Molecular Human Reproduction, Vol. 8, No. 12, 1111-1116,
December 2002
© 2002 European Society of Human Reproduction and Embryology
Molecular events in the uterus |
Altered expression of genes involved in the production and degradation of endometrial extracellular matrix in patients with unexplained infertility and recurrent miscarriages
1 Departments of Obstetrics and Gynecology, 2 Medical Biochemistry and Molecular Biology, and 3 Pathology, University of Turku, FIN-20520 Turku, Finland
Abstract
During the secretory phase of the menstrual cycle, the composition of extracellular matrix (ECM) in endometrium changes to favour implantation. In the present study, we have analysed whether some cases of unexplained infertility and recurrent abortions could be explained by abnormal production or turnover of endometrial ECM. Comparison of mRNA levels of a panel of collagens, matrix metalloproteinases (MMP), tissue inhibitors of metalloproteinases (TIMP) and cathepsins in the samples revealed higher levels of type I collagen, MMP-2 and cathepsin H and decreased levels of TIMP-3 mRNA in mid-secretory endometrium of patients with unexplained infertility and/or recurrent miscarriages when compared with normal mid-secretory endometrium. Furthermore, changes were also seen in the levels of type I collagen and TIMP-3 mRNA between the proliferative and mid-secretory phases of normal endometrium. The results suggest an altered ECM turnover in the endometrium of patients with fertility disorders prior to implantation.
collagen/endometrium/extracellular matrix/habitual abortion/infertility
Introduction
Development of histologically and functionally normal endometrium is critical for endometrial receptivity and normal implantation. Abnormalities in the remodelling of extracellular matrix (ECM) of endometrial stroma have been associated both with abnormal histology (Stenbäck, 1989
) and with bleeding disorders and implantation defects (Iwahashi et al., 1996a; Skinner et al., 1999). On the other hand, an endometrial factor—either at the tissue or molecular level—has been suggested to explain some cases of infertility (Li et al., 1991; Tabibzadeh, 1998) and recurrent miscarriages (Serle et al., 1994), which remain of unknown aetiology. However, the exact ECM components associated with these disorders remain poorly understood. The present work is based on a working hypothesis that abnormalities in endometrial ECM prior to implantation may result in a failure of reproduction.
The best characterized components of ECM in endometrium are collagens, fibronectin and laminins (Aplin et al., 1988; Stenbäck 1989; Iwahashi et al., 1996a). Of the 20 different collagen types known at present (Myllyharju and Kivirikko, 2001), type I, III, IV, V and VI collagens have been detected in human endometrium (Aplin et al., 1988; Stenbäck, 1989; Stovall et al., 1992; Iwahashi et al., 1996a). Fibrillar collagen of type I, and to some extent also types III and V, are primarily responsible for the structural integrity and strength of tissues. Type IV collagen, found in basement membranes, has been suggested to enhance trophoblast invasion by providing a substratum for cell migration (Aplin, 1996), and by retaining the invasive phenotype of the trophoblasts (Irving et al., 1995). In contrast, the role of fibrillar collagens seems to be restrictive: trophoblasts exposed to type I collagen in vitro tend to fuse to form a syncytium instead of an invasive cell column (Morrish et al., 1998; Aplin et al., 1999).
In addition to changes in the synthesis rates of collagens, turnover of collagenous ECM is regulated by two groups of enzymes, matrix metalloproteinases (MMP) and cysteine cathepsins, and their inhibitors, tissue inhibitors of metalloproteinases (TIMP) and cystatins respectively. MMP are a large family of zinc-dependent proteinases capable of degrading native collagen at a physiological pH (Kähäri and Saarialho-Kere, 1999). MMP activity in endometrium has been shown to depend on the phase of the menstrual cycle (Hampton and Salamonsen, 1994; Rodgers et al., 1994; Jeziorska et al., 1996) and on the levels of steroid hormones (Marbaix et al., 1992; Rodgers et al., 1994), whereas TIMP-1 and -2 are expressed at relatively stable levels in proliferative and secretory endometrium (Hampton and Salamonsen, 1994; Zhang and Salamonsen, 1997; Määttä et al., 2000). On the other hand, marked increases have been observed in the expression of TIMP-3 during the secretory phase (Zhang and Salamonsen, 1997; Määttä et al., 2000), suggesting a role in the preparation of endometrium for decidualization and implantation (Higuchi et al., 1995). The role of cysteine cathepsins, a family of lysosomal and pericellular proteinases active in an acidic environment (Kirschke et al., 1998), is less well understood for the endometrium. In addition to being capable of degrading several ECM molecules, some cysteine cathepsins can activate MMP and vice versa (Kirschke et al., 1998). We have previously demonstrated the presence of cathepsins B, H, K, L and S in human proliferative and secretory endometrium, and shown that the mRNA levels of cathepsins H and K decline in mid-secretory phase (Jokimaa et al., 2001) in parallel with MMP activity (Rodgers et al., 1994).
