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Departments of Gynecological Endocrinology and Reproductive Medicine (M.v.W., S.U., T.S.) and Obstetrics and Gynecology (U.H.), University of Heidelberg, 69115 Heidelberg; and Department of Obstetrics and Gynecology (R.S.), 83209 Prien am Chiemsee, Germany
Address all correspondence and requests for reprints to: Michael von Wolff, M.D., Universitaetsfrauenklinik Heidelberg, Abteilung Endokrinologie und Fertilitaetsstoerungen, Vossstrabe 9, 69115 Heidelberg, Germany. E-mail: michael.von.wolff{at}med.uni-heidelberg.de.
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Abstract |
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Introduction |
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The glucose metabolism is dependent on an adequate intracellular glucose uptake, which is catalyzed by a family of transport facilitators. The glucose transporters are characterized by the presence of 12 membrane-spanning helices and several conserved sequence motifs (1). Eight different facilitative glucose or fructose transporter isoforms, GLUT1-GLUT8 and recently GLUT9-GLUT12 (1) have been cloned. We concentrated on the analysis of the well-characterized isoforms GLUT1-GLUT5 and GLUT8.
GLUT 1 is responsible for the basal uptake and storage of glucose in all cells (2) and is especially abundant in erythrocytes and the hemochorial placenta (3). GLUT2 is a low-affinity transporter of glucose and is involved in the insulin dependent glucose uptake in the liver, small intestine, and kidney (4). GLUT3 is a high-affinity glucose transporter and is abundant in tissues with an intensive glucose metabolism such as brain, testis, and placenta (5, 6, 7, 8). GLUT 4 is the most important insulin-dependent glucose transporter that regulates the rapid glucose uptake in human skeletal and cardiac muscle cells and in adipocytes and placental cells (2, 9, 10). GLUT5 is not a glucose transporter but a fructose transporter and is abundantly expressed in spermatozoa (11). GLUT8 is expressed in placenta and is responsible for insulin-stimulated glucose uptake in the blastocyst (12, 13, 14).
Data about the expression of glucose transporters in mice and rats indicate that glucose transporters play an important role in the development of the blastocyst, the implantation, and stromal decidualization. GLUT1 and the insulin dependent GLUT8 are expressed in mouse blastocysts (13, 15). Inhibition of the facilitated glucose transporters in mice embryos reduced the morula/blastocyst transition (16). Furthermore, the endometrial mRNA expression of GLUT1 increases progressively throughout gestation (17, 18). In the rat model, endometrial GLUT1 mRNA expression is increased at the implantation site (19) and is maximally expressed in the proliferating stromal cells during decidualization.
Data about the expression of glucose transporters in human endometrium are very poor. In a preliminary study in human endometrium, we showed an increase of endometrial mRNA expression of GLUT1 in the secretory phase of the menstrual cycle and maximum expression in decidualized endometrium (20).
These data from the animal model and our first data from human endometrium indicate that glucose transporters are not only essential in the development of the mouse blastocyst and mouse and rat implantation, but they also suggest that glucose transporters play a role in the regulation of human endometrium and human implantation. We hypothesized that an impaired expression of specific glucose transporters results in insufficient glucose uptake, which might lead to impaired decidualization, contributing to endometrial dysregulation as a cause of idiopathic infertility. To support our hypothesis, we performed an analysis of the endometrial and decidual expression, regulation, and function of the transporter isoforms GLUT1-GLUT5 and GLUT8 in fertile and idiopathic infertile patients.
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Materials and Methods |
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Endometrial tissues from regularly cycling women were collected at different phases of the menstrual cycle after hysterectomy. None of the patients was hormonally stimulated. Decidual tissue was obtained from induced abortions, performed in the sixth to ninth week of pregnancy for social reasons. Ethical approval according to the principles set out in the Declaration of Helsinki, and written consent from each patient was obtained for the collection of the tissue samples. All samples were dated according to the last menstrual period, histology (21), and serum levels of estradiol, progesterone, and LH. The menstrual cycle was divided into four phases: the proliferative phase (d 1–14), early secretory phase (d 15–19), midsecretory phase (d 20–23), and late secretory phase (d 24–28).
