No 7 (2021)

Diminished ovarian reserve is an urgent problem of reproductive medicine. Currently, there are no scientifically based and proven methods for solving the problem. One of the promising directions in this area may be the use of extracellular vesicles (EVs) secreted by the cells of structures that have a high biological activity due to different molecules entering into their composition. From the point of view of therapeutic effects, EVs derived from the mesenchymal stromal cells (MSC) of different origins deserve attention. The use of MSC-EVs is currently being actively explored in different fields of regenerative medicine. According to the literature, the administration of MSC-EVs in animal models with ovarian insuff iciency could increase the ovarian reserve, reproductive potential, and the effectiveness of assisted reproductive technologies programs. The use of MSC-EVs in medicine is limited by a small number of studies, the insufficient duration of an observation of the models treated with this method, and by the study of possible side effects. Conclusion. Taking into account the promising results of utilizing MSC-EVs in different f ields of regenerative medicine and the data available in the literature on the possibility of increasing the ovarian reserve and improving the reproductive potential with MSC-EVs in the animal models, this method may be a promising treatment in patients with a low reproductive potential and ovarian insufficiency.

Many infertile couples cannot achieve pregnancy after repeatedly implemented assisted reproductive technology (ART) programs, as well as its successful prolongation, even with the transfer of good-quality euploid embryos. In this connection, repeated implantation failures (RIFs) in the in vitro fertilization (IVF) protocols and recurrent miscarriage (RM) are important medical and social problems. The generally accepted methods of examination do not explain the cause of repeated reproductive failures in 30-50% of cases. Among the causes of idiopathic reproductive losses, the immunological factor, including both systemic and local changes in the immune status, plays a leading role. Innate immune cells have been established to play a central role in the processes of implantation, placentation, formation, and maintenance of immune tolerance towards a developing embryo. Of great scientific and practical interest are natural killer (NK) cells that are the largest population of endometrial lymphocytes, changes in the quantitative and qualitative profile ofwhich in bothperipheral blood and the endometrium are associated with conditions, such as RIF, RM, uterine fibroids, endometriosis, preeclampsia and others. Conclusion. The conducted studies indicate the important role of both subpopulations of NK cells in a woman’s reproductive health. However, to date, there are insufficient data on the function and mechanisms of action of NK cells in reproductive losses, which requires further investigation.

Polycystic ovary syndrome (PCOS) is one of the most common diseases in reproductive-aged women. This is a complex disease that affects various areas of a woman’s life and causes different problems, such as metabolic, reproductive, aesthetic, psychological, and sexual ones, and can seriously worsen a woman’s quality of life. PCOS is known to negatively affect female fertility and is the leading factor of infertility of endocrine origin. To achieve pregnancy in this patient category, there are various treatments, both medical and surgical ones, which are aimed at restoring folliculogenesis and inducing ovulation, and, if these methods are ineffective, assisted reproductive technologies are also used. But numerous studies indicate that the efficiency of infertility treatment in PCOS is not always high and depends on the clinical situation. Therefore, research is currently underway to determine the optimal methods of infertility therapy for patients of this group. Conclusion. The presented literature review shows the experience with and efficiency of various methods of infertility treatment in patients with PCOS.

Objective. To carry out a systematic analysis of the data available in the world literature on the effects of various groups of drugs used in therapy for immune-mediated inflammatory rheumatic diseases (IMIRDs) on the female and male reproductive system, as well as methods to preserve reproductive function in this patient contingent. Materials and methods. The review includes Russian and foreign publications available in Pubmed on this topic over 2010-2020. Results. The authors analyze the data available in the literature on the effects of drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (GCs), cyclophosphamide (CP), methotrexate (MTX), mycophenolate mofetil (MMF), azathioprine (AZA), sulfasalazine (SUL), hydroxychloroquine (HC), leflunomide, and biological agents (BAs) on the female and male reproductive system. The possible teratogenic effects of some of these drugs used during pregnancy were studied. Procedures to preserve reproductive function were also analyzed in patients with IMIRDs. Conclusion. CP is the only drug, the negative effect of which on female and male reproductive function was significantly proven. The negative effect of MTX and a tumor necrosis factor-a inhibitor on the male reproductive system and also the teratogenic effects of MMF and leflunomide during pregnancy are discussed. The effect of other drug groups remains controversial and requires further investigation. The design and clinical introduction of individual approaches to preserving reproductive function in this patient group also require further study.

Objective. To establish regularities in the transmission spectrum of microstructural waveguides filled with isolated spermatozoa and seminal plasma from males with various disorders of spermatogenesis and, on this basis, to build a neural network that analyzes the spectral characteristics of sperm. Materials and methods. The spectral characteristics of345isolated spermatozoal samples and 209seminal plasma samples were analyzed using photonic crystal waveguides as optical sensors, and an artificial neural network, the prediction accuracy of which was 100%, was built. The patients, whose ejaculate was included in the study, were also surveyed. The main parameters in the questionnaire concerned the factors influencing spermatogenesis. Results. A neural network based on a multilayerperceptron was created, which proved to be effective in analyzing the spectral characteristics of seminal plasma and a sperm fraction. The created neural network of the ejaculate makes it possible to determine the “norm” and “pathology” with the highest accuracy. The use of artificial intelligence to analyze survey results on the male lifestyle proved to be less effective. The rate of correct answers was 88% for the test set of characteristics and 84% for the control set. Nevertheless, the developed neural network can be used for preliminary assessment and prediction of the sperm prof ile based on the results of a patient’s survey. Conclusion. Fiber optic methods in the diagnosis of the ejaculate are perspective and promising. There remains an unresolved issue regarding the absence of both natural and in vitro fertilization pregnancies in the presence of normal sperm counts. The introduction of new tests for seminal plasma and spermatozoa is an urgent task of reproductive medicine; it is especially interesting to use the capabilities of artificial intelligence to assess the fertility of both men and women.

Relevance. During the pandemic and large-scale vaccination against COVID-19, studies of the effect of various types of vaccines on human reproductive function have become particularly important. Vaccination may have a negative impact on the reproductive organs and tissues due to the development of an autoimmune process involving the gonads. Currently, there are some studies on the effect of vaccination against coronavirus infection caused by SARS-CoV2 on the male and female reproductive function. The absence of a negative effect of vaccination on spermatogenesis in men has already been demonstrated in the results of three studies. Objective. To evaluate the effect of the Gam-COVID-Vac (Sputnik V) vaccine on spermatogenesis and the level of antiphospholipid antibodies in men. Materials and methods. The prospective study included 45 men who were vaccinated against COVID-19 with Gam-COVID-Vac (Sputnik V). The criteria for inclusion in the study were the age from 18 to 55 years, the absence of a previous history of COVID-19, a negative RT-PCR result in SARS-CoV-2 testing, negative SARS-CoV-2 IgG results prior to vaccination, and the absence of severe somatic diseases. The patients were examined twice: immediately before vaccination and 90 days after the first dose was injected. We evaluated spermogram parameters, determined the levels of FSH, LH, TSH and total testosterone, and analyzed blood for IgM and IgG antiphospholipid antibodies (aPL) to cardiolipin (aCL), p2-glycoprotein-1 (afi2-GP1), annexin V(aAnV), phosphatidylserine (aPS), as well as IgG antibodies to SARS- CoV-2 using enzyme immunoassay. Results. There were no significant changes in the parameters of spermogram and hormone levels before and after vaccination; men with moderate impairment of spermatogenesis (oligoasteno- and/or teratozoospermia) did not show considerable changes either. The level of aPL after vaccination did not increase compared to the baseline level. Besides, there was no correlation between the dynamics of the level of antisperm antibodies, aPL and spermogram parameters. These findings indirectly indicate that there are no changes in the reproductive function associated with this autoimmune factor after vaccination in men. Conclusion. This is one of the first studies that has revealed the effect of the Gam-COVID-Vac vaccine on spermatogenesis, hormonal profile and aPL level in men. The obtained results demonstrate that the Gam-COVID-Vac vaccine does not have a negative effect on the reproductive function in men.

Aim. To analyze the relationship between the level of anthropogenic chemicals in female patients and the results of infertility treatment using ART. Materials and methods. The study included 300 infertile women, who applied to the Center for infertility treatment using ART. Inductively coupled plasma mass spectrometry (ICP-MS) was used to detect heavy metals concentration (mercury, lead, cadmium) in the blood of patients, chromatography-mass spectrometry was used to analyze the level of bisphenol A (BPA). A conventional scale was developed to estimate the total pollutant concentrations in patients. ROC analysis was used to estimate threshold value affecting the likelihood of pregnancy (a score = 5 points) Then the patients were stratified into groups depending on pollutant concentrations. Group 1 included 72 patients, who had high pollutant concentrations. Group 2 included 227patients, who had low pollutant concentrations. Results. The clinical and anamnestic characteristics did not differ in the comparison groups. Comparison of embryological parameters showed a significant blastulation rates decline in the group of patients with a high pollutant concedntrations. Absence of embryonic cleavage was in 17.8% of women in group 1 compared to 10.1% in group 2, p=0.0644. Assessment of clinical outcomes of ART cycles showed decreased rates of clinical pregnancy onset and births, increased incidence of early reproductive losses in the group of patients with high pollutant concentrations. Conclusion. High pollutant concentrations in the bodies of infertile patients is associated with poor embryo quality and decline in the effectiveness of ART programs.

Aim. To conduct preparatory treatment before in vitro fertilization (IVF) program and to assess its effectiveness in patients with various stages of adenomyosis. Materials and methods. The study included 198patients with infertility and ineffective past IVF attempts. They were examined and diagnosed with adenomyosis, that could be a possible cause of implantation failure in previous attempts of IVF. 128 patients were randomly divided into three groups. As a preparatory treatment before IVF program, the patients received adenomyosis treatment with GnRH-a, COC and Dienogest in a continuous mode for 3 months. 70patients did not undergo preparatory treatment before IVF program. Results. Stage I adenomyosis had no impact on the effectiveness of the IVF program and did not require pretreatment. At stages II-III adenomyosis, preparatory treatment may increase the conception rate. However, the incidence of pregnancy in women with stage III adenomyosis remains low, and this severe stage of adenomyosis is characterized as the uterine factor of infertility. Conclusion. Stage I adenomyosis is not the cause of infertility or IVF failures, and does not require pre-treatment. At stages II-III adenomyosis pre-treatment improves the effectiveness of IVF programs.

Aim. To investigate the impact of uterine microbiota on the success of embryo implantation in assisted reproductive technologies. Materials and methods. The study included 130 infertile women, who were divided into three groups. Group I (n=39) included women with the first IVF attempt. Group II (n=27) comprised patients with recurrent implantation failure following embryo transfer in the ovarian stimulation cycle. Group III (n=64) included patients with recurrent implantation failure following embryo transfer in a cryocycle. All patients underwent microbiological examination of the cervical canal discharge and samples obtained from embryo transfer catheter tips after an embryo transfer into the uterine cavity. Also, 30 samples were taken from the uterine cavity for high-throughput sequencing studies. Results. The study findings suggest that the uterine cavity is not sterile. Forty-four types of microorganisms were identified, including 26 types of opportunistic microorganisms (OpM) and 18 types of commensals (14 types of lactobacilli and four types of bifidobacteria). Obligate anaerobic microorganisms and Gardnerella vaginalis culture positivity rates were statistically significantly higher in group I compared with group III (strict anaerobes15.4 and 1.6%; G. vaginalis 12.8 and 1.6%, respectively) (p<0.05). However, this fact did not negatively affect the pregnancy rate, which was highest in group I (51.3%). Among women with recurrent implantation failure, it was 29.6 and 35.9%, respectively. Conclusion. The presence of low and moderate titers (103-105 CFU/ml) of OpM in the uterine cavity and cervical canal did not affect pregnancy rates in the study cohort. In 87.9% of patients, the microflora of the uterine cavity and cervical canal had different compositions. This observation suggests the possibility of the formation of an independent uterine microbiota. The uterine microbiota is characterized by less species diversity compared to the microbiota of the cervical canal.

