Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

Marquardt, Ryan M.; Kim, Tae Hoon; Shin, Jung Ho; Guo, Sun-Wei

doi:10.3390/ijms20153822

Cited by 253 publications

(192 citation statements)

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“…Further transcriptional regulators involved in uterine receptivity are down-regulated in eutopic endometrial tissue from endometriosis patients. These include GATA Binding Protein 2 (GATA2), SRY-Box 17 (SOX17), Indian hedgehog signaling molecule (IHH), COUP transcription factor 2 (COUPTFII), Wingless-type MMTV integration site family (WNT4), Forkhead box O1 (FOXO1), AT-rich interaction domain 1A (ARID1A), and histone deacetylase 3 (HDAC3), most of which are involved in regulation of P4-responsive pathways (17).…”

Section: Association Of Inflammation With Infertility In Patients Witmentioning

confidence: 99%

“…This alteration in the activity of hormone receptors converges in a distinctive phenotype of resistance to progesterone and of estrogen dependence. A recent and detailed revision about the role of P4 and E2 in endometriosis describes the normal molecular hormonal regulation of the physiology of endometrium and its alterations in endometriosis (17) and highlights inflammation as a known key contributor in the pathophysiology of endometriosis, which is strongly associated with chronic pelvic pain and defects in endometrial receptivity and the decidualization process (17,18). In fact, endometriosis is frequently considered as an inflammatory disease.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis

et al. 2020

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Endometriosis is a gynecological disorder characterized by the growth of endometrial tissue (glands and stroma) outside the uterus, mainly in the peritoneal cavity, ovaries, and intestines. This condition shows estrogen dependency and progesterone resistance, and it has been associated with chronic inflammation, severe pain, and infertility, which negatively affect the quality of life in reproductive women. The molecular mechanisms involved in the pathogenesis of endometriosis are not completely understood; however, inflammation plays a key role in the pathophysiology of the disease, mainly by altering the function of immune cells (macrophages, natural killer, and T cells) and increasing levels of pro-inflammatory mediators in the peritoneal cavity, endometrium, and blood. These immune alterations inhibit apoptotic pathways and promote adhesion and proliferation of endometriotic cells, as well as angiogenesis and neurogenesis in endometriotic lesions. It has been demonstrated that hormonal alterations in endometriosis are related to the inflammatory unbalance in this disease. Particularly, steroid hormones (mainly estradiol) promote the expression and release of pro-inflammatory factors. Excessive inflammation in endometriosis contributes to changes of hormonal regulation by modulating sex steroid receptors expression and increasing aromatase activity. In addition, dysregulation of the inflammasome pathway, mediated by an alteration of cellular responses to steroid hormones, participates in disease progression through preventing cell death, promoting adhesion, invasion, and cell proliferation. Furthermore, inflammation is involved in endometriosis-associated infertility, which alters endometrium receptivity by impairing biochemical responses and decidualization. The purpose of this review is to present current research about the role of inflammasome in the pathogenesis of endometriosis as well as the molecular role of sex hormones in the inflammatory responses in endometriosis.

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Section: Association Of Inflammation With Infertility In Patients Witmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis

et al. 2020

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“…Despite the importance of P4, the molecular and cellular mechanisms regulated by this hormone are still the object of intense investigation [33,34]. The biological actions of E2 and P4 are mainly mediated by their nuclear receptors, Estrogen Receptor (ESR1-2, formerly named ERα-β, transcribed from two distinct genes) and Progesterone nuclear Receptor (PGRA-B, two isoforms from the same gene; [15,35]), respectively. Upon binding with E2 or P4, the receptors translocate to the nucleus and modulate expression of E2 or P4 target genes [15,[35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

“…The biological actions of E2 and P4 are mainly mediated by their nuclear receptors, Estrogen Receptor (ESR1-2, formerly named ERα-β, transcribed from two distinct genes) and Progesterone nuclear Receptor (PGRA-B, two isoforms from the same gene; [15,35]), respectively. Upon binding with E2 or P4, the receptors translocate to the nucleus and modulate expression of E2 or P4 target genes [15,[35][36][37][38]. In the last decade, studies have identified direct target genes of ESR and PGR in humans, rodents and cattle [39].…”

