No 2 (2018)

Objective. To carry out a systematic analysis of the data available in the world literature on current methods for screening and selection of embryos to enhance the efficiency of assisted reproductive technology (ART) programs in a group of late reproductive age women. Material and methods. The review includes the data of Russian and foreign articles found in Pubmed on this topic. General provisions. There are recent trends towards late marriage and late childbearing. With increasing age, reproductive function realization is known to have a number of problems. First, women older than 35 years have diminished ovarian reserve. After 40 years, the rate of follicular atresia doubles. Second, this group of women has frequently a family history of gynecological problems. Third, patients older than 35 years of age even with intact ovarian reserve are at increased risk for the aneuploidy of oocytes and, as a consequence, embryos, which also reduces the chance of getting pregnant. Accordingly, the assessment of embryo quality is a key component of success in ART programs. Existing methods for selection of embryos are based on their detailed morphological and genetic evaluation using preimplantation genetic screening (PGS). However, even the use of PGS does not improve the efficiency of ART programs above 50%. Therefore, there is a need for additional methods to identify viable embryos. In this connection, great importance has been recently attached to the mitochondrial potential of gametes and embryos. Results. The paper comparatively characterizes main PGS techniques (array-based comparative genomic hybridization (aCGH) and high-throughput sequencing (next generation sequencing (NGS)), considers the advantages of NGS, and describes the new potential marker for the quality of oocytes and embryos, the level of mitochondrial DNA (mtDNA), which can improve the outcomes of ART programs in the group of female patients of late reproductive age. Conclusion. In the near future, it seems likely that NGS will be put into wide practical use due to its advantages. In addition, the world literature contains data that a study of the mitochondrial potential of oocytes and embryos may become an additional reliable predictor for the outcomes of ART programs in different groups of patients, including in the group of late reproductive age patients.

Objective. To carry out a systematic analysis of the data available in the current literature on the modern view on Trousseau’s syndrome Material and methods. The review included the data of foreign and Russian articles published in the past 10 years and found in e-Library and PubMed on this topic. Results. This paper provides a pathogenetic explanation for the increased thrombotic potential in cancer patients, which underlies tumor growth and metastasis. In addition to direct thrombotic events, the paper also describes hemorrhagic complications resulting from systemic coagulopathy, including disseminated intravascular coagulation, hemolytic thrombotic microangiopathy, and excessive fibrinolysis. Conclusion. At present, any manifestation of thrombohemorrhagic complications in patients with malignant tumors can be classified as a paraneoplastic syndrome (Trousseau’s syndrome). In addition to Virchow’s classic triad, hyperproduction of tissue factor (TF), the main initiator of the extrinsic coagulation pathway, underlies the pathophysiology of Trousseau’s syndrome. At the same time, the substantial release of microparticles from TF-bearing tumor cells is critical not only for clot formation, but also for the progression of tumor growth.