Immunohistochemical staining
Immunohistochemical staining was performed in duplicate as described elsewhere (22). Frozen sections (10 µm thick) were stained using commercially available kits (Histostain-SP kits, Zymed Laboratories, San Francisco, CA). Sections were incubated with polyclonal rabbit anti GLUT1 antibody at a concentration of 1:10 (Cymbus, Chandlers Ford, UK), with polyclonal rabbit anti GLUT3 antibody at a concentration of 1:1000 (Chemicon, Temecula, CA) and monoclonal anti-CD45 antibody at a concentration of 1:80 (Dako Diagnostika GmbH, Hamburg, Germany). Double immunostaining was performed using commercially available kits (Histostain DS double-staining kit, Zymed Laboratories, San Francisco, USA), FITC-conjugated goat antimouse antibody (Dako) at a concentration of 1:50, and tetramethylrhodaminisothiocyanate-conjugated swine antirabbit antibody (Dako) at a concentration of 1:50.
Positive controls included staining of erythrocytes in chorionic villi (GLUT1) and staining of syncytiotrophoblast (GLUT3). Negative controls included staining without the primary antibody and substitution of anti-GLUT1 antibody by rabbit IgG (Dako) of anti-GLUT3 antibody by rabbit nonimmune serum (Dako) and anti-CD45 antibody by mouse IgG (Dako) at the same concentration as the primary antibody.
The intensity of the immunohistochemical staining was semiquantitatively assessed (M.v.W. and S.U.).
RNase protection assay
RNA isolation and RNase protection assay (RPA) were performed as described elsewhere (23).
RNase protection assays were performed using the RiboQuant kit (PharMingen, San Diego, CA). GLUT1, GLUT2, GLUT3, GLUT4, GLUT5 probes, and negative and positive controls were also purchased from PharMingen. To reduce assay variability, all samples were analyzed in one experiment. RNAs were resolved on a denaturing 6% acrylamide sequencing gel. Unprotected probes were loaded as size markers. Identity of the RNase protected bands was established by comparing their size with the size of the bands of the positive control samples. For negative controls endometrial RNA was substituted by 5 µg yeast RNA. For positive controls human control RNA-2 from PharMingen was used. Semiquantification was achieved by normalizing the optical densities of the specific bands to the optical densities of the housekeeping genes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and L32. The OD of the specific protected bands was expressed as relative values. A 2-fold increase of the relative ODs corresponded, on average, to a 1.8-fold increase of the specific RNA, as determined in several dilution series of RNase protection assays with different concentrations of total RNA.
Endometrial mRNA expression of GLUT4 and GLUT8 was excluded by Northern blot (kindly performed by A. Schürmann and H.-G. Joost, Institute of Pharmacology and Toxicology, Medical Faculty, Technical University of Aachen, Aachen, Germany) (24).
ELISA
Concentrations of prolactin (PRL) in culture supernatants were determined using a commercial electrochemiluminescence immunoassay (Elecsys PRL Immunoassay, Roche Diagnostics, Mannheim, Germany). Concentration of IGF-binding protein-1 was determined using commercially available ELISA kits (Diagnostics Systems Laboratories, Webster, TX).
Separation of endometrial epithelial and stromal cells and leukocytes
Separation of endometrial epithelial and stromal cells and CD45-positive leukocytes was performed as described elsewhere (25). In brief, epithelial glands were separated from single stromal and immune cells by mechanical dissociation and collagenase digestion and filtration.
Epithelial glands trapped in the sieve were thoroughly washed and purified by positive selection using magnetic Dynabeads (Dynal, Oslo, Norway) against the human epithelial antigen EpCAM (Epithelial Enrich, Dynal). CD45-positive cells were isolated from the stromal and immune cells containing suspension that had passed through the 40-µm sieve by positive selection using CD45 Dynabeads (Dynal). Stromal cell suspension was purified by negative selection. All remaining and contaminating immune, endothelial, and epithelial cells were extracted by using a cocktail of magnetic beads including CD14, CD56, CD45, and CD31 as well as Dynabeads against the above-mentioned epithelial antigen EpCAM (all Dynal).
Cell culture
Isolation and culture of endometrial tissue was performed as described elsewhere (26). In brief, separation and purification of endometrial stromal cells from premenopausal patients undergoing hysterectomy for benign reasons was performed as described above. To further reduce contamination of cell cultures by nonstromal cells after separation, cells were passaged once and incubated in DMEM/F-12HAM medium without phenol red (Sigma, Deisenhofen, Germany). Cells were released by incubation with 10% trypsin (Life Technologies, Karlsruhe, Aachen) and seeded in 24-well tissue culture plates (Falcon, Oxnard, CA) with a density of 100,000 cells/well. When confluency was reached, cells were stimulated with 17ß-estradiol (10-8 M = 2.7 ng/ml) and/or progesterone (10-6 M = 310 ng/ml; Sigma; n = 8) or IL-1ß, IL-6 or TNF
(10 ng/ml) (R&D Systems, Minneapolis, MN) for 6 and 24 h (n = 4). After 6 or 24 h, supernatants were snap frozen in liquid nitrogen for RPA studies. Negative controls were cell cultures without stimulation by 17ß-estradiol and/or progesterone, IL-1ß, IL-6, or TNF.
