MODERN TRENDS. Biochemical evaluation of endometrial function at the time of implantation CYTOKINES. Edward E. Wallach, M.D.
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1 FERTILITY AND STERILITY VOL. 78, NO. 2, AUGUST 2002 Copyright 2002 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A. MODERN TRENDS Edward E. Wallach, M.D. Associate Editor Biochemical evaluation of endometrial function at the time of implantation Anette Lindhard, M.D., a Ursula Bentin-Ley, M.D., Ph.D., b Vibeke Ravn, M.D., D.M.Sc., c Henrik Islin, M.Sc., Ph.D., d Thomas Hviid, M.D., Ph.D., d Sven Rex, M.D., e Susanne Bangsbøll, M.D., b and Steen Sørensen, M.D., D.M.Sc. d Rigshospitalet, University of Copenhagen, Copenhagen; Herlev University Hospital, Herlev; Hvidovre University Hospital, Copenhagen; and Odense University Hospital, Odense, Denmark Objective: To review the literature on various endometrial factors assumed to be of importance to implantation and to evaluate their potential clinical value in the assessment of endometrial function at the time of implantation in infertile women in natural and stimulated cycles. Design: Literature review. Result(s): Cytokines such as leukemia inhibitory factor, colony-stimulating factor-1, and interleukin-1 have all been shown to play important roles in the cascade of events that leads to implantation. They participate in a synchronized cooperation between the endometrium and the preimplanting embryo under the influence of steroid hormones. The same applies to the integrin v 3, glycodelin, and the polymorphic mucin 1. The usefulness of these factors to assess endometrial receptivity and to estimate the prognosis for pregnancy in natural and artificial cycles remains to be proven. Conclusion(s): The studies performed to date have mostly included only small groups of patients with a lack of fertile controls, and only a few prospective, controlled trials have been carried out. Therefore, definite conclusions about the clinical value of these factors in the assessment of endometrial function and prognosis for pregnancy after artificial reproductive therapy cannot be drawn at present. Further evaluation of their importance for and function during implantation is needed. (Fertil Steril 2002;78: by American Society for Reproductive Medicine.) Key Words: Cytokines, integrins, glycodelin, MUC1, endometrial receptivity, implantation, infertility Received September 5, 2001; revised and accepted February 26, Reprint requests: Anette Lindhard, M.D., Fertility Clinic, Rigshospitalet, University of Copenhagen, DK-2100 Blegdamsvej 9, Copenhagen, Denmark (FAX: ; lindhard@rh.dk) a Fertility Clinic, Juliane Marie Center, Rigshospitalet, University of Copenhagen. b Fertility Clinic, Herlev University Hospital. c Department of Pathology, Herlev University Hospital. d Department of Clinical Biochemistry, Hvidovre University Hospital. e Fertility Clinic, Odense University Hospital /02/$22.00 PII S (02) Recent evidence suggests that preparation of the endometrium for implantation is not merely a question of adequate hormonal stimulation but that implantation also depends on the interaction between the blastocyst and the endometrium and is mediated by cytokines, growth factors, and adhesion molecules, which are produced and secreted by the endometrium and the blastocyst (1, 2). Several biochemical factors of presumed importance to implantation have recently been discovered, and new ones are constantly being revealed. We have selected some of the most important factors for reviewing. CYTOKINES Cytokines are cell-derived polypeptides or glycoproteins with low molecular weight. They have been shown to perform multiple biological activities and to be involved in many physiological processes. Because of the ubiquitous production, the more general term cytokine has been adopted to refer to these substances. Cytokines are critical for the normal function of the immune system and are involved in the regulation of growth, development, and activation of immune system cells and in the mediation of the inflammatory response. In general, cytokines are characterized by considerable redundancy in that different cytokines have similar functions. In addition, many cytokines are pleiotropic in that they are capable of acting on many different cell types. The cytokines usually act as intercellular (paracrine) and/or intracellular (autocrine) signals in local tissues and sometimes also as endocrine mediators. Cytokines are actively produced in human endometrium and have been shown to be important actors in the cross-talk between human embryos and the endometrium. The cytokines interleukin-1 (IL-1), leukemia inhibitory factor (LIF), and colony-stimulating factor 1 (CSF-1) 221
2 have all been shown to play important roles in the implantation process and will shortly be reviewed together with the receptors for IL-1 and LIF. LEUKEMIA INHIBITORY FACTOR Introduction LIF was first identified from its ability to induce differentiation of myeloid leukemia cells into macrophage-like cells, but LIF is in fact produced and secreted by a variety of cell types, including epithelial and stromal cells in the endometrium. Physical and Chemical Properties LIF is a glycoprotein of 180 amino acid residues, with a molecular mass ranging from approximately 38 to 67 kda depending on glycosylation (3). LIF is transcribed from a single copy gene with a high degree of sequence similarity between species. It exerts its effect via two dimerizing receptor subunits, the LIF receptor (LIF-R) and glycoprotein 130 (gp130), a common receptor for other ligands for this cytokine family, which may explain the overlapping activities. Binding of LIF to its low affinity receptor (LIF-R) causes association of this complex with gp130, which subsequently results in signal transduction. Biological Functions of LIF Protein, the LIF-R, and gp130 in Animal Models and in Humans LIF has mainly been studied using mouse models, but the effects have not been found to differ from results obtained in humans. LIF is mandatory for the successful implantation of the blastocyst. Knockout mice with a defective LIF gene are unable to implant blastocysts (4). Transferring blastocysts from the LIF-deficient mice to normal mice or infusion of LIF into the uterine lumen of LIF deficient mice results in implantation, which demonstrates that the primary action of LIF is in the endometrium. Several cell lines that support embryonic development in vitro produce LIF. Exogenous LIF added to culture media increases blastocyst formation rates, and addition of recombinant human LIF to mouse embryos grown in culture supports further embryo development (5). Homozygote LIF-R / embryos are, in contrast to LIFdeficient mice, able to implant, which implies that LIF can act via an alternative pathway (6). LIF-R mutant animals show abnormal and disrupted placentation, which leads to poor intrauterine nutrition and fetal death within 24 hours after