Abstract
Gender differences in a wide variety of physiological parameters have implicated the ovarian hormones, estrogens and progesterone, in the regulation of numerous nonreproductive tissue ...functions. Rapid, nongenomic (nonclassical) progesterone actions mediated by membrane progesterone receptors (mPRs), which belong to the progestin and adipoQ receptor family, have been extensively investigated in reproductive and nonreproductive tissues since their discovery in fish ovaries 20 years ago. The 5 mPR subtypes (α, β, γ, δ, ε) are widely distributed in vertebrate tissues and are often expressed in the same cells as the nuclear progesterone receptor (PR) and progesterone receptor membrane component 1, thereby complicating investigations of mPR-specific functions. Nevertheless, mPR-mediated progesterone actions have been identified in a wide range of reproductive and nonreproductive tissues and distinguished from nuclear PR-mediated ones by knockdown of these receptors with siRNA in combination with a pharmacological approach using mPR- and PR-specific agonists. There are several recent reviews on the roles of the mPRs in vertebrate reproduction and cancer, but there have been no comprehensive assessments of mPR functions in nonreproductive tissues. Therefore, this article briefly reviews mPR functions in a broad range of nonreproductive tissues. The evidence that mPRs mediate progesterone and progestogen effects on neuroprotection, lordosis behavior, respiratory control of apnea, olfactory responses to pheromones, peripheral nerve regeneration, regulation of prolactin secretion in prolactinoma, immune functions, and protective functions in vascular endothelial and smooth muscle cells is critically reviewed. The ubiquitous expression of mPRs in vertebrate tissues suggests mPRs regulate many additional nonreproductive functions that remain to be identified.
We studied the association of estrogen receptor (ER) and progesterone receptor (PR) with endometrial polyp (EP) formation.
A total of 129 EP patients and an equal number of disease-free women were ...evaluated for ER and PR expression in endometrial tissues. Correlation with EP incidence was analyzed, as well as diagnostic value via receiver operating characteristic curve.
ER expression was higher and PR was lower in patients than in controls (p < 0.01). ER levels positively correlated with EP incidence, and PR negatively (p < 0.01). Receiver operating characteristic curves gave ER an area under the curve of 0.6168 (95% CI: 0.5479-0.6856; p < 0.0001) and PR 0.739 (95% CI: 0.6776-0.8003; p < 0.0001).
Imbalance in ER and PR expression associates with EPs formation, offering clinical insights into EP pathology.
In the early phase of pregnancy, decidualization is an indispensable event after mammal embryo implantation, accompanied by proliferation and differentiation of uterine stromal cells. Type II ...cGMP-dependent protein kinase (Prkg2) belongs to the family of serine/threonine kinase, which plays multiple roles in cellular signaling pathways to control proliferation and differentiation. However, the regulatory function and molecular mechanism of Prkg2 in decidualization are still unknown. In this study, we show that Prkg2 has a gradually increased expression pattern during peri-implantation and artificial decidualization, and the expression of Prkg2 is induced by estrogen and progesterone in the ovariectomized mouse uteri and primary cultured uterine stromal cells, the process of which is blocked by treating with estrogen receptor (ER) antagonist (ICI-182,780) and progesterone receptor (PR) antagonist (RU-486). Inhibition of Prkg2 activity by HA-100 promotes uterine stromal cell proliferation but compromises decidualization with decreased expression of prolactin family 8, subfamily a, member 2. In addition, the functional regulation of decidualization by Prkg2 is accomplished by its induced phosphorylation of glycogen synthase kinase-3β (GSK-3β) at serine-9, which results in accumulation of β-catenin in the decidual cells. Taken together, our findings demonstrate that estrogen and progesterone upregulate the expression of Prkg2 in uterine stromal cells depending on ER and PR; Prkg2 promotes phosphorylation of GSK-3β at serine-9 and inactivates it, leading to the accumulation of β-catenin and promoting the process of decidualization. In addition to revealing the regulatory mechanism of Prkg2 that ensures the success of uterine decidualization, our findings will contribute to the understanding in the maintenance of early pregnancy.
