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Special Issue "Progesterone Receptor Signaling"

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 27884

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Special Issue Editors

Prof. Dr. James K. Pru

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Guest Editor

Department of Animal Science, University of Wyoming, Laramie, WY 82071, USA
Interests: endometrial regeneration; non-classical progesterone signaling; PGRMC1; pregnancy; uterus

Dr. Wipawee Winuthayanon

E-Mail Website
Guest Editor

School of Molecular Biosciences, Washington State University, Pullman, WA, 99163, USA
Interests: oviduct; pregnancy; progesterone receptor; single cell RNA-seq; steroid hormone signaling

Special Issue Information

Dear Colleagues,

Progesterone receptors (PR) mediate the endocrine actions of the female sex steroid progesterone (P₄), which result in cellular and physiological changes to the reproductive system that establish and maintain pregnancy. While many of the actions of P₄ are mediated by a classical mechanism involving P₄-activated nuclear translocation and transactivation/transrepression of target genes harboring the P₄ response element, non-classical P₄ signaling mechanisms also occur. While some non-classical mechanisms involve the nuclear PR signaling near the plasma membrane where it modulates various phosphorylation cascades, other non-classical mechanisms involve members of the progesterone receptor membrane component family. Epidemiological and genomic studies in women, as well as conditional mutagenesis studies in rodents not only highlight an essential role of PRs in the development and maintenance of female reproductive organs, fertility, behavior, and immune regulation during pregnancy, they also demonstrate participation of PRs in the development of diseases when disrupted. Indeed, faulty or absent P₄ signaling through classical or non-classical mechanism results in a variety of disease states that include endometriosis and women’s reproductive cancers. The objective of this Special Issue is to provide an overview of novel PR signaling mechanisms in diverse reproductive tissues both in the contexts of physiology and pathophysiology

Prof. Dr. James K. Pru
Dr. Wipawee Winuthayanon
Guest Editors

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Keywords

female reproductive tract
fertility
mammary
neurosteroid
nuclear receptor
oviduct
ovary
PGRMC1
pregnancy
progesterone
uterus

Published Papers (14 papers)

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Research

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Open AccessArticle

Progesterone Signaling in Endometrial Epithelial Organoids

and

Cells 2022, 11(11), 1760; https://doi.org/10.3390/cells11111760 - 27 May 2022

Cited by 3 | Viewed by 1642

Abstract

For pregnancy to be established, uterine cells respond to the ovarian hormones, estrogen, and progesterone, via their nuclear receptors, the estrogen receptor (ESR1) and progesterone receptor (PGR). ESR1 and PGR regulate genes by binding chromatin at genes and at distal enhancer regions, which interact via dynamic 3-dimensional chromatin structures. Endometrial epithelial cells are the initial site of embryo attachment and invasion, and thus understanding the processes that yield their receptive state is important. Here, we cultured and treated organoids derived from human epithelial cells, isolated from endometrial biopsies, with estrogen and progesterone and evaluated their transcriptional profiles, their PGR cistrome, and their chromatin conformation. Progesterone attenuated estrogen-dependent gene responses but otherwise minimally impacted the organoid transcriptome. PGR ChIPseq peaks were co-localized with previously described organoid ESR1 peaks, and most PGR and ESR1 peaks were in B (inactive) compartment regions of chromatin. Significantly more ESR1 peaks were assigned to estrogen-regulated genes by considering chromatin loops identified using HiC than were identified using ESR1 peak location relative to closest genes. Overall, the organoids model allowed a definition of the chromatin regulatory components governing hormone responsiveness. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessArticle

Intraovarian, Isoform-Specific Transcriptional Roles of Progesterone Receptor in Ovulation

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Cells 2022, 11(9), 1563; https://doi.org/10.3390/cells11091563 - 05 May 2022

