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Migraine patients often experience sensory symptoms called auras accompanying the headaches. Cortical spreading depression (CSD), a slow-propagating wave of neuroglial depolarization followed by hyperpolarization is proposed to be the neurological mechanism underlying these auras. We have previously found that progesterone regulates susceptibility to migraine through progesterone receptor (PR) activation. Here, we determined if PR signaling also regulates susceptibility to CSD. We used gonadally-intact and ovariectomized, estrogen-primed female mice expressing PRs or lacking them in the brain. CSDs were induced with dural application of KCl (1 M) and recorded using saline-filled glass electrodes placed in the cortex. PRs were modulated using agonist segesterone and antagonist RU-486. PR expression in the somatosensory cortex was evaluated using mice expressing a cre recombinase under the control of Pgr promoter, stereotaxically injected with adeno-associated virus (AAV) serotype 9 encoding flexed GFP. PR expression in excitatory or inhibitory neurons and distinctions in the cortical layer-specific expression were determined. The effect of chemogenetic silencing of PR-expressing somatosensory cortical neurons on CSD susceptibility was also evaluated using AAV9 expressing cre-driven hM4Di. PRs were expressed in the excitatory neurons of the somatosensory cortex. Their expression was stronger in layer 4-6 cortical neurons than in layer 2/3 neurons. PR activation increased CSD frequency and accelerated their propagation speed. In contrast, PR antagonism or their genetic deletion suppressed CSDs. Chemogenetic silencing of PR-expressing somatosensory cortical neurons also reduced the CSD frequency. These findings demonstrate the critical role of progesterone-PR signaling in regulating CSD and enhance our understanding of female hormonal regulation of migraine pathophysiological mechanisms., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Background: Although several risk factors have been suggested for uterine torsion, the pathogenesis is still unclear. Therefore, the current study aims to investigate the pathogenesis of uterine torsion by assessing the histological, histochemical, and immunohistochemical changes that occur in the placenta obtained from uterine torsion cases. Immunohistochemical changes include investigation of the expression of estrogen receptors (ERs), progesterone receptors (PRs), and the vascular endothelial growth factor (VEGF) in the placental tissue., Methods: Forty intrapartum dairy cows were included in this investigation. The cows were divided into two equal groups. The first group was the uterine torsion (UT) group, while the second group was the normal control group (Ctrl). After caesarian section treatment, placentas were collected from all animals in the study. Histopathological, histochemical, and immunohistochemical examinations were performed. Estrogen receptors, progesterone receptors, and vascular endothelial growth factor expression in the placenta were evaluated., Results: The results revealed numerous trophoblast giant or binucleate cells in the trophoblastic epithelium. Through Masson's trichrome technique, the distribution of collagen fibers as shiny, blue-colored stripes on the fetal mesenchyme was observed. Additionally, the results showed a strong, intense PAS-positive reaction in the cytoplasmic vesicles of most trophoblastic cells due to mucopolysaccharides. The immunohistochemical findings of the UT placenta revealed moderate to weak staining for ERs in contrast to those of the Ctrl placenta, which revealed moderate staining for ERs. In addition, non-statistical differences in the expression of PRs were found between the two tested groups. For VEGF, strong positive immunoreactivity was found in the Ctrl group compared to the UT group, which exhibits a general absence in many trophoblast cells., Conclusion: It can be concluded that significant variation was observed in the placentas obtained from buffaloes suffering from UT compared to those obtained from normal pregnant ones. These significant variations were involved in the decreased expression of ERs and VEGF in the UT group compared to the normal Ctrl one. Investigating the expression of these placental molecules may monitor the changes in the placental tissue and provide insight into the pathogenesis of UT., Competing Interests: Declarations. Ethics approval and consent to participate: The Committee on the Ethics of Animal Experiments of South Valley University, Faculty of Veterinary Medicine, and this of Aswan University, Faculty of Science, approved all the protocols employed. All procedures were followed in compliance with the applicable norms and legislation. The research was done in accordance with the ARRIVE criteria. The animals were used in the study after obtaining informed consent from their owners to use them. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Premature birth (PTB) is the most common cause of perinatal mortality and morbidity. We performed a case-control study to determine whether two selected single-nucleotide polymorphisms (SNPs) of the progesterone receptor gene ( PGR ) (rs4754732 and rs653752) play a role in the modulation of the risk for spontaneous PTB. This study included 400 mothers (199 with premature delivery and 201 with term delivery) and 400 newborns (201 term-born and 199 premature-born) of European descent. Genotyping was performed with an ABI PRISM 7500 SDS using TaqMan SNP genotyping assays. We found no statistically significant difference in the distribution of genotypes and allele frequencies between prematurely born newborns and newborns at term for either investigated SNP. There was no statistically significant difference in the distribution of genotypes and allele frequencies between groups of mothers with extremely early and early PTB compared to the group of mothers with term births. Potential association of the mothers' C allele of rs653752 with lower odds of PTB ( p = 0.03; odds ratio 1.36; 95% confidence interval 1.02-1.81; Chi-square test), and association of the mothers' CC genotype of rs653752 in the recessive inheritance model with lower odds of PTB in general ( p = 0.02; odds ratio 0.54; 95% confidence interval 0.32-0.91; Chi-square test) and with a late PTB ( p = 0.005, odds ratio 0.45, 95% confidence interval 0.23-0.79; Chi-square test), were found. It was also found that the mothers who were carriers of the haplotype T-G combination of rs4754732 and rs653752 were 1.5 times more likely to have PTB, even after correcting the p -value for multiple comparisons ( p = 0.008; odds ratio 1.59; 95% confidence interval 1.13-2.24, Chi-square test). Further research on a larger number of subjects of these and other PGR SNPs will be needed in order to confirm the presented results.

Purpose: We aim to perform radiogenomic profiling of breast cancer tumors using dynamic contrast magnetic resonance imaging (MRI) for the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) genes., Methods: The dataset used in the current study consists of imaging data of 922 biopsy-confirmed invasive breast cancer patients with ER, PR, and HER2 gene mutation status. Breast MR images, including a T1-weighted pre-contrast sequence and three post-contrast sequences, were enrolled for analysis. All images were corrected using N4 bias correction algorithms. Based on all images and tumor masks, a bounding box of 128 × 128 × 68 was chosen to include all tumor regions. All networks were implemented in 3D fashion with input sizes of 128 × 128 × 68, and four images were input to each network for multi-channel analysis. Data were randomly split into train/validation (80%) and test set (20%) with stratification in class (patient-wise), and all metrics were reported in 20% of the untouched test dataset., Results: For ER prediction, SEResNet50 achieved an AUC mean of 0.695 (CI95%: 0.610-0.775), a sensitivity of 0.564, and a specificity of 0.787. For PR prediction, ResNet34 achieved an AUC mean of 0.658 (95% CI: 0.573-0.741), a sensitivity of 0.593, and a specificity of 0.734. For HER2 prediction, SEResNext101 achieved an AUC mean of 0.698 (95% CI: 0.560-0.822), a sensitivity of 0.750, and a specificity of 0.625., Conclusion: The current study demonstrated the feasibility of imaging gene-phenotype decoding in breast tumors using MR images and deep learning algorithms with moderate performance., Competing Interests: Declarations. Conflict of Interest: The authors declare no competing interests., (© 2025. The Author(s).)

Breast cancer (BC) patient-derived xenografts (PDX) are relevant models for precision medicine. However, there are no collections derived from South American BC patients. Since ethnicity significantly impacts clinical outcomes, it is necessary to develop PDX models from different lineages. Our goals were to a) develop BC PDX from our population; b) characterize the expression of estrogen (ER), progesterone (PR), androgen (AR) and glucocorticoid (GR) receptors, basal and luminal cytokeratins, EGFR and HER2; c) identify PDX mutations; d) evaluate the response to treatments selected based on their biological and genetic features, and e) perform BC tissue cultures (BCTC) from PDX tissues and compare in vivo and ex vivo results. Surgical fragments were maintained in a culture medium and inoculated subcutaneously into untreated NSG female mice, or treated with estradiol pellets. Other fragments were fixed in formalin for diagnosis and immunohistochemistry, and a third piece was frozen at -80°C for molecular studies or whole exome-sequencing. Tumors were serially transplanted into NSG mice. Once the PDX was established, in vivo and ex vivo drug responses were evaluated. Eight PDX were established: two ER + [BC-AR685 (PR +) and BC-AR707 (PR-)], one from a triple-negative (TN) recurrence whose primary tumor was ER + (BC-AR485), one HER2 + (BC-AR474) and four TN primary tumors (BC-AR553, BC-AR546, BC-AR631 and BC-AR687). BC-AR685 had higher levels of PR isoform A than isoform B and was sensitive to mifepristone, tamoxifen, and palbociclib. BC-AR707 was inhibited by tamoxifen and testosterone. BC-AR474 was inhibited by trastuzumab and trastuzumab emtansine. BC-AR485 was sensitive to doxorubicin and resistant to paclitaxel in vivo and ex vivo. BC-AR687 carried a PIK3CA (C420R) mutation and was sensitive to alpelisib and mTOR inhibitors. All PDX expressed AR with varying intensities. GR and AR were co-expressed in the ER + tumors and in 3 TN PDX. We report the first PDX originated from South American countries that were genetically and biologically characterized and may be used in precision medicine studies. PDX expressing AR and/or GR are powerful tools to evaluate different endocrine treatment combinations even in TN tumors., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All patients signed a written informed consent to participate in this project. The study was approved by the Hospital´s authorities and from the Enrique Segura IBYME IRB # 021–2017. Animal experiments were approved by the IBYME-IACUC committee (058–2017). Consent for publication: All authors agree with the contents of the manuscript and agree for its publication., (© 2025. The Author(s).)

