Progesterone is a regulator of the reproductive function and stimulates the development of glandular tissue of the mammary gland and milk secretion. Most of its effects are mediated by nuclear receptors, which are transcription factors. There is a limited amount of data on the frequency of distribution of genotypes and alleles of the progesterone receptor gene ( PGR ) and their association with morphofunctional parameters of the mammary gland in cattle, and all of them concern transboundary breeds. The purpose of the scientific work is to study the morphofunctional parameters of the mammary gland of the Kostroma and Holstein cows of different genotypes for the PGR gene in the conditions of breeding farms of the Kostroma region. The studies were carried out in 2024–2025 on breeding first-calf cows of the Kostroma ( n = 81) and Holstein ( n = 26) breeds. The relationship between the genotype of the PGR gene and the morphofunctional parameters of the mammary gland was determined. It was revealed that in the studied samples of cows of the Kostroma and Holstein breeds, the most common genotype is AA of the PGR gene (distribution frequency 0.568 and 0.462, respectively). However, carriers of the rare PGR GG genotype had optimal morphological parameters for machine and robotic milking and a bath-shaped mammary gland. Also, based on results of the first lactation, it was found that in the sample of the Kostroma breed, the milk yield of carriers of the PGR GG genotype was 9.26% and 14.29% higher than that of the carriers of the PGR АА and PGR А G genotypes ( p ≤ 0.5), respectively. Based on the data of the study, it was determined that carriers of the PGR GG genotype have morphofunctional parameters of the mammary gland that are preferable for machine and robotic milking, therefore it is necessary to continue research in this area on a larger number of animals and within other cattle populations.

Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality worldwide. This study investigated six single-nucleotide polymorphisms (SNPs) in the maternal and fetal progesterone receptor (PGR) gene and their association with spontaneous PTB, considering environmental and clinical risk factors. We conducted a case–control study including two groups of pregnant women (term and preterm, 292 in total) and two groups of newborns (term and preterm, 292 in total), and analyzed PGR variants (rs1042838, rs1042839, rs10895068, rs4574732, rs653752, and rs1942836) in relation to maternal age, fetal gender, and pregnancy complications such as vaginal bleeding. Results showed that PGR SNPs rs1942836 (OR 0.38, CI 95% 0.15–0.98, p = 0.03), rs4574732 (OR 2.4, CI 95% 1.01–5.57, p = 0.04), and rs653752 (OR 2.27, CI 95% 1.19–4.34, p = 0.02) were associated with PTB when considered in the context of clinical factors, highlighting gene–environment interactions. Our findings underscore the importance of integrating genetic and clinical information for a better understanding of PTB risk.

Disclosure: A. Dymova: None. T. Shkeleva: None. S. Kalinchenko: None.Background: Previous studies have investigated the association between genetic variability in the progesterone receptor gene and various hormonally-related conditions, such as breast cancer (BC), endometrial and ovarian cancers. Vitamin D deficiency can also lead to oncological conditions, including BC. Progesterone and Vitamin D induce their hormonal effects on target cells by binding the active form of the hormone to its receptors. Therefore, any genetic variations that may cause the dissociation of progesterone and vitamin D receptors, as well as a reduction in the synthesis of the active hormone form, may lead to increased susceptibility to BC.Notably, earlier studies did not take into account the morphological characteristics of tumors and the influence of molecular-genetic features on the age of disease manifestation.Objective: This study aimed to assess the association between functional-reducing variants in the PGR, VDR, and CYP27B1 genes with the risk of hormone-dependent breast cancer (HBC) and the age of disease manifestation. Methods: A retrospective case-control study was conducted, involving 87 women aged 40 to 72 years. Of these, 42 women had a diagnosis of HBC, and 45 women had no history of HBC in their personal or familial medical records. Genotyping was performed using SNP genotyping methods through direct sequencing. Functional-reducing variants in the progesterone receptor gene PGR c.1486G>T; p.Val660Leu, vitamin D receptor BsmI Polymorphism IVS10+283G>A, and 1α-hydroxylase enzyme g.57764205A>G; c.1137-29T>C were investigated. Results: A significantly higher frequency of the minor allele of PGR (45% vs. 16%), VDR (29% vs. 17%), and the functional-reducing allele of the CYP27B1 enzyme (43% vs. 12%) was observed among patients with HBC compared to the control group, confirming the association of these genetic variants with the risk of developing HBC. A significant association of PGR and VDR genotypes with HBC was observed in younger patients up to 55 years old. In older patients, the frequency of PGR and VDR variants decreased and approached the control group, indicating the contribution of other factors to the pathogenesis of the disease after the age of 55. Conclusions: This report confirms the contribution of PGR, VDR, and CYP27B1 gene variants to the etiology of BC. The low sensitivity of PGR and VDR receptors is associated with earlier forms of HBC. Genotyping of vitamin D receptors (VDR), the activity of the 1α-hydroxylase enzyme (CYP27B1), and progesterone receptors (PGR) in the future will enable the development of a screening strategy for identifying women at risk of developing HBC.Presentation: Monday, July 14, 2025

