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Aim. To analyze the relationship between the expression of proteomic markers [estrogen (ER) and progesterone (PR) receptors, LIF, FOXA1, FOXA2] of endometrial receptivity and indicators of the levels of sex steroids [estradiol (E2) and progesterone (P)] in the peripheral blood during the “implantation window” in women with a history of reproductive dysfunction with “thin” endometrium (TE) and evaluate their significance for the therapeutic effect of using estradiol drugs. Materials and methods. The prospective cohort comparative study was conducted. The main group included 52 patients with TE (7 mm according to ultrasound on preovulatory days), the comparison group consisted of 62 women with normal endometrial thickness (≥7 mm according to ultrasound), women of both groups with reproductive dysfunctions of unknown reason; the control group included 16 healthy women. Aspiration biopsy of the endometrium was performed on the 6–8 days after ovulation (LH +6–8), as well as venipuncture to obtain a sample of peripheral blood to determine the E2, P levels. A combined histological and immunohistochemical study of endometrial samples was performed (ER, PR, LIF, FOXA1, FOXA2). The therapeutic effects of estradiol drugs were assessed in a cohort of women from the main group with TE (n=16 out of 26, those who have not changed their reproductive plans). Results. All women had ovulatory values of progesterone [P≥16.1 nmol/l (LH +6–8)] and normoestrogenemia in the blood (p0.05). According to the results of the correlation analysis, there were no associations between the E2, P levels and the value of M-echo, and no relationships were found between the E2, P levels and the expression of ER, PR, LIF, FOX-proteins. It was revealed that there are significant positive relationships between M-echo and FOXA2 expression in the endometrium (r=0.422; p0.001). Conditional threshold values for the ER, PR expression (LH +6–8) were determined, the excess of which is associated with abnormal expression of LIF, FOX-proteins: for PR in the glands – 105 and 285, for ER in glands – 145, for ER in the stroma – 155. It was found that usual doses of estradiol drugs (1–1.5 mg/day) are capable of increasing endometrial proliferation in women with TE, provided that the expression of ER, PR, LIF, FOX-proteins in their endometrium is similar to healthy women. Increased doses of estradiol drugs (4 mg/day) in women with TE had a significant effect in the form of an increase M-echo value and/or pregnancy in cases where the endometrial expression of LIF, FOX-proteins was comparable with healthy women, even in the presence of hormone-receptor interactions in the endometrium that are different from healthy women. Spontaneous pregnancy in participants of the main group with hypoplastic endometrium in our study occurred in 5 women in whom the expression characteristics of FOXA1 and/or FOXA2 in the endometrium were comparable to healthy women. Conclusion. TE is not the only marker of an imbalance of proteomic molecules, but it determines a greater likelihood of impaired expression of ER, PR, LIF, FOX-proteins in the endometrium. In women with an unclear reason of fertility disorders, it is necessary to conduct an in-depth examination of endometrial samples. Characteristics of endometrial expression ER, PR, LIF, FOX-proteins and the usefulness of hormone-receptor interactions in the TE in women with a history of reproductive disorders can be markers for predicting the effectiveness of the use of exogenous estradiol drugs in women in order to enhance endometrial proliferation with an initially low M-echo.

Growth factors signaling cascades and their interaction with the central regulatory targets of tumor cells and estrogens are considered as the main mechanisms of hormonal resistance in breast cancer. The integration of the transforming growth factor β1 (TGF-β1) and PI3K (phosphoinositide 3-kinase)/Akt (protein kinase B)/mTOR (mammalian target of rapamycin) signaling pathway may result in the activation of proliferation and, as a result, the development of an in-effective response to therapy and disease progression. The review summarizes a systematic analysis of the literature data on the role of TGF-β1 signaling in the mechanisms of tamoxifen resistance to in the aspect of interaction with the PI3K/Akt/mTOR. The interaction between the estrogen receptors α signaling and tamoxifen, the mechanisms of regulatory activation of TGF-β1 and PI3K/Akt/mTOR, as well as their contribution to the tamoxifen response are considered. The direct involvement of TGF-β1/PI3K in the mechanisms of tamoxifen resistance to determines the prospects for studying the effector of these cascades as molecular targets. The knowledge accumulated to date allows considering the TGF-β1/PI3K signaling pathway as a potential molecular tool for the search for effective strategies for blocking the resistance of tumor cells to tamoxifen.

Aim. To evaluate the expression of FOX proteins (FOXA1 and FOXA2) in the endometrium during the implantation window in women with a history of reproductive dysfunctions with different thickness of the endometrium. Materials and methods. The prospective cohort comparative study was conducted. The main group included patients with "thin" endometrium (7 mm according to ultrasound on preovulatory days; n=52), the comparison group consisted of women with normal endometrial thickness (7 mm according to ultrasound; n=62; women of both groups with reproductive dysfunctions of unknown reason), the control group included 16 healthy fertile women. Aspiration biopsy of the endometrium was performed on the 68 days after ovulation, as well as venipuncture to obtain a sample of peripheral blood to determine the levels of sex steroids (estradiol E2 and progesterone P). A combined histological and immunohistochemical study of endometrial biopsies was performed. Results. All women had ovulatory values of progesterone P16.1 nmol/l (68 days after ovulation) and normoestrogenemia (E2, pmol/l) in the blood. E2/P was similar in all groups (p0, 05). A pronounced expression of FOXA1 was noted in women with thin endometrium significantly more often (p0.05) with various hormone-receptor characteristics of the endometrium (42% n=22 out of 52) compared with healthy participants (0%; n=0). Reduced FOXA2 expression in the uterine mucosa was significantly more often detected on 68 days after ovulation in women with "thin" endometrium (56% n=29 of 52) than in women with normal endometrial thickness, both in women from the comparison group and in healthy women from the control group (p0.05). In a generalized analysis of the expression of FOX proteins in the endometrium on days 68 after ovulation, it was generally found that every second (50%; n=57 out of 114) women with a history of reproductive disorders (with a reduced and normal M-echo value) expression of proteomic markers differed from healthy women. In the case of "thin" endometrium, more than two thirds of patients (71%; n=37 out of 52) showed differences in endometrial expression of FOX proteins compared with women without a burdened reproductive history. Conclusion. In the majority of women (71%) with a thin endometrium and a history of reproductive dysfunctions, the expression of FOX proteins in the endometrium differed from the control group. Overall, endometrial expression of FOX proteins, which is likely to be different from healthy women, in patients with reproductive dysfunctions of unknown origin is a significant predictor of reproductive failure. At the same time, such an isolated indicator as M-echo value 7 mm according to ultrasound data is not an absolute prognostic marker of endometrial receptivity disorders.

