Natural Selection of Human Embryos: Impaired Decidualization of Endometrium Disables Embryo-Maternal Interactions and Causes Recurrent Pregnancy Loss

Salker, Madhuri S.; Teklenburg, Gijs; Molokhia, Mariam; Lavery, Stuart; Trew, Geoffrey; Aojanepong, Tepchongchit; Mardon, Helen J.; Lokugamage, Amali; Rai, Raj; Landles, Christian; Roelen, Bernard A.J.; Quenby, Siobhán; Kuijk, Ewart; Kavelaars, Annemieke; Heijnen, Cobi J.; Regan, Lesley; Macklon, Nick S.; Brosens, Jan J.

doi:10.1371/journal.pone.0010287

Cited by 338 publications

(243 citation statements)

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“…Taken together, the pieces of evidence that show an effect of 0.001 for all treatments vs control BPA on endometrial cell decidualization do raise concern, because altered transformation of the endometrium might contribute to reduced success of implantation (Singh et al 2011). Furthermore, many reports show that low levels of PRL are frequently found in cases of recurrent pregnancy loss or spontaneous early miscarriage (Salker et al 2010, Garzia et al 2013.…”

Section: Effect Of Bpa On Secretion Of Biomarkers Of Endometrial Matumentioning

confidence: 99%

Bisphenol A modulates receptivity and secretory function of human decidual cells: an in vitro study

Mannelli¹,

Szóstek²,

Łukasik³

et al. 2015

Reproduction

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The human endometrium is a fertility-determining tissue and a target of steroid hormones' action. Endocrine disruptors (EDs) can exert adverse effects on the physiological function of the decidua at the maternal-fetal interface. We examined the potential effects of an ED, bisphenol A (BPA), on endometrial maturation/decidualization, receptivity, and secretion of decidual factors (biomarkers). In vitro decidualized, endometrial stromal cells from six hysterectomy specimens were treated with 1 pM-1 mM of BPA, for 24 h and assessed for cell viability and proliferation. Three non-toxic concentrations of BPA (1 mM, 1 nM, and 1 pM) were selected to study its influence on secretion of cell decidualization biomarkers (IGF-binding protein and decidual prolactin (dPRL)), macrophage migration inhibitory factor (MIF) secretion, and hormone receptors' expression (estrogen receptors (ERa and ERb); progesterone receptors (PRA and PRB); and human chorionic gonadotropin (hCG)/LH receptor (LH-R)). The results showed a decrease in cell viability (P!0.001) in response to BPA at the level of 1 mM. At the non-toxic concentrations used, BPA perturbed the expression of ERa, ERb, PRA, PRB, and hCG/LH-R (P!0.05). Furthermore, 1 mM of BPA reduced the mRNA transcription of dPRL (P!0.05). Secretion of MIF was stimulated by all BPA treatments, the lowest concentration (1 pM) being the most effective (P!0.001). The multi-targeted disruption of BPA on decidual cells, at concentrations commonly detected in the human population, raises great concern about the possible consequences of exposure to BPA on the function of decidua and thus its potential deleterious effect on pregnancy.Reproduction (2015) 150 115-125

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Section: Effect Of Bpa On Secretion Of Biomarkers Of Endometrial Matumentioning

confidence: 99%

Bisphenol A modulates receptivity and secretory function of human decidual cells: an in vitro study

Mannelli¹,

Szóstek²,

Łukasik³

et al. 2015

Reproduction

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“…8). Thus, lack of SGK1 in the decidua of pregnant mice seems to trigger a series of pathological events that are akin to human miscarriage, including uterine bleeding, early-onset growth restriction and fetal demise.Early human pregnancy events cannot be studied directly, although the decidual response is recapitulated upon differentiation of primary human endometrial stromal cells (HESCs).Furthermore, there is evidence that an aberrant decidual response, associated with reproductive disorders such as endometriosis and RPL, is maintained in culture 27,28 . Thus, to examine the role of SGK1 in human pregnancy failure, we decidualized primary human HESCs from RPL and control subjects over a time-course lasting 8 d (Supplementary Table 1 and Supplementary Fig.…”

mentioning

confidence: 99%

“…Furthermore, there is evidence that an aberrant decidual response, associated with reproductive disorders such as endometriosis and RPL, is maintained in culture 27,28 . Thus, to examine the role of SGK1 in human pregnancy failure, we decidualized primary human HESCs from RPL and control subjects over a time-course lasting 8 d (Supplementary Table 1 and Supplementary Fig.…”

