Vol 68, No 3 (2019)

Original Researches
Clinical features of polycystic ovary syndrome phenotypes in women with normogonadotropic anovulation in reproductive age
Abashova E.I., Shalina M.A., Misharina E.V., Tkachenko N.N., Bulgakova O.L.
Abstract

Hypothesis/aims of study. Polycystic ovary syndrome (PCOS) is a common disease, the frequency of which ranges from 8 to 13% in women of reproductive age. PCOS is a complex polygenic endocrine disorder with reproductive, metabolic, and psychological features. Currently, four PCOS phenotypes are identified that are associated with metabolic disorders, insulin resistance, impaired glucose tolerance (IGT), diabetes mellitus, and an increase in the number of risk factors for cardiovascular diseases. The aim of this study was to investigate the clinical features of PCOS phenotypes in women with normogonadotropic anovulation in reproductive age.

Study design, materials, and methods. The study included 60 women of reproductive age from 24 to 37 years (mean age 28 ± 4 years) with PCOS and normogogonadotropic, normoprolactinemic anovulation. We studied the levels of anti-mullerian, follicle-stimulating, luteinizing hormone, prolactin, estradiol, and androgens from days 2 to 5 of the menstrual cycle. The serum progesterone level was studied by ELISA using test systems manufactured by Alkor Bio Ltd. (Russia) on days 20–23 of the menstrual cycle for three consecutive cycles. The average level of progesterone in the blood on days 20–23 of the menstrual cycle was 3.1 ± 1.5 nM. Echographic methods for diagnosing polycystic ovaries were used. All women included in the study underwent hysteroscopy on days 18–22 of the menstrual cycle, followed by a histological and immunohistochemical study of the endometrium.

Results. In women with anovulatory PCOS phenotypes, phenotype A (classical) was detected in 32 (53.3%) women; phenotype B (anovulatory) in 18 (30%) women; phenotype D (non-androgenic) in 10 (16.7%) women with. In 32 (53.3%) patients, changes in carbohydrate metabolism (IGT) were found. Clinical and biochemical manifestations of androgen-dependent dermopathy (acne, oily seborrhea, and hirsutism) were significantly (p < 0.05) more often observed in PCOS patients with phenotypes A (84.4%) and B (88.9%) than in women with phenotype D (30%). In the majority (93.8%) of patients with IGT, the androgenic-anovulatory PCOS phenotypes were detected: phenotype A in 20 (62.5%) women and phenotype B in 10 (31.3%) women. Phenotype D (non-androgenic) was present only in two women with PCOS and IGT. As a result of complex histological and immunohistochemical studies of endometrial biopsy specimens, chronic endometritis was detected in 44 (73.3%) examined women with PCOS and simple glandular endometrial hyperplasia was diagnosed in 13 (21.7%) PCOS patients. The incidence of chronic endometritis and simple glandular endometrial hyperplasia in women with normogonadotropic anovulation and PCOS directly depended (r = 0.35; p < 0.05) on disorders of carbohydrate metabolism and was detected more often in patients with PCOS and IGT.

Conclusion. The differential approach to the examination of patients with various PCOS phenotypes allows personalizing the therapy of this disease and determining the complex of preventive measures to improve the quality of life of women of reproductive age.

Journal of obstetrics and women's diseases. 2019;68(3):7-14
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Prospects of using cystatin c as an early predictor of diabetic nephropathy
Borovik N.V., Yarmolinskaya M.I., Glavnova O.B., Tiselko A.V., Suslova S.V., Shilova E.S.
Abstract

Hypothesis/aims of study. Using early non-invasive markers of diabetic nephropathy (DN) in clinical practice is important to early start of nephroprotective therapy and leads to improving the quality of life, while decreasing disability and mortality of diabetic patients. The aim of the study was to estimate the potential of using serum cystatin C and glomerular filtration rate (GFR) calculated by CKD-EPIcys and CKD-EPIcr-cys equations for an early diagnosis of DN in type 1 diabetic (T1D) women who were planning pregnancy or were in the I trimester of pregnancy.

Study design, materials, and methods. 47 T1D women were examined, of whom 25 individuals were pregnant and 22 ones were planning pregnancy. In all patients, glycated hemoglobin and serum cystatin C levels were determined, GFR was estimated by the creatinine clearance test, MDRD, CKD-EPIcr, CKD-EPIcys, and CKD-EPIcr-cys equations, with diabetes training done.