To test our hypothesis that abnormalities in endometrial ECM interfere with implantation and possibly account for some of the 15% of infertility cases of unknown aetiology and for some of the cases with recurrent miscarriages, we have examined the mRNA levels of a panel of collagens, MMP, TIMP and cathepsins in mid-secretory phase endometrium of patients with unexplained infertility and recurrent abortions, and compared them with those in mid-secretory phase endometrium of normal fertile women.
Materials and methods
Study subjects
The study material consisted of healthy, fertile volunteers (group 1; n = 14), patients with idiopathic infertility (group 2; n = 9) and patients with recurrent miscarriages (group 3; n = 10). The mean age of participants in group 1 was 33 ± 4.5 years (range 24–38). Exclusion criteria for the study group 1 were: present or past infertility, menstrual disorders, hormonal treatments within 6 weeks and hormonal or intrauterine contraception.
The mean age of patients in group 2 was 31 ± 3.5 years (range 26–36). Infertility was defined as unexplained if the patient exhibited regular menstrual bleedings, the ultrasound examinations revealed normal pre-ovulatory follicular development and serum progesterone levels were elevated during luteal phase of the menstrual cycle. Furthermore, the diagnosis of tubal infertility was excluded using primarily hysterosalpingography. The exclusion of male factor infertility was based on normal semen analyses.
The mean age of patients in group 3 was 31.5 ± 4.5 years (range 25–37). Habitual abortion was defined as three or more consecutive spontaneous abortions. Patients with genetic errors, anatomical malformations and endocrine disorders were excluded.
An ultrasound examination was performed during late follicular phase to confirm normal endometrial and follicular development. Endometrial samples for RNA extraction were collected with a Pipelle de Cornier catheter. Samples representing the mid-secretory phase were collected 6–9 days after the urinary LH peak. Additionally, samples representing the proliferative phase (n = 9) were collected from group 1 in the subsequent cycle between period days 8–13. The samples were frozen in liquid nitrogen and stored at –70°C. Endometrial dating (Dallenbach-Hellweg and Poulsen, 1985) was performed using formalin-fixed, paraffin-embedded mid-secretory phase samples (group 1, n = 11; group 2 = 8; group 3, n = 8). The number of out-of-phase samples was comparable between the groups (group 1, n = 4; group 2, n = 3; group 3, n = 3). Exclusion of the out-of-phase samples from the analysis did not affect the results.
The study design was approved by the Ethical Committee of Turku University and Turku University Central Hospital, and an informed consent was signed by all participants.
RNA extraction and mRNA analyses
For extraction of total RNA, the frozen endometrium samples were pulverized under liquid nitrogen in a mortar and homogenized in guanidinium isothiocyanate as described previously (Chirgwin et al., 1979). Aliquots of 10 µg of total RNA were denatured with glyoxal and formamide, fractionated on 0.75% agarose gels, and blotted onto nylon transfer membranes, and hybridized with 32P-labelled cDNA inserts at 42°C for 20 h. The hybridizations and high-stringency washes were performed for each probe as suggested by the supplier of the BiodyneTM A membrane (Pall Corporation, Ann Arbor, MI, USA). Briefly, the membranes were hybridized in 50% formamide, 1 mol/l NaCl, 1% sodium dodecyl sulphate (SDS), 10% dextran sulphate, 5xDenhardt’s, and 100 µg/ml sonicated calf thymus DNA, at 42°C overnight, and washed twice in 2xSSC, 0.1% SDS at room temperature for 10 min, and twice in 0.1xSSC, 0.1% SDS at 50°C for 20 min. All mRNAs, except that for TIMP-3, were analysed on the same filter. Due to exhaustion of three samples, only 30 RNAs were analysed for TIMP-3 mRNA (group 1, n = 14; group 2, n = 8; group 3, n = 8). Between hybridizations, the blots were stripped by adding boiling 0.5% SDS and shaking for 10 min followed by checking of the filter for loss of radioactivity, prehybridization and rehybridization with a new probe as above.