Background: Saidi sheep are one of the most important farm animals in Upper Egypt, particularly in the Assiut governorate. Since they can provide meat, milk, fiber, and skins from low-quality roughages, sheep are among the most economically valuable animals bred for food in Egypt. Regarding breeding, relatively little is known about the Saidi breed. In mammals, the uterus is a crucial reproductive organ. Therefore, the purpose of this work was to provide further details on the histological, histochemical, and immunohistochemical analyses of superoxide dismutase 2 (SOD2), glutathione reductase (GR), and progesterone receptor alpha (PRA) as well as terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling assay (TUNEL) of the uterus during the follicular phase of estrous cycle in Saidi sheep. Thus, 11 healthy Saidi ewes (38.5 ± 2.03 kg weight) ranging in age from 2 to 5 years were used to examine the histological changes in the uterus., Results: In Saidi sheep, the uterine histological and immunological picture during the follicular phase of the estrous cycle was characterized by epithelial and stromal proliferation and apoptosis. Leucocytic recruitment (lymphocytes, plasma, and mast cells) was also observed. Uterine gland adenogenesis, vascular angiogenesis, oxidative marker expression, and PRA expression in the muscles, stroma, and epithelium were the most noticeable features of the follicular phase., Conclusion: This study provides new evidence of the role of PRA, SOD2, GR, and mast cells in controlling uterine epithelial proliferation and apoptosis in the Saidi sheep during the follicular phase of the estrus cycle. These findings have growing significance in understanding the key mechanisms that characterize successful reproduction and enhancing the fertility and reproductive efficiency in Saidi Sheep., Competing Interests: Declarations. Ethics approval and consent to participate: The experimental protocol was approved by the Local Ethical Committee and by the Institutional Review Board of Molecular Biology Research and studies Institute, Assiut University (22-2023-0028) and was carried out in accordance with relevant guidelines and regulations. This research was done in compliance with the ARRIVE guidelines and regulations ( https://arriveguidelines.org ). All national and institutional guidelines for animal care and use have been followed throughout the study procedures. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Proteasomes degrade intracellular proteins. Different proteasome forms were identified. Proteasome inhibitors are used in cancer therapy, and novel drugs directed to specific proteasome forms are developed. Breast cancer (BC) therapy depends on the subtype of the tumor, determined by the expression level of Ki67, HER-2, estrogen and progesterone receptors. Relationships between the presence of specific proteasome forms and proteins that determine the BC subtype remain unclear. Here, using gene expression data in 19,145 tumor samples from 144 datasets and tissues from 159 patients with different subtypes of BC, we investigated the association between the activity and expression of proteasomes and levels of BC subtype markers., Methods: Bioinformatic analysis of proteasome subunit ( PSMB1-10 ) gene expression in BC was performed. Proteasome heterogeneity in BC cell lines was investigated by qPCR. By Western blotting, proteasome composition was assessed in cells and patient tissue lysates. Proteasome activities were studied using fluorogenic substrates. BC molecular subtypes were determined by immunohistochemistry., Results: BC subtypes demonstrate differing proteasome subunit expression pattern and strong PSMB8-10 co-correlation in tumors. A significant increase in chymotrypsin- and caspase-like proteasome activities in BC compared to adjacent tissues was revealed. The subunit composition of proteasomes in tumor tissues of BC subtypes varied. Regression analysis demonstrated a positive correlation between proteasome activities and the expression of Ki67, estrogen receptors and progesterone receptors., Conclusion: BC subtypes demonstrate differences within the proteasome pool. Correlations between the proteasome activity, hormone receptors and Ki67 indicate possible mutual influence. Obtained results facilitate development of novel drug combinations for BC therapy.

In clinical practice, the use of exogenous progesterone (Pro) is often required in assisted reproduction programs due to reduced levels of the hormone and the risk of miscarriage. Exposure to the hormone reduces anxiety in rodents, but the long-term effects of prenatal exposure in adult offspring are unknown. Therefore, the present study was designed to investigate the effect of prenatal Pro treatment on anxiety- and depression-like behavior and the effect on plasma, hippocampal corticosterone (CORT) and hippocampal progesterone receptor (PR) in young adult male and female rat offspring. The behavioral responses of offspring of both sexes were tested in the open field, and the elevated plus maze tests, and for depressive-like behavior in the sucrose preference test, the forced swimming test and the splash test. CORT levels and PR expression were measured by ELISA. The results indicate that prenatal Pro exposure at low and high doses (10 and 50 mg kg -1 , s.c. during G0-G10) induces anxiogenic and depressive-like effects compared to vehicle-treated controls, which are associated with high plasma and hippocampal CORT levels and upregulated hippocampal PR in male and female adult offspring. Our results demonstrate that prenatal Pro exposure has detrimental effects on the emotional status of male and female adult offspring, which may be associated with long-term changes in hormonal homeostasis., Competing Interests: Declaration of competing interest I declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The objective of the study was to characterize the mRNA expression patterns of specific steroid hormone receptors namely, estrogen receptors (ESRRA-estrogen related receptor alpha and ESRRB-estrogen related receptor beta) and progesterone receptors (PGR) in superovulation-induced bovine follicles during the periovulation and subsequent corpus luteum (CL) formation. The bovine ovaries (n = 5 cow / group), containing preovulatory follicles or early CL, were collected relative to injection of the gonadotropin-releasing hormone (GnRH) at (I) 0 h, (II) 4 h, (III) 10 h, (IV) 20 h, (V) 25 h (preovulatory follicles) and (VI) 60 h (CL, 2-3 days after induced ovulation). In this experiment, we analyzed the steroid receptor mRNA expression and their localization in the follicle and CL tissue. The high mRNA expression of ESRRA, ESRRB, and PGR analyzed in the follicles before ovulation is significantly reduced in the group of follicles during ovulation (25 h after GnRH), rising again significantly after ovulation in newly formed CL, only for ESRRA and PGR (P < 0.05). Immunohistochemically, the nuclei of antral follicles' granulosa cells showed a positive staining for ESRRA, followed by higher activity in the large luteal cells just after ovulation (early CL). In contrast, the lower PGR immunopresence in preovulatory follicles increased in both small and large luteal cell nuclei after follicle ovulation. Our results of steroid receptor mRNA expression in this experimentally induced gonadotropin surge provide insight into the molecular mechanisms of the effects of steroid hormones on follicular-luteal tissue in the period close to the ovulation and subsequent CL formation in the cow., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Uterine leiomyomas (ULs) are the most common benign smooth muscle cell steroid-dependent tumors that occur in women of reproductive age. Progesterone (P4) is a major hormone that promotes the ULs development and growth. P4 action in ULs is mediated mainly by its nuclear progesterone receptors (PGRs), although rapid non-genomic responses have also been observed. Data on the membrane progesterone receptors (mPRs) regulated signaling pathways in ULs in the available literature is still very limited. One of the essential characteristics of ULs is the excessive production of extracellular matrix (ECM). P4 has been shown to stimulate ECM production and collagen synthesis in ULs. Recent research demonstrated that, despite their benign nature, ULs may present with abnormal vasculature. P4 has been shown to regulate angiogenesis in ULs through the upregulation of vascular endothelial growth factor (VEGF) and by controlling the secretion of permeability factors. This review summarizes the key findings regarding the role of PGRs and mPRs in ULs, especially highlighting the potential ECM and angiogenesis modulation by P4. An increased understanding of this mechanistic role of nuclear and specifically mPRs in the biology of P4-modulated ECM and angiogenesis in the growth of ULs could turn out to be fundamental for developing effective targeted therapies for ULs., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Women develop chronic pain during their reproductive years more often than men, and estrogen and progesterone regulate this susceptibility. We tested whether brain progesterone receptor (PR) signaling regulates pain susceptibility. During the estrous cycle, animals were more sensitive to mechanical stimulus during the estrus stage than in the diestrus stage, suggesting a role for reproductive hormones, estrogen, and progesterone. Progesterone treatment of ovariectomized and estrogen-primed mice caused a delayed reduction in the mechanical threshold. Segesterone, a specific agonist of PRs replicated this effect, whereas, the segesterone-induced reduction in mechanical threshold was blocked in the mice lacking PRs in the nervous system. Segesterone treatment also did not alter mechanical threshold in adult male and juvenile female mice. PR activation increased the cold sensitivity but did not affect the heat and light sensitivity. We evaluated whether PR activation altered experimental migraine. Segesterone and nitroglycerin when administered sequentially, reduced the pain threshold but not when given separately. PRs were expressed in several components of the migraine ascending pain pathway, and their deletion blocked the painful effects of nitroglycerin. PR activation also increased the number of active neurons in the components of the migraine ascending pain pathway. These studies have uncovered a pain-regulating function of PRs. Targeting PRs may provide a novel therapeutic avenue to treat chronic pain and migraine in women. PERSPECTIVE: This article provides evidence for the role of progesterone receptors in regulating pain sensitivity and migraine susceptibility in females. Progesterone receptors may be a therapeutic target to treat chronic pain conditions more prevalent in women than men., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Currently, chronic salpingo-oophoritis (CS) is still an urgent problem in the statistics of diseases of the female genital organs. In 35% of women, its course leads to disorder of the fallopian tubes patency and infertility. An additional indirect mechanism of infertility can be the morpho-functional failure of the endometrium., Objective: To establish the morphofunctional characteristics and level of endometrial receptivity in patients of reproductive age with CS before and after surgery., Material and Methods: The study included 55 patients with unilateral or bilateral tubectomy - 1st group, 42 with preserved fallopian tubes - 2nd group. The comparison group included 30 somatically healthy fertile women. Before and 6-12 months after laparoscopic cystectomy aspiration biopsy of endometrium was performed in the middle stage of secretory phase. Firstly, the phase and stage of menstrual cycle, the percentage and degree of maturity of pinopodes were determined. Secondly, the immunohistochemical study was conducted with the assessment of the expression level of estrogen (ER) and progesterone (PR) receptors in glands and stroma of endometrium., Results: In the 1st group before surgery, we determined a decrease in the number of mature pinopodia. A decrease in ER in the endometrial stroma was detected; PR levels correlated with the comparison group. In 2nd group all parameters were associated with healthy women. In the postoperative period, pinopodia were not visualized in the majority of patients in 1st group. ER levels remained reduced in stroma, similar results were found for PR. In 2nd group an insignificant decrease in the number of mature pinopodia on the apical surface of the endometrium, a reduction of ER in the glands and stroma of the uterine mucosa were recorded; PR corresponded to the values founded before surgical treatment., Conclusion: The presence of CS and subsequent removal of the fallopian tubes is accompanied by indirect damage of the morpho-functional state and receptivity of the endometrium.