Breast diseases (BD) are among the most urgent issues of modern reproductive medicine. This organ is an integral part of the female reproductive system and undergoes cyclic changes during the menstrual cycle. The modern "nosological trio" of BD is mastodynia, benign dysplasia, and breast cancer. These diseases have an extremely high prevalence, and breast cancer, in turn, ranks 1st in the structure of mortality from malignant neoplasms of the female reproductive system. All these aspects warrant the research of the key pathogenetic mechanisms of these conditions. However, one of the most relevant topics in modern gynecology is the counseling on the selection of contraceptive methods in these patients. Therefore, it is necessary to address the safety of hormonal contraceptive methods and to analyze innovations in hormonal contraceptives, which may have several protective and risk-reducing properties for BD.

Research objectives: to study age-related changes in the structure of vaginal tissues in women with pelvic prolapse (PP). Materials and methods. The structure of the vaginal wall was studied in 29 women with PP, who were divided into three groups: the first group – 11 women aged of 45 in the reproductive period with regular menstrual function; the second group – 8 women aged 45–55 in perimenopause with irregular menstrual function; the third group – 10 women aged 55–65 who have been postmenopausal for more than three years. All women underwent immunohistochemical detection of the CD34 marker and vascular endothelial growth factor (VEGF), podoplanin, the number of estrogen receptors, type 1 matrix metalloproteinase (type 1 collagenase) and type 1 collagen were determined. Results. The reproductive age was characterized by an active metabolism, which was reflected in the fullness of all vaginal layers, their thickening, heterochromia of the nuclei, increased metabolism in the connective tissue and synthesis of vasculogenesis stimulators. The expression of estrogen receptors was not increased due to a sufficient concentration of estrogens in the body. Atrophic changes in the perimenopausal age were determined as the thinning of the vaginal layers, sclerotic changes, and a decrease in protein synthesis in the form of nuclear hyperchromia. The number of estrogen receptors was compensatory increased due to their deficiency. A feature of this age is vascular imbalance, which was subjectively expressed in climacteric symptoms. Atrophic and sclerotic changes were observed in the postmenopausal period in the form of thinning of the vaginal wall, hyperchromia of the nuclei, an increase in the collagen level relative to an unchanged collagenase level, a decrease in lymphatic drainage, and an increase in the number of estrogen receptors. Conclusions. This study shows that all groups of women with PP have characteristic signs associated with age changes, features of the mestral cycle and hormonal saturation of the body. Factors affecting the PP development include: in reproductive age – increased collagenase activity, in perimenopause and postmenopause – atrophic dyshormonal and dyscirculatory processes in tissues.

Aim. To evaluate the expression of steroid receptors (estrogen [ER] and progesterone [PR]) in the endometrium during the implantation window in females with a history of fertility disorders in "thin" and "absolutely thin" endometrium versus healthy females. Materials and methods. A prospective comparative study was conducted. The study group (n=42) included patients with "thin" endometrium (7 mm M-echo 5 mm at cycle days 1113 according to ultrasound); the comparison group (n=10) included females with "absolutely thin" (5 mm according to ultrasound in the pre-ovulatory days) endometrium (females in both groups had a history of infertility and miscarriage of unclear reasons in the anamnesis); the control group included 16 healthy fertile females. A Pipelle biopsy of the uterine mucosa was performed on day 68 after ovulation, and a peripheral blood sample was obtained to measure the concentration of sex steroids (estradiol [E2] and progesterone [P]). Endometrial samples were examined by histological and immunohistochemical methods (ER, PR expression). Results. All study participants had an ovulatory cycle of P16.1 nmol/L (day 68 after ovulation) and normal estrogen levels (E2, pmol/L). E2/P was similar in all cohorts (p0.05 for all measures). ER and PR expression in the endometrium similar to those in healthy females was detected in 20% of patients in the study and comparison groups (M-echo = 4.83.1 mm): 21% (9/42) and 20% (2/10), respectively. ER and PR expression in the endometrial glands and ER expression in the endometrial stroma were significantly different (p0.05) from healthy females in 79% (41/52) of patients with "thin" endometrium and 80% (8/10) of patients with "absolutely thin" endometrium. No differences in the ER or PR expression in the endometrium in females with hypoplastic endometrium were found (p0.05). Conclusion. The M-echo value does not accurately determine endometrial hormonal-receptor abnormalities: 20% of the study participants with hypoplastic endometrium had ER and PR expression comparable to those in healthy females. No differences were found in the expression of endometrial estrogen and progesterone receptors in females with "thin" and "absolutely thin" endometrium.

The paper presents an analysis of the latest literature data on the problem of obesity and breast cancer (BC). This review presents modern approaches to the diagnosis of BC in obese patients, new molecular methods of breast imaging, analyzes the features of the course of BC with obesity depending on menstrual status, molecular biological subtypes of the tumor, the mechanisms of the development of BC against the background of obesity.