. A non susceptible fraction in time-to-event studies arises when there is a proportion of units that never experience the event of interest. The assessment of how well a marker is capable of discriminating survival outcomes when there is a non susceptible fraction is an important task for timely decision-making. If the marker has a discriminative value, it can be used to find a cutoff point to stratify units into two groups. The Receiver Operating Characteristic (ROC) curve is a well-established tool to address measurements of marker accuracy. In this article, a frailty-based susceptibility joint model of the marker and the survival time is developed and then used to characterize the time-varying ROC curve, according to definitions of cumulative/dynamic and incident/dynamic outcomes. Inference is performed using maximum likelihood and a resampling-based method. Quantile-comparison plots for randomized quantile residuals from each conditional distribution are employed for assessing the adequacy of the model. Simulation studies are used to evaluate the finite-sample performance of the joint model and compare it to those of mainstream non parametric formulations. The methods are illustrated with a 14-year follow-up of patients diagnosed with breast cancer to assess the predictive power of the level of progesterone receptor gene expression for relapse.

Kari is a small breed of sheep found in Chitral district of Khyber Pakhtunkhwa with unique characteristics having shorter gestation length than other breeds i.e. lesser than five months. In this experiment the expression pattern of oxytocin and progesterone receptors gene in estrus cycle and early pregnancy was studied. For this experiment total seven ewes non-pregnant scanned through ultrasonography and then estrous synchronized with double PGF2α protocol. The fertile rams were allowed, and mating was observed. Blood samples was collected from ewes before and after confirmation of pregnancy. RNA was isolated from the blood and synthesized c-DNA through RT-PCR. The c-DNA was amplified using primers i.e. P4, OXTR and GABDH. No expression of OXTR was observed between 08th and 12th day in control, non-pregnant and pregnant ewes while expression of OXTR was observed on 14th day in non-pregnant and no expression in pregnant ewes. The expression of progesterone receptors was high on 10th and 12th day in pregnant ewes while low level was recorded on 16th day. In control and non-pregnant ewes the expression of P4 mRNA was lower at 08th day and highly expressed on 14th and 16th day of estrus cycle. It is concluded that early pregnancy in ewes sustained by a complex interplay between the conceptus and endometrium. This contact involves factors like IFN-t, progesterone, and growth factors, which regulate gene expression to suppress luteolysis and maintain pregnancy.

The article presents the results of the assessment of rabbits of different lines of the Poltava Silver breed using the G-BLUP method with the analysis of the influence of polymorphic variants of the myostatin (MSTN) genes on live weight and progesterone receptor (PGR) on reproductive ability. The indicators of gene diversity in different lines of the Poltava Silver breed for these polymorphisms showed a positive value of the Wright fixation index (Fis), indicating the predominance of heterozygotes for the C and T alleles. Based on the obtained heterozygosity data, Wright fixation indices were calculated. The inbreeding coefficient (Fis) for the genes – MSTN and PGR – showed different distributions between rabbit lines. A higher value of Fis for the MSTN gene indicates a greater deficit of heterozygosity, potentially indicating higher inbreeding effects. On the other hand, a lower value of Fis for the PGR gene means smaller inbreeding effects or that the population is closer to panmixia. Analysis of the influence of the SNP C34T polymorphism in the MSTN gene on the average daily gain of rabbits revealed the following patterns. Heterozygous rabbits with the ST genotype demonstrated higher average daily gains. Their gains were 2.3% higher than those of homozygotes for the C allele (39.0 ± 0.3 g vs. 38.2 ± 0.2 g, p<0.05). At the same time, the average daily gains of homozygotes for the T allele were 2.6% lower than those of heterozygotes for the ST (38.2 ± 0.2 g vs. 39.0 ± 0.3 g, p<0.05). It was found that line 1871817 is the most promising in terms of meat productivity, showing the highest values of BLUP-index (1358), estimated breeding value (EBV, 1.412) and reliability (REL, 1.827), which confirms its high genetic potential. Lines 1847213 and 1832221, on the contrary, have small negative EBV and low REL, which indicates their lower productivity. The G-BLUP method also confirmed the influence of the PGR gene on reproductive traits. Lines 1871817 and 1811231 showed the highest BLUP-index (5.57) for these indicators, which indicates their high potential for transmitting reproductive potential to offspring. In general, the line 1871817 demonstrates high genetic potential both in terms of live weight and the number of weaned rabbits, which makes it a priority in the selection of the best individuals for future breeding programs in rabbit breeding