Purpose: Neoadjuvant chemotherapy (NACT) can change invasive breast carcinomas (IBC) and influence the patients' overall survival time (OS). We aimed to identify IBC changes after NACT and their association with OS., Materials and Methods: IBC data in pre- and post-NACT samples of 86 patients were evaluated and associated with OS., Results: Post-NACT tumors changed nuclear pleomorphism score (p=0.025); mitotic count (p=0.002); % of tumor-infiltrating inflammatory cells (p=0.016); presence of in situ carcinoma (p=0.001) and lymphovascular invasion (LVI; p=0.002); expression of estrogen (p=0.003), progesterone receptors (PR; p=0.019), and Ki67 (p=0.003). Immunohistochemical (IHC) profile changed in 26 tumors (30.2%, p=0.050). Higher risk of death was significatively associated with initial tumor histological grade III (hazard ratio [HR], 2.94), high nuclear pleomorphism (HR, 2.53), high Ki67 index (HR, 2.47), post-NACT presence of LVI (HR, 1.90), luminal B-like profile (HR, 2.58), pre- (HR, 2.26) and post-NACT intermediate mitotic count (HR, 2.12), pre- (HR, 4.45) and post-NACT triple-negative IHC profile (HR, 4.52). On the other hand, lower risk of death was significative associated with pre- (HR, 0.35) and post-NACT (HR, 0.39) estrogen receptor-positive, and pre- (HR, 0.37) and post-NACT (HR, 0.57) PR-positive. Changes in IHC profile were associated with longer OS (p=0.050). In multivariate analysis, pre-NACT grade III tumors and pre-NACT and post-NACT triple negative IHC profile proved to be independent factors for shorter OS., Conclusion: NACT can change tumor characteristics and biomarkers and impact on OS; therefore, they should be reassessed on residual samples to improve therapeutic decisions.

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.

Objectives: Meningiomas, a common neoplasm of the central nervous system, is a widely studied meningeal tumor. According to the World Health Organization (WHO) 2021 classification of meningiomas, there are 15 subtypes that have been grouped into grades 1, 2, and 3. The WHO grade 1 meningiomas are generally grouped as benign while the WHO grades 2 and 3 tumors are grouped as malignant. Progesterone receptors and P63 are common immunohistochemical markers that have proven useful in the diagnosis, grading, and prognostication of many neoplasms such as breast carcinoma, prostate carcinoma, and gastrointestinal tumors in histopathology practice. The application of these immunohistochemical markers to the grading of meningiomas has been reported and their usefulness documented in reports from Africa, Europe, North America, South America, and Asia. This study, therefore, seeks to determine if these findings are applicable to the meningiomas seen in an African population., Materials and Methods: A 10-year review of results and histologically diagnosed cases of meningiomas received in the Department of Morbid Anatomy, University of Nigeria, Enugu. Immunostaining for progesterone receptors (PgRs) and P63 were done and results compared with histologic grades., Results: The three WHO grades of meningioma were assessed in this study. M: F ratio was 1:1.4 and peak age was 41-50 years age range (SD ± 16.54). The majority of the cases were WHO grade 1 (86.1%) while the WHO grades 2 and 3 tumors were 8% and 5.9%, respectively. The fibrous variant was the most common subtype (27.1%). There was no correlation between progesterone receptor and P63 immunopositivity to the WHO grades of meningioma ( P = 0.112 and P = 0.138, respectively)., Conclusion: Our study showed that progesterone receptors and P63 immunopositivity did not correlate with the WHO grades of meningiomas. This may be due to the predominant variant of meningioma seen in this study. These findings indicate that PgR antagonist may not be an effective alternative for treatment in patients with inoperable meningiomas. Furthermore, P63 immunopositivity may not be a sufficient grading tool for managing meningiomas in our population., Competing Interests: There are no conflicts of interest., (© 2024 Published by Scientific Scholar on behalf of Journal of Neurosciences in Rural Practice.)

This study investigated the effects of progesterone receptors A (PRA) and B (PRB) on proliferation, migration, invasion, anchorage-independent growth (AIG), and apoptosis of FE25 cells, a precancer p53- and retinoblastoma-defective human fallopian tube epithelial cell line. We observed that the transfection of PRA (FE25-PRA) or PRB (FE25-PRB) into FE25 cells significantly increased the expression of PRA or PRB at both RNA and protein levels without affecting cell morphology. The FE25-PRA cells exhibited slower proliferation, whereas FE25-PRB showed faster cell proliferation than the control cells. In contrast, the FE25-PRA cells showed the highest migration and invasion abilities, whereas the FE25-PRB cells showed the lowest migration and invasion abilities. After treatment with progesterone, all cell types showed decreased AIG levels, increased apoptotic rates in Terminal deoxynucleotidyl transferase (TdT) dUTP nick end labeling assay (TUNEL) staining, and increased levels of apoptotic proteins ascertained based on cleaved caspase-3 levels. The half-maximal inhibitory concentration of carboplatin increased in FE25-PRB cells, but that of paclitaxel remained unchanged. Overall, this study suggests that PRA and PRB have distinct roles in regulating the behavior of FE25 cells, and targeting these receptors could be a potential therapeutic strategy for ovarian cancer treatment. If PRA or PRB overexpression is observed in high-grade serous carcinoma, progesterone could be considered as an adjuvant therapy for these specific cancer patients. However, further research is needed to confirm these findings and investigate the mechanisms underlying these effects.

Background: Giant cell tumors (GTC) of bone are benign, locally aggressive tumors generally occurring in young people with a female predominance during reproductive age. Considering their worsening during pregnancy it has been suggested that pregnancy can accelerate GCT progression or favor recurrence but correlation between tumor growth and pregnancy has not yet been clarified. Aim of this study was to clarify clinical characteristics, timing and type of treatment through a literature review on GTCs occurring during pregnancy., Patients and Methods: An electronic search was performed in December 2020 in PubMed, Scopus, Embase, Medline, Cochrane Register using the keywords "giant cell tumor" AND "pregnancy" looking for papers reporting cases of giant cell tumors of the bone onset or recurred during pregnancy. The electronic search identified 212 papers; sixteen studies were selected, for a total of 32 cases., Results: The diagnosis was made during pregnancy in 24 cases and after the partum in 8 cases. 27 cases were new diagnoses while 5 cases were recurrences. Pulmonary metastases were reported in 3 patients. The treatment was performed during the pregnancy in 7 out of 32 cases; in the remaining 27 cases treatment was performed after delivery. The hormone receptor status was reported in 14 patients. Data regarding follow-up was reported for 26 out of 32 patients; three patients had local recurrences that were treated with wide resection and amputation in 2 and 1 case, respectively; at the last follow-up all patients were apparently without any evidence of disease except for three patients who had stable lung metastases., Discussion: In case of GCT during pregnancy, a multidisciplinary approach is necessary to offer the patients the best treatment in terms of mother and child's health. A correct diagnosis is necessary and not confusing tumor symptoms with ones of pregnancy is mandatory in order not to delay the diagnosis and let the tumor progress. Actually, even though pregnancy would seem to promote GCT growth and aggressiveness, the relationship is not clear. More studies are necessary to clarify this interesting aspect., Level of Evidence: IV, systematic review., (Copyright © 2022. Published by Elsevier Masson SAS.)