Objectives: to evaluate the hormonal status and receptor apparatus of the eutopic endometrium in patients with adenomyosis who had a history of papillary thyroid carcinoma. Materials and methods. 63 women were examined: group I consisted of 31 patients with adenomyosis and papillary carcinoma of the thyroid gland in history, group II consisted of 32 patients with adenomyosis and unencumbered thyroid status. The severity of pelvic pain was assessed using a visual analog scale. The level of luteinizing and follicle-stimulating hormones, estradiol, prolactin, thyroid-stimulating hormone and progesterone was determined in the peripheral blood serum. The material for the morphological study was obtained using endometrial pipelle biopsy. Morphological research was performed on 30 biopsies of eutopic endometrium (15 samples from patients of group I and 15 samples from patients of group II). Immunohistochemical study was performed on 20 paraffin sections (10 samples from patients of group I and 10 samples from patients of group II) using monoclonal antibodies. Results. High ER-α expression was detected in the endometrial glandular epithelial cells (EGECs) in 80 and 50% of samples of patients from groups I and II, respectively (р < 0.05), no significant difference in the number of positive cells was found between groups. High ER-α expression in endometrial stromal cells (ESCs) was detected in 50% of samples in patients from both groups, the number of positive cells was significantly higher in the endometrium specimens from I group (84.0 (10.5%) in group I versus 62.2 (12.3%) in group II, р < 0.05). High PgR expression in the EGECs was detected in 90 and 75% of samples in groups I and II respectively (р < 0.05), ESCs expressed PgR in 100% of samples of patients from both groups. Significant difference in the number of positive cells was found between groups – 96.0 (8.4%) and 84.9 (12.6%) in groups I and II respectively, р < 0.05. Conclusions. Our results suggest that the ectopic endometrium in female thyroid cancer survivors with adenomyosis has high expression of ER and PgR, that may have important implications for the survival and proliferation of the eutopic endometrial cells. Further research is needed to optimise prevention and treatment algorithms for this group of patients.

Sexual dimorphism of chronic diseases is a phenomenon determined by differences in the hormonal status of men and women. In this regard, estrogens, which have a complex effect on the body, are of great interest. In particular, estrogens play an important role in the natural control of pain and inflammation. A decrease in estrogen levels associated with menopause or iatrogenic effects (hysterectomy, use of aromotase inhibitors), as well as mutations of genes responsible for the synthesis of structural components of membrane estrogen receptors (ESR1 and ESR2), can significantly reduce the positive effects of these hormones. Deficiency of estrogen can become one of the reasons for the development of serious pathological changes in particular, the formation of chronic pain associated with the pathology of the musculoskeletal system.

The purpose of the study was to mine, compile and analyze the published data on breast cancer (BC) systematization, diagnosis and treatment. In the current review, modern approaches in BC subtypes diagnosis based on genomic profiling, miRNA expression pattern analysis, SNP analysis in BRCA1 and BRCA2 genes, as well as proteomic mapping as essential components of the disease peculiarities improving the prognostic outcome were compiled and analyzed. Further, tumor-initiating stem-like cells as a factor affecting both prognosis and treatment choice for BC are considered and evaluated. And finally, modern principles of enhancing tumor sensitivity to therapeutic effects of anticancer drugs, which comprise the use of cytostatics in condensed modes, combining drugs, which exert different mechanisms of cytotoxicity, as well as the introduction of new chemotherapy drugs into therapeutic practice, including those targeted against the common metabolic pathways both in stem-like and committed breast cancer cells, are compiled and discussed. The analysis indicates that the current paradigm in BC treatment is development and implementation of the newest methods for diagnosis of BC sybtypes, which, being combined with those already implemented, would allow the administration of treatment according to the individual peculiarities of a tumor.

Aim: to evaluate the expression of estrogen (ER) and progesterone (PR) receptors in the endometrium during the "implantation window" in women with a history of reproductive dysfunction with different endometrial thickness.Materials and Methods. A prospective single-center cohort comparative study was conducted. The main group included patients with hypoplastic (< 7 mm according to ultrasound data on preovulatory days) endometrium (n = 52), the comparison group consisted of women with normal endometrial thickness (n = 62) (women of both groups with reproductive dysfunctions of unclear cause), the control group included 16 healthy fertile women. An aspiration biopsy of the endometrium was performed on day 6–8 after ovulation with simultaneous collection of peripheral blood sample to measure level of estradiol (P). Endometrial biopsies were examined with histological and immunohistochemical (expression of ER, PR) methods.Results. All women had an ovulatory cycle, serum progesterone level ≥ 16.1 nmol/L (6–8 days after ovulation) and normoestrogenemia. E2/P was similar in all cohorts (p > 0.05). Indicators of endometrial expression of ER, PR, similar to healthy women (n = 16), were found in 21 % (n = 11 out of 52) and 32 % (n = 20 out of 62) in women from main and comparison groups, respectively. The remaining 79 % (n = 41 out of 52) of women with "thin" endometrium (main group) and 68 % (n = 42 out of 62) of patients with normal endometrial thickness (comparison group) had ER and PR expression indices in the endometrial glands and stroma with significant differences (p < 0.05) in all parameters (excepting PR in the endometrial stroma) from those of healthy women (control group), but without relevant differences between these cohorts (p > 0.05) regardless of endometrial thickness.Conclusion. In women with a history of reproductive disorders, parameters of ER and PR expression similar to those in women without reproductive problems, were noted with a "thin" (< 7 mm) endometrium by 50 % less often than those with normal thickness of the uterine mucosa. At the same time, the "thin" endometrium is not an absolute predictor of disorders of the hormone-receptor characteristics of the endometrium: in every fifth case, magnitude of endometrial expression ER, PR similar to healthy women were determined.

Overcoming infertility and reducing miscarriage are important challenges in obstetrics and gynecology. In the Russian Federation, the frequency of infertile couples reaches 24%; the percentage of miscarriage does not decrease, accounting for up to 20% of all desired pregnancies. The endometrial factor plays an important role in the causes of gravidar losses. Inadequate phase transformation of the endometrium is a predictor of fetal egg implantation failures. An integral part of endometrial cyclic transformations is the full proliferation of the mucous membrane of the uterine body. However, there is a cohort of women who, due to the insufficiency of proliferative processes in the endometrium, have a syndrome of thin endometrium. The pathogenesis of the formation of a hypoplastic endometrium in women with normal characteristics of hormonal factors is still poorly understood. Particular attention is paid to determining the function of proteomic markers (leukemia inhibiting factor, Forkhead box-protein family, etc.) in the genesis of the hypoplastic endometrium. This review presents an analysis of modern Russian and foreign sources on the receptivity of the endometrium, including the syndrome of thin endometrium in women of reproductive age.