The cDNA inserts used as probes were liberated from clones listed in Table I. The bound probes were detected and quantified on a Molecular Imager phosphoimager and the signals were corrected for variations in the 28S rRNA levels determined by hybridization. The data were analysed by Mann–Whitney–Wilcoxon test. P < 0.05 was considered to be statistically significant.
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Results
Collagens
Northern analysis revealed the presence of type I, III and IV collagen mRNA in all the endometrium samples studied except in one mid-secretory phase sample (Figure 1) which did not give a reliable hybridization signal and was excluded from these analyses. Densitometric analyses demonstrated differences in the relative levels of collagen mRNA compared with 28S rRNA between proliferative and mid-secretory phases in normal human endometrium as summarized in Figure 2. The levels of the major (5.3 kb) type I collagen transcript were significantly lower in mid-secretory phase endometrium than in proliferative endometrium (P < 0.05). There was also a decrease in the levels of the major (5.4 kb) mRNA for collagen type III in the mid-secretory phase, but the decrease did not reach statistical significance, as individual variation was considerable, particularly in samples representing the proliferative phase. No differences were observed in the mRNA levels of collagen type IV between the proliferative and mid-secretory phase samples of normal controls.
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A similar analysis was subsequently performed on mid-secretory phase samples of patients with unexplained infertility (group 2), recurrent abortions (group 3), and normal controls (mid-secretory samples of group 1) (Figure 1
). Statistically significant differences between the groups were seen in the levels of the major 5.3 kb transcript of pro
1(I) collagen between the groups (P < 0.001) (Figure 3A). However, the ratio of the larger 6.5 kb and the smaller 5.3 kb transcript was lower (0.61–0.64) in the two patient groups when compared with the ratio of 1.1 in control samples. The levels of both the larger and smaller mRNA variants of pro1(III) collagen and the levels of pro1(IV) collagen mRNA were similar in all groups (Figure 3A).
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MMP-1 and -2
The mRNA for MMP-1 and MMP-2 were analysed on the same filters as those for collagens. In normal endometrium, the signal for MMP-1 mRNA was too low for reliable quantification (not shown). No differences were seen in the mRNA levels of MMP-2 between the proliferative and mid-secretory phase (Figures 1 and 2
). In endometrium samples of patient groups 2 and 3, significantly higher MMP-2 mRNA levels were detected than in the control samples during the mid-secretory phase (P < 0.05 for both groups) (Figure 3B).
TIMP-1, -2, -3 and -4
Northern analysis revealed the presence of TIMP-1, -2 and -3 mRNA in all endometrium samples studied (Figure 1), whereas the signal for TIMP-4 mRNA was barely detectable (not shown). No differences were observed in the mRNA levels of TIMP-1 and TIMP-2 between proliferative and mid-secretory phase samples of normal controls (Figure 2). The mRNA levels for TIMP-3 were significantly higher in the mid-secretory phase endometrium than in the proliferative endometrium (P < 0.05) (Figure 2).
Transcript levels of TIMP-1 and -2 in the mid-secretory phase endometrium of all groups were similar, whereas those of TIMP-3 were significantly lower in patient groups 2 (P < 0.05) and 3 (P < 0.05) than in normal controls (group 1) (Figure 3B).
Cysteine cathepsins
Northern analysis of cathepsin B, H, K and L mRNA (Figure 1) was performed to compare mid-secretory phase samples of patients with unexplained infertility (group 2) and recurrent abortions (group 3) with mid-secretory phase samples of normal controls (group 1). The mRNA levels of cathepsin H were significantly higher in the mid-secretory phase endometrium of group 3 than in normal endometrium (Figure 3C). No differences in the mRNA levels of the other cysteine cathepsins were detected between the groups (Figure 3C).
Discussion
The results of the present study bring additional support to the hypotheses that ECM participates in endometrial receptivity and normal implantation, and that abnormalities in this ECM could explain some cases of idiopathic infertility and recurrent miscarriage. Key findings of the present study were higher mRNA levels of type I collagen, MMP-2 and cathepsin H, and decreased mRNA levels of TIMP-3 in mid-secretory phase endometrium from patients with unexplained infertility and/or recurrent miscarriages when compared with normal mid-secretory endometrium. Furthermore, changes were also seen in the levels of these transcripts between mid-secretory and proliferative phases of normal endometrium.
