Elevated levels of decidual insulin-like growth factor binding protein-1 in cervical fluid in early and mid-pregnancy are associated with an increased risk of spontaneous preterm delivery.

OBJECTIVE: To study whether elevated levels of decidual insulin-like growth factor binding protein-1 (IGFBP-1) in the cervical fluid of unselected asymptomatic women in early or mid-pregnancy are associated with spontaneous preterm delivery (PTD). DESIGN: Prospective population-based cohort study. SETTING: Maternity Clinics, University Central Hospital, Helsinki, Finland. POPULATION: A total of 5180 unselected pregnant women. METHODS: Cervical swab samples were collected during the first and second trimester ultrasound screening. The concentration of IGFBP-1 was measured by immunoenzymometric assay, which detects the decidual phosphoisoforms of IGFBP-1 (phIGFBP-1). Concentrations of 10 micrograms/l or more were considered to be elevated. MAIN OUTCOME MEASURE: Spontaneous PTD. Results In the first trimester, 24.5% of women, and in the mid-second trimester, 20.2% of women, had an elevated cervical fluid phIGFBP-1 level. The rates of spontaneous PTD before 32 and before 37 weeks of gestation were higher in women with an elevated cervical fluid phIGFBP-1 level, compared with women who had cervical phIGFBP-1 of <10 micrograms/l (1.1% versus 0.3% and 5.7% versus 3.2%, respectively). An elevated phIGFBP-1 level in the first trimester was an independent predictor for PTD before 32 and before 37 weeks of gestation, with odds ratios of 3.0 (95% CI 1.3-7.0) and 1.6 (95% CI 1.2-2.3), respectively. Cervical phIGFBP-1 levels of 10 micrograms/l or more in the first trimester predicted PTD before 32 and before 37 weeks of gestation, with sensitivities of 53.8% and 37.0%, respectively. The negative predictive values were 99.7% and 96.8%. CONCLUSIONS: Elevated cervical fluid phIGFBP-1 levels in the first trimester were associated with an increased risk of spontaneous PTD.

Factors affecting decidual IGFBP-1 levels in the vagina and cervix in the first and mid-second trimester of pregnancy.

OBJECTIVE: The aim of this study was to determine the concentrations of and factors associated with decidual insulin-like growth factor-binding protein-1 (IGFBP-1) in the lower genital tract in early- and mid-gestation in singleton pregnancies. DESIGN: Prospective population-based cohort study. SETTING: Maternity Clinic, Department of Obstetrics and Gynaecology, University Central Hospital, Helsinki, Finland. POPULATION: A total of 1702 unselected pregnant women undergoing the first- and the second-trimester ultrasound screening between April 2005 and December 2006. METHODS: The vaginal and cervical swab samples for assay of decidual IGFBP-1 and vaginal pH measurement were taken before transvaginal ultrasonography in the first trimester and in the mid-second trimester. Use of antibiotics, history of vaginal bleeding, and the history of sexual intercourse were questioned on both occasions. The concentration of IGFBP-1 was measured by a quantitative immunoenzymometric assay, which detects the decidual phosphoisoforms of IGFBP-1 (phIGFBP-1). The concentration of 10 micrograms/l was used as a cutoff when factors influencing phIGFBP-1 levels were analysed. MAIN OUTCOME MEASURES: The phIGFBP-1 concentrations in the vagina and the cervix and associations between the levels of > or =10 micrograms/l and selected factors. RESULTS: In the first trimester, the median (range) concentrations of phIGFBP-1 in vaginal and cervical samples were <0.3 micrograms/l (<0.3-176 micrograms/l) and 4.8 micrograms/l (<0.3-174 micrograms/l), respectively. During the second trimester, the corresponding values were <0.3 micrograms/l (<0.3-55 micrograms/l) in the vagina and 3.6 micrograms/l (<0.3-126 micrograms/l) in the cervix. In the vaginal samples, the frequency of phIGFBP-1 concentrations > or =10 micrograms/l was 5.8% in the first trimester and 1.5% in the second trimester (P < 0.001). In the cervical samples, the corresponding rates were 34.3 and 28.4%, respectively (P < 0.001). Of the factors studied, nulliparity (P < 0.001) and history of vaginal bleeding (P < 0.001) were independently associated with cervical phIGFBP-1 concentrations > or =10 micrograms/l during both trimesters. In addition, short cervical length (<30 mm) was associated with phIGFBP-1 concentration > or =10 micrograms/l in both vaginal and cervical samples in the second trimester in multivariate analysis. CONCLUSIONS: The rate of phIGFBP-1 concentrations > or =10 micrograms/l, both in the vagina and in the cervix, was significantly lower during the second trimester compared with the first trimester. The low rate of levels > or =10 micrograms/l in vaginal samples compared with cervical samples during both trimesters indicates that the exact site of sampling is important when phIGFBP-1 is used as a decidual marker. Nulliparity and history of vaginal bleeding were independently associated with phIGFBP-1 concentrations > or =10 micrograms/l in cervical samples during both trimesters.

Effect of maternal diabetes on phosphorylation of insulin-like growth factor binding protein-1 in cord serum.

AIMS: The insulin-like growth factor (IGF) system is considered important in the regulation of fetal growth. Binding of IGFs to specific binding proteins (IGFBPs) modifies their actions. In fetal blood, IGFBP-1 is the primary IGF binding protein whose phosphorylation generates proteins with different affinities for IGF-I. We studied cord serum IGFBP-1 phosphoisoform profiles in normal pregnancies and in diabetic pregnancies, which are frequently complicated by macrosomia. RESEARCH DESIGN AND METHODS: Cord serum IGFBP-1 phosphoisoform concentrations were measured at birth by two immunoenzymometric assays in 67 pregnancies complicated by Type 1 diabetes, in 28 pregnancies complicated by insulin-treated gestational diabetes, and in 62 normal pregnancies. RESULTS: Cord serum highly phosphorylated IGFBP-1 (hpIGFBP-1) concentrations were lower in pregnancies complicated by Type 1 diabetes (204 +/- 36 microg/l, P = 0.032) and in pregnancies complicated by gestational diabetes (170 +/- 28 microg/l, P = 0.031) than in controls (316 +/- 34 microg/l). Cord serum lesser phosphorylated IGFBP-1 (lpIGFBP-1) concentrations were similar in diabetic and normal pregnancies (P = 0.692 between groups by analysis of variance). Relative birth weight correlated negatively with cord serum hpIGFBP-1 and lpIGFBP-1 in diabetic pregnancies, and with cord serum lpIGFBP-1 in normal pregnancies. CONCLUSIONS: Maternal diabetes is associated with suppressed hpIGFBP-1 but unaltered lpIGFBP-1 concentrations in cord serum, suggesting that IGFBP-1 phosphoisoforms are differentially regulated in the fetus. Because hpIGFBP-1 has a higher affinity for IGF-I than does lpIGFBP-1, diabetes-related changes in fetal IGFBP-1 phosphorylation may increase IGF-I bioavailability and, consequently, stimulate fetal growth. This may partly explain the increased occurrence of macrosomia in diabetic pregnancies.

Effects of ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women.

Ospemifene is a novel selective estrogen receptor modulator (SERM). Here we studied the effects of ospemifene on bone turnover in postmenopausal women. This was a randomized, double-blind study in which 159 healthy postmenopausal women received 30 (n = 40), 60 (n = 40) or 90 mg (n = 40) of ospemifene or placebo (n = 39) for 3 months. Bone resorption was assessed by measuring the urinary outputs of N- and C-terminal crosslinking telopeptides of type I collagen (NTX and CTX, respectively). Bone formation was assessed by measuring the levels of procollagen type I N propeptide (PINP), procollagen type I C propeptide (PICP), and bone-specific alkaline phosphatase (bone ALP) in serum. All markers were studied at baseline, 3 months, and 2-4 weeks after cessation of the medication. Ospemifene decreased bone resorption dose-dependently, as seen from falls in NTX by 6.1, 9.4 and 12.9% in the 30, 60 and 90 mg ospemifene groups, respectively (p < 0.05 for all dose levels when compared to placebo). CTX values decreased in the 90 mg ospemifene group by 4.8% (p < 0.05). A dose-dependent decrease was also observed in the bone formation markers: PINP values decreased by 9.8 (p < 0.05) and 15.3% (p < 0.01), and PICP values by 12.0 and 11.9% in the 60 and 90 mg ospemifene groups, respectively. Bone ALP decreased in 60 and 90 mg ospemifene groups by 1.9 and 2.6%, respectively (p < 0.05 for both dose levels when compared to placebo). These results show that ospemifene is effective in reducing bone turnover in postmenopausal women.

