- Email: [email protected]
Hormonal control of implantation
+Model
ARTICLE IN PRESS
ANDO-834; No. of Pages 4
Disponible en ligne sur
ScienceDirect www.sciencedirect.com Annales d’Endocrinologie xxx (2016) xxx–xxx
Klotz Communications: Implantation
Hormonal control of implantation Contrôle hormonal de l’implantation Olivier Sandra UMR BDR, INRA, ENVA, université Paris-Saclay, 78350 Jouy-en-Josas, France
Abstract In mammals, implantation represents a key step of pregnancy and its progression conditions not only the success of pregnancy but health of the offspring. Implantation requires a complex and specific uterine tissue, the endometrium, whose biological functions are tightly regulated by numerous signals, including steroids and polypeptide hormones. Endometrial tissue is endowed with dynamic properties that associate its ability to control the developmental trajectory of the embryo (driver property) and its ability to react to embryos displaying distinct capacities to develop to term (sensor property). Since dynamical properties of the endometrium can be affected by pre- and post-conceptional environment, determining how maternal hormonal signals and their biological actions are affected by environmental factors (e.g. nutrition, stress, infections) is mandatory to reduce or even to prevent their detrimental effects on endometrial physiology in order to preserve the optimal functionality of this tissue. © 2016 Elsevier Masson SAS. All rights reserved. Keywords: Pregnancy; Implantation; Endometrium; Steroids
Résumé Chez les mammifères, l’implantation est une étape clef de la gestation, dont le déroulement conditionne non seulement la réussite de ce processus vital de la reproduction sexuée mais également la santé des nouveau-nés. L’implantation se déroule au contact d’un tissu utérin spécifique et complexe, l’endomètre, dont les fonctions biologiques sont régulées par de nombreux signaux, en particulier les hormones, qu’elles soient stéroïdiennes ou polypeptidiques. Le tissu endométrial est également doté de propriétés dynamiques, qui couvrent à la fois sa capacité à contrôler la trajectoire développementale de l’embryon indépendamment de la qualité de celui-ci (driver) et sa capacité à réagir comme un biosenseur précoce de la capacité de développement à terme de l’embryon. Dans la mesure où ces propriétés dynamiques peuvent être altérées par l’environnement préet post-conceptionnel, il apparaît crucial de déterminer comment les signaux hormonaux maternels et leurs actions biologiques sont impactés par les facteurs environnementaux (alimentation, stress, infections) afin de réduire voire de prévenir la portée de leurs effets néfastes sur la physiologie de l’endomètre et ainsi garantir la fonctionnalité optimale de ce tissu. © 2016 Elsevier Masson SAS. Tous droits réservés. Mots clés : Gestation ; Implantation ; Endomètre ; Stéroïdes
In mammals, a complex sequence of biological processes and the successful overcome of several critical points are involved in the birth of a viable and healthy progeny. Implantation appears as a critical step of pregnancy, associated with a high rate of embryo loss in all mammalian species studied so far. In humans, reproductive efficiency has been shown to be rather low, with a probability to achieve pregnancy estimated to 20–30% [1]. In addition to endogenous factors (such
E-mail address: [email protected]
as genetic mutations) that could be detrimental for pregnancy development, various environmental insults (nutrition, pollution and endocrine disruptors, infections stress) have been identified as factors that may affect gamete quality and fertilization, journey of the early embryo through the oviduct, cellular interactions between endometrium and hatched blastocyst or conceptus, foeto-placental development and parturition [2,3]. In addition, using assisted reproductive technologies (ART) and embryo transfer may alter the biological properties of the embryo with a subsequent impact on later stages of pregnancy [4]. Therefore, inadequate maternal compartment and/or in vitro
http://dx.doi.org/10.1016/j.ando.2016.04.013 0003-4266/© 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Sandra http://dx.doi.org/10.1016/j.ando.2016.04.013
O.
Hormonal
control
of
implantation.