birth. On the other hand, homozygous gp130 receptor mutant mice die before birth, possibly as a consequence of the importance of these receptors for the function of other cytokines. LIF has a regulatory role on the trophoblast. Thus LIF modulates trophoblast differentiation from the cytotrophoblast toward an anchoring extravillous phenotype (7) and regulates the expression of matrix metalloproteinases in early mouse development, thereby providing a mechanism for controlling trophoblast invasion (8). Expression of the LIF Protein and mrna in Human Endometrium During the Menstrual Cycle and Pregnancy For reproduction, the most important site of LIF production is in the endometrial glands. The expression of LIF varies during the menstrual cycle. Both LIF protein and LIF mrna can be detected in the early secretory phase, whereas LIF protein and mrna are undetectable or expressed in very low levels in the proliferative endometrium. In the mid- and late-secretory phases, LIF mrna and immunoreactive LIF protein are expressed in an abundant amount in the glandular and luminal epithelium (9, 10). In the human endometrium, the maximal increase in LIF is observed between days 19 and 25, coinciding with the implantation window (7, 9). The abundant expression of LIF in the late-secretory phase is manifested also in uterine flushings, where LIF concentrations rise from day LH 7 to a maximum at day LH 12 (11). If implantation takes place, the glandular expression of LIF is down-regulated to a low level. At the same time, a strong expression of mrna encoding LIF is detected in decidual leukocytes at the implantation site. The leukocytes expressing LIF seem to be natural killer (NK) cells and different T-cell subtypes (12, 13). In mice, LIF is also expressed in the preimplantation embryo, but this expression declines to a very low level after implantation (14). However, this seems to depend on species, since no LIF expression was found in cryopreserved human embryos (15). Expression of the LIF-R in the Endometrium During the Menstrual Cycle and Pregnancy In contrast to the LIF protein, the LIF-R and the associated gp130 component are expressed in the human endometrium in both the proliferative and secretory phases, but expression is restricted to the luminal epithelium (10). All subtypes of human trophoblast express the LIF receptor, the villous cytotrophoblast and syncytiotrophoblast in particular and extravillous trophoblast to a lesser extent (12). LIF-R is also found in endothelial cells of the fetal villi. When preimplantation blastocysts engage with the uterine wall, extravillous trophoblast cells expressing LIF receptor possibly mediate interactions with decidual LIF-expressing leukocytes. The Regulation of LIF LIF secretion is independent of the presence of the trophoblast (16), and secretion seems regulated by maternal steroid hormones, cytokines, and growth factors in the uterine environment. Some discrepancy exists about the role of estrogen and P. Up-regulation of uterine LIF expression at implantation is coincident with increased estrogen levels, and a transient increase in LIF mrna has been shown in mice after estrogen injection (17). Likewise, when using a 222 Lindhard et al. Endometrial function at implantation Vol. 78, No. 2, August 2002
3 delayed implantation model, estrogen is an absolute requirement for LIF induction in the mouse uterus, whereas P priming alone was without effect on LIF (18). With regard to P, one study has shown a reduced LIF secretion after addition of exogenous P in vitro (19). On the other hand, P seems to be responsible for the production of LIF by T-cells in the stroma immediately after implantation (13). The Role of LIF in Infertility LIF is likely involved at several stages of the reproductive process, including preimplantation, implantation, embryo development, and placentation. Thus LIF is an obvious candidate in screening for endometrial receptivity. In fact, abnormal expression of LIF in the endometrium has been associated with some forms of human infertility and this is supported by findings of mutations in the coding region of the LIF gene in some infertile women (20). Further, a greater proportion of women with unexplained infertility have undetectable levels of LIF in their flushing fluid obtained on days LH 7, LH 10, and LH 12 compared with fertile women (11). COLONY-STIMULATING FACTOR-1 Introduction CSF-1, or macrophage CSF, was originally known as a hematopoietic growth factor supporting the survival, proliferation, and differentiation of cells of the monocyte lineage (21). Later on, a role for CSF-1 in pregnancy was elucidated. CSF-1 is one of the few cytokines and growth factors that is found in measurable concentrations in various tissues such as placenta and plasma (22). Biochemical Properties The biologically active form of human CSF-1 is a glycosylated disulfide-linked homodimer with a molecular size of kda. The disulfide bond formation is required for biological activity, whereas glycosylation is not (23, 24). The human CSF-1 gene contains 10 exons and 9 introns, which span 20 kb. Alternative splicing of the CSF-1 gene results in three transcripts, encoding proteins of 224, 438, and 554 amino acids, respectively (25, 26). In transfection studies, cdna of all three transcripts results in biologically active CSF-1 proteins. Biological Functions in Reproductive Biology The osteopetrotic op/op mice, which are deficient in CSF-1, have reduced fertility and smaller litter size than wild-type mice (27). Recent studies have shown that the major effect of CSF-1 seems to be on the ovulation rate, since estrous cycles are extended and the ovulation rates are significantly lower in op/op female mice compared with wild-type mice (28). Furthermore, in mice, CSF-1 accelerates the formation of the blastocyst cavity and causes a differential increase in the number of trophoblast cells (29). In humans, in vitro experiments have shown that CSF-1 stimulates trophoblast proliferation and differentiation (30). FIGURE 1 Profiles across the menstrual cycle of factors of importance to the interaction between human blastocyst and endometrium: interleukin 1 receptor type 1 (IL-1Rt1), leukemia inhibitory factor (LIF), colony-stimulating factor-1 (CSF-1), glycodelin, integrin v 3, and MUC1. Lindhard. Endometrial function at implantation. Fertil Steril Changes in Human CSF-1 During the Menstrual Cycle and Pregnancy: Clinical Aspects CSF-1 is expressed in human endometrial tissue during the normal menstrual cycle, and levels of immunoreactive CSF-1 in endometrial glands are higher during the secretory phase compared with the proliferative phase (Fig. 1). Furthermore, normal first trimester decidual tissue expresses higher levels of CSF-1 mrna and immunoreactive CSF-1 than proliferative endometrial tissue (31). The CSF-1 receptor (c-fms) is expressed in all human endometrial and first trimester decidual tissues, including invasive extravillous trophoblasts (31). Transcripts encoding the receptor for FERTILITY & STERILITY 223