Combination of cervical interleukin-6 and -8, phosphorylated insulin-like growth factor-binding protein-1 and transvaginal cervical ultrasonography in assessment of the risk of preterm birth.

OBJECTIVE: To determine the value of combinations of cervical interleukin-6 (IL-6), cervical interleukin-8 (IL-8), the phosphorylated isoform of insulin-like growth-factor binding protein-1 (IGFBP-1), and cervical ultrasonography in the prediction of preterm birth. DESIGN: Prospective follow up. SETTING: Oulu University Hospital maternity clinic from February 1997 to July 1998. POPULATION: Women with singleton pregnancies (n = 77), referred from outpatient clinics at 22-32 weeks of gestation with symptoms (uterine contractions) or signs (cervical change) of threatened preterm birth. Symptomless women (n = 78) matched for gestational age, parity and maternal age at recruitment were studied as a reference group. METHODS: A urine sample for bacterial culture was collected, and cervical swab samples for assays of interleukin-6 and -8 and phoshorylated IGFBP-1 were taken before digital cervical examination. A Pap smear for analysis of bacterial vaginosis and samples for analysis of chlamydia and streptococci were also obtained. Cervical measurements were made by transvaginal ultrasonography. The same sampling and cervical measurement were repeated twice at two-week intervals. The cutoff values of the markers were determined by receiver-operating characteristic curve analysis. MAIN OUTCOME MEASURE: Preterm birth (<37 weeks). RESULTS: The preterm birth (<37 weeks) rate for women in the study group was 16% (12/77). The cervical interleukin-6 cutoff value (61 ng/L) at first visit had a sensitivity of 73% and a specificity of 61% in predicting preterm birth, with a positive likelihood ratio (LR+ ) of 1.9 (95% CI 1.2-3.0). An ultrasonographically measured cervical index value of > 0.36 at recruitment predicted preterm birth in 25% (5/20) of the study group compared with 9% (5/54); LR+ 2.2 (95% CI 1.03-4.7). Cervical phosphorylated IGFBP-1 > 6.4 microg/L [LR+ 1.8 (95% CI 0.7-2.9)], interleukin-8 > 3739 ng/L [LR+ 1.4 (95% CI 0.9-2.4)], and ultrasonograpic cervical length < 29.3 mm [LR+ 2.7 (95% CI 0.8-9.7)] increased the risk of preterm birth. According to the logistic regression model, a combination of IL-6, and IL-8 and cervical index increased the specificity to 97%, but the sensitivity fell to 30% in detecting preterm birth. There was a significantly increased incidence of puerperal infections if phosphorylated IGFBP-1 concentrations were elevated (> 21.0 microg/L), 36% (4/11) compared with 4.6% (3/65), LR+ 6.7 (95% CI 2.7-17), the sensitivity being 67% (4/6) and the specificity 90% (63/70). Elevated phosphorylated IGFBP-1 concentrations (> 21.6 microg/L) were also associated with an increased risk of neonatal infections; LR+ 8.0 (95% CI 3.5-18). CONCLUSIONS: An increase in cervical IL-6 concentration and the ultrasonographically measured cervical index appear to be associated with preterm birth. A combination of these markers with measurement of cervical IL-8 appears to be the best predictor of preterm birth. Neither the sensitivity nor specificity of the tests used in this study are good enough to predict preterm birth for clinical decision making. Cervical phosphorylated IGFBP-1 seems to be a marker of puerperal and neonatal infectious morbidity in cases of threatened preterm delivery, suggesting early tissue degradation at the choriodecidual interface.