Ann
Endocrinol
(Paris)
(2016),
+Model ANDO-834; No. of Pages 4
ARTICLE IN PRESS
2
O. Sandra / Annales d’Endocrinologie xxx (2016) xxx–xxx
manipulations of embryos affect the two way interactions that take place between the mother and the embryo when pregnancy initiates, precluding completion of successful pregnancy or affecting long-term health status of the offspring [5]. Focusing on ovarian steroids as essential components of maternal systemic signals required for pregnancy, this paper presents a brief overview on how these hormones regulate endometrium functionality in normal conditions and adversely alter its interactions with the embryo when maternal physiology is perturbed. 1. Endometrium as an essential tissue for progression and issue of pregnancy In terms of contribution to pregnancy, mammalian females not only produce gametes (oocytes) but they also host the whole gestation in the reproductive tract (oviduct and uterus) until term. Whereas in vitro production of embryos and embryo transfer have demonstrated the oviduct to be a dispensable organ for supporting progression of pregnancy to term, no surrogate biological or artificial system has been derived for the uterus [6]. In normal physiological conditions, the uterus and its internal part referred as the endometrium constitute the maternal site for embryo implantation. The adult endometrium is a complex tissue that consists of stromal cells, luminal and glandular epithelial cells, endothelial and vascular smooth muscle cells, as well as a complex network of leukocytes populations. The endometrium is a fascinating and unique tissue that exhibits remarkable plasticity, with regeneration, reparation and remodelling occurring during estrous cycle, following pregnancy failures, and after parturition. As the biological interface dedicated to the interactions with the embryo then with the foeto-placental unit, the endometrium represents a critical tissue for normal fertility and reproductive success in all mammals. Recent data have demonstrated that the endometrium is able to: • drive the developmental trajectory of the embryo then of the foetal-placental unit [7]; • and react to embryos that display distinct capacities to term development [8–10]. Therefore, the mammalian endometrium is a highly dynamic tissue endowed with driver and sensor properties [11] that are controlled by maternal factors in the absence of conception and by maternal factors and embryonic signals when pregnancy occurs. 2. Steroids and regulation of implantation Although implantation itself is a dynamic and tightly regulated process occurring between a competent embryo and the synchronized endometrial tissue, events priming the endometrium for implantation are maternally driven. Hormonal regulation of implantation starts with a set of maternal factors that are produced distantly from the endometrium and will sequentially act on this tissue to make it receptive to embryo that will implant during a specific period (referred to window of Please cite this article in press as: Sandra http://dx.doi.org/10.1016/j.ando.2016.04.013
O.
Hormonal
implantation) at the blastocyst stage in many species (e.g. primates, rodents, rabbit) or as an elongated conceptus in ruminants and pig [12]. In mammalian species with invasive implantation (primates including humans, rodents, rabbit), endometrial receptivity refers to a post-ovulatory process that includes decidualization of stromal endometrial fibroblasts, abundant secretory activities of endometrial glands, afflux of immune cells including specialized NK cells and spiral arteries remodelling. These events are necessary for supporting apposition, adhesion, penetration and invasion of the embryo into the endometrial wall [13]. In species with superficial implantation (ruminants, horse, pig), decidual transformation of stromal fibroblasts does not occur but endometrial receptivity in these species shares conserved molecular pathways and common genes with endometrial receptivity associated with invasive implantation [14,15], including some decidualization-related factors [16]. Progesterone-induced differentiation of oestrogen-primed endometrial stromal cells allows their transformation into secretory decidual cells. By regulating cytokines secretions and production of cell-surface proteins of endometrial cells, decidual cells control the invasion of trophoblast as well as the type and functions of immune cells in order to create a local immune privileged environment indispensable for embryo implantation and placental development [17]. In contrast to most mammals, decidualization of the human endometrium does not require embryo signalling and occurs at each cycle, irrespective of the presence or absence of an embryo. Based on the use of: • endometrial biopsies across menstrual cycle; • murine models with endometrium-targeted gene depletion; • and in vitro treatment of endometrial stromal fibroblasts, a wealth of publications has presented molecular changes (transcriptomic, epigenomic, lipidomics and proteomic analyses) associated with endometrial receptivity and decidualization in primates and rodents [18,19], leading to the identification of potential biomarkers for endometrial receptivity in women [20,21]. In all mammalian species, a large array of estrogen (E2) and progesterone P4-dependant immune related genes have been identified (e.g. indoleamine 2,3-dioxygenase [IDO], Progesterone-Induced Blocking Factor [PIBF], Tolllike receptor family [TLR]), indicating that E2 is globally a pro-inflammatory steroid whereas P4 is an anti-inflammatory and immunosuppressive factor. Overall, cyclical changes in the sex steroids production influence a variety of endometrial genes, which act to protect this tissue against pathogenic agents, while simultaneously preparing it for implantation [22]. 3. Maternal perturbations of endometrial function and consequences for pregnancy Mice carrying null mutation for genes encoding steroid hormone receptors (Esr1, Esr2, Pr-A, Pr-B) and downstream target control
of
implantation.