4 CSF-1 are expressed throughout preimplantation development of human embryos (15). In this way, the increased production of CSF-1 may play a role in implantation, decidual function, and placental growth through the expression of the CSF-1 receptor, possibly through autocrine and paracrine networks. The circulating levels of CSF-1 in natural and stimulated cycles were compared by Shinetugs and coworkers in 1999 in a study of 10 fertile women who were examined in a spontaneous cycle before laparoscopic sterilization and of 20 infertile women who were examined during an IVF treatment (32). In the fertile group, follicular fluid (FF) was sampled at laparoscopy for tubal sterilization. During spontaneous cycles, no significant variations in plasma CSF-1 concentrations were detected, but CSF-1 concentrations in FF from the dominant follicle were four times higher than those in plasma of the same patients. Furthermore, in the IVF group, peripheral levels of CSF-1 did not change significantly in samples taken before and after hyperstimulation but before oocyte retrieval. In contrast, on day 9 after hcg, the levels of CSF-1 were significantly higher compared with those before stimulation. CSF-1 levels in FF at oocyte retrieval were about seven times higher than in the blood samples. A significant correlation between CSF-1 concentrations in FF and plasma was found as well as between FF levels and plasma P. Interestingly, low levels of serum CSF-1 have been shown to be associated with recurrent spontaneous abortions. In a study of women with two or more consecutive first trimester abortions, 44 patients treated with bed rest and 43 patients receiving paternal lymphocyte therapy had significantly lower preconceptional serum CSF-1 levels than a control group of 46 healthy nonpregnant women. Serum CSF-1 levels in the eighth gestational week were also lower in the group with recurrent spontaneous abortions than for those with pregnancy failure as the outcome compared with the control group (33). Conclusion The increased production of CSF-1 in human luteal endometrium and to a higher extent in first trimester decidual tissue suggests a role of CSF-1 during implantation and placental growth (31) and CSF-1 may play an important role during folliculogenesis, ovulation, and luteinization under steroid control. Measurements of immunoreactive CSF-1 in endometrial samples may be of use in the future, but larger prospective investigations, including fertile controls, are needed for further evaluation. INTERLEUKIN-1 Introduction The cytokine IL-1 is a polypeptide produced by a variety of host cells, particularly macrophages. It was first identified as an endogenous pyrogen, producing fever at the level of the thermoregulatory center of the hypothalamus. Biochemical Properties The two interleukins IL-1 and IL-1 have a common molecular weight of approximately 17.5 kda, comprise 159 and 153 amino acids, respectively, and have only 26% amino acid sequence homology. They bind to the same receptors. The IL-1 receptors have extracellular Ig domains and belong to the Ig superfamily, representing a large number of cell surface and secreted proteins. IL-1 receptors have been shown to increase significantly during the midluteal phase in human endometrium, and high levels of embryonic IL-1 in culture media may be associated with embryonic implantation after IVF/ET. Biological Functions in Animal Models IL-1 and IL-1 mrna has been shown in the murine endometrium by in situ hybridization techniques in endometrial macrophages and endothelial cells (34). The cytokines are found in the epithelial cells, to a lesser degree in the subepithelial stroma of the endometrium during the periimplantation period, and also in murine blastocysts (35 37). Likewise, IL-1 receptor mrna has been identified in the luminal epithelium from day 1 until day 8 after ovulation (38). In the mouse, implantation takes place at day 4. Animal experiments on the significance of the IL-1 receptor for embryo implantation have given conflicting results. Gene knockout mice for the IL-1 receptor are fertile (39). Other studies, however, indicate that the IL-1 system exerts its influence on the implantation process through a direct action on the endometrium. A blockade of the murine IL-1 receptor located on the luminal epithelium using the IL-1 receptor antagonist (IL- 1ra) prevents blastocyst adhesion (40). Recent studies demonstrate a direct action of IL-1ra on the plasma membrane of endometrial epithelial cells (41) by inhibition of normal morphological changes preceding implantation, the so-called plasma-membrane transformation (42). Furthermore, immunohistochemical studies have shown that animals treated with IL-1ra express less of the integrin subunits 4, v, and 3 in the endometrium. These integrins seem to be functionally active during the adhesion process at the endometrial epithelial surface (see the INTEGRINS section below). Embryos from mice treated with IL-1ra have the capacity to implant and develop normally when transferred to normal mice. Thus the IL-1ra does not have an embryo-toxic effect but solely interferes with endometrial receptivity. The significance of the IL-1 system on embryo implantation in the mouse has not yet been resolved. Biological Functions in Humans In human endometrium, the IL-1 system comprises IL-1 and IL-1, the receptor antagonist (IL-1ra), and two receptors, the IL-1 receptor type I (IL-1RtI), and the IL-1 receptor 224 Lindhard et al. Endometrial function at implantation Vol. 78, No. 2, August 2002
5 type II (IL-1RtII). Only the type I receptor is functionally active in the endometrium. IL-1, IL-IrtI, and IL-1ra have been demonstrated in human endometrium by immunohistochemistry (43, 44). The IL-1 receptor is expressed throughout the menstrual cycle and is localized in the surface epithelium (43). The amount of IL-1 receptors increases significantly during the midluteal phase (Fig. 1) (45), and the receptor has also been identified in decidua and placenta. Human preimplantation embryos also express mrna for IL-1, IL-1RtI, and IL-1ra (46). Interestingly, the presence of IL-1ra was observed in embryos that underwent developmental arrest, but the number of embryos investigated was rather low (n 12). Secretion of embryonic IL-1 seems to be the first response of the blastocysts to the receptive endometrium, inducing a second wave of cytokines such as LIF, IL-1, and others (1). By binding to their receptors, the cytokines may induce molecular changes in the expression patterns of adhesion and anti-adhesion molecules, which are essential for attachment of the blastocyst. A study by Simon et al. indicated that embryonic secretion of IL-1 results in localized changes in the endometrium before adhesion (45). Binding of IL-1 to the IL-1 receptor present on the luminal epithelium in vitro results in increased