Progesterone Binding Research Articles

Alcohol intake and endogenous sex hormones in women: Meta-analysis of cohort studies and Mendelian randomization.

The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes. Cross-sectional associations were investigated between self-reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta-analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two-sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6-7.6) and free testosterone (7.8%; 4.1-11.5), and an inverse association with SHBG (-8.1%; -11.3% to -4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk.

Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis.

Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. This analysis included 1208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05). Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer.

Light-Driven Purification of Progesterone from Steroid Mixtures Using a Photoresponsive Metal-Organic Capsule.

Chemical separations are expensive, consuming 10-15% of humanity's global energy budget. Many current separation methods employ thermal energy for distillation, often through the combustion of carbon-containing fuels, or extractions and crystallizations from organic solvents, which must then be discarded or redistilled, with a substantial energetic cost. The direct use of renewable energy sources, such as light, could enable the development of novel separations processes, as is required for the transition away from fossil fuel use. Metal-organic capsules, which can selectively bind molecules from mixtures, can provide the foundation for these novel separations processes. Here we report a tetrahedral metal-organic capsule bearing light-responsive diazo moieties around its metal-ion vertices. This capsule can be used to selectively separate progesterone from a mixture of steroids in a process driven by visible light energy. Our process combines biphasic extraction and selective binding of progesterone with the light-driven release of this molecule in purified form. Ultimately, our process might be adapted to the purifications of the many other fine chemical products that are bound selectively by capsules.

Progesterone activation of β1-containing BK channels involves two binding sites

Progesterone (≥1 µM) is used in recovery of cerebral ischemia, an effect likely contributed to by cerebrovascular dilation. The targets of this progesterone action are unknown. We report that micromolar (µM) progesterone activates mouse cerebrovascular myocyte BK channels; this action is lost in β1-/- mice myocytes and in lipid bilayers containing BK α subunit homomeric channels but sustained on β1/β4-containing heteromers. Progesterone binds to both regulatory subunits, involving two steroid binding sites conserved in β1-β4: high-affinity (sub-µM), which involves Trp87 in β1 loop, and low-affinity (µM) defined by TM1 Tyr32 and TM2 Trp163. Thus progesterone, but not its oxime, bridges TM1-TM2. Mutation of the high-affinity site blunts channel activation by progesterone underscoring a permissive role of the high-affinity site: progesterone binding to this site enables steroid binding at the low-affinity site, which activates the channel. In support of our model, cerebrovascular dilation evoked by μM progesterone is lost by mutating Tyr32 or Trp163 in β1 whereas these mutations do not affect alcohol-induced cerebrovascular constriction. Furthermore, this alcohol action is effectively counteracted both in vitro and in vivo by progesterone but not by its oxime.

Sugammadex Use for Reversal in Nonobstetric Surgery During Pregnancy: A Reexamination of the Evidence.

Sugammadex Use for Reversal in Nonobstetric Surgery During Pregnancy: A Reexamination of the Evidence.

Insight into mitochondrial dysfunction mediated by clozapine-induced inhibition of PGRMC1 in PC12 cells

Clozapine is usually considered as the last resort for treatment-resistant schizophrenia (TRS). However, it shows limited efficacy in cognition improvement. Moreover, the metabolic side effects induced by clozapine can aggravate cognitive impairment, which is closely related to its neurotoxicity. Nevertheless, the mechanisms underlying clozapine’s neurotoxicity remain largely elusive. In this study, PC12 cells were simultaneously treated with different concentrations (0 μM, 10 μM, 20 μM, 40 μM and 80 μM) of clozapine and AG205 which functions as a blocking reagent of progesterone receptor membrane component 1 (PGRMC1). In addition, we examined the effect of PGRMC1 in clozapine-induced neurotoxicity through overexpressing or downregulating PGRMC1. Molecular docking and surface plasmon resonance (SPR) analysis indicated that clozapine and AG205 inhibited the binding of endogenous progesterone to PGRMC1. The results showed that high concentration of clozapine and AG205 induced a significant increase in cytotoxicity, reactive oxygen species (ROS) accumulation and mitochondrial membrane potential (MMP) collapse, all of which were worsened as concentration increases, while overexpression of PGRMC1 reverted the above toxic effect of clozapine on PC12 cells. Furthermore, clozapine and AG205 also downregulated the expression of PGRMC1, glucagon-like peptide-1 receptor (GLP-1R) and mitofusin2 (Mfn2). Interestingly, overexpression of PGRMC1 could revert these effects. Our data suggest that overexpression of PGRMC1 in PC12 cells prevents and restores clozapine-induced oxidative and mitochondrial damage. We propose PGRMC1 activation as a promising therapeutic strategy for clozapine-induced neurotoxicity to facilitate the relief of neuronal damage.