Ann
Endocrinol
(Paris)
(2016),
+Model ANDO-834; No. of Pages 4
ARTICLE IN PRESS O. Sandra / Annales d’Endocrinologie xxx (2016) xxx–xxx
genes (e.g. Coup-tfII, Fkbp4, Ihh, Ncoa2) have confirmed the critical contribution of steroid signalling for endometrium receptivity and implantation [19,23]. Complementary to these genetic studies, animal models with physiological challenges have illustrated how changes in maternal systemic signals target and modify endometrial function that will in turn affect embryo development. Undernutrition of pregnant mice during the postfertilization period (0.5–3.5 days post-coitum) is associated with an increased birth weight and hypertension in female offspring [24]. Neonatal treatment of mice or ewes with a P4 analogue leads to infertility in adults as a consequence of endometrial glands depletion and reduction in luminal epithelium surface [25]. In cattle, pre-implantation treatment of heifers with P4 has been shown to increase the size of bovine conceptuses that were transferred to these P4-supplemented females at the blastocyst stage. Inversely, reduced P4 levels are associated with shrinkage of conceptus length and lower interferon-tau secretion (the major signal of maternal recognition in ruminants) that might be detrimental for maternal recognition of pregnancy. Phenotypic consequences that associate elongation and variations in P4 blood levels have been correlated with quantitative and qualitative alterations in endometrial gene expression related to uterine secreted factors (collectively named histotroph), including genes encoding secreted proteins (FABP3, MIF) or amino-acid transporters (SLC2A5) [26]. In humans, environmental insults (e.g. stress) or metabolic abnormalities (e.g. obesity) have been shown to be associated with infertility, early pregnancy failure and late pregnancy complications with impaired fetal development, with altered secretion profiles of polypeptidic hormones (e.g. prolactin, adipokines) and vital hormones such as P4 [27,28]. In conclusion, in all mammalian species, although E2 and P4 do not contribute to embryo development by a direct action on embryo cells, maternal perturbations in steroids secretion and alterations in steroids-regulated expression of various membrane, intracellular and extracellular factors have undoubtedly demonstrated adverse consequences on endometrial receptivity detrimental to implantation with a subsequent impact on early and late development of the embryo. Peri-implantation period represents a short time-step of pregnancy but events taking place during this process may considerably impact progression of pregnancy and progeny health. If pregnancy initiates with the production of at least one embryo, foetal-placental development, pregnancy outcome and post-natal issue cannot be analysed without considering the contribution of the endometrium as the interface receiving maternal signals then translating them as a driving force of embryo development at the epigenetic level. When assisted reproductive technologies are applied, defining embryo quality is critical but determining endometrium quality with precision is of prime importance to estimate the reproductive capacity of this tissue [29,30]. When endometrial quality is suboptimal or seriously compromised, treating endometrium to restore functionality and ensure implantation then pregnancy will require the careful evaluation of the treatment in terms of pregnancy outcome and health status of the progeny. Please cite this article in press as: Sandra http://dx.doi.org/10.1016/j.ando.2016.04.013
O.