Results. The pregnant group and the planning pregnancy group were distinguished by glycated hemoglobin (p = 0.001), serum creatinine (p = 0.001), and GFR estimated by the creatinine clearance test (р = 0.017), CKD-EPIcr (р = 0.005), and CKD-EPIcr-cys (р = 0.046) equations. There was no difference in urinary creatinine, serum cystatin C, and GFR estimated by CKD-EPIcys equation and daily urinary protein excretion between the study groups. Most pregnant women (87.5%) were in stage C1 and only 12,5% in stage C2 as determined by estimated GFR using the CKD-EPIcr formula, which was significantly different compared to the planning pregnancy group, where the percentage of women in stages C1 and C2 was comparable (р = 0.002). In addition, most pregnant patients were in stage C1, while most of the patients planning pregnancy were referred to stage C2 by GFR estimated by CKD-EPIcysequation. Stage C3a was diagnosed in the both study groups only when CKD-EPIcys equation for GFR estimation was used. Most women from both groups were in stage C1 when GFR was estimated by the creatinine clearance test, the percentage ratio of patients in stages C1 and C2 in both groups being comparable.

Conclusion. Our results demonstrated that serum cystatin C and GFR estimation by CKD-EPIcys equation could improve nephropathy diagnostic accuracy among T1D patients with a normal serum creatinine level and intact GFR based on creatinine level.

Journal of obstetrics and women's diseases. 2019;68(3):15-24
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Retrospective analysis of pregnancies resulted from assisted reproductive technology in women with type 2 diabetes mellitus
Misharina E.V., Borovik N.V.
Abstract

Hypothesis/aims of study. Type 2 diabetes mellitus (T2D) is one of the most widespread diseases in the world. The etiology of this disease is associated with genetic, age and ethnic factors. It is generally accepted that a sedentary lifestyle and obesity can cause T2D. This illness has serious complications that affect the women’s health and quality of life. It is well known that obesity and T2D are a common cause of anovulatory infertility in women of reproductive age. The number of T2D patients who are planning pregnancy by assisted reproductive technology (ART) has increased over the past 10 years. This study was aimed at investigating the effect of carbohydrate metabolism compensation in the preconception period on the outcomes of pregnancies resulted from in vitro fertilization (IVF) in T2DM women.

Study design, materials, and methods. 51 T2D pregnancies after ART and their outcomes were analyzed retrospectively.

Results. The age of the patients who applied to ART departments ranged from 27 to 46 years. The mean body mass index was 33.9 ± 6.5 kg/m2. The duration of infertility varied from 3 to 18 years. Infertility was caused by tubal occlusion in 17 cases, by anovulation in 16 cases, by male factor in 9 cases, by genital endometriosis in 7 cases, and by hypergonadotropic hypogonadism in 2 cases. One of the patients underwent IVF procedure twice in 4 years. All T2D patients received prepregnancy care including weight loss, diabetes compensation, diabetes complications treatment, and, if necessary, a transfer to insulin therapy and insulin treatment education for 1–2 months before entering into the IVF protocol. Angiotensin-converting enzyme inhibitors and statins should be stopped if they were prescribed in case of hypertension or dyslipidemia and other medications allowed during pregnancy should be started. 26 women (51%) did not take periconceptional multivitamin supplementation before IVF procedure. The level of glycated hemoglobin (HbA1c) in this group was 6.4 ± 0.5%. 25 patients (49%) underwent incomplete preparation for pregnancy before entering into the IVF protocol but not in full. An important stage of prepregnancy care was weight loss in women with overweight and obesity. The duration of a prepregnancy care program varied from 2 to 6 months and on average was 3.8 ± 1.7 months. The mean HbA1c level in this group was 5.8 ± 0.4%. All cases of IVF pregnancies in women with T2D resulted with live birth. The incidence of preeclampsia, cesarean section delivery, and preterm labor was lower in the group of women who had been given prepregnancy care.

Conclusion. Proper prepregnancy care including weight loss, diabetes compensation, early start of insulin therapy, and diabetes complications treatment before conception is an effective method of preventing perinatal complications in women with T2D.

Journal of obstetrics and women's diseases. 2019;68(3):25-34
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Application possibilities of biguanides for fibrocystic breast disease in women of reproductive age
Musina E.V., Kogan I.Y.
Abstract

Hypothesis/aims of study. The ongoing global problem of health care and medical science is an associated increase in the frequency of endocrine and metabolic diseases and cancer, including in women of childbearing age. Thus, the frequency of diabetes in the population has been growing rapidly for many years. Similar trends were observed in the dynamics of the frequency of cancer pathology, especially of breast cancer, which is one of the leading places in the structure of the cancer incidence in the female population. It is known that diabetes and related insulin resistance have a very negative effect on the female reproductive function, leading to hyperplastic processes of the mammary glands. The least studied problem so far is understanding the mechanisms of development, timely diagnosis, prevention, and treatment of fibrocystic mastopathy, the proliferative forms of which underlie malignant tumors, while its atypical variations are regarded as a precancerous condition. It is likely that the pathogenesis of hyperplastic processes in the mammary gland and the risk of neoplastic transformation in disorders of carbohydrate metabolism may have special factors. The actual problem is the development of a method for pathogenetically substantiated correction of fibrocystic breast disease. This is essential for the development of pharmacological strategies for secondary prevention of breast cancer and, in this regard, it is of great interest to study application possibilities of biguanides. The purpose of the present study was to conduct a comparative assessment of the effectiveness of metformin therapy in fibrocystic mastopathy patients with and without insulin resistance.