Fibroids and hypertension. A cross-sectional study of women undergoing hysterectomy.

OBJECTIVE: To determine whether uterine fibroids are associated with hypertension. STUDY DESIGN: A total of 543 consecutive women, 41-89 years of age, who underwent hysterectomy in 1984 and 1994 for benign indications at Helsinki University Central Hospital were included in the study. Preoperative information on indications for the procedure, current use of hormone replacement therapy (HRT) or other medication, parity, body mass index and blood pressure (BP) was obtained from medical records. The presence of fibroids was confirmed from the pathology report. Women were classified as hypertensive if they currently used antihypertensive medication, had a history of hypertension without current medication or had a preoperatively measured BP > 140/90 mm Hg. RESULTS: Women with fibroids were significantly younger and more likely to use HRT than the other women. Uterine fibroids were more frequent among hypertensive (42%) than normotensive (37%) women. In logistic regression analysis, fibroids were statistically significantly associated with hypertension (OR 1.8, 95% CI 1.2-2.7). The association between myomas and hypertension was strongest (OR 3.6, 95% CI 1.2-10.9) among women with hysterectomies for benign adnexal tumors. CONCLUSION: Uterine fibroids and/or adnexal tumors may share pathogenic features with the development of hypertension.

Insulin-like growth factor-binding protein-1 in cervical secretion as a predictor of preterm delivery.

BACKGROUND: The aim of the study was to evaluate whether the phosphorylated isoforms of insulin-like growth factor-binding protein-1 (IGFBP-1), a protein produced by the decidua, can be detected in cervical secretions of pregnant women with preterm uterine contractions, and whether their presence predicts an increased risk of preterm delivery. METHODS: A prospective analysis of sixty-three women who presented with preterm labor but intact fetal membranes at weeks 22-36+6 days of gestation at the Antenatal clinic at the Department of Obstetrics and Gynecology, Helsinki University Central Hospital. Phosphorylated IGFBP-1 (phIGFBP-1) was measured in cervical swab samples obtained at presentation, using an immunoenzymometric assay. The values > or =10 microg/L were considered as positive. In addition, 58 asymptomatic women at the same gestational stage were studied as controls. Multiple logistic regression was applied to control for confounding variables and to obtain adjusted odds ratios. RESULTS: The concentration of phIGFBP-1 in cervical samples ranged from undetectable to 95 microg/L. In 17 of the 63 (27%) women with preterm labor it was > or =10 microg/L. Seven of these 17 (41%) women with a positive phIGFBP-1 result delivered preterm, all before 35 weeks of gestation. Among the women with preterm labor and a negative phIGFBP-1 result, three of the 46 (7%) delivered before 37 weeks of gestation (adjusted OR 24, 95% CI 1.2-487), but all after 35 weeks of gestation. In the asymptomatic control population three out of 58 (5%) women had a positive cervical phIGFBP-1 test result but none delivered preterm. Among the controls with a negative cervical phIGFBP-1 test result (55 of 58, 95%), one woman delivered preterm (1 of 55, 2%). CONCLUSIONS: Pregnant women who are in preterm labor with intact fetal membranes and who have a positive phIGFBP-1 test result in cervical secretion have an increased risk of preterm delivery.

Markers of type I and type III collagen turnover, insulin-like growth factors, and their binding proteins in cord plasma of small premature infants: relationships with fetal growth, gestational age, preeclampsia, and antenatal glucocorticoid treatment.