Highlights • The expression level of the helix-loop-helix ID1 protein is significantly increased during cancer progression, including salivary gland cancer (SGC) • Targeting ID1 using genetic methods ...and a small molecule inhibitor results in a significant reduction in SGC cell aggressiveness and formation of lung metastatic foci • Tumor-bearing mice were treated with a non-toxic and non-psychoactive cannabinoid compound in order to demonstrate that a clinically translatable drug can down-regulate ID1 expression in SGC cells • We suggest a novel approach for the treatment of patients with aggressive SGC that express high levels of ID1 gene expression
Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC ...subtyping by examining the pathologic and gene expression characteristics of genomically defined luminal A and B subtypes.
Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Español de Investigación en Cáncer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) -positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models were used to test the prognostic significance.
Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were also found to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survival differences within IHC-defined luminal A tumors independently of endocrine therapy administration. Finally, no additional prognostic value within hormonal receptor (HR) -positive/HER2-negative disease was observed with the use of the IHC4 score when intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa.
Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A tumors is HR positive/HER2 negative/Ki-67 less than 14%, and PR more than 20%.
Estrogen receptor (ER) and progesterone receptor (PR) are important prognostic and predictive biomarkers in breast cancer. PET using ER- and PR-specific radioligands enables a whole-body, noninvasive ...assessment of receptor expression. Recent investigations of ER imaging with
F-fluoroestradiol have focused on diagnosing ER-positive metastatic disease, optimizing ER-targeted drug dosage, and predicting endocrine therapy benefit. Studies of PR imaging with
F-fluorofuranyl norprogesterone have investigated how imaging changes in PR expression as a downstream target of ER activation may reflect an early response to ER-targeted therapy. This focused review highlights recent achievements in preclinical and clinical imaging of ER and PR in breast cancer.
27-hydroxycholesterol (27HC) was the first identified endogenous selective estrogen receptor modulator (SERM); 27HC promoted growth and metastasis in experimental models of estrogen receptor-positive ...mammary cancer. There are no data on prediagnosis circulating 27HC and breast cancer risk in women.
We conducted a nested case-control study in the well-characterized Heidelberg, Germany, cohort of the European Investigation into Cancer and Nutrition (EPIC) including 530 incident invasive breast cancer cases, each matched to up to two control participants (n = 1036). Serum 27HC was analyzed by liquid chromatography-mass spectrometry (LC-MS) in blood samples collected at study recruitment. Multivariable conditional logistic regression models were used to quantify the association between circulating 27HC and breast cancer risk overall, by tumor hormone receptor status (ie estrogen and progesterone receptors), and by menopausal status at blood collection. All statistical tests were two-sided.
27HC was not associated with breast cancer risk overall (relative risk RRQuartile4vsQuartile1 Q4vsQ1 = 0.90, 95% confidence interval CI = 0.66 to 1.22). The association between 27HC and breast cancer risk differed by menopausal status at blood collection (Phet = .02), but not by age at diagnosis (Phet = .78). Among women who were postmenopausal at blood collection, higher serum 27HC levels were associated with lower breast cancer risk (RRQ4vsQ1 = 0.56, 95% CI = 0.36 to 0.87). We observed no association between 27HC and breast cancer risk (RRQ4vsQ1 = 1.33, 95% CI = 0.75 to 2.38) among women who were premenopausal at blood collection.
In this first prospective study, higher circulating 27HC was associated with lower risk of breast cancer in postmenopausal women. Identification of the first endogenous SERM associated with reduced risk of invasive breast cancer in postmenopausal women may offer novel avenues for breast cancer prevention strategies.
•Progesterone cerebroprotection after stroke involves multiple effects.•Progesterone increases the density of neurons and oligodendroglial cells.•Progesterone reduces astrogliosis and AQP4 ...expression.•Progesterone reduces activated microglia.•Neural progesterone receptors play a key role in cerebroprotection.