Hyperinsulinism Gateway Between Diabetes and Cancer: New Roles for Bifunctional Antidiabetic - Anticancer Active Somatostatins, IGF - 1 Inhibitors and Insulin Sensitizers

Hyperinsulinism refers to a condition of abnormally high concentration of circulating insulin in the body commonly seen in obese and type 2 diabetic patients due to insulin resistance. Elevated circulating insulin is the main factor linking obesity, diabetes and cancer and an important mechanism of cancer therapeutic resistance and failure. The insulin receptor subfamily which is made up of the insulin receptor (IR), the type 1 IGF receptor (IGF-1) which binds insulin-like growth factors I and II, and the orphan insulin receptor-related receptor (IRRR) have been identified and linked to the process of carcinogenesis, as cancer cells require insulin for growth. IR receptors are overexpressed in various cancers and insulin activates growth mostly through these receptors and their interplays through mainly the PI3K/AKT/mTOR, MAPK and RAS signal transduction pathways. Estrogens and androgens synergistic effects worsen hyperinsulinism and accelerates its carcinogenesis properties while progesterone and Sex Hormone Binding Globulins exert modulatory effects. This review examined the various factor interplays in hyperinsulinism that links diabetes with cancer and the biomarkers involved. It equally identified the potentials and therapeutic roles for Somatostatins, IGF – 1 inhibitors and Insulin sensitizing antidiabetics in preventing and reversing the cancer linked trends.

Endogenous Steroid Hormone Concentrations and Risk of Endometriosis in Nurses' Health Study II.

Few studies have assessed the association between endogenous steroid hormone levels and a subsequent diagnosis of endometriosis. We prospectively evaluated premenopausal plasma sex hormone levels and the risk of laparoscopically confirmed endometriosis in a nested case-control study within Nurses' Health Study II. Between blood collection (1996-1999) and 2009, we ascertained 446 women with incident endometriosis and matched them to 878 controls through risk-set sampling. We conducted multivariable conditional logistic regression accounting for matching and confounders to estimate relative risks (RRs) and 95% confidence intervals (CIs). Women with greater early follicular-phase total or free estradiol levels had a nonlinear increased risk of endometriosis (early follicular total estradiol: second quartile vs. first, RR=2.23 (95% CI: 1.44, 3.47); third quartile, RR=1.83 (95% CI: 1.16, 2.88); fourth quartile, RR=1.68 (95% CI: 1.05, 2.68); early follicular free estradiol: second quartile vs. first, RR=1.63 (95% CI: 1.05, 2.54); third quartile, RR=2.02 (95% CI: 1.31, 3.12); fourth quartile, RR=1.04 (95% CI: 0.66, 1.65)). Free testosterone assessed in quartile categories was not associated with endometriosis, although a threshold effect was observed, with a positive association among women in the top 2% of free testosterone levels. Levels of mid-luteal-phase total and free estradiol, follicular and luteal estrone, total testosterone, progesterone, and sex hormone binding globulin were not associated with endometriosis risk. These results support the role of sex steroids in endometriosis etiology, although the relationships suggest complex threshold effects.

Development of an Impedimetric Aptasensor for Detection of Progesterone in Undiluted Biological Fluids.

A cost-effective, deployable, and quantitative progesterone biosensor is desirable for regular progesterone sensing in biological and environmental samples to safeguard public health. Aptasensors have been shown to be affordable as compared to antibody-based sensors, but so far, none of the progesterone aptamers could detect it in undiluted and unprocessed biological samples. Thus, to select an aptamer suitable for biosensing in unprocessed biological samples, a modified magnetic bead-based approach with counter-selection in milk and serum was performed. G-quadruplex forming progesterone aptamers were preferentially screened through in silico, gold nanoparticle-based adsorption-desorption assay and circular dichroism spectroscopy. GQ5 aptamer showed extended stability and a high progesterone binding affinity (K D 5.29 ± 2.9 nM) as compared to any other reported progesterone aptamers (P4G11 and P4G13). Under optimized conditions, GQ5 aptamer was coated on the gold electrode to develop an impedimetric aptasensor (limit of detection: 0.53, 0.91, and 1.9 ng/mL in spiked buffer, undiluted milk, and serum, respectively, with the dynamic range of detection from 0.1 to 50 ng/mL in buffer and 0.1 to 30 ng/mL in both milk and serum). The aptasensor exhibited a very high level of κ value (>0.9) with ELISA to detect progesterone in milk and serum. The aptasensor could be regenerated three times and can be stored for up to 10 days at 4 °C. Therefore, GQ5 may be used to develop a portable impedimetric aptasensor for clinical and on-site progesterone sensing in various biological and environmental samples.

Potential Disruption of Systemic Hormone Transport by Tobacco Alkaloids Using Computational Approaches.

Tobacco/nicotine is one of the most toxic and addictive substances and continues to pose a significant threat to global public health. The harmful effects of smoking/nicotine affect every system in the human body. Nicotine has been associated with effects on endocrine homeostasis in humans such as the imbalance of gonadal steroid hormones, adrenal corticosteroid hormones, and thyroid hormones. The present study was conducted to characterize the structural binding interactions of nicotine and its three important metabolites, cotinine, trans-3'-hydroxycotinine, and 5'-hydroxycotinine, against circulatory hormone carrier proteins, i.e., sex-hormone-binding globulin (SHBG), corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG). Nicotine and its metabolites formed nonbonded contacts and/or hydrogen bonds with amino acid residues of the carrier proteins. For SHBG, Phe-67 and Met-139 were the most important amino acid residues for nicotine ligand binding showing the maximum number of interactions and maximum loss in ASA. For CBG, Trp-371 and Asn-264 were the most important amino acid residues, and for TBG, Ser-23, Leu-269, Lys-270, Asn-273, and Arg-381 were the most important amino acid residues. Most of the amino acid residues of carrier proteins interacting with nicotine ligands showed a commonality with the interacting residues for the native ligands of the proteins. Taken together, the results suggested that nicotine and its three metabolites competed with native ligands for binding to their carrier proteins. Thus, nicotine and its three metabolites may potentially interfere with the binding of testosterone, estradiol, cortisol, progesterone, thyroxine, and triiodothyronine to their carrier proteins and result in the disbalance of their transport and homeostasis in the blood circulation.

Progesterone Signaling and Mammalian Ovarian Follicle Growth Mediated by Progesterone Receptor Membrane Component Family Members.

How progesterone influences ovarian follicle growth is a difficult question to answer because ovarian cells synthesize progesterone and express not only the classic nuclear progesterone receptor but also members of the progestin and adipoQ receptor family and the progesterone receptor membrane component (PGRMC) family. Which type of progestin receptor is expressed depends on the ovarian cell type as well as the stage of the estrous/menstrual cycle. Given the complex nature of the mammalian ovary, this review will focus on progesterone signaling that is transduced by PGRMC1 and PGRMC2 specifically as it relates to ovarian follicle growth. PGRMC1 was identified as a progesterone binding protein cloned from porcine liver in 1996 and detected in the mammalian ovary in 2005. Subsequent studies focused on PGRMC family members as regulators of granulosa cell proliferation and survival, two physiological processes required for follicle development. This review will present evidence that demonstrates a causal relationship between PGRMC family members and the promotion of ovarian follicle growth. The mechanisms through which PGRMC-dependent signaling regulates granulosa cell proliferation and viability will also be discussed in order to provide a more complete understanding of our current concept of how progesterone regulates ovarian follicle growth.

No Differences in Value-Based Decision-Making Due to Use of Oral Contraceptives

Fluctuating ovarian hormones have been shown to affect decision-making processes in women. While emerging evidence suggests effects of endogenous ovarian hormones such as estradiol and progesterone on value-based decision-making in women, the impact of exogenous synthetic hormones, as in most oral contraceptives, is not clear. In a between-subjects design, we assessed measures of value-based decision-making in three groups of women aged 18 to 29 years, during (1) active oral contraceptive intake (N = 22), (2) the early follicular phase of the natural menstrual cycle (N = 20), and (3) the periovulatory phase of the natural menstrual cycle (N = 20). Estradiol, progesterone, testosterone, and sex-hormone binding globulin levels were assessed in all groups via blood samples. We used a test battery which measured different facets of value-based decision-making: delay discounting, risk-aversion, risk-seeking, and loss aversion. While hormonal levels did show the expected patterns for the three groups, there were no differences in value-based decision-making parameters. Consequently, Bayes factors showed conclusive evidence in support of the null hypothesis. We conclude that women on oral contraceptives show no differences in value-based decision-making compared to the early follicular and periovulatory natural menstrual cycle phases.