Background. Mitochondria play an important role in the regulation of cellular energy metabolism. During pregnancy, there is a higher mitochondrial functional activity, while at the same time with increased mitochondrial energy generation, there is an elevated production of reactive oxygen species and nitrogen, which is attended by a compensatory rise in the activity of antioxidant protection. In contrast, mitochondrial dysfunctions varying in nature lead to uncontrolled oxidative stress (OS) that damages cells and tissues, which is considered to be one of the leading factors for the pathogenesis of pregnancy complications, such as premature birth (PB), preeclampsia (PE), and fetal growth retardation (FGR). Based on the fact that pregnancy is associated with progressive OS, even in case of its physiological course, it has been suggested that changes in the number of mitochondrial DNA (mtDNA) copies in the blood of pregnant women can serve as a biological marker for the degree of OS induction and for the increased risk of this or that complication during pregnancy. Objective. To determine plasma mtDNA level in women during physiological and complicated pregnancy. Subjects and methods. The course of pregnancy and the outcomes of labor were analyzed in 142 were analyzed. According to the results of the analysis, all the examinees were divided into 4 groups: 1) women with physiological pregnancy (PP); 2) those with PB; 3) those with pregnancy complicated by PE; 4) those with pregnancy complicated by FGR. The plasma amount of mtDNA was determined by real-time polymerase chain reaction (PCR). The number of PCR products in the reaction was estimated by the Ct value that was defined as the nth cycle of the reaction, at which fluorescence reaches a predetermined threshold value. The amount of a PCR product of the target gene (mtDNA D-loop) was normalized relative to that of a PCR product of the nuclear β-microglobulin gene. The copy number of mtDNA was expressed in the standard units 2(-ΔС). Results and discussion. In complicated pregnancy, the level of mtDNA was found to be higher just in the first trimester. The amount of mtDNA was increased by 49% in pregnant women diagnosed with FGR (p < 0.01), by 48% in those with PB (p < 0.01), and by 25% in those who developed PE (p < 0.05) versus those with PP. The relative level of mtDNA was 153±32, 292±69, 205±84, and 299±101 in the PP, PB, PE, and FGR groups, respectively. ROC analysis showed that the sensitivity and specificity of the assay of blood mtDNA levels in pregnant women in the first trimester in the diagnosis of PB was 100% and 91%, respectively; those in that of PE and FGR were 71% and 64% and 83% and 90%, respectively. The blood mtDNA threshold values associated with an increased risk of PB, PE, and FGR were determined to be 2(-ΔС) ≥209, 2(-ΔС) ≥158, and 2(-ΔС) ≥221, respectively. Conclusion. The determination of plasma mtDNA levels in the first trimester of pregnancy allows identification of a group of women at an increased risk for PB, PE, and FGR.

Objective. To identify molecular genetic markers of the formation of intrauterine synechiae to improve management tactics in reproductive-aged women. Subjects and methods. A total of 20 patients who had been operated on at the Department of Gynecology, V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, were examine during a prospective study. The patients were divided into 2 groups: 1) those with intrauterine synechiae (a main group); 2) apparently healthy women (a comparison group). Endometrial tissue samples were preoperatively taken using pipelle biopsy, then the expression profile was obtained by microarray hybridization with the GeneChip Human Exon 1.0 ST Arrays (Affymetrix, USA) according to the manufacturer’s protocol. Bioinformatic analysis of the data obtained by micrometrical analysis was carried out using the Gene Ontology service. Results. The endometrium of women with intrauterine synechiae showed a higher mRNA level in 9 genes and a lower mRNA one in 2 genes than that in the comparison group. The bioinformatic analysis revealed that 6 of the 9 genes were involved in immune response, including neutrophil activation, 4 of the 9 genes were in exocytosis. Conclusion. The involvement of most detected genes in the processes of immune response, inflammation, apoptosis, and exocytosis suggests that there is an abnormal cell-cell interaction in patients with intrauterine synechiae. The change in the level of mRNA in the S100A8, HBB, VNN2, RGS2, ERAP2, AQP9, MNDA, TUBA3E, and FSGR3B genes in the endometrium of women with intrauterine synechiae may serve as a basis for the creation of test systems to detect mRNA by RT-PCR technique as a minimally invasive test used in clinical practice to optimize management tactics in reproductive-aged women with intrauterine synechiae in order to enhance the effectiveness of treatment outcomes.