Viewed by 1391

Abstract

Progesterone receptor (PGR) activity is obligatory for mammalian ovulation; however, there is no established direct functional pathway explaining how progesterone receptor completely and specifically regulates oocyte release. This study examined the overarching cell- and isoform-specific effects of the PGR within each cellular compartment of the ovary, using mice null for the PGR (PRKO), as well as isoform-specific null mice. The PGR was expressed in ovarian granulosa and stromal cells and although PRKO ovaries showed no visible histological changes in preovulatory ovarian morphology, follicle rupture did not occur. Reciprocal ovarian transplant experiments established the necessity of ovarian PGR expression for ovulation. Cumulus–oocyte complexes of PRKO mice exhibited normal morphology but showed some altered gene expression. The examination of mitochondrial activity showed subtle differences in PRKO oocytes but no differences in granulosa cell respiration, glycolysis or β-oxidation. Concurrently, RNA-seq identified novel functional pathways through which the PGR may regulate ovulation. PGR-A was the predominant transcriptionally active isoform in granulosa cells and 154 key PGR-dependent genes were identified, including a secondary network of transcription factors. In addition, the PGR regulated unique gene networks in the ovarian stroma. Collectively, we establish the effector pathways activated by the PGR across the ovarian cell types and conclude that PGR coordinates gene expression in the cumulus, granulosa and stromal cells at ovulation. Identifying these networks linking the PGR to ovulation provides novel targets for fertility therapeutics and nonhormonal contraceptive development. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessFeature PaperArticle

SWI/SNF Antagonism of PRC2 Mediates Estrogen-Induced Progesterone Receptor Expression

Asgerally T. Fazleabas

and

Ronald L. Chandler

Cells 2022, 11(6), 1000; https://doi.org/10.3390/cells11061000 - 15 Mar 2022

Cited by 3 | Viewed by 2129

Abstract

Endometrial cancer (EC) is characterized by high estrogen levels unopposed by progesterone. Treatment with progestins is standard for early EC, but the response to progestins is dependent on progesterone receptor (PGR) expression. Here, we show that the expression of PGR in endometrial epithelial cells is dependent on ARID1A, a DNA-binding subunit of the SWI/SNF chromatin-remodeling complex that is commonly mutated in EC. In endometrial epithelial cells with estrogen receptor overexpression, we find that ARID1A promotes estrogen signaling and regulates common gene expression programs. Normally, endometrial epithelial cells expressing estrogen receptors respond to estrogen by upregulating the PGR. However, when ARID1A expression is lost, upregulation of PGR expression is significantly reduced. This phenomenon can also occur following the loss of the SWI/SNF subunit BRG1, suggesting a role for ARID1A- and BRG1-containing complexes in PGR regulation. We find that PGR is regulated by a bivalent promoter, which harbors both H3K4me3 and H3K27me3 histone tail modifications. H3K27me3 is deposited by EZH2, and inhibition of EZH2 in the context of ARID1A loss results in restoration of estrogen-induced PGR expression. Our results suggest a role for ARID1A deficiency in the loss of PGR in late-stage EC and a therapeutic utility for EZH2 inhibitors in this disease. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessArticle

EZH2 and Endometrial Cancer Development: Insights from a Mouse Model

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Cells 2022, 11(5), 909; https://doi.org/10.3390/cells11050909 - 07 Mar 2022

Cited by 2 | Viewed by 1839

Abstract

Enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive complex 2, plays an important role in cancer development. As both oncogenic and tumor suppressive functions of EZH2 have been documented in the literature, the objective of this study is to determine the impact of Ezh2 deletion on the development and progression of endometrial cancer induced by inactivation of phosphatase and tensin homolog (PTEN), a tumor suppressor gene frequently dysregulated in endometrial cancer patients. To this end, we created mice harboring uterine deletion of both Ezh2 and Pten using Cre recombinase driven by the progesterone receptor (Pgr) promoter. Our results showed reduced tumor burden in Pten^d/d; Ezh2^d/d mice compared with that of Pten^d/d mice during early carcinogenesis. The decreased Ki67 index in EZH2 and PTEN-depleted uteri versus that in PTEN-depleted uteri indicated an oncogenic role of EZH2 during early tumor development. However, mice harboring uterine deletion of both Ezh2 and Pten developed unfavorable disease outcome, accompanied by exacerbated epithelial stratification and heightened inflammatory response. The observed effect was non-cell autonomous and mediated by altered immune response evidenced by massive accumulation of intraluminal neutrophils, a hallmark of endometrial carcinoma in Pten^d/d; Ezh2^d/d mice during disease progression. Hence, these results reveal dual roles of EZH2 in endometrial cancer development. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Review