Background: The risk of breast cancer progression is one of the most difficult factors to predict as it is studied in different populations, patient groups, or time frames, resulting in conflicting estimates of incidence rates reported in the literature. The purpose of this study is to identify predictive factors for breast cancer recurrences in a sample of the Middle Eastern population., Methodology: A cohort retrospective study included all eligible breast cancer patients at the National Guard Health Affairs (NGHA) Hospital in Jeddah, Western region, from 2015 to 2021. Our primary outcome was the progression status of the patients; we adjusted for demographic, clinical, and molecule characteristics of the population. From 2015 to 2021, there were 319 patients diagnosed with breast cancer. Multiple logistic regression analysis was used to estimate predictors of breast cancer progression., Results: One of five breast cancer patients had breast cancer progression (20.83%), while 66.15% of the progression patients were between the ages of 41-65. In multivariate analysis, age, progesterone receptor (PR), family history, and tumor size were significant predictors of breast cancer progression. The age group of 20-40 years was a protective predictor of breast cancer progression, patients in the young age group were less likely to be diagnosed with progression (OR = 0.35; CI = 0.15, 0.81). While negative PRs and tumor size greater than 2 cm were significant predictor factors of breast cancer progression (OR = 2.07; CI = 1.09, 3.91, OR = 2.02; CI = 1.9, 3.78)., Conclusion: Although the effect of young age as a protective factor for the progression of breast cancer remains controversial, our study revealed that patients between 41 and 60 years of age had a higher rate of progression. Future larger prospective studies are needed to delineate the role of age and PR hormone receptors in determining the best treatment options for women with breast cancer in the Saudi population., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Purpose: Our previous study on the idiopathic progressive subglottic stenosis (IPSS) highlighted a possible hormonal mechanism, with over-expression of estrogen receptors alpha (ER-α) and progesterone receptors (PR). We tested whether such over-expression take place in non-idiopathic subglottic stenosis (NISS) as well., Methods: 37 specimens of iatrogenic NISS were analyzed (20 females; mean age, 59 ± 12 years; range 41-85). Immunoreactivity of ER-α and PR was calculated as the product of intensity (1 = weak, 2 = moderate, 3 = strong) and positive cells percentage (1 to 4, for < 10%, 10-50%, 50-80%, and > 80%). This score was calculated on the stenotic tissue (ST), and stenosis margins (SM)., Results: The expression of PR was significantly higher in ST of IPSS compared with female and male NISS patients (8.7 ± 3.1 vs. 4.9 ± 3.2, p < 0.001 for IPSS vs. female and 8.7 ± 3.1 vs. 2.1 ± 2.7, p < 0.01 for IPSS vs. male NISS patients). Contrarily, ER-α showed gender differences, as both IPSS and female NISS patients had similar, yet higher ER-α expression compared with male NISS patients (7.0 ± 4.2 vs. 6.5 ± 2.5, p = NS for IPSS vs. female and 7.0 ± 4.2 vs. 3.4 ± 2.0, p < 0.02 for IPSS vs. male NISS patients). There was no difference in fibroblast receptor expression between ST and SM. However, ER-α and PR expression was significantly lower in marginal mucous glands when compared with ST., Conclusions: The IPSS pathogenesis appears to be driven by hormonal mechanisms, in particular, by over-expression of PR. Marginal cells display a reduced hormone receptor density. This finding could be interpreted as a compensatory mechanism. These findings could open up for targeted IPSS treatment., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Intrauterine growth restriction (IUGR) is manifested by lower maternal progesterone levels, smaller placental size, and decreased placental vascularity indicated by lower expression of vascular endothelial growth factor (VEGF). Studies showed that progesterone increases angiogenesis and induces VEGF expression in different tissues. Therefore, the aim of the present study is to evaluate the effect of progesterone on placental vascular bed and VEGF expression and the modulation of nuclear and membranous progesterone receptors (PR) in dexamethasone-induced rat IUGR model., Methods: Pregnant Sprague-Dawley rats were allocated into four groups and given intraperitoneal injections of either saline, dexamethasone, dexamethasone, and progesterone or progesterone. Injections started on gestation day (DG) 15 and lasted until the days of euthanization (19 and 21 DG). Enzyme-linked immunosorbent assay was used to evaluate plasma progesterone levels. Real-time PCR and western blotting were used to evaluate gene and protein expressions of VEGF, and PR in labyrinth and basal placental zones. Immunohistochemistry was used to locate VEGF and different PRs in placental cells. Immunofluorescence was used to monitor the expression of blood vessel marker (αSMA)., Results: Dexamethasone decreased the vascular bed fraction and the expression of VEGF in both placental zones. Progesterone co-treatment with dexamethasone prevented this reduction. Nuclear and membrane PRs showed tissue-specific expression in different placental zones and responded differently to both dexamethasone and progesterone., Conclusions: Progesterone treatment improves the outcomes in IUGR pregnancy. Progesterone alleviated DEX-induced IUGR probably by promoting placental VEGF and angiogenesis., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

In patients with high serum E 2 embryo transfer is often postponed, as high E 2 levels adversely affect embryo transfer outcome. We aimed to determine if stratified serum oestradiol (E 2 ) and progesterone (P 4 ) levels differentially affect endometrial histology and endometrial oestrogen and progesterone receptor protein levels. Endometrial biopsies were collected from oocyte donors. Samples were divided based on peak serum E 2 levels into three groups: (i) low-E 2 ( n  = 33) E 2 ≤2999pg/mL; (ii) mid-E 2 ( n  = 40) E 2 3000-4999 pg/mL; and (iii) high-E 2 ( n  = 15) E 2 ≥5000 pg/mL. Oestrogen receptor alpha (ERα) and progesterone receptors A and B (PR) protein levels in endometrial stroma (S), glandular (GE) and luminal (LE) epithelia were assessed by immunohistochemistry. Samples in high-E 2 group demonstrated strongest association with accelerated endometrial maturation (2 (1-2); 2 (1-3); and 3 (2.8-3) median days of advancement of endometrial maturation respectively in low, mid, high-E 2 groups, p  = 0.046). There were significant differences in ERα and PR immunoexpression in S, GE and LE among the groups ( p  < 0.05). Higher E 2 levels were associated with decreased ERα expression ( p  < 0.017) in GE and LE, and increased PR expression in S and GE ( p  < 0.011 and p  < 0.0001, respectively). Higher serum E 2 levels were associated with impaired endometrial steroid hormone receptor expression, higher serum P 4 and more advancement of endometrial maturation.

Placentation is one of the most important determinants for a successful pregnancy, and this is dependent on the process of trophoblast migration and invasion. Progesterone receptors (PGR) are critical effectors of progesterone (P4) signaling that is required for trophoblast migration and invasion conducive to a successful gestation. In immune complicated pregnancies, evidence has shown that abnormal placentation occurs because of aberrant expression of PGR. Therapeutic intervention with tacrolimus (FK506) was able to restore PGR expression and improve pregnancy outcomes in immune-complicated gestations; however, the exact mode of action of tacrolimus in assisting placentation is not clear. Here, we attempt to uncover the mode of action of tacrolimus by examining its effects on trophoblast invasion and migration in the human-derived extravillous trophoblast (EVT) cell line, the HTR-8/SVneo cells. Using a variety of functional assays, we demonstrated that low-dose tacrolimus (10 ng/mL) was sufficient to significantly (p < 0.001) stimulate the migration and invasion of the HTR-8/SVneo cells, inducing their cytosolic/nuclear progesterone receptor expression and activation, and modulating their Nitric Oxide (NO) production. Moreover, tacrolimus abrogated the suppressive effect of the NOS inhibitor Nω- Nitro-L-Arginine Methyl Ester (L-NAME) on these vital processes critically involved in the establishment of human pregnancy. Collectively, our data suggest an immune-independent mode of action of tacrolimus in positively influencing placentation in complicated gestations, at least in part, through promoting the migration and invasion of the first trimester extravillous trophoblast cells by modulating their NO production and activating their cytosolic/nuclear progesterone-receptors. To our knowledge, this is the first report to show that the mode of action of tacrolimus as a monotherapy for implantation failure is plausibly PGR-dependent.

