Gunvor Ekman

Ripening of the human uterine cervix related to changes in collagen, glycosaminoglycans, and collagenolytic activity

Connective tissue in biopsy specimens taken from the lower part of the uterine cervix in 40 pregnant women at various gestational ages was compared to that in similar biopsy specimens from 15 nonpregnant women. The concentrations of collagen, sulfated glycosaminoglycans, and hyaluronic acid decreased during pregnancy. At the gestational age of 10 weeks, the collagen concentration was 70%, and at term 30%, of that in the nonpregnant cervix. After delivery, no further decrease was observed. The extractability of collagen increased during pregnancy, as well as during labor. Also, the water concentration increased. An increase in the collagenolytic activity was observed with advancing gestational age. The 2,4-dinitrophenyl-Pro-Gln-Gly-Ile-Ala-Gly-Gin-D-Arg hydrolytic activity (collagenase) and the concentration of leukocyte elastase increased gradually by a factor of 10. The physiologic importance of the collagen was also demonstrated, since the cervical dilatation time during spontaneous labor was long in women with high concentrations of collagen and short in women with low concentrations of collagen.

Different biochemical composition of connective tissue in continent and stress incontinent women

The collagen content in biopsies from skin and ligamentum rotundum of 7 women with a long history of stress incontinence was compared with that of continent controls. The collagen was extracted with 0.5 M acetic acid, followed by digestion with pepsin and quantitated as hydroxyproline. The skin of stress incontinent women contained 40% less collagen than that of continent women. The findings for ligamentum rotundum were similar. These results suggest a deteriorated connective tissue in stress‐incontinent women and cast new light on the etiology of the disease

Increased Level of Matrix Metalloproteinases 2 and 9 in the Ripening Process of the Human Cervix

Abstract The human uterine cervix is a fibrous organ with a high connective tissue content. An extensive remodeling of the connective tissue prior to parturition, i.e., cervical ripening, requires the presence of proteolytic enzymes. The exact mechanism of cervical ripening has not been clarified. We evaluated in vivo distribution and expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) in the human cervix at term pregnancy and immediately after parturition compared with the nonpregnant state. Cervical biopsies were obtained from term pregnant, postpartum, and nonpregnant women. MMP-2 and MMP-9 proteins were localized by immunohistochemistry. Messenger RNA levels of MMP-2 and MMP-9 were evaluated by relative quantitative reverse transcription-polymerase chain reaction (RT-PCR) using an invariable internal standard. The mRNA levels of MMP-2 and MMP-9 were increased in the cervix at term pregnancy and postpartum compared with the nonpregnant state. Cervical stromal fibroblasts and smooth muscle cells were identified as main sources of MMP-2, whereas the MMP-9 protein was observed exclusively in invading leukocytes. These data indicate the involvement of MMP-2 and MMP-9 in the cervical ripening process.

Comparison of umbilical-artery velocimetry and cardiotocography for surveillance of small-for-gestational-age fetuses

Intrauterine growth retardation is associated with an increased risk of fetal asphyxia as well as greater perinatal morbidity and mortality. Ultrasound fetometry enables detection of fetuses that are small for gestational age. Doppler velocimetry of the umbilical artery has good predictive ability for fetal distress, but it is not yet clear whether it could replace cardiotocography in antenatal surveillance of small-for-gestational-age fetuses. We have done a randomised comparison of the two methods. At four obstetric departments in Sweden, women with fetuses found to be small on ultrasound examination at 31 completed weeks of pregnancy or later were randomly assigned to antenatal surveillance with either doppler velocimetry (doppler; 214) or cardiotocography (CTG; 212). Pregnancies in the doppler group were managed according to a protocol based on blood-flow classes deriving from the semiquantitative evaluation of umbilical-artery velocity waveforms; unless the pregnancy was complicated by any other disorder, no antenatal cardiotocography was done. By comparison with the CTG group, the doppler group had fewer monitoring occasions (mean 4.1 [SD 3.1] vs 8.2 [6.2], p < 0.01), antenatal hospital admissions (68 [31.3%] vs 97 [45.8%], p < 0.01), inductions of labour (22 [10.3%] vs 46 [21.7%], p < 0.01), emergency caesarean sections for fetal distress (11 [5.1] vs 30 [14.2%], p < 0.01), and admissions to neonatal intensive care (76 [35.5%] vs 92 [43.4%], p = 0.10). The groups did not differ in gestational age at birth, birthweight, Apgar scores, or total number of caesarean deliveries. Umbilical-artery doppler velocimetry of small-for-gestational-age fetuses allows antenatal monitoring and obstetric interventions to be aimed more precisely than does cardiotocography.