Guest encapsulation and self-assembly of a box-like metalla-rectangle featuring Cp*Rh fragments

A box-like metalla-rectangle with a solvophobic pocket was designed and obtained by using polyaromatic building blocks. Polyaromatic hydrocarbons were encapsulated in the pocket of the metalla-rectangle, which was evidenced by NMR spectroscopy and single crystal X-ray diffraction analysis. Besides, owing to the solvophobic property of the pocket of the metalla-rectangle, we observed binding of progesterone, a bioactive molecule with a lipophilic steroid skeleton, which was evidenced by NMR spectroscopy.

Molecular modeling, mutational analysis and steroid specificity of the ligand binding pocket of mPRα (PAQR7): Shared ligand binding with AdipoR1 and its structural basis

The 7-transmembrane architecture of adiponectin receptors (AdipoRs), determined from their X-ray crystal structures, was used for homology modeling of another progesterone and adipoQ receptor (PAQR) family member, membrane progesterone receptor alpha (mPRα). The mPRα model identified excess positively charged residues on the cytosolic side, suggesting it has the same membrane orientation as AdipoRs with an intracellular N-terminus. The homology model showed identical amino acid residues to those forming the zinc binding pocket in AdipoRs, which strongly implies that zinc is also present in mPRα. The homology model showed a critical H-bond interaction between the glutamine (Q) residue at 206 in the binding pocket and the 20-carbonyl of progesterone. Mutational analysis showed no progesterone binding to the arginine (R) 206 mutant and modeling predicted this was due to the strong positive charge of arginine stabilizing the presence of an oleic acid (C18:1) molecule in the binding pocket, as observed in the X-rays of AdipoRs. High Zn2+ concentrations are predicted to form a salt with the carboxylate group of the oleic acid, thereby eliminating its binding to the free fatty acid (FFA) binding pocket, and allowing progesterone to bind. This is supported by experiments showing 100 µM Zn2+ addition restored [3H]-progesterone binding of the Q206R mutant to levels in WT mPRα and increased [3H]-progesterone binding to mPRγ and AdipoR1 which have arginine residues in this region. The model predicts hydrophobic interactions of progesterone with amino acid residues surrounding the binding pocket, including valine 146 in TM3, which when mutated into a polar serine resulted in a complete loss of [3H]-progesterone binding. The mPRα model showed there is no hydrogen bond donor in the vicinity of the 3-keto group of progesterone and ligand structure-activity studies with 3-deoxy steroids revealed that, unlike the nuclear progesterone receptor, the 3-carbonyl oxygen is not essential for binding to mPRα. Interestingly, the small synthetic AdipoR agonist, AdipoRon, displayed binding affinity for mPRα and mimicked progesterone signaling, whereas D-e-MAPP, a ceramidase inhibitor, blocked progesterone signaling. Thus, critical residues around the binding pocket and steroid structures that bind mPRα, as well as similarities with AdipoRs, can be predicted from the homology model.

Loss of β-Arrestins or six Gα proteins in HEK293 cells caused Warburg effect and prevented progesterone-induced rapid proteasomal degradation of progesterone receptor membrane component 1

Hormonal dysregulation plays a significant role in the metabolic switching during malignant transformation. Progesterone Receptor Membrane Component 1 (PGRMC1) is a single-pass transmembrane receptor activated by the binding of progesterone (P4), a sex hormone. In a previous study, P4 treatment caused rapid (within 30 min) induction of aerobic glycolysis in transformed HEK293 cells, a hallmark malignant phenotype known as the Warburg effect. This metabolic reprogramming was associated with the proteasomal degradation of a 70 kilodalton (kDa) PGRMC1. PGRMC1 interacts with a variety of proteins, including G protein-coupled receptors (GPCRs) and P4-PGRMC1 signaling modulates cyclic adenosine monophosphate (cAMP) production. Therefore, we hypothesized that the P4-induced Warburg effect and proteasomal degradation of PGRMC1 involve G proteins and β-Arrestins (ARRBs). In the present study, we investigated P4-induced aerobic glycolysis, proteasomal degradation of p70 PGRMC1, as well as abundance and subcellular translocation of PGRMC1 along with two key glycolytic enzymes Hexokinase 1 (HK1) and Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) in six Gα subunit (Gsix) proteins or ARRB1/2-deficient HEK293 cells. Loss of ARRB1/2 or Gsix proteins inhibited P4-induced p70 PGRMC1 degradation but failed to prevent the P4-induced Warburg effect. Also, deficiency of ARRB1/2 or Gsix proteins differentially affected the basal as well as P4-induced abundance and subcellular translocation of PGRMC1, HK1, and GAPDH proteins. Overall, the findings indicate that P4-PGRMC1-mediated metabolic reprogramming in HEK293 cells depends on β-Arrestins and Gα proteins suggesting the involvement of an underlying GPCR signal transduction pathway.