Decidualization of stromal cells was achieved by stimulating confluent stromal cell cultures with 17ß-estradiol (0.5 ng/ml) and progesterone (50 ng/ml) for 7, 14, and 21 d. Decidualization was confirmed by high levels of PRL and IGF-binding protein-1. For inhibition experiments cells were incubated for 10 min with different concentrations of cytochalasin B (Sigma), an inhibitor of facilitative glucose transporter molecules. Decidualization was semiquantitated by the level of PRL in culture supernatants.
Deoxyglucose uptake assays were performed in a final volume of 0.5 ml, containing 300,000 cells and 6 µl 2-(1,2-3H)deoxy-D-glucose (25–50Ci/mmol, NEN Life Science Products, Boston, MA) and 0.5 mmol deoxyglucose. Uptake was performed at room temperature for 1 min and stopped by adding 10 volumes of cold PBS. The cells were collected by centrifugation and washed twice with cold PBS. Cells were dissolved in lysis buffer [10 mM Tris-HCl (pH 8.0) containing 0.2% sodium dodecylsulfate], and the incorporated radioactivity was assayed by liquid scintillation spectrometry.
Endometrial biopsies
To analyze whether impaired endometrial glucose uptake might play a role in idiopathic infertility, endometrial biopsies were collected from women with idiopathic infertility of both partners and as controls from women with tubal occlusion or a partner with poor sperm quality, which required performance of intracytoplasmatic sperm injection.
Patients were between 22 and 39 yr of age (idiopathic infertile patients mean age 33.1 ± 5.2 yr; control group 31.2 ± 4.6 yr) with regular menstrual cycle and did not receive hormonal therapy within the last 3 months. Levels of 17ß-estradiol (idiopathic infertile patients mean level 135.3 ± 49 pg/ml; control group 153.7 ± 86.8 pg/ml) and progesterone (idiopathic infertile patients mean level 11.6 ± 4.2 ng/ml; control group 12.8 ± 4.6 ng/ml) were similar in both groups at the time when the biopsy was taken. Patients were advised to refrain from sexual intercourse or use barrier contraception during the month of investigation. Endocrine and uterine infertility factors were excluded by pelvic examination; transvaginal ultrasound; serum determination of PRL, TSH, dehydroepiandrosterone sulfate, androstenedione, and testosterone; and basal temperature charts. Endometrial biopsies were taken 8–9 d after the LH surge. Biopsies were obtained with an endometrial sampler (Wallace endometrial sampler; Sims Portex, Hythe, UK). Histological dating and evaluation was done in all endometrial biopsy specimens to exclude samples with endometrial pathologies.
Statistics
Wilcoxon signed rank test (see Figs. 1
, 2, 7, and 8) and Mann-Whitney test (see Figs. 4–6) were used for statistical evaluation. Significance was established at the P < 0.05 and P < 0.01 level.
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Results |
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Endometrial tissue was first screened for the mRNA expression of GLUT1-GLUT5 and GLUT8 by RPA and Northern blot. Endometrial mRNA expression of GLUT4 and GLUT8 in total endometrium was excluded by Northern blot (kindly performed by A. Schürmann and H.-G. Joost) (24). Endometrial mRNA expression of GLUT2, GLUT4, and GLUT5 was excluded by RPA. Human total endometrium expressed mRNA of only the GLUT1 and GLUT3 isoforms as analyzed by RPA.
Analysis of total endometrium and decidua by RPA revealed weak expression of GLUT1 mRNA in the proliferative phase and early/midsecretory phase (Fig. 1
). Expression increased significantly in the late secretory phase (P < 0.05) and in decidua of the sixth to ninth week of pregnancy (P < 0.01). Increase of GLUT1 mRNA expression was approximately 3-fold in decidua.
The mRNA expression of GLUT3 was also weak in the proliferative and early/midsecretory phase (Fig. 1). Expression increased in the late secretory phases and in decidua (P < 0,05); increase of mRNA expression in decidua was approximately 2-fold.