Objective. To evaluate the influence of controlled mechanical microvibration on oocyte fertilization rate and embryo during the first five days of development. Materials and methods. The quality of 952 embryos obtained from 166 patients was evaluated in the microvibration group. The quality of3369 embryos obtained from 757patients was assessed in the control group. In the microvibration group, the incubator was placed on the ArisTT180-s platform (K&S Advanced Systems Ltd, Israel) in the active vibration mode with a frequency of 40 Hz for 30 seconds with intervals of 30 minutes. Results. The number of embryos scored as grades one and five (according to Gardner’s classification), with grades AA and BA increased during the cultivation under the conditions of controlled mechanical microvibration. The rate of embryo cryopreservation was 1.22 times higher in the microvibration group in comparison with the control group. The average number of cryopreserved embryos was 1 (0 - 3) in patients of the microvibration group and 0 (0 - 2) in patients of the control group (p=0.003). Conclusion. Controlled mechanical microvibration can be used in oocyte fertilization and cultivation of embryos to increase the quality of embryos on the fifth day of cultivation and to improve the possibility of obtaining embryos suitable for cryopreservation.

Women experiencing infertility compared to fertile women are more likely to have sexual dysfunction, including lack of genital arousal, dyspareunia. Sex steroids have a key effect on the morphological and functional condition of the urogen ital tract. Aim. To explore specific features of gene expression of vaginal transcellular secretion factors (AQP3, ESR1, VEGF121, and VEGF165) in ovarian stimulation (OS) for IVF and in natural cycle IFV (NC-IVF) in women with decline in sexual function. Materials and methods. The study included 47 women with decline in sexual function: 24 women underwent OS for IVF, and 23 women underwent treatment for NC-IVF. Female sexual function was assessed using clinical interviews and the FSFI questionnaire. Results. The patients in group 1 (OS for IVF) were younger (p <0.001) and duration of their infertility was shorter (p<0.001), the level of serum anti-Mullerian hormone (AMH) was higher (p<0.001) and the level of follicle-stimulating hormone (FSH) was lower (p<0.001) compared to patients in group 2 (NC-IVF). Group 1 showed higher median values for the female sexual function index (FSFI) in 3 domains “erousal” (p=0.05), “lubrication” (p=0.04), and “desire” (p=0.09). PCR analysis in patients with OS found a high level of ESR1 expression (p=0.012), VEGF121 (p=0.01), a tendency for high AQP3 values (p=0.09) compared to patients in group 2 (NC-IVF); the level of VEGF165 expression was comparable in both groups. High levels of ESR1, VEGF121, AQP3 expression in patients with OS were associated with higher FSFI scores in domains “erousal”, “lubrication”, “desire”. Conclusion. The obtained results allowed to determine some pathogenetic mechanisms of impairment of vaginal secretion, genital sexual arousal, as well as development of dyspareunia.

