We have not found an association between the quantitative and qualitative compositions of vaginal microorganisms in the first trimester of pregnancy and early miscarriages. The microbial factor was established to be important in late miscarriages. Further studies are needed to assess the prognosis of late miscarriages at the time of pregnancy registration.

Background: Premature ovarian insufficiency is a syndrome characterized by secondary hypergonadotropic ovarian insufficiency and a decrease in the ovarian function in women under 40 years of age, thereby leading to impaired reproductive function, metabolic changes, and a decrease in the quality of life. Increased production of reactive oxygen species inhibits the mitochondrial respiration chain and leads to mitochondrial dysfunction and oxidative stress, which are considered as the triggers of premature ovarian insufficiency. To date, there is no universal method of premature ovarian insufficiency prevention, and accepted treatment methods can only compensate for clinical symptoms, but not restore the lost ovarian reserve.

Aim: The aim of this study was to develop a new method of premature ovarian insufficiency treatment based on an experimental ovarian granulosa cell model using omaveloxolone (RTA 408).

Materials and methods: The cell model of premature ovarian insufficiency used in the study was realized according to the Patent RU 2 815 539 C1, 2023 (by M.I. Yarmolinskaya, K.A. Zakuraeva, A.Yu. Vinokurov, M.Yu. Pogonyalova). Ovarian granulosa cells isolated from three-month Wistar rats were subcultivated five times with subsequent seeding on coverslips. The cells on the coverslips were divided into three groups (three coverslip in each group). In Group 1 (comparison group — premature ovarian insufficiency model without treatment), cells were treated with cyclophosphamide (0.1 mg/ml) during 6 h. In Group 2 (main group — premature ovarian insufficiency model with experimental treatment) cells were pretreated with RTA 408 (2 µl/ml) during 1 h with subsequent addition of cyclophosphamide (0.1 mg/ml) and cultivation during 6 h. And in Group 3 (control group), cells were added no substances.

Results: Compared to Groups 2 and 3, the use of omaveloxolone (RTA 408) led to an increase in reduced glutathione level and a decrease in reactive oxygen species production rate, which indicates the antioxidant and anti-inflammatory effects of the drug and may be considered as a perspective strategy of premature ovarian insufficiency treatment. The claimed method expands the number of premature ovarian insufficiency treatment strategies and avoids the use of hormonal medications and surgical procedures, thus reducing the risk of side effects and complications associated with their use.

Background: The treatment strategy for patients with a history of multiple failures in in vitro fertilization cycles remains a subject of active research. Embryo transfer in cryocycles is known to be more successful than “fresh” embryo transfer, when ovarian stimulation, follicle puncture, fertilization, and embryo culture were performed but the overall efficiency of in vitro fertilization cycles decreases with maternal age and transfer of poor quality embryos. One of the key factors influencing the failure of high quality embryo implantation is the deficiency of the adhesive matrix, which ensures the interaction between the embryo and the endometrium. The implementation of protocols that include the use of hyaluronic acid-enriched transfer media in the process of embryo transfer is a promising direction for improving implantation outcomes. Special attention of researchers is paid to determining the indications for the use of this technique.

Aim: The aim of this study was to evaluate the effect of hyaluronic acid-enriched transfer media on the pregnancy rate in cryocycles.

Materials and methods: This retrospective cohort comparative study, included 609 women who underwent controlled ovarian stimulation and frozen-thawed embryo transfer.

Results: The main outcomes of frozen-thawed embryo transfer cycles were analyzed, taking into account the quality of the transferred embryos and the use of hyaluronic acid-enriched transfer media. The latter was not shown to be associated with an increase in biochemical and clinical pregnancy rates in women under 35 years of age with a history of repeated implantation failures or after transfer of poor quality embryos. However, in patients over 40 years of age with poor quality embryos, the use of hyaluronic acid-enriched transfer media was effective, since it increased the clinical pregnancy rate. As expected, our data showed an increase in the clinical pregnancy rate in women with high quality embryos on the day of transfer, regardless of the patient’s age. At the same time, in patients with a thin (thickness less than 7 mm) endometrium or a history of miscarriage, the use of hyaluronic acid-enriched transfer media was also associated with an increase in the clinical pregnancy rate and live birth during embryo transfer in cryocycles.

Conclusions: The data obtained have shown that the use of hyaluronic acid-enriched transfer media in cryocycles may be recommended for women over 40 years of age, regardless of the quality of the transferred embryos, as well as for women of any reproductive age with a thin endometrium and a history of miscarriage when transferring good quality embryos.

Background: Type 1 diabetes mellitus and endometriosis significantly reduce the quality of patient’s life and hinder the implementation of reproductive plans. Studying the features of the clinical course of endometriosis in patients with type 1 diabetes mellitus will help in the development of new effective and safe therapeutic strategies and diagnostic methods.

Aim: The aim of this study was to analyze the clinical course of the diseases, hormonal status and blood vitamin D (25-hydroxycalciferol) levels in patients with type 1 diabetes mellitus combined with endometriosis.