To analyze which cell types were responsible for the increase of GLUT mRNA expression in total endometrium and in decidua, we separated endometrial tissue and decidua by collagenase digestion, filtration, and magnetic Dynabeads into epithelial cells, stromal cells, and CD 45-positive leukocytes.
Analysis by RPA revealed low expression of GLUT1 in stromal cells in the proliferative phase and significantly increasing concentrations in the secretory phase and in the sixth to ninth week of gestation (Fig. 2). In contrast, GLUT1 mRNA levels in epithelial cells were constantly high and GLUT1 mRNA expression in CD45-positive leukocytes was constantly low. When we compared expression patterns in all cell types, stromal cells were responsible for the mRNA increase in the late secretory phase and in decidua as shown in Fig. 1.
GLUT3 expression did not change in all studied cell fractions throughout the cycle and in decidua. However, in comparison to GLUT1 mRNA, GLUT3 mRNA expression was significantly higher in CD45 positive leukocytes. High GLUT3 mRNA concentration in leukocytes suggests endometrial leukocytes to be responsible for the increasing expression of GLUT3-mRNA in total endometrium in the late secretory phase and in decidua (Fig. 1) as leukocyte concentration increases throughout the menstrual cycle and in decidua (27, 28, 29).
To confirm the expression pattern of GLUT1 and GLUT3 in human endometrium and decidua on the protein level, we performed several experiments of immunohistochemistry (Fig. 3). In tissue samples taken during the proliferative and early secretory phase, only weak reactivity of GLUT1 was observed in endometrial stromal cells (Fig. 3a). As already shown by RPA, stromal reactivity increased gradually in the mid- and late secretory phase (Fig. 3b) with maximum staining in decidual cells of the sixth to ninth week of gestation (Fig. 3c). Immunohistochemistry revealed concentration of stromal GLUT1 expression to be increased in the secretory phase and in decidua, whereas the number of cells expressing GLUT1 did not substantially increase. Immunohistochemistry of GLUT3 revealed staining patterns (Fig. 3e) similar to that of endometrial CD45 leukocytes (Fig. 3f), suggesting endometrial leukocytes to stain positively for GLUT3. Double immunostaining with anti-GLUT3 and anti-CD45 antibodies showed GLUT3-positive cells to be identical with CD45-positive leukocytes (Fig. 3g), confirming the above-described RPA results.
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Because only GLUT1 is expressed at different concentrations in endometrium and decidua, we focused on GLUT1 and analyzed the function of GLUT1 in endometrial decidualization. GLUT3 was used as negative control.
We first performed glucose uptake assays to confirm that stromal glucose transporters are responsible for stromal glucose uptake. Confluent stromal cells were incubated with different concentrations of cytochalasin B, a potent inhibitor of glucose transporters (30), and with 2-(1,2-3H)deoxy-D-glucose. Glucose uptake was significantly inhibited by incubation with increasing concentrations of cytochalasin B (Fig. 4), clearly demonstrating stromal glucose transporters to be involved in the regulation of stromal glucose uptake.
Regulation of GLUT1 and GLUT3 expression by steroids and cytokines was excluded by stimulation stromal cells in vitro by 17ß-estradiol (10-8 M = 2,7 ng/ml), progesterone (10-6 M = 310 ng/ml), IL-1ß, IL-6, or TNF (10 ng/ml) for 6 and 24 h (data not shown).
Because stromal GLUT1 mRNA expression correlated with the degree of stromal decidualization, we speculated that GLUT1 mRNA expression is not directly stimulated by progesterone but indirectly by the process of decidualization, which is regulated by progesterone and 17ß-estradiol. We, therefore, decidualized stromal cells in vitro with progesterone and 17ß-estradiol for up to 21 d and analyzed the mRNA expression of GLUT1 and GLUT3 (Fig. 5). GLUT1 mRNA expression but not GLUT3 mRNA expression correlated significantly with the degree of stromal decidualization, reflected by increasing PRL levels. These results raised the question of whether stromal GLUT expression is just a secondary effect of cell transformation or, in contrast, is an essential prerequisite for the process of decidualization.
To address this question we incubated decidualizing stromal cells with increasing concentrations of cytochalasin B (Fig. 6). Decidualization was confirmed by concentration of PRL in culture supernatants. PRL secretion was significantly reduced after 21 d of decidualization in culture supernatants of cells treated with cytochalasin B. Cells incubated with 3 µM cytochalasin B did not produce significant amounts of PRL, indicating total inhibition of decidualization.