mentioning

confidence: 99%

Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure

Salker

Christian

Steel

et al. 2011

Nat Med

Self Cite

177

140

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Conflict of interest:The authors have declared that no conflict of interest exists.Nonstandard abbreviations used: SGK1, serum-and glucocorticoid-inducible kinase 1; RPL, recurrent pregnancy loss; ENaC, epithelial sodium channel; HESC, human endometrial stromal cells; ROS, reactive oxygen species; IVF, in vitro fertilization; dpc, days post coitus. 2Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations 1,2 .Analysis of mid-secretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival [3][4][5][6] , is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional significance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus. This prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling, and abolished embryo implantation.By contrast, implantation was unhindered in Sgk1 -/-mice but pregnancy was often complicated by bleeding at the decidual-placental interface, fetal growth retardation and subsequent demise. Compared to WT animals, pregnancy-dependent induction of genes involved in oxidative stress defenses was grossly impaired in Sgk1 -/-mice. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from RPL subjects and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the feto-maternal interface vulnerable to oxidative damage.The sustained rise in postovulatory circulating progesterone levels renders the endometrium transiently receptive to embryo implantation. This 'window of implantation', confined to 2 to 4 days during the mid-secretory phase of the cycle, enables the embryo to contact and stably adhere to the endometrial luminal epithelium before invading the decidualizing stroma 7-9 . Decidualization, which denotes the transformation of stromal fibroblasts into specialized secretory decidual cells, is indispensable for pregnancy as it governs local immune responses, controls trophoblast invasion, and protects the conceptus against a variety of physiological stressors associated with pregnancy [10][11][12] . Failure of the endometrium to express a receptive phenotype is a major cause of conception delay and IVF 3 treatment failure. On the other hand, perturbations in the maternal decidual response inevitably lead to pregnancy complications, most prevalent of which is miscarriage 2 . SGK1, a serine/threonine protein kinase homologous to AKT, is rapidly induced in response to a rise in progesterone levels in both human and mouse endometrium, first in epithelial cells and then in the decidualizing st...

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“…Cytokina ta promuje proces implantacji. Co ciekawe, gonadotropina kosmówkowa (hCG), produkowana przez zarodek, wpływa na poziom PROK1 [14,15].…”

Section: Opis Stanu Wiedzyunclassified

The role of immunological markers in assessment of implantation uterus receptivity - clinical implications.

Macura¹,

Szczepanik²,

Sura³

et al. 2017

Med Og Nauk Zdr.

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Macura B, Szczepanik M, Sura P, Śliwa L. Rola markerów immunologicznych w ocenie właściwości implantacyjnych endometrium macicyimplikacje kliniczne. Med. Og Nauk Zdr. 2017; 23(2): 143-147. doi: 10.26444/monz/75293 Streszczenie Wprowadzenie i cel pracy. Problemy nawracających poronień u kobiet, jak również niepowodzeń w implantacji wszczepianych zarodków w metodzie zapłodnienia in vitro (IVF) mogą być związane z nieprawidłowym funkcjonowaniem błony śluzowej macicy. Do przyczyn tych zjawisk zalicza się m.in. nieprawidłowości immunologiczne w funkcjonowaniu endometrium. Skrócony opis stanu wiedzy. Implantację można zdefiniować jako proces wnikania zarodka w głąb błony śluzowej macicy. Przebieg procesu implantacji jest uzależniony od wielu molekularnych interakcji pomiędzy "receptywnym" endometrium a dojrzałą blastocystą. Dojrzała blastocysta może rozpocząć implantację w endometrium macicy tylko podczas tzw. "okienka implantacyjnego". Ograniczony czas "okienka implantacyjnego" umożliwia skoordynowaną komunikację molekularną pomiędzy zarodkiem a endometrium. Obecnie znanych jest wiele czynników pochodzenia macicznego i zarodkowego związanych z implantacją i wczesnym utrzymaniem ciąży. Niestety, chociaż teoretyczna znajomość procesów immunologicznych w endometrium macicy jest powszechnie znana, to jednak trudno jest przełożyć tę wiedzę na praktykę kliniczną. Podsumowanie. Istnieje nadzieja, że nowe procedury diagnostyczne tych zaburzeń będą opierać się o bezpośredni pomiar stężeń określonych markerów w wydzielinie endometrium. Być może w niedługiej przyszłości wiedza o immunologicznych zaburzeniach endometrium zostanie lepiej wykorzystana, co umożliwi skuteczniejszą terapię par z problemem niepłodności. Słowa kluczoweczynniki immunologiczne, endometrium, implantacja, poronienia nawykowe, zapłodnienie in vitro (IVF)

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Natural Selection of Human Embryos: Impaired Decidualization of Endometrium Disables Embryo-Maternal Interactions and Causes Recurrent Pregnancy Loss

Cited by 338 publications

References 32 publications

Bisphenol A modulates receptivity and secretory function of human decidual cells: an in vitro study

Bisphenol A modulates receptivity and secretory function of human decidual cells: an in vitro study

Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure

The role of immunological markers in assessment of implantation uterus receptivity - clinical implications.

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