The role of the androgen receptor (AR) in breast cancer (BC) remains incompletely understood. Here, we conducted a meta-analysis of large-scale microarray transcriptomic datasets to evaluate whether the mRNA expression levels of the androgen receptor gene, relative to those of the estrogen receptor gene (AR/ESR1 ratio) and the progesterone receptor gene (AR/PGR ratio), can help differentiate BC tumor subtypes. Additionally, we used qRT-PCR assays to assess the mRNA levels of the AR/ESR1 and AR/PGR ratios in four cell lines representative of different BC subtypes (MCF7, BT474, MDA-MB453, and MDA-MB231), as well as in breast tissue from a small group of patients (11 cases) stratified by estrogen receptor (ER) status. Our results showed that higher AR gene expression relative to ESR1 and PGR (≥ 2.0 and ≥ 1.54, respectively) were associated with BC patients classified under the Luminal B and HER2-enriched subtypes. Positive values of AR/ESR1 and AR/PGR ratios were also observed in the ER-negative (ER-) cell line MDA-MB453, as well as in tumor tissue from ER- BC patients. Our findings confirm that higher or even positive AR/ESR1 and AR/PGR ratios may be associated with BC cases exhibiting more aggressive clinical and biological features, leading to a worse prognosis.

Effects of cannabidiol, cannabichromene, cannabidivarin, cannabigerol and cannabinol in endometrial cells: Implications for endocrine and senescence modulation.

Endometriosis is a hereditary condition defined as the growth of endometrium-like tissue outside the uterus, affecting an estimated 5-10% of women of reproductive age (1) and imposing great economic and healthcare burdens (2). The growth occurs mostly on the pelvic peritoneum, rectovaginal septum, and ovaries, and in rare cases in the abdominal wall, diaphragm, pleura, pericardium, and peripheral and central nervous systems (3, 4). Endometriosis is generally thought to result from retrograde menstruation of endometrial cells through the fallopian tubes to reach the abdomino-pelvic cavity where they settle and implant, thereby eliciting an inflammatory response that leads to the formation of scars and adhesions, pelvic pain, dysmenorrhea, dyspareunia, dysuria, and infertility (5, 6). A variant on this theory assumes that endometrial cells reach through the lymph vessels to cause endometriosis in lymphatic nodes and distal locations (7). Alternatively, endometriosis could be caused by coelomic metaplasia, i.e. the transformation of peritoneal epithelium lining under the influence of stimuli (8). Current diagnosis depends mainly on surgical examination, which is expensive and could mis the disease altogether. Furthermore, the necessary infrastructure and skills for such a procedure could be lacking in undeveloped regions and regions with increased instability due to armed conflicts and/or natural disasters. There is, therefore, a growing need for simple, non-invasive diagnostic tools to facilitate early detection and treatment initiation. Despite great efforts, this has not been achieved yet, mainly because the disease mechanism is still far from clearly understood. The contribution of genetic factors to the variation in endometriosis has been estimated to be 47%, with the other 53% attributed to unique environmental factors (9). However, endometriosis is a heterogenous condition, involving many genetic factors each with a small effect size (10, 11). This means that very large studies are required to identify genetic factors that can only explain a small fraction of disease variance. Genetic studies of endometriosis have been performed both at single gene level (SNP analysis) (reviewed in 12) and genome level (genome wide association studies, GWAS) (13; 14). The former is based on assumptions about the etiology of the disease whereas the latter is agnostic to such assumptions. Both approaches have contributed to our current understanding of the underlying biology in endometriosis. In this minireview we focus on association studies of the estrogen receptor 1 alpha (ESR1) and progesterone receptor (PGR) genes. We also discuss the relevance of progesterone resistance or estrogen dominance (defined here as higher estrogen to progesterone ratio) in light of these genetic changes.

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.