Adenomyosis is a common gynaecological disease associated with the presence of endometrial lesions in the uterine myometrium. Estrogens have been proven to be the crucial hormones driving the growth of adenomyosis. Little is known about the distinct mechanisms of progesterone action in adenomyosis. Hence, in this study, we decided to characterize the expression of all nuclear and membrane estrogen and progesterone receptors. Additionally, as a functional investigation, we monitored prolactin production and cell proliferation after estradiol and progesterone treatments. We confirmed the presence of all nuclear and membrane estrogen and progesterone receptors in adenomyotic lesions at gene and protein levels. The expression of membrane progesterone receptors α and β (mPRα, mPRβ) as well as estrogen receptor β (ERβ) was upregulated in adenomyosis compared to normal myometrium. Estradiol significantly increased adenomyotic cell proliferation. Progesterone and cAMP upregulated prolactin secretion in adenomyosis in the same pattern as in the normal endometrium. In the present study, we showed the functional link between estradiol action and adenomyotic cell proliferation, as well as progesterone and prolactin production. Our findings provide novel insights into the sex steroid receptor expression pattern and potential regulated pathways in adenomyosis, suggesting that all receptors play an important role in adenomyosis pathophysiology.

The aim of the study was to determine the metabolic characteristics of saliva depending on the molecular biological subtype of breast cancer, as well as depending on the expression levels of HER2, estrogen receptors (ER), and progesterone receptors (PR). The study included 487 patients with morphologically verified breast cancer and 298 volunteers without breast pathologies. Saliva samples were obtained from all patients strictly before the start of treatment and the values of 42 biochemical indicators were determined. It has been established that the saliva of healthy volunteers and patients with various molecular biological subtypes of breast cancer differs in 12 biochemical indicators: concentrations of protein, urea, nitric oxide, malondialdehyde, total amino acid content, and activity of lactate dehydrogenase, alkaline phosphatase, gamma-glutamyltransferase, catalase, amylase, superoxide dismutase, and peroxidases. The saliva composition of patients with basal-like breast cancer differs from other subtypes in terms of the maximum number of indicators. Changes in biochemical indicators indicated an increase in the processes of lipid peroxidation and endogenous intoxication and a weakening of antioxidant protection, which correlates with the severity of the disease and the least favorable prognosis for this subtype of breast cancer. An analysis was made of the individual contribution of the expression level of HER2, estrogen, and progesterone receptors to changes in the biochemical composition of saliva. The HER2 (-)/HER2 (+) group, which should be considered as a single group, as well as ER-positive breast cancer, differ statistically significantly from the control group. For ER/PR-positive breast cancer, a more favorable ratio of saliva biochemical indicators was also noted compared to ER/PR-negative breast cancer.

Background: The luminal subtype accounts for ~70% of newly diagnosed breast cancer patients. Although it has a better prognosis, approximately 30% of them develop a late relapse. Identifying those patients is of interest to improve treatment decisions., Methods: A retrospective observational, single-centre study based on data from medical records of 572 non-metastatic (I-III) invasive ductal breast carcinoma patients, 448 with luminal tumours and 124 with triple-negative tumours. Kaplan-Meier, Cox regression and time-dependent Cox regression were carried out to obtain the prognosis value of risk factors., Results: During a median observation of 5.5 years, 105 distant metastasis events and 105 all-cause deaths were observed. In addition to known clinicopathological factors (i.e., age, tumour size and lymph node metastasis), the high semi-quantitative expression of both hormone receptors was associated with distant metastasis-free survival (DMFS) (adjusted hazard ratio (HaR): 0.524 (0.316-0.867), p = 0.012) and overall survival (OS) (adjusted HaR: 0.486 (0.286-0.827), p = 0.008). The stratified analysis made it possible to identify risk modification factors. Subsequent stratification by histological grade, Ki-67 and semi-quantitative PR expression or, mainly, the composite semi-quantitative expression of hormone receptors (cHR) enabled the identification of luminal breast cancer patients of adjuvant schema at higher risk for metastasis and death. However, initial analyses including patients of neoadjuvant therapy pointed to a path of subsequent stratification by cHR and histological grade, also enabling grouping of luminal breast cancer patients with similar prognosis for DMFS (cHR ≤ 4+ G2 or G3 versus triple-negative, adjusted HaR: 0.703 (0.415-1.189), p = 0.189) and OS (cHR ≤4+ G2 or G3 versus triple-negative, adjusted HaR: 0.662 (0.403-1.088), p = 0.104)., Conclusion: The semi-quantitative expression of both cHR, Ki-67 proliferation index and histological grade can identify luminal breast cancer patients at greater risk of developing metastasis and death when combined in a hierarchical fashion, and could be useful for a better prognosis stratification in services from low- and middle-income countries., Competing Interests: The authors declared no conflicts of interest., (© the authors; licensee ecancermedicalscience.)

Breast cancer treatment is tailored to molecular subtypes, which are classified by cell type and by presence of estrogen and progesterone receptors, HER2 overexpression and Ki-67 proliferation index. In routine pathological practice, these markers are detected in tumor tissue using immunohistochemistry, which requires four immunohistochemical antibodies for each patient. We developed a new tissue microarray procedure using a punch device with a 6 mm core diameter. The presence of estrogen and progesterone receptors, HER2 expression and the Ki-67 proliferation index of tumor tissues of 50 breast carcinoma patients had been determined using the conventional approach. We created three tissue microarray blocks, each containing samples from 14 main tumor tissues. One tissue microarray block was created with samples taken from eight main tumor tissues. Sections were cut from the four blocks and subjected to immunohistochemical staining; the original samples and the microarrays then were compared. We found significant agreement between estrogen receptor, progesterone receptor and HER-2 expression as well as Ki-67 proliferation index status of the original tumor tissues and the tissue microarray. Our tissue microarray technique using a single 6 mm core is a reliable and cost-effective method for determining estrogen and progesterone receptors, HER-2 status and Ki-67 proliferation index levels in patients with early breast carcinoma.

Aim: To evaluate the roles of four selected genetic variations in fetal and maternal progesterone receptor gene (PGR) and to identify women who may have higher or lower odds for spontaneous premature birth compared to the general population., Methods: A preliminary case-control study with two groups of pregnant women (with term and premature delivery, 218 in total) and two groups of newborns (term and preterm, 218 in total) was performed. Four single nucleotide polymorphisms (SNPs) of the progesterone receptor gene (rs1042838, rs1042839, rs10895068, and rs1942836) were genotyped., Results: There was statistically significant difference between cases and controls in the distribution of newborns' allele frequency of minor C allele of the PGR SNP rs1942836 (p = 0.03, Fishers' exact test) in favor of premature birth. A statistically significant difference between the frequency of the mothers' minor T allele of rs1042838 (p = 0.005; chi-squared test) and the mothers' minor T allele of rs1042839 (p = 0.005; chi-squared test) in favor of extremely premature birth has been found. There was a statistically significant difference between the frequency of the newborns' minor C allele of rs1942836 (p = 0.03; chi-squared test) and newborns' heterozygotes CT genotype of rs1942836 (p = 0.03; Fishers' exact test) when comparing the group of term births and the group of early premature birth., Conclusion: Our study suggests that patients with selected genetic variants of the progesterone receptor gene could have greater odds for premature birth compared to term birth. Replication studies with a larger population and different ethnicity are needed in order to confirm these findings., (© 2022 Japan Society of Obstetrics and Gynecology.)

Background: Clinical characteristics including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) are important biomarkers in the treatment of breast cancer, but how genomic mutations affect their status is rarely studied. This study aimed at finding genomic mutations associated with these clinical characteristics., Methods: There were 160 patients with breast cancer enrolled in this study. Samples from those patients were used for next-generation sequencing, targeting a panel of 624 pan-cancer genes. Short nucleotide mutations, copy number variations, and gene fusions were identified for each sample. Fisher's exact test compared each pair of genes. A similarity score was constructed with the resulting P -values. Genes were clustered with the similarity scores. The identified gene clusters were compared to the status of clinical characteristics including ER, PR, HER2, and a family history of cancer (FH) in terms of the mutations in patients., Results: Gene-by-gene analysis found that CCND1 mutations were positively correlated with ER status while ERBB2 and CDK12 mutations were positively correlated with HER2 status. Mutation-based clustering identified four gene clusters. Gene cluster 1 ( ADGRA2 , ZNF703 , FGFR1 , KAT6A , and POLB ) was significantly associated with PR status; gene cluster 2 ( COL1A1 , AXIN2 , ZNF217 , GNAS , and BRIP1 ) and gene cluster 3 ( FGF3 , FGF4 , FGF19 , and CCND1 ) were significantly associated with ER status; gene cluster 2 was also negatively associated with a family history of cancer; and gene cluster 4 was significantly negatively associated with age. Patients were classified into four corresponding groups. Patient groups 1, 2, 3, and 4 had 24.1%, 36.5%, 38.7%, and 41.3% of patients with an FDA-recognized biomarker predictive of response to an FDA-approved drug, respectively., Conclusion: This study identified genomic mutations positively associated with ER and PR status. These findings not only revealed candidate genes in ER and PR status maintenance but also provided potential treatment targets for patients with endocrine therapy resistance., Competing Interests: YZ and LL are employees of Shanghai OrigiMed Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hao, Wang, Lu, Zhao, Li, Zhang, Meng, Wang, Tong, Zeng and Lu.)