Treatment with progesterone limits brain damage after stroke. However, the cellular bases of the cerebroprotective effects of progesterone are not well documented. The aims of this study were to determine neural cells and functions that are affected by progesterone treatment and the role of neural progesterone receptors (PR) after stroke. Adult male PRNesCre mice, selectively lacking PR in the central nervous system, and their control PRloxP/loxP littermates were subjected to transient ischemia by middle cerebral artery occlusion (MCAO) for 30 min. Mice received either progesterone (8 mg/kg) or vehicle at 1-, 6- and 24- hrs post-MCAO and outcomes were analyzed at 48 h post-MCAO. In PRloxP/loxP mice, progesterone exerted multiple effects on different neural cell types, improved motor functional outcomes and reduced total infarct volumes. In the peri-infarct, progesterone increased the density of neurons (NeuN+ cells), of cells of the oligodendroglial lineage (Olig2+ cells) and of oligodendrocyte progenitors (OP, NG2+ cells). Progesterone decreased the density of activated astrocytes (GFAP+ cells) and reactive microglia (Iba1+ cells) coexpressing the mannose receptor type 1 CD206 marker. Progesterone also reduced the expression of aquaporin 4 (AQP4), the water channel involved in both edema formation and resorption. The beneficial effects of progesterone were not observed in PRNesCre mice. Our findings show that progesterone treatment exerts beneficial effects on neurons, oligodendroglial cells and neuroinflammatory responses via PR. These findings demonstrate that progesterone is a pleiotropic cerebroprotective agent and that neural PR represent a therapeutic target for stroke cerebroprotection.
Studies in teleosts suggest that progestins have crucial functions during early spermatogenesis. However, the role of the different progestin receptors in these mechanisms is poorly understood. In ...this work, we investigated the expression pattern and hormonal regulation of the classical nuclear progestin receptor (Pgr) in the gilthead seabream at three different stages of spermatogenesis: the resting (postspawning) phase, onset of spermatogenesis, and spermiation. Immunolocalization experiments using a seabream specific Pgr antibody revealed that the receptor was expressed in Sertoli and Leydig cells, and also in a subset of spermatogonia type A, throughout spermatogenesis. Short-term treatment of testis explants with 17β-estradiol (E2) increased pgr mRNA expression at all stages, while the progestin 17α,20β-dihydroxy-4-pregnen-3-one (17,20βP) had the opposite effect. At the resting stage, Sertoli cell Pgr expression was positively correlated with the occurrence of proliferating spermatogonia type A in the tubules, and both processes were incremented in vitro by E2 likely through the estrogen receptor alpha (Era) expressed in Sertoli and Leydig cells. In contrast, treatment with 17,20βP downregulated Pgr expression in somatic cells. The androgen 11-ketotestosterone (11-KT) upregulated pgr expression in Leydig cells and promoted the proliferation of mostly spermatogonia type B, but only during spermiation. No relationship between the changes in the cell type-specific expression of the Pgr with the entry into meiosis of germ cells was found. These data suggest a differential steroid regulation of Pgr expression during seabream spermatogenesis and the potential interplay of the E2/Era and 17,20βP/Pgr pathways for the maintenance of spermatogonial renewal rather than entry into meiosis.
The aim of this systematic review and meta-analysis was to conduct a comprehensive assessment of the evidence on the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone ...(MVP) for luteal phase support. Embase and MEDLINE were searched for studies that evaluated the effect of luteal phase support with daily administration of oral dydrogesterone (20 to 40 mg) versus MVP capsules (600 to 800 mg) or gel (90 mg) on pregnancy or live birth rates in women undergoing fresh-cycle IVF (protocol registered at PROSPERO CRD42018105949). Individual participant data (IPD) were extracted for the primary analysis where available and aggregate data were extracted for the secondary analysis. Nine studies were eligible for inclusion; two studies had suitable IPD (full analysis sample: n = 1957). In the meta-analysis of IPD, oral dydrogesterone was associated with a significantly higher chance of ongoing pregnancy at 12 weeks of gestation (odds ratio OR, 1.32; 95% confidence interval CI, 1.08 to 1.61; P = 0.0075) and live birth (OR, 1.28; 95% CI, 1.04 to 1.57; P = 0.0214) compared to MVP. A meta-analysis combining IPD and aggregate data for all nine studies also demonstrated a statistically significant difference between oral dydrogesterone and MVP (pregnancy: OR, 1.16; 95% CI, 1.01 to 1.34; P = 0.04; live birth: OR, 1.19; 95% CI, 1.03 to 1.38; P = 0.02). Safety parameters were similar between the two groups. Collectively, this study indicates that a higher pregnancy rate and live birth rate may be obtained in women receiving oral dydrogesterone versus MVP for luteal phase support.
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