endometrial secretion of prostaglandin E 2 (47). The expressions of the integrin 3 -subunit and LIF secretion have been found to increase simultaneously (45, 48). LIF seems to be regulated in the human like it is in the mouse, where endometrial LIF secretion is decisive for embryo implantation (4). LIF and CSF-1 have also been shown to support embryo development and blastocyst hatching (49). Observations on the correlation of high levels of IL-1 secreted by human embryos before ET and establishment of pregnancy after ET may partly be explained by this paracrine loop (50). Conclusion IL-1 seems to be the first cytokine active in the embryoendometrial cross-talk, which results in a second wave of cytokines (Fig. 2). It still remains to be shown in the human whether a defect or missing IL-1 receptor in the endometrium has detrimental effects on the cascade system of secreted cytokines and glycoproteins, which leads to unsuccessful implantation, or whether the redundancy of the many factors involved in embryo implantation are able to overcome this missing link. Further prospective studies are needed to examine the benefit of immunohistochemical measurement of IL-1 receptors in midluteal endometrial samples before the method can be used to evaluate endometrial function. Investigations of whether a higher implantation rate can be accomplished by adding IL-1 to embryo culture media are also needed. INTEGRINS Introduction Cell adhesion molecules fall into four major groups: integrins, cadherins, selectins, and members of the Ig superfamily. Integrins are present in the endometrium throughout the menstrual cycle, and their expression is hormonally regulated. Several studies have provided indirect evidence that integrins are potential markers of endometrial receptivity and that they participate in embryo-endometrial interactions. Biochemical Properties Integrins are transmembrane heterodimeric glycoproteins consisting of two noncovalently associated - and -subunits. About 20 integrin heterodimers, made from 14 types of -subunits and nine types of -subunits, have been identified, and new ones are still being discovered. Many matrix proteins in vertebrates are recognized by multiple integrins, i.e., at least eight integrins bind fibronectin and at least five integrins bind laminin. Integrins are involved in cell-to-cell binding and in cell interactions with the extracellular matrix. They function as two-way signaling molecules, both regulating the affinity and conformation of the receptor from inside the cell (insideout signaling) and triggering intracellular events by ligand occupation of the receptor (outside-in signaling). The intracellular domain binds via talin and -actinin to actin filaments in the cytoskeleton. Integrins differ from cell-surface receptors for hormones and for soluble signaling molecules in that they bind their ligands with relatively low affinity and they are usually present at very high concentrations on the cell surface. This arrangement makes sense, since binding simultaneously but weakly to large numbers of matrix molecules allows cell motility without losing all attachment to the receptors. Biological Functions in the Human Endometrium Natural Cycle The expression of integrins on the luminal surface of the endometrial epithelium changes throughout the menstrual cycle (51, 52). At the time of implantation, the integrins 1 1, 4 1, and v 3 predominate. The integrin v 3 can be demonstrated immunohistochemically at the apical plasma membrane of the surface epithelium from day 20 onward during a 28-day spontaneous cycle (Fig. 1) (53 55) and in addition has been demonstrated at the surface of the embryo (56). This integrin recognizes the sequential order of the Arg-Gly-Asp (RGD) tripeptide that is involved in trophoblast adhesion and migration. It therefore also recognizes osteopontin, a glycoprotein specifically secreted by human endometrium during the window of implantation. It has been hypothesized that the epithelial expression and secretion of FERTILITY & STERILITY 225
6 FIGURE 2 Localization of factors of importance to the interaction between the human blastocyst and endometrium before implantation: interleukin-1 and (IL-1, IL-1 ), interleukin 1 receptor type 1 (IL-1Rt1) and interleukin 1 receptor antagonist (IL-1ra), leukemia inhibitory factor (LIF) and the receptor (LIF-R), colony-stimulating factor-1 (CSF-1), CSF-1-receptor (CSF-1-R), glycodelin, integrin v 3, and the polymorphic glycoprotein MUC1. Embryonic secretion of IL-1 induces localized changes in the endometrial luminal epithelium, and the binding of IL-1 to the IL-R on the luminal epithelium may up-regulate the expression of v 3 and LIF. Adhesion is facilitated by the interaction between glycodelin, LIF, CSF-1, and the corresponding embryonic receptors. The blastocyst may also induce a cleavage of endometrial epithelial MUC1 at the implantation site, thereby making a small zone of the luminal epithelium adhesive, while the remaining parts continue to be nonadhesive. Lindhard. Endometrial function at implantation. Fertil Steril osteopontin in the secretory phase endometrium may participate in the initial adhesion of trophoblast cells to the endometrial epithelium (57). The expression of the 3 -subunit seems to depend on the down-regulation of estrogen and P receptors in the endometrial glands during the midluteal phase (58). Furthermore, IL-1 (59), transforming growth factor- (TGF ), and epidermal growth factor (EGF) all exert an influence on 3 expression (60). Recent investigations indicate that v 3 binds to and activates matrix metalloproteinases and plasminogen activators in the extracellular matrix (61). This enables the integrin to act both as a receptor for the embryo at the endometrial surface epithelium and as a stimulator of trophoblastic penetration and invasion. Role in Infertility Several conditions associated with infertility seem to be accompanied by an insufficient expression of integrin v 3, e.g., luteal phase insufficiency (58), endometriosis (62), unexplained infertility (63), and presence of hydrosalpinges. To investigate the expression of integrins in women with endometriosis, 241 in-phase endometrial biopsies obtained after cycle day 19 were assessed for the presence of 3 (62). A lack of 3 -subunit expression was closely related to the diagnosis of endometriosis. The defect integrin expression was associated with null parity, and the integrin expression declined in progressive stages of endometriosis, despite the presence of in-phase histological features. 226 Lindhard et al. Endometrial function at implantation Vol. 78, No. 2, August 2002