Breast cancer (BC) has one of the highest incidences and mortality worldwide. Single nucleotide polymorphisms (SNPs) in TOX3 rs3803662 and MMP7 rs1943779 have been associated with susceptibility to BC. In this case-control study, we evaluated the association of rs3803662 ( TOX3 )/rs1943779 ( MMP7 ) SNPs with clinical features, immunohistochemical reactivity, and risk association with BC in women from northeastern Mexico. We compared 212 BC cases and 212 controls. DNA was isolated from peripheral blood to perform the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. We calculated genotype frequencies, odds ratios, and 95% confidence intervals. We found that CT (Cytocine-Thymine) and TT (Thymine -Thymine) genotypes, and T alleles of TOX3 rs3803662, were associated with BC risk ( p = 0.034, p = 0.011, respectively). SNP TOX3 rs3803662 was associated with positive progesterone receptors (PR) and triple-negative BC (TNBC) but not with estrogen receptor (ER) or HER2 reactivity. CT and TT genotypes ( p = 0.006) and T alleles ( p = 0.002) of SNP MMP7 rs1943779 were associated with risk of BC. We found that T alleles of TOX3 rs3803662 and MMP7 rs1943779 SNPs are associated with BC risk. These findings contribute to personalized medicine in Mexican women.

Purpose: The long-term use of cyproterone acetate (CPA) is associated with an increased risk of developing intracranial meningiomas. CPA discontinuation most often induces a stabilization or regression of the tumor. The underlying biological mechanisms as well as the reasons why some meningiomas still grow after CPA discontinuation remain unknown. We reported a series of patients presenting CPA-induced meningiomatosis with opposed tumor evolutions following CPA discontinuation, highlighting the underlying histological and genetic features., Methods: Patients presenting several meningiomas with opposite tumor evolution (coexistence of growing and shrinking tumors) following CPA discontinuation were identified. Clinical and radiological data were reviewed. A retrospective volumetric analysis of the meningiomas was performed. All the growing meningiomas were operated. Each operated tumor was characterized by histological and genetic analyses., Results: Four women with multiple meningiomas and opposite tumor volume evolutions after CPA discontinuation were identified. Histopathological analysis characterized the convexity and tentorial tumors which continued to grow after CPA discontinuation as fibroblastic meningiomas. The decreasing skull base tumor was characterized as a fibroblastic meningioma with increased fibrosis and a widespread collagen formation. The two growing skull base meningiomas were identified as meningothelial and transitional meningiomas. The molecular characterization found two NF2 mutations among the growing meningiomas and a PIK3CA mutation in the skull base tumor which decreased., Conclusion: To our knowledge, this is the first report describing an atypical tumor evolution of CPA-associated meningiomas after CPA discontinuation. The underlying biological mechanisms explaining this observation and especially the close relationship between mutational landscapes and embryologic origins of the meninges in CPA-related meningiomas as well as their clonal origin require further research., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

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.

Cancer and the fetal-placental semi-allograft share certain characteristics, e.g., rapid proliferation, the capacity to invade normal tissue, and, related to the presence of antigens foreign to the host, the need to evade immune surveillance. Many present-day methods to treat cancer use drugs that can block a key molecule that is important for one or more of these characteristics and thus reduce side effects. The ideal molecule would be one that is essential for both the survival of the fetus and malignant tumor, but not needed for normal cells. There is a potential suitable candidate, the progesterone induced blocking factor (PIBF). The parent 90 kilodalton (kDa) form seems to be required for cell-cycle regulation, required by both the fetal-placental unit and malignant tumors. The parent form may be converted to splice variants that help both the fetus and tumors escape immune surveillance, especially in the fetal and tumor microenvironment. Evidence suggests that membrane progesterone receptors are involved in PIBF production, and indeed there has been anecdotal evidence that progesterone receptor antagonists, e.g., mifepristone, can significantly improve longevity and quality of life, with few side effects.

Objective: A disintegrin and metalloproteinase with thrombospondin motifs 4 ( ADAMTS-4 ) and ADAMTS-5 normal expression levels are essential for ovulation and subsequent fertilization. The objective of the present study was to assess expression pattern of these genes in cumulus cells (CCs) taken from patients with polycystic ovary syndrome (PCOS) and to investigate any possible relationship with the oocyte quality., Methods: ADAMTS-4 and -5 expression levels within CCs containing oocytes at the metaphase II (MII) and germinal vesicle (GV) stages, taken from 35 patients with PCOS and 35 women with normal ovarian function, were investigated using RT-qPCR. Moreover, possible correlations between ADAMTS-4 , ADAMTS-5 , and progesterone receptors (PRs) expression as well as oocyte quality were evaluated., Results: ADAMTS-4 and -5 expression levels were dramatically diminished in the CCs of the PCOS patients when compared to the controls. ADAMTS-4 and -5 expression levels were correlated with each other and with the oocyte quality. Furthermore, lower expression levels of ADAMTS-4 and -5 in the PCOS patients were strongly correlated with the diminished PRs expression levels., Conclusion: Downregulation of ADAMTS-4 and -5 in the human CCs of the PCOS patients correlated with the decline in the PRs expression, and impaired oocyte quality may cause lower oocyte recovery, maturation, and fertilization rate.

Our previous studies showed that intranasal delivery of progesterone offers a good bioavailability and neuroprotective efficacy after experimental stroke. We have also demonstrated that progesterone receptors (PR) are essential for cerebroprotection by endogenous progesterone and by progesterone treatment. The identification of PR as a potential drug target for stroke therapy opens new therapeutic indications for selective synthetic progestins. Nestorone® (16-methylene-17α-acetoxy-19-nor-pregn-4-ene-3, 20-dione, also known as segesterone acetate) is a 19-norprogesterone derivative that more potently targets PR than progesterone. The objective of this study was to evaluate the cerebroprotective efficiency of intranasal administration of Nestorone after middle cerebral occlusion (MCAO) in mice. We show here that intranasal administration is a very efficient route to achieve a preferential delivery of Nestorone to the brain and confers a slow elimination and a sustained bioavailability. Furthermore, intranasal administration of Nestorone (at 0.08 mg/kg) improved the functional outcomes and decreased the ischemic lesion in male but not in female mice at 48 h post MCAO. Use of PR NesCre mice, selectively lacking expression of PR in neural cells, and their control PR loxP/loxP littermates showed that the cerebroprotective effects of Nestorone in male mice depended on neural PR as they were not observed in PR NesCre mice. Our findings show that intranasal delivery of Nestorone may be an efficient strategy to promote recovery after stroke in males and confirm the key role of PR in cerebroprotection. Furthermore, they point to sex differences in the response to Nestorone treatment and emphasize the necessity to include males and females in experimental studies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Endometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis. Graphical Abstract., (© 2021. The Author(s).)

Background: Non-Hispanic black women (NHB) are diagnosed with triple negative breast cancer (TNBC) more often than other ethnic or racial groups in the United States (US). This study describes regional differences in TNBC incidence among NHB women in the US from 2011 to 2015., Methods: We analyzed data from the United States Cancer Statistics (USCS) that includes incidence data from the Centers for Disease Control and Prevention's National Program of Cancer Registries (NPCR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) programs., Results: Compared to the incidence rate for NHB women in the South, rates were significantly lower in the Northeast (22.6 per 100,000), higher in the Midwest (25.5 per 100,000) and similar in the West. These regional differences might be explained by genetic admixture among people with different geographic ancestral origins., Conclusions: Results from this study highlight the need to extend etiological research and evidence-based cancer prevention and control efforts to women at high risk of this disease in order to decrease cancer disparities., (Published by Elsevier Inc.)

Surgical management of node positive breast cancer requires axillary dissection. Interpectoral nodes (IPNs) or Rotter's nodes removal is controversial as there is hardly any tissue in this region. IPNs involvement is rarely seen among breast cancer patients. Developing an effective protocol for surgical management of axilla is necessary for uniformity, to reduce the risk of regional recurrence and to avoid the morbidity of interpectoral lymphatic tissue clearance. This study aimed to evaluate the detection of lymph nodes in Rotter's region and positive metastasis rate of IPNs in patients with node positive breast cancer for analyzing the prognostic and therapeutic value of IPN excision during axillary clearance. Fifty-six patients undergoing axillary clearance, aged ≥ 18 years, were studied. Patients with recurrence or those who underwent neoadjuvant chemotherapy were excluded. Baseline investigations were done pre-operatively along with core needle biopsy, estrogen receptor (ER), progesterone receptor (PR), and Ki-67 status. Association between IPN status, age, and clinicopathological parameters were assessed by Kruskal Wallis and Chi-square test using R v 3.6.0. P value of ≤ 0.05 was considered statistically significant. Majority of patients had upper outer quadrant tumor location (22/56), and the most common histopathological type was invasive ductal carcinoma (46/56). IPNs were identified in 35.71% (20/56) of 56 patients, with metastasis prevalence of 27.27% (9/33 node positive patients). Patients having IPN metastasis had larger tumor size, later TNM classification, lower ER/PR, and higher Ki-67 positivity. Dissection of IPNs can be practiced routinely during axillary clearance and should be subjected to histopathological examination separately., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© Indian Association of Surgical Oncology 2021.)

