A preliminary study comparing the endometrial expression of inhibin, activin and follistatin in women with a history of implantation failure after IVF treatment and a control group

Prakash, Anjali; Tuckerman, E.; Laird, Susan; Ola, B.; Li, Tin‐Chiu; Ledger, William

doi:10.1111/j.1471-0528.2007.01624.x

Cited by 16 publications

(13 citation statements)

References 10 publications

(10 reference statements)

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“…Aberrant levels of uterine FST, activins, and inhibins are reported in women with recurrent miscarriage (11,12), repeated implantation failure after in vitro fertilization (14), and impending abortion during early pregnancy (10). Our study suggests that regulation of activin signaling by FST during early pregnancy may play important roles in uterine receptivity and decidualization, critical events for the success of early pregnancy.…”

Section: (A) Expression Ofmentioning

confidence: 60%

“…There are two major isoforms of FST, FST288, which is anchored to the cell surface by interactions with heparin sulfate proteoglycans (9), and FST315, which is the predominant form found in circulation. In humans, aberrant expression of FST and activins are implicated in infertility; dysregulation of FST, activins, and inhibins was reported in women with impending abortion (10), recurrent miscarriage (11,12), hypertensive disorders during pregnancy (13), and repeated implantation failure after in vitro fertilization (14). However, the role that FST plays in normal pregnancy remains uncertain.…”

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confidence: 99%

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Follistatin is critical for mouse uterine receptivity and decidualization

Fullerton

Monsivais

Kommagani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Embryo implantation remains a significant challenge for assisted reproductive technology, with implantation failure occurring in ∼50% of in vitro fertilization attempts. Understanding the molecular mechanisms underlying uterine receptivity will enable the development of new interventions and biomarkers. TGFβ family signaling in the uterus is critical for establishing and maintaining pregnancy. Follistatin (FST) regulates TGFβ family signaling by selectively binding TGFβ family ligands and sequestering them. In humans, FST is upregulated in the decidua during early pregnancy, and women with recurrent miscarriage have lower endometrial expression of FST during the luteal phase. Because global knockout of Fst is perinatal lethal in mice, we generated a conditional knockout (cKO) of Fst in the uterus using progesterone receptor-cre to study the roles of uterine Fst during pregnancy. Uterine Fst-cKO mice demonstrate severe fertility defects and deliver only 2% of the number of pups delivered by control females. In Fst-cKO mice, the uterine luminal epithelium does not respond properly to estrogen and progesterone signals and remains unreceptive to embryo attachment by continuing to proliferate and failing to differentiate. The uterine stroma of Fst-cKO mice also responds poorly to artificial decidualization, with lower levels of proliferation and differentiation. In the absence of uterine FST, activin B expression and signaling are up-regulated, and bone morphogenetic protein (BMP) signals are impaired. Our findings support a model in which repression of activin signaling by FST enables uterine receptivity by preserving critical BMP signaling.female infertility | implantation failure | TGFβ signaling | activin antagonism M ouse models are powerful tools for improving our understanding of uterine receptivity because mice can be easily manipulated with well-established genetic tools and experimental approaches (1). Studies using mice have shown that TGFβ family growth factors play critical roles in establishing uterine receptivity. The TGFβ family operates through a shared mechanism. The signaling cascade is initiated by binding of homodimeric or heterodimeric ligands to a cell-surface receptor complex composed of a type 2 receptor kinase and its partner type 1 receptor kinase. Once the ligand binds, the type 2 receptor phosphorylates and activates the type 1 receptor. The activated type 1 receptor kinase phosphorylates receptor SMADs, enabling them to form a complex with the co-SMAD, SMAD4. The resulting heterotrimeric SMAD complex concentrates in the nucleus where it regulates gene expression in conjunction with of a multitude of cofactors. Uterine conditional knockout (cKO) of TGFβ superfamily growth factors bone morphogenetic protein 2 (BMP2), type 1 receptors ALK2 and ALK3, and type 2 receptor bone morphogenetic protein receptor 2 (BMPR2) in mice have shown that local uterine TGFβ family signaling plays key roles in regulating embryo attachment and invasion as well as endometrial stromal cell decidualization (2-5)....