Interleukin-8 is a mediator of the final cervical ripening in humans

OBJECTIVE The aim of the present study was to investigate the presence of interleukin-8 (IL-8) in the human cervix and whether the levels of interleukin-8 could be related to the ripening process during pregnancy. STUDY DESIGN Cervical biopsies were obtained in twelve term pregnant and in eight vaginally delivered women. Seven non-pregnant fertile women served as controls. After homogenisation and centrifugation, IL-8 levels were determined in the supernatant by an enzyme-immunoassay (EIA). RESULTS In women at term, the concentration of IL-8 increased six-fold from median 330 pg/ml to median 2190 pg/ml (P < 0.001). After the final cervical ripening it increased in additional 11-fold to median 26,100 pg/ml (P < 0.001). These changes are highly significant. CONCLUSION To our knowledge, this is the first time IL-8 has been identified in human cervix. Our results support the involvement of IL-8 in the connective tissue remodelling during the final cervical ripening just before onset of labour.

Changes in the connective tissue of corpus and cervix uteri during ripening and labour in term pregnancy

The composition of the connective tissue of human cervix and corpus uteri was studied in tissue specimens from seven nonpregnant women and 14 pregnant women, delivered at term by section, to examine spontaneous cervical ripening and labour‐induced changes in both the uterine and the cervical connective tissue. The main finding in both the cervix and the corpus was a large (40–60%) decrease of the collagen concentration. The collagen extractability, obtained by pepsin digestion, was increased twofold, suggesting a change of the organization of the collagen fibrils. This reorganization process could also be demonstrated by a large increase of the collagenolytic activity demonstrated with an artificial DNP‐peptide substrate. The concentrations of sulphated glycosaminoglycans was lower in pregnant women than in non‐pregnant women. The results show that both the cervix and the corpus uteri contain substantial amounts of connective tissue components (collagen, sulphated glycosaminoglycans and hyaluronic acid) and that during ripening, reconstruction of the connective tissue components occurs in both sites. This indicates that the cervical state reflects that of the myometrium.

Young women with genital prolapse have a low collagen concentration

Background.  Genital prolapse is a common and handicapping form of pelvic floor dysfunction. To explain its genesis as a result of endopelvic connective tissue weakness, the collagen state was analyzed in women with and without genital prolapse.

Differential expressions of mRNA for proteoglycans, collagens and transforming growth factor-beta in the human cervix during pregnancy and involution.