MiRNome and Functional Network Analysis of PGRMC1 Regulated miRNA Target Genes Identify Pathways and Biological Functions Associated With Triple Negative Breast Cancer.

BackgroundIncreased expression of the progesterone receptor membrane component 1, a heme and progesterone binding protein, is frequently found in triple negative breast cancer tissue. The basis for the expression of PGRMC1 and its regulation on cellular signaling mechanisms remain largely unknown. Therefore, we aim to study microRNAs that target selective genes and mechanisms that are regulated by PGRMC1 in TNBCs.MethodsTo identify altered miRNAs, whole human miRNome profiling was performed following AG-205 treatment and PGRMC1 silencing. Network analysis identified miRNA target genes while KEGG, REACTOME and Gene ontology were used to explore altered signaling pathways, biological processes, and molecular functions.ResultsKEGG term pathway analysis revealed that upregulated miRNAs target specific genes that are involved in signaling pathways that play a major role in carcinogenesis. While multiple downregulated miRNAs are known oncogenes and have been previously demonstrated to be overexpressed in a variety of cancers. Overlapping miRNA target genes associated with KEGG term pathways were identified and overexpression/amplification of these genes was observed in invasive breast carcinoma tissue from TCGA. Further, the top two genes (CCND1 and YWHAZ) which are highly genetically altered are also associated with poorer overall survival.ConclusionsThus, our data demonstrates that therapeutic targeting of PGRMC1 in aggressive breast cancers leads to the activation of miRNAs that target overexpressed genes and deactivation of miRNAs that have oncogenic potential.

Adverse Effects of Selected Markers on the Metabolic and Endocrine Profiles of Obese Women With and Without PCOS.

The aim of the present study, is to investigate the influence of obesity, with and without polycystic ovarian syndrome (PCOS), on the levels of kisspeptin, vitamin D (Vit D), and vascular endothelial growth factor (VEGF) and to explore the relationship between these parameters and endocrine and metabolic variables. The study group included 126 obese Saudi females. Of these 63 were suffering from PCOS while the rest were normo-ovulatory obese women (non-PCOS obese). In the obese PCOS, VEGF was almost four times as high as in the non-PCOS obese, while kisspeptin and Vit D did not differ. A highly significant elevation was recorded in the waist/hip (WHR), cholesterol, LDL-C, fasting glucose, LH, LH/FSH ratio, estradiol (E2), and testosterone, while hip circumference, leptin, progesterone, and sex hormone binding globulin (SHBG) were lower in the obese PCOS subjects. BMI, HDL-C, ghrelin, insulin, and FSH levels did not differ significantly between the two groups. The obese PCOS had the same level of insulin resistance as the non-PCOS group, as judged by QUICK Index. Correlation studies showed a significant negative correlation between kisspeptin and glucose and LH levels, and a positive correlation with LH/FSH ratio in obese PCOS while in the non-PCOS obese, the kisspeptin correlated positively with glucose, and there was no correlation with LH or LH/FSH. VEGF negatively correlated with FSH and positively with LH/FSH ratio in the non-PCOS obese but this was lost in the obese PCOS. PCOS had no effect on the correlation between Vit D and all studied parameters. Multiple regression analysis showed triglyceride as predictor variable for kisspeptin as a dependent variable, while, leptin is a predictor variable for VEGF as a dependent variable. ROC studies showed the highest sensitivity and specificity for VEGF (AOC=1.00), followed by LH/FSH ratio (AOC=0.979). In conclusion, our study shows that PCOS results in significant elevation of VEGF in obese females, while kisspeptin and Vit D levels are not affected. It also leads to elevation in several of the lipid and hormonal abnormalities in the obese females. In addition, PCOS influences relationship between Kisspeptin and VEGF and some parameters such as glucose, LH or FSH and LH/FSH ratio in obese females, but does not affect Vit D relationship with other parameter.