PurposeWe 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.MethodsThe 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.ResultsFor 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.ConclusionThe current study demonstrated the feasibility of imaging gene-phenotype decoding in breast tumors using MR images and deep learning algorithms with moderate performance.

Introduction: In European couples infertility varies 5–24%. The progesterone receptor (PGR) encoded by the PGR gene plays a key role in many reproductive pathways. In our study, for the first time among European populations, the potential association of PGR rs1042838 with spontaneous abortions (SA), was investigated. Materials and methods: The TaqMan SNP assay was used in a group of 154 women with SA and 154 controls – mothers with at least 1 live-born child for genotyping the rs1042838 of PGR gene. Results: The prevalence of genotypes GG, GT, TT in women with and without SAs were: 72.8%, 22.7%, 4.5% and 61.0%, 34.4% and 4.6%, respectively (p = 0.080). Conclusions: Due to the fact that in some populations rs1042838 is rare, its confirmation as a genetic marker of SA requires further studies in larger groups and different populations.

Background: Pregnancy complications have a high prevalence and important medical and social implications. Genetic factors are involved in their development. The aim of the study: To study the characteristics of interlocus interactions in the formation of isolated and combined pregnancy complications. Materials and methods: The sample for the study consisted of 786 pregnant women, including 462 women were with various pregnancy complications (isolated preeclampsia (PE) (n=190); 2) isolated fetal growth retardation (FGR) (n=196); 3) a combination of PE and FGR (n=76)) and 324 women with a physiological course of pregnancy. Genotyping was performed for 13 polymorphic loci of growth factor genes and their receptors (rs4444903 EGF, rs833061 VEGFA, rs2981582 FGFR2, rs6214 IGF1, rs1800469 TGFß1), estrogen and progesterone receptor genes (rs2234693 ESR1, rs9340799 ESR1, rs3798577 ESR1, rs484389 PGR, rs1042838 PGR) and hereditary thrombophilia genes (rs1126643 ITGA2, rs5918 ITGB3 and rs5985 F13A1). The interaction of polymorphic loci associated with the studied pregnancy complications, visualization and determination of the nature (synergism, independent effect, antagonism) and strength (proportion of contribution to the entropy of the trait) of these interactions were studied using MB-MDR and MDR methods. Results: The risk of developing isolated FGR is determined by three models of interlocus interactions of 5 polymorphisms: rs4444903 EGF, rs6214 IGF1, rs2234693 ESR1, rs484389 PGR and rs5985 F13A1 with the most pronounced effects of the polymorphic locus rs6214 IGF1. Susceptibility to isolated PE is determined by the interlocus interactions of five loci: rs4444903 EGF, rs833061 VEGFA, rs2981582 FGFR2, rs2234693 ESR1, rs9340799 ESR1, in which the two-locus interaction rs9340799 ESR1xrs2234693 ESR1 plays a key role (it is part of all 3 models). The formation of a combination of FGR and PE is associated with two models of intergenic interactions of 4 polymorphisms: rs2234693 ESR1, rs9340799 ESR1, rs484389 PGR, rs5918 ITGB3. Three high-risk genotype combinations of genotypes showed the highest level of statistical significance of associations (p<0.005) with pregnancy complications: TT-rs2234693 ESR1xGA-rs6214 IGF1 – isolated FGR (β = 1.86, p=0.003); AA-rs9340799 ESR1xTT-rs2234693 ESR1 – isolated PE (β = 2.45, p=0.0009) and the combination of PE and FGR (β = 2.38, p=0.002). Conclusion: The risk of pregnancy complications is largely determined by the genetic combinatorics of the three polymorphic loci rs2234693 ESR1, rs9340799 ESR1, rs6214 IGF1.

In the work, a comprehensive BLUP AM evaluation of the breeding value of the Poltava silver rabbit breed was carried out according to myostatin and progesterone receptor genes, taking into account paratypic factors. A detailed analysis of the components of the reproductive capacity of female rabbits of the Poltava silver breed was carried out, and the most promising of them, from the point of view of selection, were considered. When compiling linear models according to the BLUP Animal Model, it is proposed to evaluate the reproductive characteristics of rabbits based on indicators of the number of rabbits born (excluding stillbirths) at the age of 40 days and the value of average daily growth. A selection index was developed for evaluating the reproductive capacity of female rabbits, which includes BLUP AM - evaluation of reproductive and maternal traits. The values of the selection index of female rabbits of the Poltava silver breed in terms of reproductive ability ranged from -0.035 to +0.140. When selecting animals, it is advisable to use the value of the selection index taking into account the age and serial number of lactation, and to improve the reproducibility of the BLUP AM value - estimates based on individual characteristics.