During pregnancy and involution, an extensive remodelling of the human cervical connective tissue occurs. This cervical ripening is one of the most pronounced physiological remodelling processes known in human connective tissue. To investigate how the remodelling is accomplished, the levels of mRNA for collagen I and III, versican and three small proteoglycans, biglycan, decorin and fibromodulin, were evaluated using Northern blots at different stages of cervical ripening. In the corresponding biopsies the concentration of collagen and of small and large proteoglycans were determined. The role of transforming growth factor-beta (TGF-beta) as a mediator of the remodelling process was also investigated. The concentration of collagen decreased and 1 week before partus, 50% of the nonpregnant level was attained. No further decrease was noted after partus. The mRNA for collagen I and III did, however, not decrease in the term pregnant cervix 1 week before partus. Only 20-30% decrease during the final ripening just before partus was recorded. Neither did the mRNA levels of the small proteoglycans change significantly during the ripening, despite an almost 50% decrease in the concentration of the small proteoglycans. The message for versican was, however, 5-fold increased at partus and then gradually returned to nonpregnant levels within 4 days after delivery. These changes corresponded to similar changes in the concentration of the large proteoglycan. Thus, the remodelling of the cervical connective tissue is achieved by two different mechanisms, on one hand an increased turnover of collagen and the small proteoglycans, on the other a changed transcription followed by an increased production of versican. During the involution 2- to 3-fold increases in the messages for collagen I and III, and the small proteoglycans, biglycan and decorin, corresponded to increases in the concentration of the small proteoglycans and non-extractable collagen. The message for TGF-beta was increased 2-fold immediately after delivery compared with the term pregnant state. Thus, TGF-beta may be of importance for the reconstruction of the cervix, which starts immediately after partus.

Cervical collagen: an important regulator of cervical function in term labor.

This study provides the first clear evidence of a close correlation between the biochemical composition of the cervix and the clinical course of delivery in terms of cervical dilatation. Cervical biopsy specimens were obtained from three groups of patients: Group A, ten women with favorable cervix and spontaneous labor; group B, 12 women with unfavorable cervix given 0.5 mg prostaglandin E2 in gel intracervically for cervical priming and induction of labor; and group C, five women with unfavorable cervix and spontaneous labor. Cervical dilatation time was significantly longer (18 hours) for women in group C compared with women in group A (6.7 hours) and in group B (5.0 hours; P less than .001). The total amount of cervical collagen was significantly higher in women in group C at 8.58 micrograms/mg compared with 6.7 micrograms/mg in women in group A and 5.47 micrograms/mg in prostaglandin E2-treated women in group B. The amount of nonextractable collagen also was significantly higher in women in group C, 23.6% compared with 11.3% in group A, and 12.4% in group B (P less than .01). The collagenolytic activity was significantly increased in cervical biopsy specimens from prostaglandin E2 gel-treated patients--520 U/100 mg wet weight compared with 380 U/100 mg wet weight in untreated patients in group A (P less than .05). From these results it is concluded that cervical collagen is an important regulator of cervical function in late pregnancy and term labor; that prostaglandin E2 is involved in cervical priming, initiation, and progress of term labor.(ABSTRACT TRUNCATED AT 250 WORDS)

Cervical ripening in humans: potential roles of estrogen, progesterone, and insulin-like growth factor-I.

OBJECTIVE During pregnancy in humans a gradual connective tissue remodeling takes place in the cervix. The aim of this study was to examine a possible relationship between the action of gonadal steroids and growth factors and the biochemically identifiable changes in connective tissues during cervical ripening. STUDY DESIGN Cervical biopsy specimens and serum samples were taken from 20 term pregnant and 20 nonpregnant menstruating women. Estrogen receptors and progesterone receptors were measured with enzyme immunoassays. The messenger ribonucleic acid levels for estrogen receptors, progesterone receptors, and insulin-like growth factor-I were determined by solution hybridization with human complementary deoxyribonucleic acid probes. The concentration of collagen and its solubility by pepsin digestion were measured. Statistical evaluations were done with the Student t test. RESULTS In term pregnancy the estrogen receptor level decreased to 14% and the progesterone receptor level to 24% of nonpregnant levels (p <0.001 and p <0.01). The insulin-like growth factor-I messenger ribonucleic acid level increased 400% (p <0.01), whereas the messenger ribonucleic acid levels for estrogen receptors and progesterone receptors were unchanged. The changes coincided with a twofold decrease in collagen concentration (hydroxyproline) and a twofold increase in collagen solubility. CONCLUSION Estrogen receptors and progesterone receptors are present in human cervix. A significant down-regulation of estrogen receptors and progesterone receptors and a fourfold increase in the insulin-like growth factor-I messenger ribonucleic acid level were registered in term pregnant cervix. These findings coincided with the remodeling of the cervical connective tissue.