Objective. To investigate the amount of adipose tissue, the nature of its distribution, and serum leptin levels in patients with functional hypothalamic amenorrhea (FHA), by determining the threshold values of the indicators that are informative for the diagnosis of adipose tissue deficiency and hypoleptinemia. Subjects and methods. Clinical and laboratory examinations were made in 134 women of reproductive age. A study group consisted of 75 patients with FHA (mean age, 26.4±5.2 years; mean body mass index (BMI) was 20.1±2.17 kg/m2); a control group included 59 healthy women (mean age, 27.8±4.1 years; mean BMI, 24.2±5.6 kg/m2). The examination involved the determination of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and leptin and the estimation of adipose tissue content by dual-energy X-ray absorptiometry (DXA). Results. Normogonadotropic amenorrhea was diagnosed in 20% of the patients; hypogonadotropic amenorrhea with a low LH level in 60%, that concurrent with a low FSH level in 20%. Underweight in terms of BMI was diagnosed in 28% of the patients with FHA and in 25.4% of the healthy women in the control group. %Total Fat was of the greatest diagnostic value for FHA. Its threshold for the diagnosis of adipose tissue deficiency was 30% (AUC, 0.75 (0.71 to 0.81; 95% CI). Moderate deficiency (%Total Fat <20%) is 4.6 times more frequently encountered in FHA and is significant for its development (OR = 5.45; 95% CI; p = 0.0046). The threshold of leptin in FHA was 4.8 ng/ml; hypoleptinemia was found in 83%. Conclusion. In FHA for the diagnosis of body composition and for the quantification of adipose tissue, it is preferable to use DXA for the identification of its latent deficiency. Unlike BMI, latent adipose tissue deficiency, as evidenced by DXA, and hypoleptinemia suggest that there is decreased energy availability and a negative energy balance in FHA.

The spontaneous hatching inability of human blastocysts in ART programs may lead to failure of implantation and to the lack of pregnancy. The mechanism of spontaneous hatching and the predictors of its efficiency are not fully known and require further study. Objective: To investigate the role of cellular, genetic, clinical, laboratory, and iatrogenic factors in the efficiency of spontaneous hatching of human blastocysts in ART programs. Material and methods. The investigation enrolled 83 human blastocysts donated for researches. Light microscopy was used to determine the degree of maturity and quality of oocytes and embryos and the thickness of the pellucid zone, to reveal oocyte dysmorphisms, and to monitor hatching. The expression of CTSL-2, GATA3, and CGB mRNA was estimated using a real-time polymerase chain reaction assay. Results. The state of the pellucid zone and the quality of the gametes that were employed to derive blastocysts had no significant effect on hatching with the exception of extracytoplasmic dysmorphisms of the oocytes, in the presence of which the hatching efficiency increased 4.3-fold. The values of all three components of the Gardner’s blastocyst grade were significantly higher in the effective hatching group. The hatching success was influenced by the lower level of follicle-stimulating hormone (FSH), by superovulation stimulated with recombinant FSH, and by the use of GnRH agonists as an ovulation trigger. The effectively hatched blastocyst group displayed a higher expression of CTSL2, GATA3, and CGB mRNA. Embryo maturity and quality were associated with the CTSL2 and GATA3 mRNA expression that was higher in developmental stages 5-6 embryos and in class A embryos. Conclusion. The efficiency of spontaneous human blastocyst hatching is mainly affected by the quality of blastocysts themselves rather than by that of the pellucid zone and gametes. The blastocyst can model its further development through its own genetic factors. The expression of CTSL2, GATA3, and CGB mRNA is higher in best-quality blastocysts, which allows them to spontaneously hatch. The choice of a superovulation protocol plays a role in the efficiency of hatching.

Objective. To investigate the effect of energy metabolic hormones on the activity of the components of the hypothalamic-pituitary-gonadal axis in female adolescents with abnormal uterine bleeding (AUB), by taking into account different body weights. Subjects and methods. A total of 166 female adolescents aged 13-18 years with AUB were examined. The patients were divided into groups according to their body mass index (BMI). Thirty-four patients were found to be underweight (Group 1); BMI in 75 patients was within the normal physiological range (Group 2); that in 57 patients was higher (Group 3). The examination algorithm included the quantification of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, estradiol (E2), testosterone (T), cortisol, insulin, leptin, insulin-like growth factor 1 (IGF-1), and sex hormone-binding globulin (SHBG). Results. On the basis of a systematic analysis of the relationship of leptin and insulin to the levels of gonadotropins, sex steroids, SHBG, and IGF-1, the investigators built a model for the association of leptin and insulin with FSH, LH, T, E, IGF-1, and SHBG, by applying the factor analysis. The mechanisms whereby the energy status influenced the formation of reproductive function in puberty were shown to have their own characteristics related to BMI. Conclusion. Adolescent patients with AUB show several ways of an interaction between the energy balance control system and the reproductive system. The metabolic hormones leptin and insulin were ascertained to be involved in the feedback mechanisms for stimulating the synthesis of pituitary gonadotropins between the peripheral component of the endocrine system and its central component - the hypothalamus and pituitary gland. The energy metabolic hormones were found to have a significant impact on the activity of sex steroids through the regulatory mechanisms of their bioavailability, i.e. by influencing the synthesis of SHBG in the liver.