Aim. To assess the expression of estrogen (ER) and progesterone receptors (PR) in the endometrium during the implantation "window" in women with impaired reproductive function with low (16.1P30 nmol/l) and high (P30 nmol/l)) functional activity of the corpus luteum of the ovary. Materials and methods. A prospective single-center cohort comparative study. The main group included patients with infertility (n=93) and miscarriage (n=47) of unclear reason in the anamnesis, the control group 16 healthy fertile women. In all cases, vacuum-aspiration endometrial biopsy was performed on the 68 days after ovulation with simultaneous collection of a peripheral blood sample to determine the levels of estradiol and progesterone. Endometrial samples were studied by histological and immunohistochemical (ER, PR expression) methods. Results. Women of the main (1) and control (2) groups had an ovulatory menstrual cycle. The serum estradiol (E2) level was 691.326.5 pmol/l (1) and 707.466.1 pmol/l (2); progesterone (P) 46.11.8 nmol/l (2) and 39.14.9 nmol/l (2). Mid-secretory endometrium (results of histological examination) was determined in all healthy women (n=16) and in 46% (n=64) of the patients of the main group. All women in the control group had adequate hormone-receptor characteristics of the endometrium, in women in the main group in 45% (n=63). Comparative analysis of the expression of ER, PR in the endometrium in patients with different functional activity of the corpus luteum of the ovary was carried out in the groups 1 and 2, in women with different reproductive dysfunctions in the anamnesis (without significant differences; p0.05); subgroup analysis was performed in cohorts of women with normal (63 women in group 1 and 16 in group 2) and inadequate (77 patients in group 1) hormone-receptor status of the endometrium. There were no significant differences in the expression of ER, PR in the endometrium with low/high functional activity of the corpus luteum of the ovary with similar morphological characteristics of the endometrium (p0.05). Correlation analysis did not reveal significant relationships between the level of P in the blood and indicators of endometrial expression ER, PR (p0.05). Conclusion. In the studied cohorts, the prognostic significance of the functional activity of the corpus luteum of the ovary for the adequate expression of estrogen and progesterone receptors has not been established. To clarify the presence/absence of endometrial dysfunction in women with a history of reproductive failures, a morphological examination of the endometrium of the middle secretion phase should be carried out.

The problem of resistance of non atypical endometrial hyperplasia (NEH) to traditionally accepted, pathogenetically sound therapy with different types of progestins is currently an unsolved problem. In about 17-20% of cases there is a recurrence or even progression of atypical forms of endometrial hyperplasia (AEH), which required the use of surgical treatments. The aim of the study was to investigate the results of hormone therapy with different types of progestins for the treatment of endometrial hyperplasia in women with different types of expression of estrogen and progesterone receptors in combination with the expression of intercellular adhesion molecules E-cadherin and β-catenin to determine the cause of hormonal resistance, formation of groups of women with progestogensensitive endometrial hyperplasia (EH) non atypical type NEH (+), which can use progestogens for treatment, and progestogen-resistant forms of endometrial hyperplasia with non atypical NEH (-), which should be offered alternative therapy. The study was performed on the morphological material of the endometrium obtained by diagnostic biopsy in women with abnormal uterine bleeding who were diagnosed with NEH by histological examination. For immunohistochemical study, 80 endometrial samples were taken from women with abnormal uterine bleeding (AUВ) and in the same women after treatment of endometrial hyperplasia without atypia in 3 and 6 months of therapy. The control group (CG) consisted of a group of 20 women who were followed-up without treatment tactics. All women were divided into 3 groups in which different types of progestins were used for treatment: group I – continuous intake of 100 mg of micronized progesterone per os twice a day for 6 months, group II – 20 mg of dihydrogesterone per os twice a day for 6 months, group III – in which LNG-IUD was used. The state of proliferation and differentiation in the studied tissues was assessed by the expression of their key molecular participants – estrogen receptors (ERα) and progesterone (PGR), transmembrane glycoproteins of E-cadherin and β-catenin. ERα and PGR expression were determined by immunohistochemistry and calculated by the semi-quantitative H-index method. Evaluation of the expression of E-cadherin and β-catenin was performed by determining the percentage of IHH-positive cells to these antigens depending on the degree of their color. The criterion for the effectiveness of NEH treatment was considered to be a biopsy in 3 and 6 months of treatment in the absence of pathological changes in the endometrium. The results showed that after the use of progestogens in group I there was a change in the endometrium to the secretory type in 45% of cases, in group II with dydrogesterone therapy – in 55% there was a reduction of EH to normal histological picture. The intrauterine system with levonorgestrel (LNG-IUD) showed the greatest efficiency, with the use of which in 75% of cases normalization of the endometrial structure was observed. In the control group in 32% of cases the structure of the endometrium normalized. After 6 months of treatment with gestagens, both oral forms (micronized progesterone, dydrogesterone) and the use of LNG-IUDs showed a positive effect from their use; the therapeutic form of gestagens for therapy is not significant in reducing excessive endometrial proliferation. In the control group of patients who did not receive therapy or discontinued therapy for various reasons, it was shown that 47% of patients had spontaneous regression of EH. The overall percentage of no effect from treatment was 20% in groups I, II and III. Determination of ERα expression in all groups showed a pronounced expression in glands and stroma, which did not differ significantly in the group with NEH (+) and in NEH (-). Analysis of PGR expression of NEH in endometrium (-) showed that in glandular cells (50.82±0.73) and in the stroma (47.34±0.82) it was lower than in the endometrium of women with NEH (+) (gland 187±3.1; stroma 166.4±2.3; p<0.05), as well as in the unchanged endometrium in the proliferative phase (glands 193.2±8.5; stroma 178.7±6.3; p<0.05) and the secretory phase (glands 140.2±4.4; stroma 116.6±3.1; p<0.05). A study of E-cadherin expression in women with EH (-) showed that in 86.4% of cases the expression was absent and in 13.6% it decreased. In NEH (+) women, 49.2% of E-cadherin expression was weak, in 34.4% – moderate, and in 16.4% – negative, indicating an association between PGR and E-cadherin expression. In women with NEH (-) there was marked cytoplasmic expression of β-catenin up to 80%, which can be interpreted as potentially threatening the progression of NEH in atypical forms and relapses. Thus, the study of molecular mechanisms of resistance of endometrial hyperplasia to progestogen therapy will help to develop a differential approach to its diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most commonly diagnosed cancers and the leading cause of cancer mortality among women. Approximately 70–80 % of breast cancers are estrogen (ER) and/or progesterone receptor-positive, thus making endocrine therapy an important stage of treatment. Receptor expression in breast cancer cells is usually assessed by tissue immunohistochemistry. The method of positron emission tomography, combined with computed tomography (PET/CT), makes it possible to evaluate not only anatomical and structural, but also metabolic changes in tumor tissue. 18F-Fluoroestradiol (18F-FES) is a radiopharmaceutical drug, an estradiol analogue, which is used in the diagnostics of ER-expressing tumors and is utilized for detection and quantification of ER expression in vivo. Various studies show that 18F-FES accumulation indicates presence of ER-positive tumor tissue, which, in most cases, is confirmed by tissue immunohistochemistry. Although current guidelines recommend 18F-fluorodeoxyglucose PET/CT when routine examinations demonstrate ambiguous results, 18F-FES PET/CT can be the preferable imaging modality in the diagnostics of ER-positive breast cancer. It should be noted, that PET/CT with 18F-FES can also be effective for evaluation of tumors with a high level of ER expression, like ovarian cancer.