Aim: To evaluate HER2-negative breast cancer (BC) with a low hormone receptor (HR) expression, with regard to pathological complete response (pCR) and survival, in comparison to triple-negative BC (TNBC) and strong HR-positive BC., Methods: We compared negative [oestrogen (ER) and progesterone receptor (PR) <1%], low-positive (ER and/or PR 1-9%) and strong-positive (ER or PR 10-100%) HR-expression in neoadjuvant clinical trial cohorts (n = 2765) of BC patients. End-points were disease-free survival (DFS), distant-disease free survival (DDFS) and overall survival (OS). We performed RNA sequencing on available tumour tissue samples from patients with low-HR expression (n = 38)., Results: Ninety-four (3.4%) patients had low HR-positive tumours, 1769 (64.0%) had strong HR-positive tumours, and 902 (32.6%) had TNBC. There were no significant differences in pCR rates between women with low HR-positive tumours (27.7%) and women with TNBC (35.5%). DFS and DDFS were also not different [for DFS, hazard ratio 1.26, 95%-CI (confidence interval) : 0.87-1.83, log-rank test p = 0.951; for DDFS, hazard ratio 1.17, 95%-CI: 0.78-1.76, log-rank test p = 0.774]. Patients with strong HR-positive tumours had a significantly lower pCR rate (pCR 9.4%; odds ratio 0.38, 95%-CI: 0.23-0.63), but better DFS (hazard ratio 0.48, 95%-CI: 0.33-0.70) and DDFS (hazard ratio 0.49, 95%-CI: 0.33-0.74) than patients with low HR-positive tumours. Molecular subtyping (RNA sequencing) of low HR-positive tumours classified these predominantly into a basal subtype (86.8%)., Conclusion: Low HR-positive, HER2-negative tumours have a similar clinical behaviour to TNBC showing high pCR rates and poor survival and also a basal-like gene expression signature. Patients with low HR-positive tumours should be regarded as candidates for therapy strategies targeting TNBC., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AS reports grants from Celgene, grants from Roche, grants from AbbVie, grants from Molecular Partner, personal fees from Roche, personal fees from AstraZeneca, personal fees from Celgene, personal fees from Roche, personal fees from Roche, personal fees from Celgene, personal fees from Pfizer, personal fees from AstraZeneca, personal fees from Novartis, personal fees from MSD, personal fees from Tesaro, personal fees from Lilly, personal fees from Pfizer, other from Roche, outside the submitted work. CD reports grant support from the European Commission (Responsify and Oncobiome project) as well as from the German Cancer Aid (Deutsche Krebshilfe, TransLuminal-B and Integrate-TN project) during the conduct of the study; ownership interest in Sividon Diagnostics outside the submitted work; and honoraria from Pfizer, Merck, Sharp & Dohme, Amgen, Myriad, Teva, Celgene, Roche, and AstraZeneca outside the submitted work. CH reports personal fees from Novartis, personal fees from Celgene, personal fees from Lilly, personal fees from Astra Zeneca, personal fees from Amgen, outside the submitted work. CJ reports personal fees from Roche, personal fees from Celegen, personal fees from Amgen, outside the submitted work. FM reports personal fees from Roche, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Tesaro, personal fees from Novartis, personal fees from Amgen, personal fees from PharmaMar, personal fees from GenomicHealth, personal fees from CureVac, personal fees from EISAI, personal fees from Clovis, personal fees from Celgene, outside the submitted work. HT reports personal fees and non-financial support from Roche, personal fees and non-financial support from Pfizer, personal fees and non-financial support from Novartis, personal fees and non-financial support from AstraZeneca, outside the submitted work. JH reports grants and personal fees from Novartis, personal fees from Lilly, personal fees from Abbvie, personal fees from Pfizer, personal fees from Roche, personal fees from MSD, personal fees from Astra Zeneca, grants and personal fees from Celgene, outside the submitted work. KEW reports personal fees and other from Myriad, outside the submitted work. MK reports grants from Deutsche Krebshilfe (German Cancer Aid), grants from DFG/BMBF, grants from Senator Roesner Foundation, grants from Dr. Pommer-Jung Foundation, personal fees from Springer Press, personal fees from Biermann Press, personal fees from Celgene, personal fees from Astra Zeneca, personal fees from Myriad Genetics, personal fees from TEVA, personal fees from Bavarian KVB, personal fees from DKMS Life, personal fees from BLÄK, other from Therawis Diagnostics GmbH, other from Busenfreundin GmbH, outside the submitted work. MU reports personal fees and non-financial support from Abbvie, personal fees and non-financial support from Amgen GmbH, personal fees and non-financial support from Astra Zeneca, personal fees from BMS, personal fees and non-financial support from Celgene GmbH, personal fees and non-financial support from Daiji Sankyo, personal fees and non-financial support from Eisai GmbH, personal fees from Lilly Deutschland, personal fees and non-financial support from Lilly Int., personal fees and non-financial support from MSD Merck, personal fees and non-financial support from Mundipharma, personal fees and non-financial support from Myriad Genetics, personal fees and non-financial support from Odonate, personal fees and non-financial support from Pfizer GmbH, personal fees from PUMA Biotechnology, personal fees and non-financial support from Roche Pharma AG, personal fees and non-financial support from Sanofi Aventis Deutschland GmbH, personal fees and non-financial support from TEVA Pharmaceuticals Ind Ltd, personal fees and non-financial support from Novartis, personal fees from Pierre Fabre, outside the submitted work. MVM reports personal fees from Amgen, personal fees from AstraZeneca, personal fees from Genomic Health, non-financial support from Novartis, non-financial support from Lilly, outside the submitted work. NP reports personal fees from Roche, personal fees from Novartis, outside the submitted work. PAF reports grants from Novartis, grants from BioNTech, personal fees from Novartis, personal fees from Roche, personal fees from Pfizer, personal fees from Celgene, personal fees from Daiichi-Sankyo, personal fees from TEVA, personal fees from Astra Zeneca, personal fees from Merck Sharp & Dohme, personal fees from Myelo Therapeutics, personal fees from Macrogenics, personal fees from Eisai, personal fees from Puma, grants from Cepheid, personal fees from Lilly, during the conduct of the study. SL reports grants and other from Abbvie, grants and other from Amgen, grants and other from AstraZeneca, grants and other from Celgene, grants and other from Novartis, grants and other from Pfizer, grants and other from Roche, other from Seattle Genetics, other from Prime/Medscape, personal fees from Chugai, grants from Teva, grants from Vifor, grants and other from Daiichi-Sankyo, other from Lilly, other from Samsung, other from Eirgenix, outside the submitted work; In addition, Dr. Loibl has a patent EP14153692.0 pending. WDS reports personal fees from AstraZeneca, outside the submitted work. WW reports personal fees from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Amgen, Astellas and grants from Roche, MSD, BMS, Bruker outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Extensive studies of the rudimental tissues taken from patients with aplasia of the uterus and vagina are aimed at elucidation of the mechanisms of the genesis of these malformations and at the search of the ways of their correction. We performed a histological examination of human uterine rudiments and immunohistochemical analysis of the expression of estrogen and progesterone receptors, VEGF, and stem/progenitor cell markers in these tissues. We found that the rudimental tissues show signs of disorganized histogenesis, but retain activity and contain cells expressing estrogen and progesterone receptors and VEGF as well as poorly differentiated precursor cells or stem cells. The presented data contribute to the in-depth studies of the mechanisms of formation of uterine rudiments and development of methods of their correction.

Progesterone (Pg) and estrogen (E) receptors (PgRs and ERs) are expressed in normal and neoplastic adrenal cortex, but their role is not fully understood. In literature, Pg demonstrated cytotoxic activity on AdrenoCortical Carcinoma (ACC) cells, while tamoxifen is cytotoxic in NCI-H295R cells. Here, we demonstrated that in ACC cell models, ERs were expressed in NCI-H295R cells with a prevalence of ER- β over the ER- α .Metastasis-derived MUC-1 and ACC115m cells displayed a very weak ER- α / β signal, while PgR cells were expressed, although at low level. Accordingly, these latter were resistant to the SERM tamoxifen and scarcely sensitive to Pg, as we observed a lower potency compared to NCI-H295R cells in cytotoxicity (IC 50 : MUC-1 cells: 67.58 µM (95%CI: 63.22-73.04), ACC115m cells: 51.76 µM (95%CI: 46.45-57.67) and cell proliferation rate. Exposure of NCI-H295R cells to tamoxifen induced cytotoxicity (IC 50 : 5.43 µM (95%CI: 5.18-5.69 µM) mainly involving ER- β , as their nuclear localization increased after tamoxifen: Δ A.U. treated vs untreated: 12 h: +27.04% (p < 0.01); 24 h: +36.46% (p < 0.0001). This effect involved the SF-1 protein reduction: Pg: -36.34 ± 9.26%; tamoxifen: -46.25 ± 15.68% (p < 0.01). Finally, in a cohort of 36 ACC samples, immunohistochemistry showed undetectable/low level of ERs, while PgR demonstrated a higher expression. In conclusion, ACC experimental cell models expressed PgR and low levels of ER in line with data obtained in patient tissues, thus limiting the possibility of a clinical approach targeting ER. Interestingly, Pg exerted cytotoxicity also in metastatic ACC cells, although with low potency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rossini, Tamburello, Abate, Beretta, Fragni, Cominelli, Cosentini, Hantel, Bono, Grisanti, Poliani, Tiberio, Memo, Sigala and Berruti.)