Endometriosis is a chronic inflammatory, estrogenic disorder caused by endometrial tissue growth places other than uterine lumen, resulting in infertility and severe pelvic pain. Thymol, an extract of Thymus vulgaris, processes diverse biological properties, including anti-inflammatory, local anesthetic, decongestant, and antiseptic effects. However, the efficacy of thymol in treating endometriosis has still not been explored. Herein, this research aimed to investigate the role of thymol in the treatment of endometriosis using a murine model and Ishikawa cells. Thirty C57BL/6 mice were administered 17β-E2 (100 ng/mouse) subcutaneously for three consecutive days to induce synchronous estrus. On the last day of injection, the mice underwent surgical induction of endometriosis. After that, the mice were divided into three groups, i.e., Control (CTRL), Thymol 30 mg/kg and Thymol 60 mg/kg, receiving oral administration of either saline or thymol (30 mg/kg/d or 60 mg/kg/d, as 0.1 mL/kg/d, respectively) for a three-week duration. Each group consisted of ten mice and was evenly divided into estrus and diestrus according to the vaginal cytology on the last day of treatment. Thymol significantly (p < 0.05) reduced the weight and volume of ectopic tissue, hindered cell proliferation, and stimulated apoptosis compared to the CTRL group. Additionally, in the thymol-treated group, the levels of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, as well as the numbers of neutrophils and macrophages, were significantly (p < 0.05) decreased. Moreover, a novel role of thymol in rebalancing estrogen and progesterone (E2-P4) signaling was explored, and it was distributed in the ectopic endometrium. Next, the role of thymol on Ishikawa cells was determined. The results demonstrated that thymol significantly (p < 0.05) suppressed the E2-induced proliferation of Ishikawa cells. Furthermore, molecular docking analyses suggested that thymol potentially binds to ESR1-like estrogens, indicating its antagonistic activity against estrogens. The estrogen receptor 1 (ESR1) and its target gene expression exhibited significant (p < 0.05) downregulation, while progesterone receptor (PGR) and target genes were markedly (p < 0.05) upregulated following thymol treatment in the ectopic endometrium. Most importantly, our data revealed the minimal impact of thymol treatment on the eutopic endometrium and its crucial role in supporting pregnancy, thus indicating the safety of thymol in treating endometriosis. Overall, our study suggests that thymol holds promising therapeutic implications for endometriosis by virtue of its anti-inflammatory properties and ability to antagonize estrogen activity.

Triple-negative breast cancer (TNBC) lacks effective targeted, endocrine therapeutic agents and the development of novel agents is costly and time-consuming. The objective of this study was to identify pharmaceuticals and natural products utilized in clinical practice that have the potential to inhibit the expression of Cellular-myelocytomatosis oncogene (c-Myc), based on a review of the current literature. The aim was to assess the effect of the specified drugs on c-Myc expression in TNBC cells, determine the most potent inhibitor, and evaluate its impact on TNBC cell proliferation, invasive migration, and apoptosis, as well as the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) at both the gene and protein levels. Explore its potential for treatment or adjuvant therapy for triple-negative breast cancer. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to quantify gene and protein expression levels. Flow cytometry was employed to measure cell proliferation and apoptosis, while the Transwell assay was utilized to assess cell invasion and migration. Harmaline emerged as the strongest inhibitor, significantly decreasing the expression of c-Myc at both the gene and protein levels in TNBC cells. It also inhibited cell proliferation, invasion, and migration while promoting apoptosis in TNBC cells. Additionally, there was a varying increase in the expression of ER and PR genes and proteins. While the expression of the HER-2 gene was elevated, there was no significant change in HER-2 protein levels. Notably, the expression of the phosphorylated HER-2 protein increased. Harmaline was found to promote apoptosis and inhibit cell proliferation, invasion, and migration in TNBC cells by targeting the inhibition of c-Myc. It also induced the re-expression of the ER, PR, and HER-2 genes, as well as the ER and PR proteins.