The article analyzes data from the world literature for the period from 2005 to 2020 on the relationship between the variability of immunohistochemical expression of estrogen and progesterone receptors, HER2/neu protein and the index of proliferative activity in invasive breast cancer with the course of the disease and the response to medication.

The aim of the review was systematization of the data on discordance in expression of estrogen receptors between primary and metastatic breast cancer, different metastases and repeated analyses of the same tissue. The possible reasons for the phenomenon are discussed. The authors emphasize the need to analyze estrogen receptors in breast cancer metastases, regardless of the receptor status of the primary tumor, for predicting the course of the metastatic disease and providing an adequate treatment of the metastatic tumor in strict accordance with its receptor status during drug therapy. The works cited in the search engine Pub Med to May 2013 were analyzed.

A review of the literature data on expression of estrogen receptor alpha and beta (ERa and ERβ) in tumors different from breast cancer. The results regarding the ERa and ERβ expression frequency in non-small cell and small cell lung cancer, colorectal cancer, esophageal, ovarian, prostate and brain tumors are presented. High frequency of estrogen receptor expression (in up to 50 and more per cent of cases) in various types of tumors, differences between ERa and ERβ in expression frequency, prognostic significance and prediction of the neoplastic process aggressiveness as well as in biological implications of interaction with antiestrogens (antagonistic and/or agonistic effect) are shown. The data on comparative evaluation of ERa and ERβ expression in lung, ovarian, prostate tumor cells and corresponding nonneoplastic tissues are reported. Authors consider necessary to include the ERa and ERβ detection into the routine clinical practice not only in breast cancer but in other tumors as well. Prospects of the clinical application of antiestrogens, in particular tamoxifen, in adjuvant therapy of different tumors with positive ER status are discussed.

Aim. To analyze and systematize the available information on pathogenetic mechanisms of hormonal carcinogenesis. Materials and methods. The review includes data from foreign articles published in PubMed and Medline and national works posted on elibrary.ru over the past 20 years. Results. Currently, the term estrogen is often used in the context of hormonal carcinogenesis. According to most researchers, it should not fit into the narrow framework of receptor-mediated proliferation induced by estrogens in target tissues. The concept of estrobiome as a combination of all mechanisms providing the realization of estrogen effects should include not only hormones and native receptors themselves, but also the enzymes involved in their synthesis, estrogen metabolites, intestinal microbiota, as well as genetic and epigenetic factors. Conclusions. When analyzing cancer risk, it is necessary to comprehensively assess contributing factors and hormonal-metabolic preconditions for neoplastic process.

Breast cancer is one of the most common female cancers and the leading cause of cancer death in women. The method of positron emission tomography, combined with computed tomography, makes it possible to assess not only anatomical and structural, but also metabolic changes in tumor tissue. The increased accumulation of 18F-fluoroestradiol in the pathological focus correlates with the estrogen receptor-positive status of the tumor, which is confirmed by tissue immunohistochemistry studies. The receptor status of a tumor formation fundamentally affects the choice of therapeutic tactics. The presented clinical examples demonstrate the capabilities of positron emission tomography, combined with computed tomography, with 18F-fluoroestradiol in the diagnosis of the estrogen receptor-positive tumor lesions.

Background. Assessment of hormone receptor status plays a crucial role in treatment of patients with breast cancer. currently, clinicians are limited to determining the expression status of estrogen receptor (ER), progesterone receptor (pR) and HER2 only in primary breast cancer tissues, even in the presence of regional metastases.The purpose of the study was to review available data on heterogeneity of ER, pR and HER2/neu expressions in primary breast cancer and regional metastases.Material and methods. We analyzed publications available from pubmed, medline etc. using the keywords «discordance», «breast cancer», «locally advanced», «regional lymph nodes», «ER», «pR», and «HER2».Results. The clinical and prognostic role in assessing the heterogeneity of the receptor status of primary tumors and synchronous regional metastases, as well as the effect of detected discordance on treatment tactics was assessed.Conclusion. Data on the frequency of discordance in hormone receptor status between primary and metastatic breast cancer tumors and its effect on the further prognosis in breast cancer are still contradictory. However, the fact of the presence of such heterogeneity suggests that some patients with affected lymph nodes will have significant benefits from determining the status of steroid hormones and HER2 not only in the primary tumor, but also in the lymph nodes, since it will open up new opportunities for subsequent targeted therapy.

The leading role of ovarian steroid hormones in the pathogenesis of uterine fibroids is confirmed by epidemiological, clinical and experimental studies. The new approaches to the treatment of this disease may be developed on the basis of the biological and genetic mechanisms underlying the occurrence and development of leiomyomas. The use of ulipristal acetate in patients with uterine leiomyoma may be a promising method for preparing them to the surgical procedures, but also for avoiding surgical treatment and related hypoestrogenic conditions, which results in the improvement of the women’s quality of life.