7 In a prospective case-control study (58), the expression of endometrial P receptor (PgR) and of three cycle-specific integrins were compared in 181 endometrial biopsies obtained between cycle days 20 and 24 from 156 normally cycling women. Epithelial PgR were significantly lower in the group with luteal phase defect (LPD) compared with all other groups. Integrin v 3 expression was significantly reduced in groups with LPD and endometriosis, whereas the levels of 1 1 and 4 1 expression did not differ among groups. This study showed that delay in endometrial histological development, consistent with LPD, is associated with a failure of PgR down-regulation and a lack of integrin subunit 3 expression (58). In women with endometriosis, this defect seems to be regulated differently, since they showed a normal PgR down-regulation. Also women with unexplained infertility show a lack of endometrial integrin subunit 3 expression (63). In this casecontrol study, 65% of endometrial samples from 87 women with unexplained infertility showed a significantly reduced staining intensity for 3 compared with 21 normal controls. Two distinct defects were identified: 26% of the infertile women had an endometrium out of phase, whereas 39% of the samples failed to express integrin subunit 3, although the endometrium was histologically in phase. The expression of the integrin subunits 1 and 1 did not differ between the groups. These findings suggest that defective uterine receptivity as defined by a lack of integrin subunit 3 expression may be an unrecognized cause of infertility in women with unexplained infertility. In another prospective case-control study, endometrial biopsies from 103 women with hydrosalpinges were compared with endometrial biopsies from 44 fertile and 55 infertile controls with male factor infertility (64). All biopsies were taken between days 20 and 24, analyzed by conventional histological criteria, and stained for presence of integrins 1 1, 4 1, and v 3. In endometrial biopsies obtained from women with hydrosalpinges, 32% demonstrated delayed histological development and impaired 3 expression and 29% had aberrant v 3 expression despite in-phase endometrial histology. Both numbers were significantly higher than in infertile and fertile controls. There were no differences regarding the two other integrins. Endometrial biopsies were obtained after removal of hydrosalpinges in 20 of the women. Seventy percent of these biopsies demonstrated increased v 3 expression. The results suggest that the presence of hydrosalpinges may have an adverse effect on v 3 integrin expression and that removal of the hydrosalpinges may overcome this effect. Interestingly, removal of hydrosalpinges improves the implantation rates after IVF treatment, as shown in a Scandinavian randomized controlled multicenter trial (65). In vitro experiments have shown that human embryos cultured in hydrosalpinx fluid can implant on normal human endometrial cell cultures (66). Thus, it can be hypothesized that the presence of hydrosalpinges results in lower endometrial receptivity, possibly by impairing the 3 expression in the endometrium. A recently published experimental study showed that blockage of murine endometrial integrin v 3 resulted in impaired implantation (67). It appears that v 3 has no influence on embryo development and implantation potential in humans. Conclusion The expression of integrin subunit 3 seems to be significantly reduced in endometrium from women with unexplained infertility, endometriosis, hydrosalpinges, and LPD. Subunit 3 is likely implicated in early embryo-endometrial interactions during human blastocyst implantation. The immunohistochemical expression of v 3 in midluteal endometrial samples seems to be a marker of endometrial receptivity. GLYCODELIN Introduction Glycodelin is one of the most abundant products of glandular cells in the late secretory endometrium. It has been proposed as the most reliable noninvasive marker of endometrial function in women. Owing to independent isolation and identification, many names have been used for this protein in the literature, such as progestagen-associated endometrial protein, chorionic 2 -microglobulin, -uterine protein, placental protein 14 (PP14), pregnancy-associated endometrial 2 -globulin, and endometrial protein 15. Because of the inaccuracy of these names with respect to the site of synthesis and function, the name glycodelin was introduced owing to its unique oligosaccharide structure (68). Glycodelin is detectable only in reproductive tissues and has been shown in seminal plasma, fallopian tubes, endometrial tissue, ovarian carcinoma tissue, ovarian FF, and fluid from ovarian cysts. It is now clear that glycodelin is synthesized by secretory and decidualized endometrium and secreted primarily into the glandular and uterine lumen and to a much lesser extent into the circulatory system. Biochemical Properties Glycodelin is a glycoprotein consisting of 162 amino acids with a molecular weight of 18,787, but because of its high carbohydrate content of 17.5%, the molecular mass is about 28 kda as measured by sodium dodecyl sulphate polyacrylamide gel electrophoresis. The glycodelin mrna is approximately 1 kb, and the amino acid sequence is highly homologous to equine -lactoglobulin, showing a 53.4% identity. To a minor extent it is also homologous to retinalbinding protein, with 22.7% homology. A Hinf I restriction enzyme polymorphism in the gene has been identified with a frequency of allele A1 of 5% and of allele A2 of 95%. Glycodelin can be measured in plasma and in human endometrium during the secretory phase. FERTILITY & STERILITY 227
8 Biological Functions The biological functions of glycodelin in relation to implantation and pregnancy are still uncertain. The similarity to -lactoglobulins and retinal-binding protein suggests a possible role in the transport of small molecules within or across tissues, but such a function has not yet been found. In vitro studies have shown an inhibitory effect of glycodelin on the binding of human spermatozoa to zona pellucida without affecting other prefertilization events (69). It has been proposed that glycodelin provides an immunosuppressive microenvironment that protects the fertilized egg/preembryo because of its ability to suppress the activity of natural killer cells in vitro (70). Thus, theoretically, the absence of glycodelin in the periovulatory endometrium should allow fertilization to occur and a subsequent rise of glycodelin levels should prevent supernumerary fertilizations and aid successful implantation of the human embryo. Glycodelin Changes During the Natural Cycle and Pregnancy In the luteal phase, plasma glycodelin levels increase significantly from the fourth postovulatory day (day LH 5), peaking around the onset of the menstrual period in a nonconception cycle, and are maintained for the first days of the following cycle to return to baseline during the midfollicular phase (Fig. 1) (71). In a conceptional cycle, plasma glycodelin levels rise rapidly after implantation, reaching a maximum at approximately 8 10 weeks of gestation and subsequently declining, a pattern similar to that of plasma hcg. Until now, histological dating has been used to assess endometrial