Proinflammatory environment and role of TNF-α in endometrial function of obese women having polycystic ovarian syndrome

Meng

et al. 2017

EBioMedicine

Adult rats treated concomitantly with insulin and human chorionic gonadotropin exhibit endocrine, metabolic, and reproductive abnormalities that are very similar to those observed in polycystic ovary syndrome (PCOS) patients. In this study, we used this rat model to assess the effects of metformin on PCOS-related uterine dysfunction. In addition to reducing androgen levels, improving insulin sensitivity, and correcting the reproductive cycle, metformin treatment induced morphological changes in the PCOS-like uterus. At the molecular and cellular levels, metformin normalized the androgen receptor-mediated transcriptional program and restored epithelial–stromal interactions. In contrast to glucose transport, uterine inflammatory gene expression was suppressed through the PI3K–Akt–NFκB network, but without affecting apoptosis. These effects appeared to be independent of AMPK subunit and autophagy-related protein regulation. We found that when metformin treatment partially restored implantation, several implantation-related genes were normalized in the PCOS-like rat uterus. These results improve our understanding of how metformin rescues the disruption of the implantation process due to the uterine defects that result from hyperandrogenism and insulin resistance. Our data provide insights into the molecular and functional clues that might help explain, at least in part, the potential therapeutic options of metformin in PCOS patients with uterine dysfunction.

Section: Discussionmentioning

confidence: 60%

Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

Meng

et al. 2017

EBioMedicine

“…For example, there is a noticeable increase in the inflammatory cytokines such as IL-6 and TNFα in the peripheral circulation of PCOS patients 50,51 . Similarly, several studies by our laboratory and others have described increased gene expression of IL-6, TNFα, and Mcp-1 (CCL-2) in PCOS patient endometrium and the PCOS-like rat uterus 10,28,[52][53][54] . Moreover, P4 has been shown to suppress TNFα-stimulated IL-6 and Mcp-1 production in human endometriotic stromal cells in vitro 55 .…”

Section: Commentmentioning

confidence: 91%

“…Our data suggest that regulation of uterine ERK1/2 expression in vivo is time-dependent 20-22 , which is similar to the regulation of PGR isoforms and PGR-targeted gene expression. The MAPK/ERK/p38 signaling pathway contributes to the regulation of inflammation and cytokine production 60,61 , and the dysregulation of inflammation-related molecules is associated with PCOS conditions [52][53][54]62 . Furthermore, like the activation of NFκB signaling that induces the transcriptional levels of inflammation-related gene expression in ovarian granulosa cells and in serum in PCOS patients 51,63 , our previous study has shown that the sustained metformin treatment markedly suppresses uterine inflammatory gene expression, especially the Il-6 and TNFα mRNAs that are associated with inhibition of nuclear NFκB translocation in PCOS-like rats 28 .…”

Section: Commentmentioning

confidence: 99%

Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats

Feng

et al. 2017

Preprint

Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2, two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions.

“…Our data suggest that regulation of uterine ERK1/2 expression in vivo is time dependent (Thienel et al 2002, Lee et al 2013, Tapia-Pizarro et al 2017, which is similar to the regulation of PGR isoforms and PGR-targeted gene expression. The MAPK/ERK/p38 signaling pathway contributes to the regulation of inflammation and cytokine production (Cuadrado & Nebreda 2010, Arthur & Ley 2013, and the dysregulation of inflammation-related molecules is associated with PCOS conditions (Matteo et al 2010, Piltonen et al 2013, Orostica et al 2016. Furthermore, like the activation of NFκB signaling that induces the transcriptional levels of inflammation-related gene expression in ovarian granulosa cells and in serum in PCOS patients (Liu et al 2015, Zhao et al 2015, our previous study has shown that the sustained metformin treatment markedly suppresses uterine inflammatory gene expression, Figure 8 Schematic representation of the actions of metformin on the uterine progesterone signaling in the PCOS-like rats.…”

Section: Esr1mentioning

confidence: 99%

Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats

Journal of Endocrinology

Feng

et al. 2018

Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here, we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of and, two genes that contribute to the development of uterine P4 resistance. and studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions.