Ylva Stjernholm

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.

Changed indications for cesarean sections

Objective. The aim of this study was to investigate the indications for cesarean sections in the early 1990s as compared to the middle 2000s. Design. Retrospective cohort study. Methods. Data were collected from original obstetrical records in a tertiary hospital in 1992 and 2005. Results. The total cesarean delivery rate rose from 11% to 20%. The main indications for an elective cesarean in 1992 were a pathological fetal lie or a uterine factor. The dominant indication for an elective cesarean in 2005 was a psychosocial indication defined as maternal fear of childbirth or maternal request without any co‐existing medical indication. Presumed fetal compromise and prolonged labor remained the main indications for urgent and emergency cesareans. No apparent alterations in population characteristics could be identified for these years. Conclusions. The increased rate of elective cesareans for psychosocial indications would reflect altered attitudes towards mode of delivery in the childbearing population and among obstetricians. We suggest that extended support from community antenatal care should be provided and that standardized keys aiding a physician in decision‐making procedures concerning the cesarean section practice should be developed.

Potential Roles for Gonadal Steroids and Insulin-like Growth Factor I During Final Cervical Ripening☆

Objective To determine whether gonadal steroids and insulin-like growth factor I influence the final cervical remodeling during parturition. Methods Cervical biopsies were obtained transvaginally before labor (n = 10) and after spontaneous cervical ripening and vaginal delivery (n = 20). Levels of estrogen and progesterone receptors, their messenger RNAs, insulin-like growth factor I messenger RNA, and serum estradiol and progesterone were measured. Collagen and proteoglycan concentrations and compositions were measured to estimate the degree of cervical ripeness. Results The concentrations of estrogen and progesterone receptors decreased in comparison with the clinically unripe cervix before labor. The median estrogen receptor concentration (range) decreased from 10 (2–18) to 4.5 (2–14) fmol/mg protein (P < .01), and the progesterone receptor concentration from 105.5 (32–153) to 74 (30–115) fmol/mg protein (P < .05), whereas their messenger RNA levels were unchanged. The insulin-like growth factor I messenger RNA concentration declined from 16.1 (8.4–20.4) at term to 8.9 (1.5–18.5) amol/μg DNA after parturition (P < .01). The collagen solubility by pepsin increased, but not significantly, and the collagen concentration was unchanged. The concentration of small proteoglycans, mainly decorin, decreased from 1.59 (1.20–1.97) to 0.84 (0.24–1.41) μg/mg wet weight (P < .001), and the concentration of versican increased, but not significantly (P = .07). Conclusion Concentrations of estrogen and progesterone receptors and insulin-like growth factor I messenger RNA were decreased significantly after spontaneous cervical ripening in comparison to levels before labor. These changes coincided with a tendency toward increased collagen solubility and a decline in concentration of small proteoglycans, which probably alters collagen organization, thus allowing for cervical softening and dilation. These observations suggest that gonadal steroids influence the final cervical remodeling during parturition, an influence perhaps mediated by insulin-like growth factor I.

Endocrine regulation of cervical ripening in humans—potential roles for gonadal steroids and insulin-like growth factor-I

Cervical softening is crucial for a normal parturition and corresponds to remodeling of the dominating cervical extra cellular matrix (ECM). The onset of labor as well as cervical ripening is under hormonal control. To get further information about the endocrine regulation of term cervical ripening the following study was undertaken: cervical biopsies were obtained vaginally at elective caesareans, after normal vaginal delivery and after PGE2 or antiprogestin RU486. Biopsies from non-pregnant women served as controls. The concentrations of estrogen receptor (ER) and progesterone receptor (PR) protein were quantitated by EIA and the mRNA levels by solution hybridization. The ERalpha and beta were localized by immunohistochemistry, identified by RT-PCR and quantitated by solution hybridization. The co-localizations of CD45 (leukocyte antigen) and CD68 (macrophage antigen) were studied by immunohistochemistry. The cervical concentrations of ER and PR proteins decreased at term to 15 and 25%, respectively, compared to the non-pregnant levels. A further decrease was measured in the maximal ripened cervix at parturition. The mRNA levels were unchanged but IGF-I mRNA reached a maximum at term. ERalpha mRNA was significantly decreased until delivery, whereas ERbeta mRNA, like IGF-I; was maximum at term. By immunostaining ERbeta could be co-localized with CD45 leukocyte antigen and CD68 macrophage specific antigen. Oral administration of RU486 induced a significant increase in ER protein concentration, whereas PGE2 and spontaneous ripening did not. These findings indicate that cervical ripening is related to significant local hormonal changes.