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Section: (A) Expression Ofmentioning

confidence: 60%

mentioning

confidence: 99%

Follistatin is critical for mouse uterine receptivity and decidualization

Fullerton

Monsivais

Kommagani

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Altered expression of integrin receptors in endometrium has also been associated with reduced endometrial receptivity and implantation rates (9). Endometrial biopsies from women with RIF have also been reported to have lower expression of follistatin in glandular epithelium than fertile controls, suggesting a possible role for this binding protein in successful implantation (10). Our study aimed to investigate the role of identification and treatment of CE in women with RIF, and its impact on the success of subsequent IVF cycles.…”

Section: Discussionmentioning

confidence: 99%

Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization

Johnston-MacAnanny

Hartnett

Engmann

et al. 2010

Fertility and Sterility

316

309

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“…The sections were observed on an EVOS XL Core microscope (Thermo Fisher Scientific) at magnifications of 1009, 2009 and 4009 to evaluate and score the immunostain. Each section was examined by two observers who were blind to the source of tissue and the intensity of staining was assessed in 5 random fields of each section at 2009 magnification and by using 'H score' which was calculated as follow [33,41]: H score = RP i 9 (i 9 ?1), where i 9 represents the intensity of staining (0 = negative; 1 = weak; 2 = moderate and 3 = strong) and P i 9 is the percentage of cells (0-100 %) stained at each intensity. In the case of a wide disagreement between both observers, the slides were reanalysed by a third independent reviewer.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Aberrant expression of interleukin-6 and its receptor in Fallopian tubes bearing an ectopic pregnancy with and without tubal cytomegalovirus infection

Ashshi

2016

VirusDis.

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Cytomegalovirus (CMV) has recently been suggested as a potential risk factor for the development of ectopic pregnancy (EP) following upper genital tract infection in women. However, little is known about its associated underlying pathogenic mechanisms. This was a prospective case-control study that measured the prevalence of CMV infection in Fallopian tubes (FT) bearing an EP and its effects on the tubal expression of interleukin (IL)-6 and its signaling molecules, which are known to play significant roles in the immune response against CMV infection as well as embryo implantation. Fresh FTs from 96 EPs during salpingectomy and another 61 women at the midluteal phase during total abdominal hysterectomy (TAH) were collected to measure the rate of CMV by an IVD CE PCR kit. The participants were then classified to measure the expression of IL-6, its receptor (IL6R) and intracellular mediators (gp-130, STAT3) by immunohistochemistry and quantitative RT-PCR. The results showed significantly higher (P = 0.01) rates of CMV in FTs obtained from EP (22.9 %) compared with controls (8.2 %). IL-6 (P = 0.003), IL6Ra (P = 0.02), gp 130 (P = 0.008) and STAT3 (P = 0.03) were significantly higher in TAH-positive (n = 5) compared with TAHnegative FTs by immunohistochemistry. Furthermore, the expression in the non-infected EP samples was significantly higher for IL-6 (P = 0.004), IL6R (P = 0.007), gp130 (P = 0.006) and STAT3 (P = 0.007) compared with negative TAH. Similar results were observed by quantitative PCR. CMV-positive EP samples showed the highest significant increase of the studied molecules by all techniques. In conclusion, Fallopian tubal infection with CMV is higher in EP and could predispose to embryo implantation by up-regulating the expression of IL-6 and its related molecules as part of tubal innate immune response. Further in vitro and in vivo studies are compulsory to illustrate the roles of IL-6 and CMV in the pathogenesis of EP.

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A preliminary study comparing the endometrial expression of inhibin, activin and follistatin in women with a history of implantation failure after IVF treatment and a control group

Cited by 16 publications

References 10 publications

Follistatin is critical for mouse uterine receptivity and decidualization

Follistatin is critical for mouse uterine receptivity and decidualization

Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization

Aberrant expression of interleukin-6 and its receptor in Fallopian tubes bearing an ectopic pregnancy with and without tubal cytomegalovirus infection

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