Materials and methods: This clinical prospective study included 339 women, of whom 79 patients were with type 1 diabetes mellitus combined with endometriosis (mean age 31.7 ± 5.0 years), 51 patients were with endometriosis (mean age 31.4 ± 3.7 years), and 209 patients were with type 1 diabetes mellitus (mean age 30.2 ± 4.9 years). The control group consisted of 31 healthy women of reproductive age. The immunochemiluminescent method was used to determine the blood serum levels of anti-Müllerian hormone, follicle-stimulating hormone, luteinizing hormone, prolactin, and estradiol (days 2–5 of the menstrual cycle), progesterone (days 20–23 of the menstrual cycle) during three consecutive menstrual cycles, and the blood serum level of glycated hemoglobin was also studied in patients with type 1 diabetes mellitus. The diagnosis of endometriosis in all patients was confirmed based on laparoscopic surgery with verification by histological examination.

Results: When assessing the levels of gonadotropins, prolactin, and anti-Müllerian hormone in patients with endometriosis, a decrease in blood anti-Müllerian hormone level was noted in comparison with the other study groups. The levels of gonadotropins and prolactin in patients in all of the study groups were comparable. In all of the study groups, the progesterone level on days 20–23 of the cycle was lower than in the control group. The concentration of vitamin D (25-hydroxycalciferol) in the patients’ peripheral blood in all of the study groups was lower compared to the control group, with the minimum value of 16.3 ± 4.1 ng/ml found in the group of patients with type 1 diabetes mellitus combined with endometriosis. In patients with type 1 diabetes mellitus and in those with the disease combined with endometriosis, no differences were found between the age of onset of type 1 diabetes mellitus and its duration, the total daily insulin dose, and the insulin dose per kilogram of the patient’s weight. The glycated hemoglobin level was higher in the group of patients with type 1 diabetes mellitus. When distributing patients by the grades of endometriosis prevalence, it was found that grades III and IV were more common in patients without type 1 diabetes mellitus. The incidence of deep infiltrating endometriosis was higher in the group of patients with endometriosis only, as was the number of reoperations.

Conclusions: The asymptomatic preclinical period of endometriosis in patients with type 1 diabetes mellitus may lead to untimely and erroneous diagnosis and delayed treatment of the disease. In patients with type 1 diabetes mellitus onset in puberty and suffering from endometriosis, the risk of vascular complications increases and the ovarian reserve decreases, which requires the implementation of reproductive goals as early as possible. When choosing therapy for endometriosis in patients with type 1 diabetes mellitus, the presence of vascular complications should be taken into account.

Background: Polycystic ovary syndrome is an urgent problem of gynecological endocrinology. Currently, a number of genes have been studied that control glucose metabolism and are involved in the synthesis, conversion into an active form and transport of steroid hormones, mutations in which with a certain degree of reliability can serve as a diagnostic criterion for polycystic ovary syndrome.

Aim: The aim of this study was to evaluate the PPARG Pro12Ala, INS 223HphI A>T, and SHBG (TAAAA)n gene polymorphisms in patients with polycystic ovary syndrome and in healthy individuals.

Materials and methods: The polymerase chain reaction method and restriction fragment length polymorphism analysis were used. The frequencies of alleles and genotypes of polymorphic variants were studied in 136 women with polycystic ovary syndrome and 47 women in the control group: Pro12Ala (PPARG gene), 223HphI A>T, (INS gene) and (TAAAA)n repeats (SHBG gene).

Results: The distribution of the allele and genotype frequencies for the PPARG (rs1801282) and INS (rs689) genes in patients with polycystic ovary syndrome and in healthy individuals did not differ. The distribution of the genotype frequencies in the group of women with polycystic ovary syndrome differed (p = 0.02) from that in the control group for the (TAAAA)n polymorphism in the SHBG gene. In the presence of a long repeat in the SHBG gene in at least one of the homologous chromosomes, the probability of a woman having polycystic ovary syndrome increases by 2.5 times. Patients with a verified A/A genotype (INS), in the presence of an SHBG gene allele with a long repeat, have a ten-fold higher risk of developing polycystic ovary syndrome than women with SHBG gene short alleles.

Conclusions: Patients with long repeats in the SHBG gene are at risk for developing polycystic ovary syndrome with phenotypes A, B, and C, especially in combination with the presence of the A/A genotype, class I (INS).

Background: Preconception screening is testing for carriage of recessive mutations of monogenic diseases in healthy spouses at the stage of pregnancy planning. In the Russian Federation, genetic testing and subsequent consultation by obstetricians and gynecologists are only carried out in two or three specialized centers. Obstetricians and gynecologists of the outpatient care service as the primary level of prevention do not often have information about these diseases and know where to refer patients for examination. It is not their responsibility to provide advice on this matter, but they should know the genetic centers where the patient or couple can be referred for further consultation. Increasing the level of knowledge of obstetricians and gynecologists will allow the widespread introduction of preconception screening as the primary stage of the prevention of hereditary diseases.

Aim: The aim of this study was to determine, based on the analysis of questionnaire data, the current level of knowledge and interest of obstetricians and gynecologists regarding issues of preconception screening.

Materials and methods: This study was conducted in the categorical field of medical sociology as one-time continuous research. A hundred of obstetricians and gynecologists from St. Petersburg, Russia who work in antenatal clinics, hospitals and private medical institutions participated in this sociological study on a voluntary and anonymous basis. To conduct the survey, an original questionnaire was developed, which included 21 questions. The survey was carried out using an electronic questionnaire (Google form).

Results: As a result of the survey, a hundred of obstetricians and gynecologists took part, including local doctors at district antenatal clinics, inpatient doctors, heads of departments, as well as obstetricians and gynecologists from private medical organizations. Analysis of the sociological survey data showed a satisfactory level of theoretical knowledge of obstetricians and gynecologists regarding preconception screening. At the same time, there is no general algorithm for managing data of the patients, their routing, and the scope of examination and diagnosis.

Conclusions: Our study emphasizes that the problem of preconception screening is relevant and requires a deeper understanding by obstetricians and gynecologists. The development of a methodological manual for obstetricians and gynecologists will increase the level of awareness of specialists, optimize the routing of potential patients and increase the effectiveness of the prevention of hereditary diseases with a recessive type of inheritance.

Background: To date, the etiology and pathogenesis of endometriosis are still unclear and are determined by a number of factors (genetic, immunological and endocrine), including microbiological ones.

Aim: The aim of this study was to characterize the clinical course of endometriosis in papillomavirus infection.

Materials and methods: This retrospective analysis included 185 outpatient records of patients with genital endometriosis and comprised complaints, anamnesis data, objective examination, cytological and molecular biological examination results. All patients were divided into two study groups. Group 1 (main) consisted of patients with endometriosis and human papillomavirus (n = 56), and group 2 (comparison) included patients with endometriosis and no human papillomavirus (n = 129).

Results: The frequency of human papillomavirus detection among patients with endometriosis was 30.3 (95% confidence interval 24–38)%. The most frequent types detected were 31 (20%), 16 (18%), 18 (18%), 56 (16%), and 53 (13%). The conclusion of cervical cytological examination: in group 1 was the following 54/56 patients had negative for intraepithelial lesion or malignancy (NILM) and 2/56 patients had low grade squamous intraepithelial lesion (LSIL), all patients in group 2 had NILM. The average duration of endometriosis was 8.2 ± 5.0 years for patients in group 1 and 9.4 ± 5.9 years for patients in group 2 (p = 0.15). We found differences between the study groups with respect to the following parameters: the average age of sexual debut was 17.82 ± 1.47 years and 18.53 ± 1.43 years for groups 1 and 2, respectively. Dyspareunia occurred in 77 (95% confidence interval 63–87)% of women in Groups 1 and in 42 (95% confidence interval 33–51)% in groups 2 (p < 0.001). The average pain severity score according to the visual analogue scale was 6.7 ± 2.4 and 5.9 ± 2.8 points, respectively (p = 0.039). In group 1, impaired vaginal microbiocenosis was more common.

Conclusions: Human papillomavirus was detected in every third woman with endometriosis, most often in genotypes of high carcinogenic risk. Among the features of the clinical course of endometriosis in the presence of human papillomavirus, more pronounced pain syndrome and symptoms of dyspareunia were noted. In the group of women with human papillomavirus, impaired vaginal microbiocenosis was more often observed.

Asherman syndrome is characterized by the appearance of clinical symptoms of pain syndrome, as well as menstrual and reproductive dysfunction, which develop as a result of obliteration of the uterine cavity and/or cervical canal by connective tissue synechiae. It is believed that the leading cause of Asherman syndrome is mechanical damage to the basal layer of the endometrium due to intrauterine interventions performed during pregnancy, the postpartum period, or in the detection of uterine cavity pathologies. They lead to impaired cervico-uterine-tubal sperm transport, fibrotic changes in the endometrium, and resistance to hormonal stimulation.

The primary surgical treatment for Asherman syndrome is hysteroscopic adhesiolysis. It is known that this type of surgical intervention is associated with high risks of synechiae reformation, complicated course of gestation and unsatisfactory reproductive outcomes. For this reason, in the postoperative period, it is advisable to carry out preventive measures aimed at restoring female reproductive function. Most of the currently available methods of secondary prevention have no effect on the pregnancy rate and live birth rate. Low efficacy of the complex therapy creates a need to search for new alternative approaches to the treatment of Asherman syndrome and to develop tactics for postoperative management of patients. Cell therapy with mesenchymal stem cells is of particular interest.

This literature review examines the relationship between various treatment and secondary prevention options for Asherman syndrome and their impact on improving reproductive outcomes.