Purpose: study of uveal melanoma (UM) cells receptor status to estrogen (ER) and progesterone (PR). Material and methods. 22 patients (8 men and 14 women) with UM aged 22 to 76 (mean 54.3 ± 2.2 years) were subjected enucleation (n = 20) or fine-needle aspiration biopsy, depending on clinical indications. The material for cytological examination (n =22) was obtained from enucleated eyes by imprinting. A routine cytological study was performed to confirm the diagnosis, while at the second stage the method of immunocytochemistry (ICC) was used to differentiate the melanocytic nature of the tumor. Results. The cytological diagnosis of melanoma was established in all patients, including two urgent cytological tests on the operating table. In 80 % of melanomas, a positive expression of HMB 45 (melanocytic differentiation marker) and cocktail Melan (a melanoma-associated marker) were observed, which confirmed the melanocytic nature of the tumor. A weak reaction to S100 (neuronal differentiation marker) was noted. In all cases, a pronounced reaction to vimentin was observed, which manifested itself as a brown coloration of the cytoplasm. When studying the expression of ER and PR, a negative result was obtained; none of the studied samples displayed a quantitatively positive reaction. Conclusions. In our investigation, based on UM samples study, 22 patients had no positive expression of estrogen and progesterone receptors in the tumor tissue, which correlates with literary data. For citation: Saakyan S.V., Zhiltsova M.G., Valskiy V.V., Tsygankov A.Yu. Estrogen and progesterone receptors expression in uveal melanoma tumor cells. Russian ophthalmological journal. 2018; 11 (1): 17-23. doi: 10.21516/2072-0076-2018-11-1-17-23 (In Russian).

Aim. The article is devoted to the research of morphological features and activity of estrogen receptors of endometrium and foci of adenomyosis in postmenopausal patients. Materials and methods. 30 cases of adenomyosis were investigated in the presence of the hyperplastic processes in the endometrium (endometrial adenocarcinoma of the uterine body and endometrial hyperplasia) and without it (age changes) in patients aged 51-73 years. We conducted immunohistochemical research and hematoxylin and eosin stain. IHC blocks were produced by the method of Tissue Microarray. The expression of estrogen markers was evaluated according to point system of general staining method for ER-status determining. Results. Morphological structure of eu- and ectopic endometrium was studied in the work in detail, according to comorbidity. Moderately differentiated adenocarcinoma (G2) was diagnosed in 4 cases out of 10 in the group with the endometrial adenocarcinoma, and in 6 cases - level 2 of the nuclear atypia. It was revealed that morphological picture of adenomyosis in the presence of hyperplastic processes in the endometrium is characterized by the predominance of glandular component over stromal one in the ectopic endometrium. Significant differences between all the groups of the studied women during the estimation of the levels of the estrogen activity of the components of the eutopical endometrium were not revealed, with the exception of endometrial adenocarcinoma. Comparative analysis of our results with data of the other researchers was conducted. Conclusion. It was established that the foci of adenomyosis retain their activity, that is morphologically manifested as the foci of proliferation and secretion. The level of ER expression of eutopical endometrium dominates over the endometrium of adenomyosis foci in the presence of the endometrial adenocarcinoma and the atrophy of the endometrium. Low level of ER expression in stromal cells in comparison with the glandular was demonstrated both in the foci of endometrial heterotopias and in eutopical endometrium in endometrial carcinoma. Low level of intensity of stromal component expression of the foci of endometrial heterotopias was found in the group with endometrial adenocarcinoma in comparison with the other groups. Further studying of the activity level of progesterone receptors in eutopical endometrium and in the foci of the internal endometriosis is perspective for this category of women.

Objective: A comparative study of detection of breast cancer markers (estrogen receptors, progesterone receptors, HER2/neu, Ki-67) by immunohistochemical method with antibodies produced by PrimeBioMed (Russia) and antibodies produced by Roche Ventana (USA)., Material and Methods: Surgical specimens and biopsies from 37 patients with invasive breast cancer were used. Sections were stained with antibodies of clones ER SP1 and GM030, PR 1E2 and PBM-5B8, HER2/neu 4B5 and PBM-46A6, Ki-67 30-9 and GM010., Results: There was a high positive and significant correlation between the immunohistochemistry results and antibodies of the clones ER-SP1 and GM030, PR1E2 and PBM-5B8, HER2/neu4B5 and PBM-46A6, Ki-67 30-9 and GM010., Conclusion: The study showed the possibility of using antibodies of clones GM030, HER2/neu 4B5, PBM-46A6, GM010 (PrimeBioMed) on the Ventana Bench Marck Ultra automatic immunostainer using the detection system UltraView Universal DAB Detection Kit.

Endometrial cancer occupies the sixth place among oncological morbidity structure in women worldwide. The aim. To compare the expression levels of estrogene receptors – α and progesterone receptors, regulatory proteins p16 and p53, a marker of proliferation Ki-67 and the apoptotic degradation enzyme caspase-3, matrix metalloproteinase 9 (MMP 9) and its tissue inhibitor TIMP-1 in tumor and stromal cells of the invasive non-metastatic endometrioid endometrial carcinoma and also in invasive metastatic endometrioid endometrial carcinoma. Materials and methods: Immunohistochemical and morphometric study of invasive non-metastatic рТ1-4N0Mx endometrioid endometrial carcinoma (n=56; age 42-83 years), invasive metastatic рТ1-4N1-2Mx endometrioid endometrial carcinoma (n=30; age 48-79 years) was performed. Results: Statistically significantly higher expression level of estrogen receptor-α was detected in tumor cells of endometrioid endometrial carcinoma with metastasis to the regional lymph nodes in comparison with the expression level of these receptors in tumor cells of non-metastatic endometrioid endometrial carcinoma. The progesterone receptors expression levels in the tumor and stromal cells of invasive endometrioid endometrial carcinoma with metastasis to regional lymph nodes were lower in comparison with the corresponding expression levels of progesterone receptor in corresponding cells of non-metastatic endometrioid endometrial carcinoma. In stromal cells of endometrioid endometrial carcinoma with metastasis to the regional lymph nodes the expression level of caspase-3 was significantly lower too in comparison with the expression level of this enzyme in stromal cells of non-metastatic endometrioid endometrial carcinoma. In tumor and stromal cells of endometrioid endometrial carcinoma with metastasis to the regional lymph nodes the expression levels of MMP-9 and TIMP-1 are decreased significantly compared to the expression level of these markers in the respective cells of non-metastatic endometrioid endometrial carcinoma. Conclusions. The expression level of estrogen receptor-α in the tumor cells was higher, the expression level of caspase 3 in stromal cells was lower and the expression levels of progesterone receptors, MMP 9 and TIMP-1 in tumor and stromal cells were lower in metastatic endometrioid endometrial carcinoma compared to non-metastatic endometrioid endometrial carcinoma. The obtained data can be used for individual prediction of metastasis to regional lymph nodes in patients with endometrioid endometrial carcinoma.