Hormonal
3
Disclosure of interest The author declares that he has no competing interest. References [1] Santos MA, Kuijk EW, Macklon NS. The impact of ovarian stimulation for IVF on the developing embryo. Reproduction 2010;139:23–34. [2] Fleming TP, Kwong WY, Porter R, Ursell E, Fesenko I, Wilkins A, et al. The embryo and its future. Biol Reprod 2004;71:1046–54. [3] Leroy JL, Van SA, Opsomer G, Goovaerts IG, Bols PE. Reduced fertility in high-yielding dairy cows: are the oocyte and embryo in danger? Part II. Mechanisms linking nutrition and reduced oocyte and embryo quality in high-yielding dairy cows. Reprod Domest Anim 2008;43:623–32. [4] Grace KS, Sinclair KD. Assisted reproductive technology, epigenetics, and long-term health: a developmental time bomb still ticking. Semin Reprod Med 2009;27:409–16. [5] Douglas AJ. Mother–offspring dialogue in early pregnancy: impact of adverse environment on pregnancy maintenance and neurobiology. Prog Neuropsychopharmacol Biol Psychiatry 2001;35:1167–77. [6] Chavatte-Palmer P, Lévy R, Boileau P. Reproduction without a uterus? State of the art of ectogenesis. Gynecol Obstet Fertil 2012;40: 695–7. [7] Hue I, Degrelle SA, Campion E, Renard JP. Gene expression in elongating and gastrulating embryos from ruminants. Soc Reprod Fertil Suppl 2007;64:365–77. [8] Bauersachs S, Ulbrich SE, Zakhartchenko V, Minten M, Reichenbach M, Reichenbach HD, et al. The endometrium responds differently to cloned versus fertilized embryos. Proc Natl Acad Sci U S A 2009;106:5681–6. [9] Mansouri-Attia N, Sandra O, Aubert J, Degrelle S, Everts RE, GiraudDelville C, et al. Endometrium as an early sensor of in vitro embryo manipulation technologies. Proc Natl Acad Sci U S A 2009;106:5687–92. [10] Brosens JJ, Salker MS, Teklenburg G, Nautiyal J, Salter S, Lucas ES, et al. Uterine selection of human embryos at implantation. Sci Rep 2014;4:3894. [11] Sandra O, Mansouri-Attia N, Lea RG. Novel aspects of endometrial function: a biological sensor of embryo quality and driver of pregnancy success. Reprod Fertil Dev 2011;24:68–79. [12] Hue I. Determinant molecular markers for peri-gastrulating bovine embryo development. Reprod Fertil Dev 2016;28:51–65. [13] Bazer FW, Spencer TE, Johnson GA, Burghardt RC, Wu G. Comparative aspects of implantation. Reproduction 2009;138:195–209. [14] Bauersachs S, Mitko K, Ulbrich SE, Blum H, Wolf E. Transcriptome studies of bovine endometrium reveal molecular profiles characteristic for specific stages of estrous cycle and early pregnancy. Exp Clin Endocrinol Diabetes 2008;116:371–84. [15] Eozenou C, Vitorino Carvalho A, Forde N, Giraud-Delville C, Gall L, Lonergan P, et al. FOXL2 is regulated during the bovine estrous cycle and its expression in the endometrium is independent of conceptus-derived interferon tau. Biol Reprod 2012;87:32. [16] Johnson GA, Burghardt RC, Joyce MM, Spencer TE, Bazer FW, Pfarrer C, et al. Osteopontin expression in uterine stroma indicates a decidualizationlike differentiation during ovine pregnancy. Biol Reprod 2003;68:1951–8. [17] Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev 2014;35:851–905. [18] Haouzi D, Dechaud H, Assou S, De Vos J, Hamamah S. Insights into human endometrial receptivity from transcriptomic and proteomic data. Reprod Biomed Online 2012;24:23–34. [19] Large MJ, DeMayo FJ. The regulation of embryo implantation and endometrial decidualization by progesterone receptor signaling. Mol Cell Endocrinol 2012;358:155–65. [20] Cheong Y, Boomsma C, Heijnen C, Macklon N. Uterine secretomics: a window on the maternal-embryo interface. Fertil Steril 2013;99:1093–9. [21] Garrido-Gomez T, Ruiz-Alonso M, Blesa D, Diaz-Gimeno P, Vilella F, Simon C. Profiling the gene signature of endometrial receptivity: clinical results. Fertil Steril 2013;99:1078–85. [22] Lea RG, Sandra O. Immunoendocrine aspects of endometrial function and implantation. Reproduction 2007;134:389–404.
control
of
implantation.
Ann
Endocrinol
(Paris)
(2016),
+Model ANDO-834; No. of Pages 4
ARTICLE IN PRESS
4
O. Sandra / Annales d’Endocrinologie xxx (2016) xxx–xxx
[23] Sandra O, Chaouat G, Lédée N. Interactions mère-embryon en période préimplantatoire chez les mammifères. In: Saint-Dizier M, Chastant-Maillard S, editors. La reproduction animale et humaine. Versailles: Editions Quae; 2014. p. 345–65. [24] Watkins AJ, Ursell E, Panton R, Papenbrock T, Hollis L, Cunningham C, et al. Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease. Biol Reprod 2008;78:299–306. [25] Cooke PS, Spencer TE, Bartol FF, Hayashi K. Uterine glands: development, function and experimental model systems. Mol Hum Reprod 2013;19:547–58. [26] Forde N, Lonergan P. Transcriptomic analysis of the bovine endometrium: what is required to establish uterine receptivity to implantation in cattle? J Reprod Dev 2012;58:189–95.