Study design, materials, and methods. The study involved 120 women, aged 18 to 40 years inclusive, with clinical and / or ultrasound signs of fibrocystic breast disease. According to the results of calculating HOMA index, patients were divided into two groups: the first group comprised 66 patients with insulin resistance (HOMA > 2.5) and the second group consisted of 54 patients with no insulin resistance (HOMA < 2.5). Assessment of mastalgia was performed using the Visual Analogue Scale. Breast ultrasound examination was performed on days 5 to 7 of the menstrual cycle. For the purpose of quantitative image analysis of the breast parenchyma, the following parameters were evaluated: a) thickness of the parenchyma (fibroglandular zone); b) diameter of the milk ducts; c) echogenicity. All patients received metformin at a dose of 1500 mg per day. Dynamic control of the clinical picture of the disease, as well as of mammographic breast parenchymal pattern, was performed after 3 and 6 months from the start of therapy.

Results and conclusion. After 6 months of therapy, there was a decrease in the frequency of mastalgia, and significant changes in breast ultrasound picture were observed. The data obtained on the positive effect of metformin on clinical mastitis and structural changes in the mammary parenchyma in patients with mastopathy allow considering such an approach as a promising therapeutic strategy in this pathological association.

Journal of obstetrics and women's diseases. 2019;68(3):35-40
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Risk factors of pathological glycemic variability in pregnant women with type 1 diabetes mellitus
Tiselko A.V.
Abstract

Hypothesis/aims of study. Academician Vasily G. Baranov’s statement that achieving normal glycemia is the main condition for successful pregnancy outcomes in women with diabetes mellitus has already been proven. Unfortunately, these tight glycemic targets are hard to be achieved especially in metabolic changes during pregnancy. Glycemic variability is a new glycemic parameter available due to continuous glucose monitoring (CGM). Pathological glycemic variability can be an important risk factor for oxidative stress along with chronic hyperglycemia in patients with type 1 diabetes mellitus (T1D). However, there is no enough literature confirming the effect of pathological glycemic variability on pregnancy course and outcomes in T1D women. The aim of the study is to analyze different modes of insulin therapy for glycemic targets achievement and glycemic variability reduction in T1D pregnant women.

Study design, materials, and methods. 100 women treated with continuous subcutaneous insulin infusion (CSII) and another 100 women treated with multiple daily injections (MDI) of insulin were examined. Indices of glycemic variability were estimated.

Results. Glycemic variability was significantly lower in CSII patients compared to the MDI group. The influence of glycemic variability on endothelial dysfunction was confirmed for T1D pregnant women. CSII proved advantages in achieving glycemic targets without increasing glycemic variability and hypoglycemia.

Conclusion. CSII combined with CGM is the most optimal insulin therapy for glycemic targets achievement without an increased risk for glycemic variability and hypoglycemia.

Journal of obstetrics and women's diseases. 2019;68(3):41-50
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Genital endometriosis and melatonin: a role in the pathogenesis and its possible use in the treatment of the disease
Yarmolinskaya M.I., Tkhazaplizheva S.S., Molotkov A.S., Tkachenko N.N., Borodina V.L., Andreyeva N.Y., Kleymyonova T.S., Lysenko V.V.
Abstract

Hypothesis/aims of study. Melatonin is found in almost all living organisms, the range of its effects being quite diverse. Effects of this hormone in the human body are realized via two ways, through specific receptors and non-receptor pathways. Melatonin may act through both membrane and nuclear receptors. In the present work, the expression of MTR1 and MTR2 melatonin receptors was studied in the eutopic endometrium and endometrioid heterotopies, and the level of melatonin metabolite, 6-sulfatoxymelatonin, in daily urine in patients with genital endometriosis (GE) was analyzed.