Expression of endometrial glucose transporters in infertile patients
Our experiments demonstrated that GLUT1 expression is increased in decidualized cells and is crucial for decidual transformation of stromal cells. Because decidualization is essential for the successful implantation of the embryo, we speculated whether endometrial GLUT expression might be impaired in patients with idiopathic infertility.
We, therefore, collected endometrium 8–9 d after the LH surge at the end of the implantation window in which the endometrium is still receptive for the implanting embryo and stromal cells begin to decidualize.
We first studied the concentration of endometrial immune cells (CD4, CD8, CD14, CD19, CD45, and CD56) and the expression of the cytokines granulocyte-macrophage stimulating factor, macrophage-colony stimulating factor, granulocyte-colony stimulating factor, TGFß, and vascular endothelial growth factor to exclude other endometrial pathologies (data not shown). The expression of these factors was similar in infertile patients and the control group.
We then compared the mRNA expression and immunohistochemical staining pattern of GLUT1 and GLUT3 in endometrial biopsies from women with idiopathic infertility with biopsies from women with definite infertility factors such as tubal pathology or poor sperm quality, in which normal endometrial function was assumed. Progesterone levels and clinical data were matched in both groups. Analysis of total endometrium by RPA revealed reduced mRNA expression of GLUT1 in idiopathic infertile patients (Fig. 7). Only 10% of samples from idiopathic infertile patients expressed more than 10 arbitrary units of GLUT1 mRNA, whereas 85% of the control group expressed high concentrations of GLUT1. In contrast, endometrial mRNA expression of GLUT3 did not reveal significant differences in either group of patients (data not shown).
To evaluate which cell type was responsible for the reduced GLUT1 mRNA expression in idiopathic infertile patients, we performed immunohistochemistry of endometrial biopsies (Fig. 8). Immunohistochemical staining revealed similar staining patterns as described above. Glandular staining was moderate to strong in most samples, and endometrial immune cells did not stain at all for GLUT1. Staining of stromal cells, however, was different in both groups of patients. Twenty-five percent of biopsies obtained from idiopathic infertile patients revealed strong immunostaining in stromal cells, compared with 54% in the control group (Fig. 8).
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Discussion |
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Our studies revealed that among all well-characterized glucose transporters, only GLUT1 and GLUT3 are expressed. Because human placenta (9) and rat endometrium (31) were described to express the insulin dependent glucose transporter GLUT4, human endometrium and decidua were double-checked by RPA and Northern blot to definitely exclude GLUT4 mRNA expression.
GLUT3 is the typical transporter isoform of cells with high glucose requirement because of its particularly high affinity for glucose. In human endometrium GLUT3 mRNA was found at low concentrations in endometrial epithelial cells, moderate concentrations in endometrial stromal cells, and high concentrations in endometrial CD45-positive immune cells. These results are in parallel with immunohistochemistry studies in the rat model by Korgun et al. (31), who found constant moderate endometrial stromal expression and maximum endometrial epithelial concentrations on d 3–4 of gestation, 1–2 d before implantation. Interestingly, highest GLUT3 levels were found by Korgun et al. (31) in decidual cells, which is in contrast to the relatively little GLUT3 mRNA detected there by in situ hybridization (19). Such divergent results have also been described by others (32).
The divergent results indicate the necessity to use different cell biological techniques to achieve reproducible and convincing data on the expression of GLUT3. We, therefore, performed not only RPAs but also immunohistochemistry. We used an anti-GLUT3 antibody, which clearly stained human placental cytotrophoblast, a cell type that has recently been shown by Hahn et al. (33) to definitely stain for GLUT3. The combination of both techniques and use of double-immunostaining techniques revealed a marked mRNA and protein expression of GLUT1 in CD45-positive leukocytes. GLUT3 expression in peripheral leukocytes had already been studied by Korgun et al. (18), who found a significant increase of GLUT3 expression in peripheral monocytes in the second trimester. Because it is technically not possible to reproducibly separate the endometrial leukocyte subgroups such as monocytes/macrophages, T-lymphocytes, B-lymphocytes, and large granular lymphocytes, we were not able to concisely define the immune cell type that maximally expressed GLUT3.