Antarctica has long been considered a continent free from anthropic interference. Unfortunately, recent evidence indicate that metal contamination has gone so far and that its effects are still unknown. For this reason, in the present work, the potential endocrine disrupting effect of two highly polluting metals, copper and cadmium, were examined in the Antarctic teleost Trematomus bernacchii. After a 10 days waterborne exposure, ovarian metal uptake was determined by atomic absorption; in parallel, classical histological approaches were adopted to determine the effects on oocyte morphology, carbohydrate composition and presence and localization of progesterone and estrogen receptors. Results show that both metals induce oocyte degeneration in about one third of the previtellogenic oocytes, no matter the stage of development. In apparently healthy oocytes, changes in cytoplasm, cortical alveoli and/or chorion carbohydrates composition are observed. Cadmium but not copper also induces significant changes in the localization of progesterone and beta-estrogen receptors, a result that well correlates with the observed increase in ovarian metals concentrations. In conclusion, the acute modifications detected are suggestive of a significantly impaired fecundity and of a marked endocrine disrupting effects of copper and cadmium in this teleost species., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest that could be perceived as prejudging the impartiality of the research reported., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Estrogen receptors (ER), progesterone receptors (PR) and the human epidermal growth factor receptor-2 (HER2) are basic breast cancer molecular markers that are also best recognized prognostic factors and predictors of type of targeted therapy to be given. The objectives are to study the correlation of expression of hormone and HER2receptors with various clinico-pathological prognostic parameters like patient's age at diagnosis, menopausal status, tumor size, histological grade and lymph node status of tumor and with each other in malignant breast lesion., Methods: For this study histopathology (HP) and immunohistochemistry (IHC) slides of excised specimens of 330 female patients with a palpable breast lump deposited to the pathology department of a hospital as a part of routine diagnostic procedure, were evaluated under the guidance of trained doctors who have minimum 5 years of experience in oncopathology. The author has no direct involvement with patients, informed consent was not necessary and data were collected after getting permission from concerned authority., Results: This study finds significant relationship between hormone receptors and all clinico-pathological prognostic parameters taken for comparison except age at diagnosis. HER2 status has significant relationship with all clinico-pathological prognostic parameters; hormone and HER2 status suggests an inverse relationship., Conclusions: Mien of hormone receptors expression in breast cancer is related with better prognostic factors such as older age, postmenopausal status, smaller tumor size, low histological grade and negative lymph node status, however the opposite is correct for HER2. Hormone receptors and HER2 have an inversely proportionate relationship with each other., (Copyright © 2020. Published by Elsevier Inc.)

Progesterone acts on neurons directly by activating its receptor and through metabolic conversion to neurosteroids. There is emerging evidence that progesterone exerts excitatory effects by activating its cognate receptors (progesterone receptors, PRs) through enhanced expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Progesterone metabolite 5α,3α-tetrahydro-progesterone (allopregnanolone, THP) mediates its anxiolytic and sedative actions through the potentiation of synaptic and extrasynaptic γ-aminobutyric acid type-A receptors (GABA A Rs). Here, we review progesterone's neuromodulatory actions exerted through PRs and THP and their opposing role in regulating seizures, catamenial epilepsy, and seizure exacerbation associated with progesterone withdrawal., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: recent studies show a good relationship between breast cancer (BC) and human papillomaviruses (HPV) wich is responsible for about 18% of BC cases. This study aimed to assess the relationship between different genotypes of HPV and the expression of P53 and retinoblastoma (RB) genes and estrogen and progesterone receptors in BC among Sudanese women., Methods: one hundred and fifty tissue blocks were obtained from females diagnosed with BC. Positive samples were used to determine genotypes with an applied biosystem (ABI 3730XL) genetic analyzer for sequencing and immunohistochemistry., Results: 13/150 samples showed HPV DNA. High-risk HPV-16 was detected in 5 cases, high-risk-HPV-58 was found in four cases, and HPV-18 was detected in three cases. Low-risk-HPV-11 was detected in a single invasive lobular carcinoma (ILC) case. P53 and RB gene mutations were detected in 35 and 30 BC cases, respectively. P53 gene mutation was frequently identified in grade (III) BC while RB gene mutation was positive in grade (II). Grade (II) BC had a higher incidence of HPV-16 and 58. On the other hand, HPV-18 had a higher incidence in grade (III). Estrogen and progesterone receptors were expressed in 94 and 79 HPV cases among the study group, respectively., Conclusion: this study elucidates the associations between HPV genotypes and BC. A statistically significant association was observed among p53 and RB gene mutations and different BC histological types. On the other hand, there was a statistically insignificant association between HPV genotyping and different BC gradings, BC histological types, P53 and RB genes mutations, and estrogen and progesterone receptor expression. Also, there was a statistically insignificant association among estrogen and progesterone receptors expression and BC grading. RB gene mutation was significantly associated with different BC grades. On the other hand, there was a statistically insignificant association between progesterone receptor expression and BC., Competing Interests: The authors declare no competing interests., (Copyright: Abdallah Mohammed Elagali et al.)

Objectives: This study aims to investigate the relationship between estrogen receptors (ERs) and progesterone receptors (PRs) and histopathological findings in synovial tissue in rheumatoid arthritis (RA) and osteoarthritis (OA) patients., Patients and Methods: Synovial tissue samples obtained from synovial surgery from 30 RA (10 males, 20 females) and 92 OA (27 males, 65 females) patients with median age of 59 (range, 50 to 67) years were analyzed retrospectively between January 2010 and January 2019. The relationship between histopathological features and hormone receptor presence was analyzed., Results: There was a meaningful relationship between histopathological parameters and RA and OA (p=0.01). The sex hormone receptor's presence was significantly higher in females with RA (p=0.01). Additionally, in the RA group, there was a remarkable relationship between ER and focal aggregates of lymphocytes (p=0.01), perivascular infiltrates of lymphocytes (p=0.03), and diffuse infiltrates of lymphocytes (p=0.01). In the OA group, a significant relationship was observed between PR and subchondral inflammation (p=0.01). In multivariate analysis, it was observed that ER was an independent risk factor for focal aggregates of lymphocytes in RA group (odds ratio [OR]=1.51 [1.02-2.25], p=0.04). Besides, PR was found to be an independent risk factor for subchondral inflammation in OA group (OR=3.90 [1.28-11.80], p=0.02)., Conclusion: The presence of the sex hormone receptor in the synovium may change histopathological features and affect the clinical course., Competing Interests: Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article., (Copyright © 2021, Turkish League Against Rheumatism.)

This review summarizes the current opinions on the mechanisms of action of nuclear, mitochondrial, and membrane progesterone receptors. The main aspects of the pharmacological action of progestins have been studied. Data on the clinical use of gestagens by nosological groups are presented. Particular attention is paid to progesterone, megestrol acetate, medroxyprogesterone acetate due to broadening of their spectrum of action. The possibilities of using gestagens as neuroprotectors, immunomodulators, and chemosensitizers are considered., Competing Interests: Conflict of interest. The authors have no conflict of interest to disclose.

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.

The selective progesterone receptor modulator mifepristone (MF) may act as a potent antiproliferative agent in different steroid-dependent cancers due to its strong antagonistic effect on the nuclear progesterone receptor (PGR). Hereby, we analyzed the effects of MF treatment on Leydig cell tumor (LCT) progression in a transgenic mouse model (inhibin-α promoter-driven SV40 T-antigen), as well as on LCT (BLTK-1 and mLTC-1) cell proliferation. MF significantly stimulated the proliferation of LCT in vitro. Similarly, a 1-mo MF or P4 treatment stimulated LCT tumor growth in vivo. Traceable/absent classical Pgr or nonclassical membrane PRs α, β, γ and Pgrmc2, but abundant membrane Pgrmc1 expression, was found in LCTs. MF did not activate glucocorticoid or androgen receptors in LCTs. Functional analysis showed that PGRMC1 is required for MF and P4 to stimulate the proliferation and invasiveness of LCTs. Accordingly, MF and P4 induced PGRMC1 translocation into the nucleus and thereby stimulated the release of TGFβ1 in LCT cells. MF and P4 treatments upregulated Tgfbr1 , Tgfbr2, and Alk1 expression and stimulated TGFβ1 release in LCT cells. Our findings provide novel mechanistic insights into the action of MF as a membrane PR agonist that promotes LCT growth through PGRMC1 and the alternative TGFβ1 signaling pathway.