Please cite this article in press as: Sandra http://dx.doi.org/10.1016/j.ando.2016.04.013
O.
Hormonal
[27] Nakamura K, Sheps S, Arck PC. Stress and reproductive failure: past notions, present insights and future directions. J Assist Reprod Genet 2008;25:47–62. [28] Dos Santos E, Duval F, Vialard F, Dieudonné MN. The roles of leptin and adiponectin at the fetal-maternal interface in humans. Horm Mol Biol Clin Investig 2015;24:47–63. [29] Edgell TA, Rombauts LJ, Salamonsen LA. Assessing receptivity in the endometrium: the need for a rapid, non-invasive test. Reprod Biomed Online 2013;27:486–96. [30] Galliano D, Bellver J, Díaz-García C, Simón C, Pellicer A. ART and uterine pathology: how relevant is the maternal side for implantation? Hum Reprod Update 2015;21:13–38.
control
of
implantation.
Ann
Endocrinol
(Paris)
(2016),
ARTICLE IN PRESS
ANDO-834; No. of Pages 4
Disponible en ligne sur
ScienceDirect www.sciencedirect.com Annales d’Endocrinologie xxx (2016) xxx–xxx
Klotz Communications: Implantation
Hormonal control of implantation Contrôle hormonal de l’implantation Olivier Sandra UMR BDR, INRA, ENVA, université Paris-Saclay, 78350 Jouy-en-Josas, France
Abstract In mammals, implantation represents a key step of pregnancy and its progression conditions not only the success of pregnancy but health of the offspring. Implantation requires a complex and specific uterine tissue, the endometrium, whose biological functions are tightly regulated by numerous signals, including steroids and polypeptide hormones. Endometrial tissue is endowed with dynamic properties that associate its ability to control the developmental trajectory of the embryo (driver property) and its ability to react to embryos displaying distinct capacities to develop to term (sensor property). Since dynamical properties of the endometrium can be affected by pre- and post-conceptional environment, determining how maternal hormonal signals and their biological actions are affected by environmental factors (e.g. nutrition, stress, infections) is mandatory to reduce or even to prevent their detrimental effects on endometrial physiology in order to preserve the optimal functionality of this tissue. © 2016 Elsevier Masson SAS. All rights reserved. Keywords: Pregnancy; Implantation; Endometrium; Steroids
Résumé Chez les mammifères, l’implantation est une étape clef de la gestation, dont le déroulement conditionne non seulement la réussite de ce processus vital de la reproduction sexuée mais également la santé des nouveau-nés. L’implantation se déroule au contact d’un tissu utérin spécifique et complexe, l’endomètre, dont les fonctions biologiques sont régulées par de nombreux signaux, en particulier les hormones, qu’elles soient stéroïdiennes ou polypeptidiques. Le tissu endométrial est également doté de propriétés dynamiques, qui couvrent à la fois sa capacité à contrôler la trajectoire développementale de l’embryon indépendamment de la qualité de celui-ci (driver) et sa capacité à réagir comme un biosenseur précoce de la capacité de développement à terme de l’embryon. Dans la mesure où ces propriétés dynamiques peuvent être altérées par l’environnement préet post-conceptionnel, il apparaît crucial de déterminer comment les signaux hormonaux maternels et leurs actions biologiques sont impactés par les facteurs environnementaux (alimentation, stress, infections) afin de réduire voire de prévenir la portée de leurs effets néfastes sur la physiologie de l’endomètre et ainsi garantir la fonctionnalité optimale de ce tissu. © 2016 Elsevier Masson SAS. Tous droits réservés. Mots clés : Gestation ; Implantation ; Endomètre ; Stéroïdes
In mammals, a complex sequence of biological processes and the successful overcome of several critical points are involved in the birth of a viable and healthy progeny. Implantation appears as a critical step of pregnancy, associated with a high rate of embryo loss in all mammalian species studied so far. In humans, reproductive efficiency has been shown to be rather low, with a probability to achieve pregnancy estimated to 20–30% [1]. In addition to endogenous factors (such
E-mail address: [email protected]
as genetic mutations) that could be detrimental for pregnancy development, various environmental insults (nutrition, pollution and endocrine disruptors, infections stress) have been identified as factors that may affect gamete quality and fertilization, journey of the early embryo through the oviduct, cellular interactions between endometrium and hatched blastocyst or conceptus, foeto-placental development and parturition [2,3]. In addition, using assisted reproductive technologies (ART) and embryo transfer may alter the biological properties of the embryo with a subsequent impact on later stages of pregnancy [4]. Therefore, inadequate maternal compartment and/or in vitro
http://dx.doi.org/10.1016/j.ando.2016.04.013 0003-4266/© 2016 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Sandra http://dx.doi.org/10.1016/j.ando.2016.04.013
O.
Hormonal
control
of
implantation.
Ann
Endocrinol
(Paris)
(2016),
+Model ANDO-834; No. of Pages 4
ARTICLE IN PRESS
2
O. Sandra / Annales d’Endocrinologie xxx (2016) xxx–xxx
manipulations of embryos affect the two way interactions that take place between the mother and the embryo when pregnancy initiates, precluding completion of successful pregnancy or affecting long-term health status of the offspring [5]. Focusing on ovarian steroids as essential components of maternal systemic signals required for pregnancy, this paper presents a brief overview on how these hormones regulate endometrium functionality in normal conditions and adversely alter its interactions with the embryo when maternal physiology is perturbed. 1. Endometrium as an essential tissue for progression and issue of pregnancy In terms of contribution to pregnancy, mammalian females not only produce gametes (oocytes) but they also host the whole gestation in the reproductive tract (oviduct and uterus) until term. Whereas in vitro production of embryos and embryo transfer have demonstrated the oviduct to be a dispensable organ for supporting progression of pregnancy to term, no surrogate biological or artificial system has been derived for the uterus [6]. In normal physiological conditions, the uterus and its internal part referred as the endometrium constitute the maternal site for embryo implantation. The adult endometrium is a complex tissue that consists of stromal cells, luminal and glandular epithelial cells, endothelial and vascular smooth muscle cells, as well as a complex network of leukocytes populations. The endometrium is a fascinating and unique tissue that exhibits remarkable plasticity, with regeneration, reparation and remodelling occurring during estrous cycle, following pregnancy failures, and after parturition. As the biological interface dedicated to the interactions with the embryo then with the foeto-placental unit, the endometrium represents a critical tissue for normal fertility and reproductive success in all mammals. Recent data have demonstrated that the endometrium is able to: • drive the developmental trajectory of the embryo then of the foetal-placental unit [7]; • and react to embryos that display distinct capacities to term development [8–10]. Therefore, the mammalian endometrium is a highly dynamic tissue endowed with driver and sensor properties [11] that are controlled by maternal factors in the absence of conception and by maternal factors and embryonic signals when pregnancy occurs. 2. Steroids and regulation of implantation Although implantation itself is a dynamic and tightly regulated process occurring between a competent embryo and the synchronized endometrial tissue, events priming the endometrium for implantation are maternally driven. Hormonal regulation of implantation starts with a set of maternal factors that are produced distantly from the endometrium and will sequentially act on this tissue to make it receptive to embryo that will implant during a specific period (referred to window of Please cite this article in press as: Sandra http://dx.doi.org/10.1016/j.ando.2016.04.013
O.