Section: Introductionmentioning

confidence: 99%

“…In the last decade, studies have identified direct target genes of ESR and PGR in humans, rodents and cattle [39]. These genes are involved in the repression of the E2 signalling pathway (NR2F2/COUP-TFII; [38]), proliferation of endometrial cells (i.e., IGF1 and EGR1; [35,38]), uterine receptivity (FOXO1, [40]) and decidualisation (NR2F2/COUP-TFII, WNT4, HOXA10; [38]). This non-exhaustive list of steroids targeting genes in the endometrium includes transcription factors that represent regulation nodes of endometrial receptivity and physiology.…”

Section: Introductionmentioning

confidence: 99%

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FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants

Eozénou

Lesage-Padilla

Mauffré

et al. 2020

IJMS

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Forkhead Box L2 (FOXL2) is a member of the FOXL class of transcription factors, which are essential for ovarian differentiation and function. In the endometrium, FOXL2 is also thought to be important in cattle; however, it is not clear how its expression is regulated. The maternal recognition of pregnancy signal in cattle, interferon-Tau, does not regulate FOXL2 expression. Therefore, in the present study, we examined whether the ovarian steroid hormones that orchestrate implantation regulate FOXL2 gene expression in ruminants. In sheep, we confirmed that FOXL2 mRNA and protein was expressed in the endometrium across the oestrous cycle (day 4 to day 15 post-oestrus). Similar to the bovine endometrium, ovine FOXL2 endometrial expression was low during the luteal phase of the oestrous cycle (4 to 12 days post-oestrus) and at implantation (15 days post-oestrus) while mRNA and protein expression significantly increased during the luteolytic phase (day 15 post-oestrus in cycle). In pregnant ewes, inhibition of progesterone production by trilostane during the day 5 to 16 period prevented the rise in progesterone concentrations and led to a significant increase of FOXL2 expression in caruncles compared with the control group (1.4-fold, p < 0.05). Ovariectomized ewes or cows that were supplemented with exogenous progesterone for 12 days or 6 days, respectively, had lower endometrial FOXL2 expression compared with control ovariectomized females (sheep, mRNA, 1.8-fold; protein, 2.4-fold; cattle; mRNA, 2.2-fold; p < 0.05). Exogenous oestradiol treatments for 12 days in sheep or 2 days in cattle did not affect FOXL2 endometrial expression compared with control ovariectomized females, except at the protein level in both endometrial areas in the sheep. Moreover, treating bovine endometrial explants with exogenous progesterone for 48h reduced FOXL2 expression. Using in vitro assays with COS7 cells we also demonstrated that progesterone regulates the FOXL2 promoter activity through the progesterone receptor. Collectively, our findings imply that endometrial FOXL2 is, as a direct target of progesterone, involved in early pregnancy and implantation.

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Reproductive and Developmental Toxicology

et al. 2023

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This chapter provides a practical overview of reproductive and developmental toxicology, with a focus on considerations for human health risk assessment. It provides a brief overview of normal reproduction and development, as well as examples of how toxic agents may impact these processes. Default assumptions for risk assessment of reproductive and developmental toxicants are discussed, and the types of endpoints typically evaluated in animal toxicology studies and epidemiology studies are summarized. A brief overview is also provided of other data that can be useful for hazard identification of reproductive and developmental toxicants, including mechanistic and new approach methodologies, pharmacokinetics/pharmacodynamics, and considerations for the risk assessment of mixtures. Testing procedures and guidelines for reproductive and developmental toxicants (including pharmaceuticals and industrial or environmental chemicals) are summarized.

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Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

Cited by 253 publications

References 237 publications

Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis

Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis

FOXL2 is a Progesterone Target Gene in the Endometrium of Ruminants

Reproductive and Developmental Toxicology

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