Earlier studies, based on light and electron microscopy, immunohistochemistry and collagen extraction methods, have demonstrated the presence of type I and III collagen in endometrium (Aplin et al., 1988; Stenbäck, 1989; Stovall et al., 1992; Iwahashi et al., 1996a). As these methods measure the content and distribution of collagens, which exhibit long half-lives often measured in years, little is known of changes in the rates of collagen production in endometrium. For this purpose, we measured (pro)collagen mRNA levels, which provide a better estimate of synthesis rates. Decreased transcription of the type I collagen gene in secretory endometrium may be one of the changes that prepare endometrium for implantation.
In the present study, Northern analyses revealed significantly higher mRNA levels of type I collagen in mid-secretory phase endometrium of patients with unexplained infertility or with recurrent miscarriages than of normal controls. This observation is in line with the suggested restrictive role of type I collagen on the formation of invasive trophoblast columns (Morrish et al., 1998; Aplin et al., 1999). Thus, increased production of type I collagen fibrils might reduce endometrial receptivity. Further studies are needed to establish the possible role of an altered ratio of the larger and the smaller pro1(I) collagen mRNA variant in the patient samples.
Although the changes in type III collagen transcripts resembled those in type I collagen mRNA, the differences between the study groups did not reach statistical significance. This was somewhat unexpected, as earlier immunohistochemical studies have shown weaker staining for type III collagen in secretory endometrium than in proliferative endometrium (Aplin et al., 1988; Stenbäck, 1989). Moreover, the ratio of type III collagen to type I, which reflects connective tissue repair, has been shown to be lower in secretory phase than in proliferative phase (Iwahashi et al., 1996a). In the present study, the ratio of type III to type I mRNA remained essentially unchanged in the mid-secretory phase endometrium compared with the proliferative phase endometrium. This indirectly suggests that the type III/I collagen ratio in endometrium is not controlled at the transcriptional level, but through differential breakdown rates of collagen types. Recently, Okada et al. reported on a morphological change in type III collagen fibre arrangement between proliferative and secretory phase, suggesting increased degradation of this collagen type during the latter phase (Okada et al., 2001).
Type IV collagen has previously been localized to basement membranes of endometrial glands and blood vessels during proliferative and mid-secretory phases (Aplin et al., 1988; Iwahashi et al., 1996a). During the late secretory phase and in decidualizing endometrium, type IV collagen has also been found in the pericellular basement membrane of stromal cells (Wewer et al., 1985; Aplin et al., 1988; Iwahashi et al., 1996a). In the present study, the mRNA levels for type IV collagen were found to be similar in the proliferative and mid-secretory phase endometrium. Decreased levels of type IV collagen have been observed in the decidual tissues of spontaneous abortions (Iwahashi et al., 1996b). In the present study, the mRNA levels of type IV collagen did not differ in the mid-secretory phase endometrium of controls and patients with recurrent miscarriages. However, the results of the present study cannot be interpreted to exclude the proposed association of miscarriage and diminished expression of type IV collagen, as the decrease in expression could develop during a later phase of the cycle or during decidualization. Also, the significantly elevated mRNA levels of MMP-2 in mid-secretory phase endometrium of patients with unexplained infertility and recurrent miscarriages could lead to a reduction in type IV collagen, as active MMP-2 is able to degrade this basement membrane collagen.
Although the MMP/TIMP system in endometrium has been under extensive research (Hulboy et al., 1997), little is known of the breakdown rates of different collagen types in the endometrium. Expression of several MMPs has been observed in the endometrium during the menstrual cycle. In general, the levels of MMP are low in the endometrial stroma during the proliferative and particularly during the secretory phase, but increase dramatically in the premenstrual and menstrual endometrium (Rodgers et al., 1994; Marbaix et al, 1996; Hulboy et al., 1997). MMP-2 and membrane-type-2-MMP (MMP-15) are the only MMP reported to be present in the endometrial stroma throughout the menstrual cycle (Rodgers et al., 1994; Soini et al., 1997; Zhang et al., 2000). Thus MMPs capable of degrading fibrillar collagens appear to be absent in the mid-secretory phase endometrium (Hampton and Salamonsen, 1994; Rodgers et al., 1994). By in-situ hybridization analyses, MMP-2 production has been suggested to decrease during the mid-secretory phase (Rodgers et al., 1994). In the present study, Northern blot analysis revealed stable levels of MMP-2 mRNA in proliferative and mid-secretory phase endometrium. This finding is in good agreement with another study (Soini et al., 1997). It has to be kept in mind, however, that MMP-2 mRNA levels (coding for the pro-MMP-2 enzyme) do not necessarily correlate with MMP-2 enzyme activity in the tissue as the proenzyme may be stored for extended periods before activation.