The Relationship Between Androgens and Days per Month of Period Pain, Pelvic Pain, Headache, and TLR4 Responsiveness of Peripheral Blood Mononuclear Cells in Young Women with Dysmenorrhoea.

PurposeWomen bear a disproportionate burden of persistent pain conditions when compared to men. To determine whether the hormonal environment affects the clinical experience of pain, as measured by the days per month of pelvic pain (DPelvicPM), period pain (DPeriodPM), headache (DHeadachePM) or the in vitro EC50 for Interleukin-1β (IL-1β) release following TLR4 stimulation with Lipopolysaccharide from Peripheral Blood Mononuclear Cells (PBMCs). Findings were stratified according to use or non-use of the oral contraceptive pill.Patients and MethodsFifty-six women aged 16–35 years, with minimal or severe dysmenorrhea, and use or non-use of the OC, were enrolled. Blood was collected on two occasions in a single menstrual cycle: Days 1–2 and Days 7–10. Hormonal analysis for testosterone, dihydrotestosterone, dehydroepiandrosterone, Androstenedione, 3α-Androstanediol, 3β-androstanediol, estradiol, estrone, 17α-hydroxyprogesterone, progesterone, cortisol and sex-hormone binding globulin was undertaken using ultra-sensitive Liquid Chromatography Mass–Spectrometry (LC-MS). PBMCs were exposed to lipopolysaccharide (LPS) and the resulting Interleukin-1β output was determined.ResultsNon-users of the OC showed a strongly inverse correlation between a reducing free androgen index (FAI) and increasing DPelvicPM (p=0.0032), DPeriodPM (p=0.013), DHeadachePM (p=0.041). Non-users of the OC showed a significant increase in DPelvicPM (p=0.049) on Days 7–10. Modestly significant associations were found between reduced androgens and potentiated LPS-induced IL-1β (lower EC50).ConclusionThis is the first study to investigate the relationship between the hormonal environment and activation of the immune system in young women with dysmenorrhoea-related pain conditions. Low androgen levels were consistently associated with increased pain. Translational implications for the findings are discussed.

Sugammadex Administration in Pregnant Women: A Case Series of Maternal and Fetal Outcomes.

Sugammadex, given its high affinity for amino-steroid neuromuscular blockers, offers rapid and reliable neuromuscular blockade reversal, making it a popular reversal agent. This characteristic can be very useful in pregnant women, where incomplete reversal can have poor maternal and fetal outcomes. However, its use antenatally in pregnancy is controversial given concerns for progesterone binding, a hormone that is crucial for maintenance of pregnancy. This case series presents obstetric and fetal outcomes in 25 pregnant women who received sugammadex during the antenatal period, thus highlighting the need for further research into the safety of sugammadex during pregnancy.

ATI1 (ATG8-interacting protein 1) and ATI2 define a plant starvation-induced reticulophagy pathway and serve as MSBP1/MAPR5 cargo receptors

ABSTRACT Reticulophagy, the selective autophagy of endoplasmic reticulum (ER) components, is known to operate in eukaryotes from yeast and unicellular algae to animals and plants. Thus far, only ER-stress induced reticulophagy was reported and analyzed in plants. In this study we characterize a reticulophagy pathway in Arabidopsis thaliana that is triggered by dark-induced starvation but not by ER stress. This pathway is defined by the previously reported ATG8-interacting proteins, ATI1 and ATI2. We further identified the ER-localized MSBP1 (Membrane Steroid Binding Protein 1) as an ATI1- and ATI2-interacting protein and an autophagy cargo, and show that ATI1 and ATI2 serve as its cargo receptors. Together, these findings expand our knowledge on plant responses during energy deprivation and highlight the role of this special type of reticulophagy in this process. Abbreviations: AGO1: ARGONAUTE 1; ATI: ATG8-Interacting Protein; BiFC: Bimolecular Fluorescence Complementation; BR: brassinosteroid; conA: concanamycin A; DMSO: dimethyl sulfoxid; DTT: dithiothreitol; ER: endoplasmic reticulum; GFP: green fluorescent protein; MAPR: Membrane-Associated Progesterone Binding Protein; MSBP: Membrane Steroid Binding Protein; SD: standard deviation; SE: standard error; TM: tunicamycin; TOR: target of rapamycin; Y2H: yeast two-hybrid.