Over the last forty years antiestrogen tamoxifen belongs to the most effective antitumor drugs widely used in the treatment of breast cancer, however, the efficiency of tamoxifen therapy is often limited by development of tumor hormonal resistance. The study of the mechanism of hormonal resistance led to the significant progress in the insight in signaling pathways respondent for the cancer cell growth in the absence of estrogen. In the review we have analyzed the recent data including our results obtained in the N. N. Blokhin RCRC, concerned with the study of the new aspects of hormonal resistance – the involvement of hypoxia-dependent HIF-1α / VEGF pathway, epithelial-mesenchymal transition and mTOR / AMPK in the formation of estrogen-independent phenotype. Some of the signaling proteins are considered as the potential targets for the therapy of the estrogen-resistant breast cancer.

Based on clinical data, case histories, ultrasound studies, hormonal status, steroid hormone receptor levels, and estrogen metabolic enzyme activities, which are of the greatest informative value, the authors have determined a regression function for assessing a risk for endometrial cancer (EC) in patients with endometrial hyperplastic processes and calculating an individual risk. The application of this model could make an objective assessment of EC progress in these patients and use a treatment option on an individual basis. In patients with endometrial hyperplasia, the sensitivity of the EC risk prediction model was 87.5%; its specificity was 90%; these were 80 and 85.7 in the perimenopause and 92 and 83% in the postmenopause, respectively. For patients with endometrial hyperplasia con- current with uterine myoma, these indices were 87 and 85%, respectively.The mathematical model makes it possible to objectively assess the risk of EC in patient with endometrial hyperplasia in different age groups, to make up increased cancer risk groups, and to plan an individual treatment option, by taking into account both the tradi- tional indicators and the specific features of estrogen reception and metabolism.

This paper presents the results of a molecular pharmacologicalanalysis of prothrombotic effects of oral estrogen drugs,as well asthe actual problem resoving methods of bioinformatics and systems biology. At the same time, the transdermal administration of estrogensallows not only to maintain a stable blood concentration, but alsoalmost completely avoid liver metabolism. Transdermal estrogen ischaracterized by pronounced pharmacokinetic advantages that can reducethe dosage of estrogen without losing effectiveness; avoidingundesirable effects of excessive activation of blood coagulation.

The article presents a review of current data on the features of the etiology and pathogenesis of colorectal cancer in peri - and postmenopausal women. Discusses the protective role of female sex hormones against colon cancer. Set out the principles of prevention and screening for colorectal cancer in women in the peri - and postmenopausal women.

Introduction: Stereotactic radiosurgery is one of the main treatments for vestibular schwannomas (VS). Their feature is frequent post-radiation pseudoprogression. This may be due to hormonal status of patients., Objective: To analyze expression of progesterone and estrogen receptors in women and men with VS., Material and Methods: Immunohistochemical analysis of expression of progesterone (PR) and estrogen receptors (ER) after biopsy was performed in 240 patients with VS between 2018 and 2021. ER/PR expression was assessed in men ( n =120) and women ( n =120) in 3 age subgroups: young age (18-44 years), middle age (45-59 years) and old age (60-79 years). Each subgroup included 40 patients. Statistical analysis was performed using the Mann-Whitney test and MedCalc software., Results: ER expression is not typical for VS (men - 1 (0.01%), women - 3 (2.5%)). At the same time, PR expression was found in 29 (24.2%) men and 21 (17.5%) women. We found no significant difference in expression of ER and PR between men and women. However, variability in PR expression was revealed, i.e. predominance of this indicator in young women ( p =0.0463) and middle-aged men ( p =0.0110). Expression of PR was similar in elderly patients ( p =0.2382)., Conclusion: The established incidence of PR expression may be one of the probable causes affecting development and duration of VS pseudoprogression after radiosurgery without clear relationship between sex and age. Further prospective research is needed to predict the risks of pseudoprogression.

Sexual dimorphism of chronic diseases is a phenomenon determined by differences in the hormonal status of men and women. In this regard, estrogens, which have a complex effect on the body, are of great interest. In particular, estrogens play an important role in the natural control of pain and inflammation. A decrease in estrogen levels associated with menopause or iatrogenic effects (hysterectomy, use of aromotase inhibitors), as well as mutations of genes responsible for the synthesis of structural components of membrane estrogen receptors (ESR1 and ESR2), can significantly reduce the positive effects of these hormones. Deficiency of estrogen can become one of the reasons for the development of serious pathological changes in particular, the formation of chronic pain associated with the pathology of the musculoskeletal system.

Background. Benign ovarian tumors (BOT) occupy the 2 nd place in the structure of diseases of the female genital organs. In 20% of women of reproductive age, BOT are associated with infertility. One of the causes of infertility caused by ovarian tumors is morphofunctional inferiority with impaired endometrial receptivity., Objective: To reveal the morphological and functional features of the endometrium and the level of receptivity to sex hormones in patients with BOT before and after organ-preserving operations., Material and Methods: The study included 77 patients with epithelial ovarian tumors (EOT) - I group, 52 with mature teratomas (MT) - II group. Before and 6-12 months after laparoscopic cystectomy aspiration biopsy of endometrium was performed in the middle stage of secretory phase. The percentage and degree of maturity of pinopodes were determined, and the level of expression of estrogen (ER) and progesterone (PR) receptors in the glands and stroma of the endometrium was assessed., Results: At the preoperative stage, a decrease in the number of mature pinopodes in patients with EOT was revealed. Normal levels of ER were determined in glands and stroma of endometrium, PR was reduced both in stroma and glands of uterine mucosa. In patients with MT all markers corresponded to those of healthy women. In the postoperative period an increase in the number of developed pinopodes on the apical surface of endometrium in patients of I group was found. The ER level did not differ from control values, PR remained reduced in stroma. In II group a persistent decrease in quantity of mature pinopodes, ER in stroma, PR in glands and stroma of uterine mucosa was recorded., Conclusion: The presence of BOT and unintentional intraoperative removal of healthy ovarian tissue lead to indirect disorders of the morphofunctional state and endometrial receptivity.