The levels of TIMP-1 and -2 in endometrial stroma and epithelium have also been found to remain relatively stable during proliferative and secretory phases (Hampton and Salamonsen, 1994; Zhang and Salamonsen, 1997; Määttä et al., 2000), whereas TIMP-3 expression has been reported to increase in the mid-secretory phase endometrium (Zhang and Salamonsen, 1997; Määttä et al., 2000). In vitro, TIMP-3 mRNA expression is stimulated by progesterone (Higuchi et al., 1995). Our finding of increased production of TIMP-3 mRNA in the mid-secretory phase endometrium is in line with the previous reports. TIMP-3 has been suggested to participate in the preparation of endometrium for implantation (Higuchi et al., 1995). In our study, the transcript levels of TIMP-3 in the endometrium of patients with unexplained infertility and recurrent miscarriages were significantly lower than in fertile controls. We postulate that the decreased level of TIMP-3 in endometrium during the early stages of trophoblast invasion leads to an imbalance in the control of ECM degradation by trophoblasts, and subsequently to endometrial breakdown and failure of implantation. Alternatively, decreased levels of TIMP-3 may predispose the predecidualized endometrial cells to apoptosis, as suggested by others (Whiteside et al., 2001). In addition, TIMP-3 may have a role in the regulation of trophoblast cell behaviour. Such a function would be in line with earlier observations in other cell types, as TIMP have been implicated in a variety of processes involving cell growth, steroidogenesis, germ cell development and modulation of cell morphology and cell attachment (Gomez et al., 1997).
Cysteine cathepsins are also multifunctional enzymes. Apart from their proteolytic effects on collagens and other ECM molecules, they are able to activate proenzymes, prohormones, growth factors and their receptors into active forms (Kirschke et al., 1998). Through their capability to activate prorenin into renin (Luetscher et al., 1982), cathepsins B and H may affect the endometrial renin–angiotensin system and thereby play a role also in fertility (Vinson et al., 1997). Renin immunostaining has been reported to be moderate in stromal cells of proliferative endometrium, but negligible in secretory endometrium (Li and Ahmed, 1997). This pattern parallels that of cathepsin H (Jokimaa et al., 2001). In this study, mRNA levels for cathepsin H were elevated in the mid-secretory phase endometrium of patients with recurrent miscarriages. Whether this association is linked to endometrial renin–angiotensin system, remains to be determined.
In conclusion, the altered transcript levels of type I collagen, MMP-2, TIMP-3 and cathepsin H in mid-secretory phase endometrium from patients with unexplained infertility and/or recurrent miscarriages suggest altered ECM turnover in these patients. These changes may reflect alterations in the preparation of endometrium for decidualization and implantation. The increased levels of type I collagen and cathepsin H and low levels of TIMP-3 mRNA could possibly be explained with delayed maturation of endometrium, but such an explanation is not valid for the increased production of MMP-2 mRNA. As endometrial dating did not reveal significant histological differences between the study groups, we propose that an alteration independent of endometrial histology may explain some of the cases of unexplained infertility and recurrent miscarriages.
Acknowledgements
The cDNA clones for TIMPs were a generous gift from Dr Veli-Matti Kähäri. The expert technical help of Merja Lakkisto and Tuula Oivanen is gratefully acknowledged. This study was supported by the Turku University Central Hospital (projects no. 13449 and no. 13576) and the Academy of Finland (project no. 52940). Sanna Oksjoki is a recipient of a training grant from the Turku Graduate School of Biomedical Sciences (TuBS).
Notes
4 To whom correspondence should be addressed. E-mail: varpu.jokimaa{at}tyks.fi 
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Submitted on June 21, 2002; accepted on September 17, 2002.
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