Objective. Improve the course and outcome of labor through the use of modern methods of prenatal psychoprophylactic preparation of pregnant women and alternative methods of vaginal delivery. Subjects and methods. The study involved 300 primiparas women, 27.8 ± 0.2 years old at the 33-37 weeks of gestation period, randomly distributed into two groups: 1 group - 150patients underwent the course of prenatal psychoprophylactic preparation program, the birth was conducted using vaginal delivery technique: horizontal, vertical and delivery into water (discussed with each patient individually); 2 group - 150 patients were observed according standard obstetric practice, the birth was conducted according routine obstetric practice, in the dorsal position. The study assessed the course of pregnancy, outcomes and complications of childbirth, the condition of a newborn on the Apgar scale, and the level of anxiety of women at the beginning of the study and on the eve of birth. Results. Using the program of prenatal psycho prophylactic preparation of pregnant women in combination with the most preferred methods of vaginal delivery for the woman improves the course and outcome of labor: the duration of labor is reduced from 9.5 to 8.3 hours, the incidence of primary and secondary weakness of labor is reduced, the share of birth trauma is reduced. In the ma in group, a lower incidence of caesarean section and the use of epidural anesthesia was noted, as well as a lower level of anxiety before the birth. Conclusion. Based on the data obtained it can be concluded that effective improvement in the course and outcome of labor is achieved through the use of prenatal psycho-preventive preparation of pregnant women in combination with the most preferred methods of vaginal delivery for the woman herself.

Objective. To investigate the efficiency of using cranberry (Oxycoccus) extract capsules in pregnant women with urinary tract infections and to assess the frequency of disease exacerbations, perinatal outcomes, and the efficiency of the preparation for pregnancy-induced edemas. Subjects and methods. The investigation enrolled 195pregnant women aged 20 to 44 years in the first and second trimesters after an infection exacerbation or asymptomatic bacteriuria identified by urinalysis. The women were proposed to take one capsule containing cranberry extract (phytolysin prenatal) thrice daily during antibiotic therapy and then one capsule once daily for 28-30 days. Results. There was term labor in 188 (96.4%), premature birth in 2 (1%), and late miscarriage at 21-22 weeks’ gestation in 1 (0.5%) patient with type 1 diabetes mellitus and fetal congenital malformations. Eleven (5.6%) of the 195 women taking cranberry extract capsules were found to have adverse reactions: heartburn (n = 6 (3.1%)) gastric pain (n = 4 (2.1%)), nausea/vomiting (n = 1 (0.5%)), and diarrhea (n = 1 (0.5%)). With the use of phytolysin prenatal, there was a reduction of edema in the lower extremities, hands, and face. Conclusion. The clinical research covering 195 pregnant women with urinary tract diseases confirmed the efficacy of cranberry extract in preventing urinary tract infection exacerbations during pregnancy. Rare side effects confirmed the safety of the agent. Phytolysin prenatal may also be recommended for pregnant women with edemas.

Background. Chronic cicatricial tracheal stenosis occurs in 1% to 22% of cases after resuscitation accompanied by long-term mechanical ventilation. The literature describes single cases of pregnancy concurrent with tracheal stenosis. Case report. The paper describes a case of pregnancy and childbirth in a 23-year-old woman with circular resection and endoprosthesis of the trachea for a history of chronic cicatricial stenosis. Conclusion. Patients with a history of tracheal resection and endoprosthesis should undergo a comprehensive examination by an otolaryngologist and an obstetrician/gynecologist on planning a pregnancy. Timely examination during pregnancy planning can increase the likelihood of spontaneous labor at full-term. It is appropriate to manage pregnancy in a collegial manner and to discuss the choice of the mode and timing of delivery jointly with an obstetrician and an otolaryngologist.