The second glucose transporter isoform that is expressed at high concentration in human endometrium is GLUT1. In contrast to GLUT3, GLUT1 mRNA was found in only low concentrations in endometrial and decidual CD45-positive immune cells. The most striking finding in vivo and in vitro was the increasing expression of GLUT1 in decidualizing stromal cells. GLUT1 mRNA was expressed at very low concentrations throughout the proliferative phase but increased significantly in the secretory phase and in decidua, the phase in which endometrium is characterized by stromal decidualization. These findings are similar to those by Korgun et al. (31), who found in the rat model by immunohistochemistry low endometrial stromal expression of GLUT1 in the first 3 d of gestation and a sharp increase of GLUT1 expression on d 4–5 of gestation, the time of implantation. In mice the level of GLUT1 increased further after midpregnancy not only in decidua but also in placenta (17). Human placenta has already been described to express high concentrations of GLUT1. GLUT1 is expressed in the blood-tissue barrier and basal membranes of the placental syncytiotrophoblast, mediating the transplacental glucose transport (32, 34).
Our studies revealed that stromal GLUT1 expression is not regulated by direct stimulation with proinflammatory cytokines and steroids but by the process of decidualization. GLUT1 mRNA expression was still very low after 7 d of continuous stimulation with the decidualizing steroids 17ß-estradiol and progesterone but increased significantly after 14 d of stimulation. These results raise the question of whether the expression of GLUT1 mRNA is a prerequisite for decidualization or whether it is just a consequence of decidualization. Our experiments revealed impaired decidualization of stromal cells by inhibition of glucose transporters, suggesting adequate GLUT function to be crucial for decidualization and cellular function.
Experiments by Ogura et al. (35) are in favor of GLUT1 and decidualization to be regulated by similar pathways. Ogura et al. demonstrated by Northern and immunoblot analyses that the levels of GLUT1 in a human choriocarcinoma cell line was stimulated by 8-bromo-cAMP. Because 8-bromo-cAMP also stimulates decidualization, it can be speculated decidual GLUT1 expression and stromal decidualization are mediated through a common cAMP signal transduction pathway.
The process of decidualization is an essential prerequisite for human implantation. Decidual cells are temporally and spatially positioned at the fetomaternal interphase to create a local homeostatic milieu. Decidual cells produce several key cytokines such as IGF-binding protein (36) and PRL (37), which have multiple roles in endometrial development and interactions between the decidua and invading trophoblast.
Our experiments revealed inhibition of PRL secretion in progesterone-stimulated stromal cells, treated by cytochalasin B. Cytochalasin B not only inhibits facilitative glucose transporters but also has an effect on the cytoskeleton, disrupting the cortical actin filaments and consequently on the cellular production of PRL and steroid hormones. Studies on the effect of cytochalasin B on the synthesis of PRL in anterior pituitary cells (38) and the PRL-stimulated progesterone synthesis in porcine theca cells (33) demonstrated stimulation or inhibition of PRL secretion, depending on the duration of cytochalasin B stimulation and the cotreatment of the anterior pituitary cells and stimulation of progesterone synthesis in porcine theca cells. It remains, therefore, unclear whether inhibition of glucose transporters by cytochalasin B inhibits decidualization or whether cytochalasin B has an effect on PRL secretion by affecting the cytoskeleton.
Even though our knowledge about the regulation of GLUT expression is still poor, there is a growing body of evidence that inadequate GLUT expression in the reproductive tract is associated with impaired cellular function and an impaired reproductive performance. Dysregulation of placental GLUT expression seems to be associated with macrosomia and fetal growth retardation (39, 40). Inhibition of facilitative glucose transporters in mouse embryos inhibited the morula/blastocyst transition (16). We found suppressed GLUT1 expression in patients with idiopathic infertility in comparison with a control with tubal occlusion or infertility of the partner. It is a matter of debate whether GLUT1 and other endometrial factors, suppressed in idiopathic infertility, are crucial for regulation of endometrial and decidual function or whether these factors are just end points of a regulatory cascade, which is suppressed by a more basically dysregulated factor. However, because oxidative metabolism is mandatory for sustaining normal cellular function, an adequate expression of glucose transporters can be assumed to be a basic prerequisite for endometrial and decidual cell function.
Our results suggest stromal GLUT plays a role in the regulation of endometrial function and is compromised in the preparation of the endometrium for the implanting embryo.
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Acknowledgments |
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Footnotes |
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Received November 20, 2002.
Accepted April 10, 2003.
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) in human endometrium and uterine secretion: an evaluation by immunohistochemistry, ELISA and semiquantitative RT-PCR. Mol Hum Reprod 5:146–152This article has been cited by other articles:
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