Objective. To reduce the risk of inflammatory complications after miscarriage in the first trimester. Materials and methods. The investigation enrolled 117 patients aged 18 to 35 years after vacuum aspiration for the ovum remains. On the first day and after 1 month, all the patients were examined using Inbioflor, Femoflor and blood IgA, IgM, and IgG tests, a hemostasiogram, and pelvic ultrasound. Twenty-five patients were excluded from the study because they had been detected to have pathogenic obligate bacteria. The remaining patients were divided into 2 groups: 45 and 47 individuals. All the patients received preventive anti-inflammatory therapy: oral doxycycline hydrochloride and a probiotic (Lactobacillus rhamnosus and Lactobacillus reuteri); sertaconazole was once administered intravaginally in patients with candidiasis. Group 1 had additionally magnet-and-laser and ozone therapy. Results. On the first day, the mean number of lactobacilli in the bioassays was 42.5±8.2% of the total bacterial mass (TBM) and that of opportunistic pathogenic bacteria was 2 to 10%. After treatment, the number of lactobacilli increased (p<0.05) and reached normal values, and that of opportunistic pathogens decreased (p<0.05), with the exception of anaerobes (more than 10% of the TBM) in Group 2. During treatment, IgA and IgM levels normalized; IgG increased significantly (p<0.05). There was hypercoagulation before treatment and normal coagulation after treatment (p<0.05). Pelvic ultrasound revealed no changes characteristic of the inflammatory process in Group 1 and showed expansion of the uterine cavity with a heterogeneous mass, as well as M-echo thickening in 10.6% of cases in Group 2; additional treatment was performed. Conclusion. The investigators could restore the vaginal microbiota and the state of hemostasis, improve the immune status, and prevent possible inflammatory complications. In Group 1, the results of treatment were better; physiotherapy enhanced its efficiency

The diagnosis of preeclampsia in clinical practice causes certain difficulties due to the non-specificity of symptoms, the polymorphism of the clinical picture, and the discrepancy between the magnitude of clinical symptoms and the severity of multiple organ dysfunction. Therefore, the accurate diagnosis and prediction of preeclampsia is of great importance for practical obstetrics. The paper presents the results of the basic studies devoted to the clinical interpretation of the sFlt-1/PlGF ratio for the diagnosis and prediction of preeclampsia and shows the informative value and significance of the ratio for the objectification of the diagnosis of preeclampsia, as well as the possibility of predicting this obstetric complication according to sFlt-1/PlGF data. It shows the experience of using sFlt-1/PlGF in the obstetric service in the Moscow Region and formulates indications for the study of sFlt-1/PlGF in clinical practice and approaches to its interpretation. Conclusion. The application of sFlt-1/PlGF allows the differential diagnosis of preeclampsia with an exacerbation or a manifestation of a number of somatic diseases that occur with similar clinical symptoms. The use of sFlt-1/PlGF provides an economic effect, by improving the routing and decreasing the number of severe perinatal and maternal outcomes, as well as reducing unjustified hospitalization. sFlt-1/PlGF is an informative marker for the diagnosis and prediction of preeclampsia and its adverse outcomes and can be recommended for use in clinical practice

Background. The low effectiveness of assisted reproductive technology (ART) programs in older reproductive-aged patients is associated with a finite pool of high-quality oocytes and with a high risk for aneuploid embryos. According to the results of preimplantation genetic testing for aneuploidy (PGT-A), the pattern of embryonic chromosomal disorders differs on days 3 and 5 after fertilization, which may be due to a high degree of mosaicism in the embryo on day 3 of development and to its ability to compensate for these disorders by day 5. Case report. A 49-year-old patient came to the unit with a 5-year history of infertility with repeated failed ART attempts. The patient underwent an IVF/ICSI and PGT-A program with subsequent transfer of a mosaic embryo into the uterine cavity. She had a physiological pregnancy that ended in premature operative delivery. At the time of writing this paper, the baby is somatically healthy, developing according to age. Conclusion. Mosaic embryos may be the only available ones to be transferred to the uterine cavity in ART programs. Despite the fact that the clinical significance of mosaicism remains to be unestablished, it is known that mosaic embryos with a high proportion of euploid cells can lead to the birth of a healthy baby. The analysis of literature sources indicates that the outcomes of ART programs during the transfer of a mosaic embryo depend on the degree of mosaicism and the type of aneuploidy. Mosaicism can be physiological in nature and it is necessary to be very balanced in the analysis of PGT-A results.