Study design, materials and methods. The experimental group included 67 patients of reproductive age with a verified diagnosis of GE, and the control group consisted of 18 individuals with an ovulatory menstrual cycle without gynecological pathology. The 6-sulfatoxymelatonin level in daily urine was determined by enzyme immunoassay. The study of MTR1 and MTR2 melatonin receptor expression in the endometrium and endometrioid heterotopies was performed in 24 patients with GE and in 10 women of reproductive age who were examined for infertility who did not have gynecological pathology based on diagnostic laparoscopy. To study the expression of melatonin receptors, the endometrium and endometrial heterotopy sampling was carried out from day 18 to day 22 of the menstrual cycle. Morphological assessment included histological and immunofluorescence studies using confocal laser scanning microscopy.

Results. In patients with GE, there was found a tendency to a decrease in 6-sulfatoxymelatonin excretion in daily urine compared to the control group. It was also found that the total relative expression area of melatonin receptors in the endometrium of women with GE was significantly lower compared to the endometrium of patients from the control group. Significant differences between the average brightness and optical density were not found. In addition, it was revealed that the relative expression areas of MTR1 and MTR2 melatonin receptors in the eutopic endometrium and in endometrioid heterotopies did not differ significantly. A negative correlation was stated between the relative expression area of melatonin receptors and GE prevalence. Particular attention is paid to the role of melatonin in the development of GE and to the possibilities of working out new treatment regimens with its use.

Conclusion. The data obtained confirm the undoubted role of melatonin in the pathogenesis of GE, however, the development of new treatment regimens with its use requires further study.

Journal of obstetrics and women's diseases. 2019;68(3):51-60
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Reviews
Inhibin as a reproductive biomarker. Part 1
Abdulkadyrova Z.K., Abashova E.I.
Abstract

Inhibin is one of the most important hormones of the reproductive system, which is secreted by the granulose cells of the ovary and the Sertoli cells of the testes. Inhibin regulates follicle-stimulating hormone secretion involving a negative feedback loop, participates in ovarian folliculogenesis and spermatogenesis, and has great diagnostic potential in assessing the reproductive status and treating reproductive disorders. More than 90 years have passed since the discovery of inhibin, and it is becoming increasingly clear that its action is not limited to the reproductive system, as the hormone subunits and dimers are found in many organs. Further research is needed to study physiological functions of inhibin and diagnostic possibilities of its use in modern medicine. This review examines the structure and various biological functions of inhibin, as well as its role in human reproduction.

Journal of obstetrics and women's diseases. 2019;68(3):61-70
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The role of growth factors in the pathogenesis of endometriosis
Florova M.S.
Abstract

Endometriosis is a chronic inflammatory hormone-dependent disease characterized by abnormal proliferation in the endometrium, nerves, blood vessels, fibroblasts, etc. and accompanied by immunological disorders. Growth factors are an important part of the mechanisms that underlie intercellular communication, auto- and paracrine regulation. This literature review presents data on abnormal expression of growth factors in patients with endometriosis, relationship of growth factors and hormonal status in normal and endometrial tissues, and the supposed role of growth factors in the pathogenesis of the disease.

Journal of obstetrics and women's diseases. 2019;68(3):71-80
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Metabolic syndrome in older women
Shalina M.A.
Abstract

This paper presents the current literature data on the pathogenesis of metabolic disorders in menopause. The association of metabolic syndrome with a high risk of coronary heart disease, hypertension, diabetes, and insulin resistance is of great medical and social importance. It emphasizes the need for early diagnosis of metabolic syndrome in older women and optimization of therapeutic and preventive measures. The article highlights the role of pathogenetic, multi-component therapy, including menopausal hormone one, in the treatment of metabolic disorders in menopause.

Journal of obstetrics and women's diseases. 2019;68(3):81-88
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The role of oxytocin in the pathogenesis of endometriosis: various aspects of the problem
Yarmolinskaya M.I., Khobets V.V.
Abstract

Hypothesis/aims of study. Endometriosis is a chronic recurrent disease that leads to a significant decrease in the quality of life. Despite the existing therapeutic methods, the prevalence of the disease is steadily increasing. The pathogenesis of endometriosis has not been studied enough, resulting in failure to achieve high efficiency in its treatment. Due to chronic pelvic pain, infertility, and dissatisfaction with the quality of life, women suffering from endometriosis present with various mental disorders of different degrees of severity. This study aims to summarize the literature discussing the possible role of oxytocin in the pathogenesis of both endometriosis and affective disorders.

Study design, materials, and methods. Literature data for the period from 1986 to 2019.

Conclusion. The role of oxytocin in the pathogenesis of endometriosis needs further study. Oxytocin receptor antagonists can be considered promising in the treatment of this medical condition, as well as in prevention and management of affective disorders in patients with endometriosis.

Journal of obstetrics and women's diseases. 2019;68(3):89-98
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