Progesterone regulates reproductive processes and affects many functions of various non-reproductive organs. Its effects in mammals and humans are mediated by nuclear (nPRs) and membrane progesterone receptors (mPRs). The action of progesterone through different types of receptors may differ significantly and has tissue specific features. The expression of known types and subtypes of progesterone receptors in the tissues of male and female rats has been studied fragmentarily. The purpose of our work was to study the expression of five mPRs genes, as well as the nPRs gene and the membrane component of the progesterone receptor PGRMC I in the reproductive organs and in 17 non-reproductive tissues of male and female rats using reverse transcription followed by real-time PCR. In this study, it was shown that a high level of nPRs gene expression in rats is found not only in reproductive organs of females (uterus, ovary, mammary glands), but also in seminal vesicles of males, in the brain and trachea of both sexes, in blood vessels, and in the pancreas of females. The highest level of expression of mPRs genes of all subtypes was found in the testes, while expression of the gene encoding nPRs was practically undetectable in them. Expression of genes encoding mPRs was also detected in the liver and spleen of male and female rats, while expression of the gene encoding nPRs was at background levels. Virtually no expression of nPRs, mPRs, and membrane component of progesterone receptor (PGRMC I) genes was detected in muscle, and its level was very low in the heart in animals of both sexes. We found sex-specific differentiation of nuclear and membrane receptor mRNA levels in rats in non-reproductive tissues, characterized by a predominance of nPRs transcripts and three subtypes of mPRs (α, β, δ) in females and two subtypes of mPRs (γ, ε) in males. Data on the presence of progesterone receptors in tissues not involved in reproduction confirm the effect of progesterone on these organs. High levels of mRNA for various progesterone receptors in the tissues of male rats, such as the pancreas, lungs, kidney, and trachea, indicate an important physiological role of progestins not only in females, but also in males, which is still poorly understood. The work also discusses the known functions of progesterone receptors in the tissues studied.

Levonorgestrel enhanced Toxoplasma gondii infection risk via progesterone receptor upregulation

Reproductive function in mammals depends on the ability of progesterone to suppress pulsatile gonadotrophin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion in a homeostatic negative feedback loop. Previous research identified that cells upstream from GnRH neurons expressing the nuclear progesterone receptor (PGR) are required for progesterone-negative feedback. However, the identity of these cells and the mechanism by which they reduce GnRH/LH pulsatile secretion is unknown. We aimed to address the hypothesis that PGR expressed by a neural population in the arcuate nucleus recently identified as the GnRH pulse generator, cells expressing Kisspeptin, Neurokinin B, and Dynorphin (KNDy cells), mediate progesterone negative feedback. To achieve this, we utilized female mice with the PGR gene conditionally deleted from kisspeptin cells (KPRKO mice) and observed a substantial decrease in the percentage of KNDy neurons co-expressing PGR mRNA (11% in KPRKO mice versus 86% in wildtype mice). However, KPRKO mice did not display changes in the frequency or amplitude of LH pulses in diestrus or estrus, nor in the ability of exogenous progesterone to blunt a post-castration rise in LH. Further, mRNA expression of arcuate kisspeptin and dynorphin, which are excitatory and inhibitory to GnRH secretion, respectively, remained unaltered in KPRKO mice compared to wildtype controls. Together, these findings show that the near-complete loss of PGR signaling from KNDy cells does not impact negative feedback regulation of GnRH pulse generation in mice, suggesting that feedback through this receptor can occur via a small number of KNDy cells or a yet unidentified cell population.

The steroid hormone progesterone regulates a wide range of functions in the uterus, including menstruation, pregnancy establishment, pregnancy maintenance, and labor. The cellular effects of progesterone are mediated by the nuclear progesterone receptor (PGR). Progesterone resistance, a decreased cellular response to progesterone,is implicated in a wide range of pathologies including endometriosis, preterm birth, and endometrial cancer. Up to 10% of females within reproductive age are impacted by endometriosis, and no cure is available. This study hypothesizes that misregulation of PGR by upstream regulators is a potential cause of progesterone resistance. However, much remains unknown about the regulation of PGR expression, including the location of enhancers and the identity of transcriptional regulators that control PGR expression. In this study, candidate regulatory elements of PGR were identified by integrative analysis of genomic data, and their function was tested using the CRISPR activation system, with PGR mRNA levels as the readout. Using these methods, two PGR enhancers located at the PGR 3’ untranslated region and 200 kbs upstream of the PGR transcription start site were identified. These enhancers permitted the identification of candidate upstream regulators of PGR expression in the uterus, including GATA2, ARID1A, KLF9, and ESR1. Activation of ESR1 increased PGR mRNA levels in the presence of estradiol in cultured uterine cells. Through the discovery of PGR regulators, we can improve our understanding of molecular mechanisms of progesterone resistance. Ultimately, these regulators could be evaluated in cases of progesterone resistance and targeted in the development of therapies.