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Open AccessReview

Rapid Actions of the Nuclear Progesterone Receptor through cSrc in Cancer

Claudia Bello-Alvarez

Carmen J. Zamora-Sánchez

and

Ignacio Camacho-Arroyo

Cells 2022, 11(12), 1964; https://doi.org/10.3390/cells11121964 - 18 Jun 2022

Cited by 3 | Viewed by 1139

Abstract

The nuclear progesterone receptor (PR) is mainly known for its role as a ligand-regulated transcription factor. However, in the last ten years, this receptor’s extranuclear or rapid actions have gained importance in the context of physiological and pathophysiological conditions such as cancer. The PR’s polyproline (PXPP) motif allows protein–protein interaction through SH3 domains of several cytoplasmatic proteins, including the Src family kinases (SFKs). Among members of this family, cSrc is the most well-characterized protein in the scenario of rapid actions of the PR in cancer. Studies in breast cancer have provided the most detailed information on the signaling and effects triggered by the cSrc–PR interaction. Nevertheless, the study of this phenomenon and its consequences has been underestimated in other types of malignancies, especially those not associated with the reproductive system, such as glioblastomas (GBs). This review will provide a detailed analysis of the impact of the PR–cSrc interplay in the progression of some non-reproductive cancers, particularly, in GBs. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessReview

Membrane Progesterone Receptors (mPRs, PAQRs): Review of Structural and Signaling Characteristics

Peter Thomas

Cells 2022, 11(11), 1785; https://doi.org/10.3390/cells11111785 - 30 May 2022

Cited by 7 | Viewed by 1469

Abstract

The role of membrane progesterone receptors (mPRs), which belong to the progestin and adipoQ receptor (PAQR) family, in mediating rapid, nongenomic (non-classical) progestogen actions has been extensively studied since their identification 20 years ago. Although the mPRs have been implicated in progestogen regulation of numerous reproductive and non-reproductive functions in vertebrates, several critical aspects of their structure and signaling functions have been unresolved until recently and remain the subject of considerable debate. This paper briefly reviews recent developments in our understanding of the structure and functional characteristics of mPRs. The proposed membrane topology of mPRα, the structure of its ligand-binding site, and the binding affinities of steroids were predicted from homology modeling based on the structures of other PAQRs, adiponectin receptors, and confirmed by mutational analysis and ligand-binding assays. Extensive data demonstrating that mPR-dependent progestogen regulation of intracellular signaling through mPRs is mediated by activation of G proteins are reviewed. Close association of mPRα with progesterone membrane receptor component 1 (PGRMC1), its role as an adaptor protein to mediate cell-surface expression of mPRα and mPRα-dependent progestogen signaling has been demonstrated in several vertebrate models. In addition, evidence is presented that mPRs can regulate the activity of other hormone receptors. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessReview

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

John J. Peluso

Cells 2022, 11(10), 1632; https://doi.org/10.3390/cells11101632 - 13 May 2022

Cited by 4 | Viewed by 1309

Abstract

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. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessFeature PaperReview

Progesterone-Induced Sperm Release from the Oviduct Sperm Reservoir

Supipi Mirihagalle

Jennifer Rose Hughes

and

David Joel Miller

Cells 2022, 11(10), 1622; https://doi.org/10.3390/cells11101622 - 12 May 2022

Cited by 2 | Viewed by 1351

Abstract

In mammalian females, after sperm are deposited in the reproductive tract, a fraction of sperm migrates to the lower oviduct (isthmus) and forms a sperm storage site known as the functional sperm reservoir. The interactions between sperm membrane proteins and oviduct epithelial cells facilitate sperm binding to the oviductal epithelium and retention in the reservoir. Sperm are bound by glycans that contain specific motifs present on isthmic epithelial cells. Capacitated sperm are released from the reservoir and travel further in the oviduct to the ampulla where fertilization occurs. For decades, researchers have been studying the molecules and mechanisms of sperm release from the oviductal sperm reservoir. However, it is still not clear if the release of sperm is triggered by changes in sperm, oviduct cells, oviduct fluid, or a combination of these. While there is a possibility that more than one of these events are involved in the release of sperm from the reservoir, one activator of sperm release has the largest accumulation of supporting evidence. This mechanism involves the steroid hormone, progesterone, as a signal that induces the release of sperm from the reservoir. This review gathers and synthesizes evidence for the role of progesterone in inducing sperm release from the oviduct functional sperm reservoir. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessReview

Physiological Action of Progesterone in the Nonhuman Primate Oviduct

Ov D. Slayden

Fangzhou Luo

and

Cecily V. Bishop

Cells 2022, 11(9), 1534; https://doi.org/10.3390/cells11091534 - 03 May 2022

Cited by 3 | Viewed by 1613

Abstract

Therapies that target progesterone action hold potential as contraceptives and in managing gynecological disorders. Recent literature reviews describe the role of steroid hormones in regulating the mammalian oviduct and document that estrogen is required to stimulate epithelial differentiation into a fully functional ciliated and secretory state. However, these reviews do not specifically address progesterone action in nonhuman primates (NHPs). Primates differ from most other mammals in that estrogen levels are >50 pg/mL during the entire menstrual cycle, except for a brief decline immediately preceding menstruation. Progesterone secreted in the luteal phase suppresses oviductal ciliation and secretion; at the end of the menstrual cycle, the drop in progesterone triggers renewed estrogen-driven tubal cell proliferation ciliation secretory activity. Thus, progesterone, not estrogen, drives fallopian tube cycles. Specific receptors mediate these actions of progesterone, and synthetic progesterone receptor modulators (PRMs) disrupt the normal cyclic regulation of the tube, significantly altering steroid receptor expression, cilia abundance, cilia beat frequency, and the tubal secretory milieu. Addressing the role of progesterone in the NHP oviduct is a critical step in advancing PRMs as pharmaceutical therapies. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessReview

Progesterone Receptor Signaling in the Uterus Is Essential for Pregnancy Success

Dominique I. Cope

and

Diana Monsivais

Cells 2022, 11(9), 1474; https://doi.org/10.3390/cells11091474 - 27 Apr 2022

Cited by 6 | Viewed by 1728

Abstract

The uterus plays an essential role in the reproductive health of women and controls critical processes such as embryo implantation, placental development, parturition, and menstruation. Progesterone receptor (PR) regulates key aspects of the reproductive function of several mammalian species by directing the transcriptional program in response to progesterone (P4). P4/PR signaling controls endometrial receptivity and decidualization during early pregnancy and is critical for the establishment and outcome of a successful pregnancy. PR is also essential throughout gestation and during labor, and it exerts critical roles in the myometrium, mainly by the specialized function of its two isoforms, progesterone receptor A (PR-A) and progesterone receptor B (PR-B), which display distinct and separate roles as regulators of transcription. This review summarizes recent studies related to the roles of PR function in the decidua and myometrial tissues. We discuss how PR acquired key features in placental mammals that resulted in a highly specialized and dynamic role in the decidua. We also summarize recent literature that evaluates the myometrial PR-A/PR-B ratio at parturition and discuss the efficacy of current treatment options for preterm birth. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessReview

Towards an Improved Understanding of the Effects of Elevated Progesterone Levels on Human Endometrial Receptivity and Oocyte/Embryo Quality during Assisted Reproductive Technologies

Nischelle R. Kalakota

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Cells 2022, 11(9), 1405; https://doi.org/10.3390/cells11091405 - 21 Apr 2022

Cited by 3 | Viewed by 2656

Abstract

Ovarian stimulation is an indispensable part of IVF and is employed to produce multiple ovarian follicles. In women who undergo ovarian stimulation with gonadotropins, supraphysiological levels of estradiol, as well as a premature rise in progesterone levels, can be seen on the day of hCG administration. These alterations in hormone levels are associated with reduced embryo implantation and pregnancy rates in IVF cycles with a fresh embryo transfer. This article aims to improve the reader’s understanding of the effects of elevated progesterone levels on human endometrial receptivity and oocyte/embryo quality. Based on current clinical data, it appears that the premature rise in progesterone levels exerts minimal or no effects on oocyte/embryo quality, while advancing the histological development of the secretory endometrium and displacing the window of implantation. These clinical findings strongly suggest that reduced implantation and pregnancy rates are the result of a negatively affected endometrium rather than poor oocyte/embryo quality. Understanding the potential negative impact of elevated progesterone levels on the endometrium is crucial to improving implantation rates following a fresh embryo transfer. Clinical studies conducted over the past three decades, many of which have been reviewed here, have greatly advanced our knowledge in this important area. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessReview

MicroRNAs and Progesterone Receptor Signaling in Endometriosis Pathophysiology

Warren B. Nothnick

Cells 2022, 11(7), 1096; https://doi.org/10.3390/cells11071096 - 24 Mar 2022

Cited by 2 | Viewed by 1676

Abstract

Endometriosis is a significant disease characterized by infertility and pelvic pain in which endometrial stromal and glandular tissue grow in ectopic locations. Altered responsiveness to progesterone is a contributing factor to endometriosis pathophysiology, but the precise mechanisms are poorly understood. Progesterone resistance influences both the eutopic and ectopic (endometriotic lesion) endometrium. An inability of the eutopic endometrium to properly respond to progesterone is believed to contribute to the infertility associated with the disease, while an altered responsiveness of endometriotic lesion tissue may contribute to the survival of the ectopic tissue and associated symptoms. Women with endometriosis express altered levels of several endometrial progesterone target genes which may be due to the abnormal expression and/or function of progesterone receptors and/or chaperone proteins, as well as inflammation, genetics, and epigenetics. MiRNAs are a class of epigenetic modulators proposed to play a role in endometriosis pathophysiology, including the modulation of progesterone signaling. In this paper, we summarize the role of progesterone receptors and progesterone signaling in endometriosis pathophysiology, review miRNAs, which are over-expressed in endometriosis tissues and fluids, and follow this with a discussion on the potential regulation of key progesterone signaling components by these miRNAs, concluding with suggestions for future research endeavors in this area. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessReview

Progesterone and Inflammatory Response in the Oviduct during Physiological and Pathological Conditions

Emily A. McGlade

Akio Miyamoto

and

Wipawee Winuthayanon

Cells 2022, 11(7), 1075; https://doi.org/10.3390/cells11071075 - 23 Mar 2022

Cited by 1 | Viewed by 2237

Abstract

Progesterone has been shown to be a potent suppressor of several inflammatory pathways. During pregnancy, progesterone levels increase, allowing for normal pregnancy establishment and maintenance. The dysregulation of progesterone, as well as inflammation, leads to poor pregnancy outcomes. However, it is unclear how progesterone imbalance could impact inflammatory responses in the oviduct and subsequently result in early pregnancy loss. Therefore, in this review, we describe the role of progesterone signaling in regulating the inflammatory response, with a focus on the oviduct and pathological conditions in the Fallopian tubes. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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Open AccessReview

Progesterone Actions and Resistance in Gynecological Disorders

James A. MacLean II

and

Kanako Hayashi

Cells 2022, 11(4), 647; https://doi.org/10.3390/cells11040647 - 13 Feb 2022

Cited by 16 | Viewed by 3991

Abstract

Estrogen and progesterone and their signaling mechanisms are tightly regulated to maintain a normal menstrual cycle and to support a successful pregnancy. The imbalance of estrogen and progesterone disrupts their complex regulatory mechanisms, leading to estrogen dominance and progesterone resistance. Gynecological diseases are heavily associated with dysregulated steroid hormones and can induce chronic pelvic pain, dysmenorrhea, dyspareunia, heavy bleeding, and infertility, which substantially impact the quality of women’s lives. Because the menstrual cycle repeatably occurs during reproductive ages with dynamic changes and remodeling of reproductive-related tissues, these alterations can accumulate and induce chronic and recurrent conditions. This review focuses on faulty progesterone signaling mechanisms and cellular responses to progesterone in endometriosis, adenomyosis, leiomyoma (uterine fibroids), polycystic ovary syndrome (PCOS), and endometrial hyperplasia. We also summarize the association with gene mutations and steroid hormone regulation in disease progression as well as current hormonal therapies and the clinical consequences of progesterone resistance. Full article

(This article belongs to the Special Issue Progesterone Receptor Signaling)

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