development and presumed ability to receive a blastocyst, but measurements of glycodelin in plasma throughout the menstrual cycle may reflect the implantation capacity of the secretory endometrium. However, other (unknown) factors than estrogen and P may influence the glycodelin level in the luteal phase without affecting the pregnancy rate. Clinical Value of Glycodelin for Implantation Plasma Glycodelin in Women With Ovarian Function Plasma glycodelin has been measured during treatment cycles in several infertility studies that include women with functional ovaries. In nonconceptional cycles, no differences were found in plasma glycodelin levels on days LH 7 to LH 12 in spontaneous cycles in regularly menstruating women with unexplained infertility compared with normal fertile women (72). Westergaard et al. found significantly lower plasma glycodelin levels throughout two spontaneous cycles in seven women who conceived in the subsequent cycle, compared with 12 women who did not. In the third cycle, all women were stimulated with clomiphene and hmg combined with IUI or IVF (71). In contrast, significantly increased plasma glycodelin levels from hcg day to ET day were found in eight women with conceptional IVF cycles compared with 18 women with nonconceptional cycles after a short treatment with GnRH-a and stimulation with a combination of FSH and hmg (73). Also, in conceptional cycles after IVF (55 cycles) and natural cycles with frozen embryo replacement (13 cycles), the mean serum glycodelin concentrations were significantly higher 12 days after ET compared with 27 nonconceptional cycles (74). However, compared with normal pregnancies, serum glycodelin was lower during the first trimester of pregnancy after IVF treatment, using the long protocol with GnRH-a down-regulation and stimulation with hmg, and much lower when a combination of clomiphene and hmg was used (75). The latter result may be due to the antiestrogenic effect of clomiphene. In another study, serum glycodelin levels were not compromised in 32 infertile women with functional ovaries whose pregnancies followed IVF treatment with pituitary down-regulation using buserelin, ovarian stimulation with hmg and P support, or FER. The glycodelin concentrations were measured during a conceptional cycle on days 9 10, 14 15, and after hcg injection (76). Plasma Glycodelin in Women With No Ovarian Function Women with idiopathic premature ovarian failure have insufficient E 2 synthesis, which causes inadequate endometrial priming and which together with the lack of corpus luteum formation and P synthesis affects glycodelin production. In women with premature ovarian failure, hormone replacement therapy (HRT) with E 2 and P resulted in the majority of cases (75%) having concentrations of glycodelin similar to those in natural cycles of regularly menstruating women (74). However, serum glycodelin failed to rise and was significantly reduced during the first trimester in pregnancies after HRT, ovum donation, and ET compared with natural conceptions (77). These findings demonstrate that serum glycodelin concentrations do not increase in pregnant women who experience ovarian failure, probably because the corpus luteum is essential for the increase in circulating glycodelin during the first trimester. Endometrial Glycodelin Endometrial glycodelin measured by immunohistochemical staining as well as serum levels was significantly lower in the late secretory phase (day LH 13) in eight women with retarded endometrial development than in 16 women with an endometrium in phase; all of the women had unexplained infertility (78). Thus, retarded endometrial development may be associated with deficient glycodelin production. Lower intensity of immunohistochemical staining of glycodelin was found in the endometrial epithelium in biopsies taken in stimulated test cycles between days 21 and 23 in 10 infertile women who conceived in subsequent FER cycles, 228 Lindhard et al. Endometrial function at implantation Vol. 78, No. 2, August 2002
9 compared with 15 women who did not. Both groups were down-regulated with GnRH-a, and E 2 and P were used as HRT (79). Glycodelin in Uterine Flushing Fluid Measurements of glycodelin in uterine flushing fluid may be more informative compared with plasma levels in the evaluation of endometrial function and receptivity, as the former may better reflect the events that occur in the endometrium. Furthermore, measuring glycodelin in the uterine flushing fluid is less harmful and less invasive than taking a biopsy. In a prospectively designed study including 29 regularly cycling women with unexplained infertility, the presence of detectable amounts of glycodelin in uterine flushing fluid was strongly associated with normal endometrial development, as evaluated by the method of Noyes et al. (80). In contrast, glycodelin concentrations in plasma were not related to histological dating or to morphometric analyses and did not differ between patients with normal and retarded endometrial development (81). In another study, uterine flushings were examined throughout the menstrual cycle in regularly cycling fertile women. Glycodelin was not detectable in significant amounts in the follicular and early luteal phase. However, after day LH 6, the concentration rose rapidly and in the late luteal phase the concentrations in the uterine flushing fluid were over 100 times higher than in the corresponding plasma samples (82). Women with unexplained infertility showed lower glycodelin concentrations in uterine flushings than normal fertile women on days LH 10 and LH 12. Other investigators found no such difference in glycodelin levels in flushing fluid from women with different causes of infertility (83). This discrepancy may be explained by the fact that uterine flushing is an inconsistent procedure and variations in glycodelin measurements could be due to differences in the sampling procedure. Glycodelin measurement in uterine flushings may be a more valuable method of assessing endometrial function than plasma glycodelin, but it needs standardization and further investigations to establish its future use in the evaluation of endometrial receptivity. Conclusion Glycodelin in plasma seems to be a simple, noninvasive, and reliable biochemical marker of endometrial receptivity. However, several studies have shown a substantial overlap between circulating glycodelin levels in normal and pathological states. Therefore, it still remains to be determined whether or not measurement of plasma glycodelin can become a useful clinical test of endometrial function. Measurements of glycodelin levels in uterine flushing fluid seem to be promising, but further evaluation under standardized conditions is required. More prospective studies with a larger number of patients and fertile controls are required for evaluation of both methods. The less invasive quantitative measurements of glycodelin should be preferred to