Hormonal
implantation) at the blastocyst stage in many species (e.g. primates, rodents, rabbit) or as an elongated conceptus in ruminants and pig [12]. In mammalian species with invasive implantation (primates including humans, rodents, rabbit), endometrial receptivity refers to a post-ovulatory process that includes decidualization of stromal endometrial fibroblasts, abundant secretory activities of endometrial glands, afflux of immune cells including specialized NK cells and spiral arteries remodelling. These events are necessary for supporting apposition, adhesion, penetration and invasion of the embryo into the endometrial wall [13]. In species with superficial implantation (ruminants, horse, pig), decidual transformation of stromal fibroblasts does not occur but endometrial receptivity in these species shares conserved molecular pathways and common genes with endometrial receptivity associated with invasive implantation [14,15], including some decidualization-related factors [16]. Progesterone-induced differentiation of oestrogen-primed endometrial stromal cells allows their transformation into secretory decidual cells. By regulating cytokines secretions and production of cell-surface proteins of endometrial cells, decidual cells control the invasion of trophoblast as well as the type and functions of immune cells in order to create a local immune privileged environment indispensable for embryo implantation and placental development [17]. In contrast to most mammals, decidualization of the human endometrium does not require embryo signalling and occurs at each cycle, irrespective of the presence or absence of an embryo. Based on the use of: • endometrial biopsies across menstrual cycle; • murine models with endometrium-targeted gene depletion; • and in vitro treatment of endometrial stromal fibroblasts, a wealth of publications has presented molecular changes (transcriptomic, epigenomic, lipidomics and proteomic analyses) associated with endometrial receptivity and decidualization in primates and rodents [18,19], leading to the identification of potential biomarkers for endometrial receptivity in women [20,21]. In all mammalian species, a large array of estrogen (E2) and progesterone P4-dependant immune related genes have been identified (e.g. indoleamine 2,3-dioxygenase [IDO], Progesterone-Induced Blocking Factor [PIBF], Tolllike receptor family [TLR]), indicating that E2 is globally a pro-inflammatory steroid whereas P4 is an anti-inflammatory and immunosuppressive factor. Overall, cyclical changes in the sex steroids production influence a variety of endometrial genes, which act to protect this tissue against pathogenic agents, while simultaneously preparing it for implantation [22]. 3. Maternal perturbations of endometrial function and consequences for pregnancy Mice carrying null mutation for genes encoding steroid hormone receptors (Esr1, Esr2, Pr-A, Pr-B) and downstream target control
of
implantation.
Ann
Endocrinol
(Paris)
(2016),
+Model ANDO-834; No. of Pages 4
ARTICLE IN PRESS O. Sandra / Annales d’Endocrinologie xxx (2016) xxx–xxx
genes (e.g. Coup-tfII, Fkbp4, Ihh, Ncoa2) have confirmed the critical contribution of steroid signalling for endometrium receptivity and implantation [19,23]. Complementary to these genetic studies, animal models with physiological challenges have illustrated how changes in maternal systemic signals target and modify endometrial function that will in turn affect embryo development. Undernutrition of pregnant mice during the postfertilization period (0.5–3.5 days post-coitum) is associated with an increased birth weight and hypertension in female offspring [24]. Neonatal treatment of mice or ewes with a P4 analogue leads to infertility in adults as a consequence of endometrial glands depletion and reduction in luminal epithelium surface [25]. In cattle, pre-implantation treatment of heifers with P4 has been shown to increase the size of bovine conceptuses that were transferred to these P4-supplemented females at the blastocyst stage. Inversely, reduced P4 levels are associated with shrinkage of conceptus length and lower interferon-tau secretion (the major signal of maternal recognition in ruminants) that might be detrimental for maternal recognition of pregnancy. Phenotypic consequences that associate elongation and variations in P4 blood levels have been correlated with quantitative and qualitative alterations in endometrial gene expression related to uterine secreted factors (collectively named histotroph), including genes encoding secreted proteins (FABP3, MIF) or amino-acid transporters (SLC2A5) [26]. In humans, environmental insults (e.g. stress) or metabolic abnormalities (e.g. obesity) have been shown to be associated with infertility, early pregnancy failure and late pregnancy complications with impaired fetal development, with altered secretion profiles of polypeptidic hormones (e.g. prolactin, adipokines) and vital hormones such as P4 [27,28]. In conclusion, in all mammalian species, although E2 and P4 do not contribute to embryo development by a direct action on embryo cells, maternal perturbations in steroids secretion and alterations in steroids-regulated expression of various membrane, intracellular and extracellular factors have undoubtedly demonstrated adverse consequences on endometrial receptivity detrimental to implantation with a subsequent impact on early and late development of the embryo. Peri-implantation period represents a short time-step of pregnancy but events taking place during this process may considerably impact progression of pregnancy and progeny health. If pregnancy initiates with the production of at least one embryo, foetal-placental development, pregnancy outcome and post-natal issue cannot be analysed without considering the contribution of the endometrium as the interface receiving maternal signals then translating them as a driving force of embryo development at the epigenetic level. When assisted reproductive technologies are applied, defining embryo quality is critical but determining endometrium quality with precision is of prime importance to estimate the reproductive capacity of this tissue [29,30]. When endometrial quality is suboptimal or seriously compromised, treating endometrium to restore functionality and ensure implantation then pregnancy will require the careful evaluation of the treatment in terms of pregnancy outcome and health status of the progeny. Please cite this article in press as: Sandra http://dx.doi.org/10.1016/j.ando.2016.04.013
O.
Hormonal
3
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