Protein gene product 9.5‐immunoreactive nerve fibers and cells in human cervix of late pregnant, postpartal and non‐pregnant women

BACKGROUND The aim of this study was to examine the occurrence and distribution of the general neuronal marker protein gene product (PGP) 9.5 in the cervix uteri. METHODS Cervical biopsies were obtained from late pregnant (n=5), postpartal (n=5) and non-pregnant (n=5) women. The samples were prepared for immunohistochemistry using antibodies to PGP 9.5. RESULTS Nerve fibers were found consistently in all biopsies. There were differences in the occurrence and distribution of PGP 9.5 immunoreactive nerve fibers and cells between the three groups. Immunoreactive nerve fibers were observed at a moderate to abundant frequency in the stroma and around arterial vessel walls, in all groups. Immunoreactive nerve fibers were also observed at high frequency within and around glandular epithelium in the late pregnant and postpartal groups. PGP 9.5 immunoreactive cells were seen occasionally in the stroma of the non-pregnant group, but at a high frequency in the stroma, around arterial blood vessel walls, around and within the glandular epithelium in the late pregnant and postpartal groups. The total frequency of immunoreactive nerve fibers and cells was the highest in the late pregnant group, slightly lower in the postpartal group, and the lowest in the non-pregnant group. CONCLUSIONS These findings show that changes in the general innervation take place during human cervical ripening until late pregnancy and parturition.

Neurochemical and cellular markers in human cervix of late pregnant, postpartal and non-pregnant women

Background. The aim was to evaluate the peptidergic innervation and the dendritic cell content in the cervix uteri.

Plasma membrane receptor mediated MAPK signaling pathways are activated in human uterine cervix at parturition

BackgroundCervical ripening resembles an inflammatory reaction. Estrogens induce leukocyte migration into tissue and factors promoting cervical remodeling and labor, although the mechanisms are only partially known. The aim of this study was to investigate whether plasma membrane receptor mediated pathways, known to be activated by estrogens and proinflammatory compounds, are involved in cervical ripening before labor.MethodsThe expression and distribution of mitogen activated protein kinases (MAPK), which transduce extracellular signals into intracellular responses through phosphorylation, and their intracellular targets transcription factors c-Jun and c-Fos proteins (AP-1) were analysed in cervical biopsies from term pregnant women (TP), immediately after parturition (PP), and from non-pregnant women (NP). Immunohistochemistry and RT-PCR techniques were used.ResultsCell-specific alterations in the immunostaining pattern for MAPK were observed. The expressions of activated, phosphorylated MAPK forms pERK1/2, pJNK and p38MAPK were significantly increased in cervical stroma until TP and pERK1/2 expression was significantly enhanced in PP group. c-Jun was significantly increased in cervical stroma and smooth muscle in TP as compared to NP group. c-Fos was significantly increased in stroma, squamous epithelium and glandular epithelium in PP as compared to TP group.ConclusionWe report, for the first time, cell-specific activation of pMAPKs and their targets transcription factors c-Fos and c-Jun (AP-1) proteins in human uterine cervix until term pregnancy, and immediately after parturition. These results suggest a role for MAPK activation in cervical ripening before labor.

The expression of prostaglandin receptors EP3 and EP4 in human cervix in post‐term pregnancy differs between failed and successful labor induction

To investigate expression and localization of prostaglandin receptors EP1‐4 and FP and localization of stromal factors CTGF (connective tissue growth factor), furin, calgranulin B and ALOX15 (arachidonate 15‐lipooxygenase) in human cervical tissue from post‐term women with failed or successful labor induction after prostaglandin priming.

How to improve healthcare quality in uncomplicated pregnancy

1. Stjernholm YV, Petersson K, Eneroth E. Changed indications for cesarean sections. Acta Obstet Gynecol Scand. 2010;89: 49–53. 2. Öppna Jämförelser av hälsooch sjukvårdens kvalitet och effektivitet – Jämförelser mellan landsting 2009 [Quality and Efficiency in Swedish Health Care – Regional Comparisons 2009] In Swedish. ISBN 978-91-7164-485-5. Available online at: http://www.socialstyrelsen.se/publikationer2009/200911-2. 3. Quality and Efficiency in Swedish Health Care – Regional Comparisons 2008. ISBN 978-91-7164-452-7. Available online at: http://www.socialstyrelsen.se/publikationer2009/ 2009-126-144. 4. Quality and Efficiency in Swedish Health Care – Regional Comparisons 2009. County council comparisons – figures. Description of indicators. Available online at: http://www. socialstyrelsen.se/publikationer2010/2010-4-37. 5. Gunnervik C, Sydsjo G, Sydsjo A, Selling KE, Josefsson A. Attitudes towards caesarean section in a nationwide sample of obstetricians and gynaecologists. Acta Obstet Gynecol Scand. 2008;87:438–44.