the more qualitative immunohistochemical staining of glycodelin in endometrial samples. MUC1 Introduction MUC1, also known as polymorphic epithelial mucin (PEM), episialin, MAM-6 antigen, and epithelial membrane antigen (EMA), is expressed in many secretory epithelia and is a cell surface associated and secretory product of the endometrial epithelium (84). MUC1 ectodomains, which are large and highly extended structures, are likely to be among the first cell surface components encountered during blastocyst attachment to the luminal endometrial epithelium (85). Several studies suggest a role for MUC1 in human implantation, however, its exact role is not yet clear. Biochemical Properties MUC1 is a highly glycosylated and high molecular weight glycoprotein. The anti-adhesive properties of MUC1 are likely related to the structure of the molecule. It has a large extracellular domain containing a variable number of tandem repeat (VNTR) units of a conserved 20 amino acid sequence, each of which contains five potential O-glycosylation sites (86). A large domain in the MUC1 gene contains a variable number of 60-bp tandem repeats, leading to polymorphism in the expressed gene product (87). The mouse sequence contains 16 repeats, while in humans, the number varies from 20 to 125 (88). Accordingly, the number of potential O-glycosylation sites in human MUC1 shows substantial variation. The presence of MUC1 can be examined at the DNA, mrna, or protein level. Several antibodies that detect different MUC1 epitopes have been developed. Masking of MUC1 ectodomain epitopes by different oligosaccharides may explain the conflicting reports on MUC1 expression in human endometrium. Biological Functions Mucins make the cell surface enzymatically resistant, limit access to receptors, severely impair cell-cell and cellextracellular matrix adhesion, and may, in addition, protect the cell from the host immune system. A delicate balance between adhesion and anti-adhesion forces in MUC1-expressing cells has been proposed, which can be shifted toward adhesion by strengthening the integrin-mediated adhesion or toward anti-adhesion by increasing the MUC1 level of expression (89). However, since MUC1 has been shown to carry selectin ligands, it may also promote cell adhesion (90). FERTILITY & STERILITY 229
10 Biological Functions of MUC1 in the Endometrium (Animal Studies) The expression of MUC1 in the endometrium varies with the menstrual cycle, but also from species to species. In all species examined, MUC1 is highly expressed in the epithelial cells and in many species, including the mouse, MUC1 is down-regulated in the surface epithelium during the implantation phase (91, 92). In mice, the reduction in MUC1 expression is seen both at the mrna and protein level, and MUC1 expression is inversely correlated with uterine receptivity. By virtue of its anti-adhesive properties and its reduced expression in the uterine epithelium at the time of implantation in many species, it has been proposed that MUC1 hinders implantation (91). In rabbits, the marked reduction in MUC1 has been shown to be restricted to implantation sites. A high level of MUC1was maintained in nonimplantation regions. Based on these findings, it has been hypothesized that the downregulation of MUC1 is accomplished locally via signals apparently produced by the blastocyst (93). Expression of MUC1 in the Human Endometrium The presence of MUC1 in the human endometrium has been studied by immunohistochemical analysis of endometrial tissue sections, endometrial explants, and cultured uterine epithelial cells (84, 85, 94) and by using gel electrophoresis and ELISA on secretory endometrial extracts and uterine flushing fluid (84, 95). MUC1 protein and mrna levels increase during the implantation window in endometrial samples from women with well-defined menstrual cycle phases (Fig. 1), in contrast to mice (84). MUC1 is particularly abundant on microvilli and cilia that extend from the apical cell surface of endometrial epithelial cells and is expressed at elevated levels during the implantation phase. However, the expression of some MUC1 glycosylation variants changes during the receptive phase (84, 85, 95, 96). Endometrial MUC1 carries highly sulphatated lactosaminoglycan chains and sialokeratan sulphate epitopes recognized by the monoclonal antibodies 5D4 and D9B1. Both epitopes are produced and secreted by the epithelial cells in the secretory phase, achieving maximal levels in secretions 6 7 days after the LH peak (94). In addition, the carbohydrate recognition structures for L-selectin expressed at early stages of preimplantation development of the human embryo (56), the S-Lewis-a and S-Lewis-X histo-blood group related oligosaccharide antigens, have been shown to be associated with the MUC1 core protein from uterine flushing fluid and are expressed by normal cycling endometrial epithelial cells in a manner similar to that reported for MUC1 (90, 97, 98). MUC1 is likely the carrier of other histo-blood group related antigens, which are expressed by endometrial epithelial cells. MUC1 and Human Implantation MUC1 is important for human implantation and may either inhibit intercellular adhesion by steric hindrance or may actually promote adhesion. It has recently been postulated that women with unexplained infertility may have a genetic susceptibility to failure of embryo implantation due to small MUC1 allele size (88). It is hypothesized that such a polymorphism leads to implantation failure due to a substantial reduction in the number of glycosylation sites (88). Recent in vitro studies have shown a coordinated hormonal and embryonic regulation of MUC1. During the apposition phase, the presence of a human embryo induces an up-regulation of endometrial epithelial MUC1 protein. However, at the adhesion phase, the embryo induces a paracrine cleavage of endometrial epithelial MUC1 at the implantation site. These findings suggest that MUC1 acts as an endometrial anti-adhesive molecule that must be locally removed by the human blastocyst during the adhesion phase (92, 93). Changes in MUC1 glycoforms also seem to correlate with the receptive window. It has been suggested that a regionally restricted glycosylation generates an altered external structure of MUC1, which may decrease accessibility to the MUC1 protein core region in luminal epithelium at the receptive phase, facilitating adhesion (85). In addition, MUC1-associated glycans could be ligands for selectins, glycosyltransferases, or lectins present on the trophectoderm and may either promote or inhibit embryo attachment. In support of this hypothesis, studies in mice have suggested that histo-blood group related carbohydrate antigens play a direct role in the implantation process (99). Clinical Value of MUC1 in Evaluation of Endometrial Function at the Time of Implantation Studies have shown that the expression of MUC1 core protein in uterine flushing fluid and in midsecretory endometrium from women suffering from recurrent spontaneous miscarriages was significantly reduced compared with the expression in fertile controls (95, 96). Endometrial samples from women with unexplained infertility and from women with LPD have revealed a reduced expression of the D9B1 epitope compared with samples from normal fertile women (100). Moreover, compared with normal endometrium from fertile women, endometrial samples from 28 intrauterine device (IUD) users showed a reduced expression of both the D9B1 and the 5D4 epitopes, which are both markers of secretory differentiation (100). These findings suggest that the IUD may affect specific late post-translational events, leading to a reduction of specific glycan structures on MUC1, which may be important for implantation (100). It has recently been hypothesized, that the highly poly- 230 Lindhard et al. Endometrial function at implantation Vol. 78, No. 2, August 2002