Immunohistochemical study of breast cancer has been practiced for several decades; however, the standardization of this process has not yet been achieved, despite substantial advances in methodology. The paper presents practical guidelines and standards for testing breast carcinomas, which can be used as day-to-day control of the work of an immunohistochemistry laboratory. It considers the concept of external quality control in the immunohistochemical detection of estrogen (ER) and progesterone (PR) receptors, as well as the problems of harmonization in the immunohistochemical analysis of breast carcinomas, by using the nuclear biomarkers, such as ER and PR, as an example. The agreed standard-based external control in determining the optimal result may yield reproducible data for use in clinical practice.

BRCA1 (breast cancer 1) protein is involved in the genome stability maintenance participating in homologous recombination-dependent DNA repair. Disruption of BRCA1 functioning is associated with breast and ovarian cancer. Despite the important role of BRCA1 in DNA repair in all cell types, the development of BRCA1-associated cancer takes place mainly in estrogen-dependent tissues such as breast and ovarian ones. Using breast cancer cell line MCF-7 it was demonstrated in in vitro experiments that the estrogen 17β-estradiol (E2), phytoestrogens (genistein and apigenin) and antiestrogens (tamoxifen and fulvestrant) inhibited estrogen receptor (ERα) expression while only genistein influenced BRCA1 increasing its expression. In hypoxia, that is an important factor of solid tumors progression, the decrease of BRCA1 and ERα expression was demonstrated in MCF-7 cells. Therefore, hypoxia influences both BRCA1-dependent DNA repair and hormonal regulation of breast cancer cell growth. Taken together, obtained results demonstrate a relationship between BRCA1 and steroid hormones signal transduction pathways in breast cancer cells and point out to the importance of complex BRCA1 and ERa expression regulation mechanisms studies including epigenetic gene expression regulation.

Objective: To present the histological and immunohistochemical characteristics of pituitary lactotroph adenomas (PLAs) resistant to dopamine agonist treatment., Subject and Methods: The investigators examined paraffin-embedded blocks and histological sections obtained from 19 patients (13 women, 6 men), whose median age was 29 (19, 38) years, after surgical treatment (adenomectomy) for PLAs resistant to dopamine agonist treatment. Immunohistological examination was performed using antibodies against prolactin (PRL), growth hormone (GH), thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), type 2 dopamine receptors (DR 2 ), estrogen receptors-α (ERα), the proliferation marker Ki-67, and the endothelial cell marker CD34., Results: The expression of PRL by adenoma cells was revealed in all the patients. The coexpression of PRL and GH without clinical and laboratory signs of acromegaly was established in 3 cases. No expression of TSH, ACTH, LH, or FSH was revealed in any cases. Positive immunoreaction using antibodies against DR 2 and ERα was detected in 8 and 6 cases, respectively. No expression of any of the studied receptors was found in 6 patients. Ki-67 was more than 3% in 3 patients and higher in patients with supra- or retrosellar growth. There was a positive correlation between the serum level of Ki-67 and that of PRL at the onset of the disease. There were 37 (25, 85) adenoma vessels, as measured by CD34 immunoexpression. It was ascertained that the patients with parasellar adenoma had more tumor vessels than those without parasellar growth of adenoma and that with the latter invading the cavernous vessels, the number of vessels was statistically significantly more., Conclusion: PLAs resistant to dopamine agonists in addition to PRL (100%) can express GH in 16% of cases are characterized by the immunoexpression of DR 2 (42%) and ERα (32%), a low proliferative activity, increased angiogenesis in the adenomas with parasellar growth and invasion into the cavernous sinus.

The main goal of this work was to study the intracellular signaling pathways responsible for the development of hormone resistance and maintaining the autonomous growth of breast cancer cells. In particular, the role of PAK1 (p21-activated kinase 1), the key mitogenic signaling protein, in the development of cell resistance to estrogens was analyzed. In vitro studies were performed on cultured breast cancer cell lines: estrogen-dependent estrogen receptor (ER)-positive MCF-7 cells and estrogen-resistant ER-negative HBL-100 cells. We found that the resistant HBL-100 cells were characterized by a higher level of PAK1 and demonstrated PAK1 involvement in the maintaining of estrogen-independent cell growth. We have also shown PAK1 ability to up-regulate Snail1, one of the epithelial-mesenchymal transition proteins, and obtained experimental evidence for Snail1 importance in the regulation of cell proliferation. In general, the results obtained in this study demonstrate involvement of PAK1 and Snail1 in the formation of estrogen-independent phenotype of breast cancer cells showing the potential role of both proteins as markers of hormone resistance of breast tumors.

The paper presents the current data available on the etiology of tumor diseases, among other things, shows the role of hormones, namely: estrogens and their receptors, in the mechanism responsible for the occurrence of these diseases. Each tumor was shown to have its receptor status and to be unresponsive to this or that therapy differently. The efficiency of treatment and its prognosis may be determined if the receptor composition of an involved organ is estimated correctly. The authors summarize the data available in the literature, as well as the results of their own investigations explaining the selective effect of estradiol receptor agonists and antagonists in various tissues. The mRNA varieties that potentially encoding for the synthesis of different subtypes of estrogen receptors (ER) - ER-α and ERβ, which are also coded by various genes located in different chromosomes. Pituitary adenomas as hormone-dependent masses are described in detail. The authors data on the concentration of nuclear estrogen receptors in different types of adenomas are given.