11 morphic genetic variation in the human MUC1 gene is linked to pregnancy outcome. In a pilot study, Horne et al. record a higher frequency of smaller MUC1 alleles in DNA extracted from blood samples from 10 women with unexplained infertility and at least three failed IVF cycles compared with 10 normal fertile women (88). They also found that the difference between the size of the upper and lower alleles was greatest in the infertile women with apparent failure of embryo implantation. They conclude that unexplained infertility may be associated with a polymorphism in the MUC1 VNTR, resulting in a protein with a substantial reduction in the number of candidate O-glycosylation sites, thereby causing implantation failure. Conclusion The highly polymorphic, heavily glycosylated MUC1 is involved in the early stages of human implantation, and it is hypothesized that MUC1 is one of the molecules that the human endometrium expresses to regulate blastocyst adherence and that its expression is qualitatively modulated locally by signals produced by the blastocyst, making a small zone of the luminal epithelium adhesive while the remaining parts remain nonadhesive. The clinical value of MUC1 as a marker of uterine receptivity is at present uncertain, and we must await results of more extended and detailed studies. SUMMARY In the present paper, we have reviewed current knowledge about some biochemical factors implicated in the implantation process. These factors are produced, expressed, and secreted by the endometrium and regulated by hormones. Initiation of endometrial receptivity seems to depend on the down-regulation of epithelial PgR and estrogen receptors induced by P. When the embryo has arrived in the uterine cavity, a preprogrammed sequence of events occurs, which involves the production and secretion of a multitude of biochemical factors such as cytokines, growth factors, and adhesion molecules by the endometrium and the embryo, thus leading to the formation of a receptive endometrium. These factors, which include glycodelin, cytokines like LIF, IL-1, and CSF-1, integrins like v 3, and the polymorphic MUC1, provide the basis for a dialogue between the endometrium and embryo under the influence of steroid hormones, and their expression and/or secretion into the uterine cavity may be used as markers of endometrial receptivity. A hypothesis for explaining the presence of an implantation window in human endometrium could be that some factors like integrin v 3 make the endometrium receptive and others like the glycoprotein MUC1 make it resistant to implantation except in small areas. The methods used to demonstrate these factors include biochemical evaluations of their presence in plasma and flushing fluid as well as immunohistochemical studies of endometrial samples from both fertile and infertile women. Glycodelin in plasma seems to be a simple, noninvasive biochemical marker of endometrial receptivity. However, a substantial overlap in circulating glycodelin levels in normal and pathological states have been found. The large interindividual variations in CSF-1 plasma levels limit its possible use as a tool to evaluate endometrial function. Measuring the levels of glycodelin and LIF in uterine flushing fluid seems to be a promising method to assess endometrial luteal function, but these methods also need further evaluation. The factor best studied by immunohistochemical analysis on endometrial samples is the 3 integrin subunit. Endometrial samples from infertile women with a normal endometrial histology, i.e., an endometrium in phase, show a lack of 3 integrin expression during the window of implantation, irrespective of the cause of infertility, i.e., hydrosalpinges, endometriosis, or unexplained infertility. Apart from a lack of 3 integrin expression, endometrial samples from infertile women with an endometrium out of phase (LPD) show a reduced expression of glycodelin (PP14) and the D9B1 epitope carried by MUC1 together with a lack of PgR down-regulation. Recently, it has been hypothesized from a pilot study of Horne et al. that unexplained infertility may be associated with a polymorphism in the MUC1 VNTR, resulting in a protein with a substantial reduction in the number of candidate O-glycosylation sites. Studies performed to evaluate the usefulness of these factors as markers of uterine receptivity in general have included only small groups of patients, and only a few prospective controlled trials have been performed. Further evaluation that includes larger groups of infertile women and fertile controls are needed to elucidate whether their presence in plasma, flushing fluid, or endometrial samples can be used as some kind of a screening tool to assess endometrial function and prognosis for pregnancy before and after artificial reproductive therapy. A better understanding of their function in human implantation may lead to therapeutic intervention, thereby improving the success rate in reproduction treatment. References 1. Cross JC, Werb Z, Fisher SJ. Implantation and the placenta: key pieces of the development puzzle. Science 1994;266: Giudice LC. Potential biochemical markers of uterine receptivity. Hum Reprod 1999;14(Suppl 2): Hilton DJ, Gough NM. Leukemia inhibitory factor. In: Mire-Sluis AR, Thorpe R, eds. Cytokines. New York: Academic Press, 1998: Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Kontgen F, et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor [see comments]. Nature 1992;359: Tsai HD, Chang CC, Hsieh YY, Lo HY, Hsu LW, Chang SC. Recombinant human leukemia inhibitory factor enhances the development of preimplantation mouse embryo in vitro. Fertil Steril 1999; 71: Dani C, Chambers I, Johnstone S, Robertson M, Ebrahimi B, Saito M, et al. Paracrine induction of stem cell renewal by LIF-deficient cells: a new ES cell regulatory pathway. Dev Biol 1998;203: Nachtigall MJ, Kliman HJ, Feinberg RF, Olive DL, Engin O, Arici A. FERTILITY & STERILITY 231
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