Disorders affecting fetal growth are commonly associated with premature birth. IGFs and their binding proteins (IGFBPs) are potent regulators of fetal growth. In vitro evidence suggests that they regulate collagen turnover. Collagen turnover can be monitored by serum markers of type I collagen synthesis (PINP) and degradation (ICTP) and a marker of type III collagen synthesis (PIIINP). We examined whether these markers in fetal circulation reflect intrauterine growth and maturity, and whether any interrelationship exists between them and fetal IGFs and IGFBPs in preterm infants before 32 wk of gestation. Cord plasma PINP, ICTP, PIIINP, IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were determined for 98 preterm infants. To express birth weight in units adjusted for gestational age, a birth weight SD score (SDS) was calculated. Negative correlations existed between gestational age and PINP (r = -0.43; p < 0.0001), ICTP (r = -0.34; p = 0.002), and PIIINP (r = -0.34; p = 0.0001). Positive correlations existed between birth weight SDS and PINP (r = 0.40; p = 0.0002) and ICTP (r = 0.48; p < 0.0001) but not PIIINP. Moreover, birth weight SDS was positively correlated with IGF-I (r = 0.58; p < 0.0001) and IGFBP-3 (r = 0.44; p < 0.0001) and negatively correlated with IGF-II (r = -0.36; p = 0.003) and IGFBP-1 (r = -0.50; p < 0.0001). Gestational age correlated with IGFBP-3 (r = 0.25; p = 0.03). In preeclampsia, IGF-I was lower (p = 0.002) and IGFBP-1 higher (p < 0.0001), also after adjustment for fetal size. The number of antenatal glucocorticoid treatments was associated with lower ICTP (p = 0.04), higher IGF-I (p = 0.002), lower IGF-II (p = 0.02), lower IGFBP-1 (p = 0.05), and higher IGFBP-3 (p = 0.004), also after adjustment for potential confounders. In multiple regression analysis, the factors significantly associated with PINP (R:(2) = 0.47) were gestational age and IGF-I, and those associated with ICTP (R:(2) = 0.54) were IGF-I, gestational age, and antenatal glucocorticoid treatment. We conclude that IGF-I may be involved in regulation of type I collagen turnover in the growing fetus. Cord blood PINP and ICTP reflect both fetal growth and maturity and deserve evaluation as potential indicators of postnatal growth velocity in preterm infants, whereas PIIINP reflects fetal maturity.

Heritability and risk factors of uterine fibroids--the Finnish Twin Cohort study.

OBJECTIVES: Our aim was to study heritability, risk factors and hospitalization for uterine fibroids. METHODS: A random sample of 80 MZ and 80 DZ twins from the Finnish Twin Cohort were invited and 51% of the eligible women (n=82, 17 MZ and 16 DZ pairs, 40-47 years, mean age 43.0), underwent a transvaginal ultrasound. The entire cohort of 13872 women was linked to the national hospital discharge registry 1972-1990. RESULTS: Prevalence of fibroids was 66% and the average number of fibroids 1.7. The casewise concordance for being hospitalized for uterine fibroids was higher in MZ (0.31, 95% CI 0.24-0.37) than in DZ pairs (0.18, 95% CI 0.14-0.22). The proportion of variance in liability to fibroid hospitalization accounted for by genetic factors was 54.8% (95% CI 46.2-62.7%). Women with fibroids had higher body mass index (23.7 vs 21.7, P=0.0086), lower age at first birth (25.7 vs 29.3, P=0.012) and higher parity (3+ children 48.2 vs 29.6%, P=0.009) than women without fibroids. Risk ratio (RR) for fibroids in a MZ twin whose sister had been diagnosed with fibroids was 1.1 (95% CI 0.08;15), for a DZ twin 1.1 (95% CI 0.16;8.8) and for all twins 1.3 (95% CI 0.3; 6.1). Intraclass correlation for the number of fibroids was 0.24 for MZ and 0.11 for DZ twins, yielding an heritability estimate of 0.26. CONCLUSION: Reproductive and anthropometric factors may have at least as large role in pathogenesis of fibroids than genetic factors.

Expression of sex steroid receptors and Ki-67 in the endometria of menorrhagic women: effects of intrauterine levonorgestrel.

The levonorgestrel-releasing intrauterine system (LNG-IUS) has proven to be the most effective medical treatment in reducing the amount of menstrual blood loss. However, the molecular mechanisms underlying menorrhagia and/or accounting for the therapeutic effect of the LNG-IUS are still obscure. In this study, we used immunohistochemistry to compare the distribution of sex steroid receptors and the proliferation marker Ki-67 in the endometria of women with and without menorrhagia before and after 6 and 12 months of treatment with an LNG-IUS. The study sample included 67 women (aged 35-49 years) who had spontaneous ovulatory cycles. In women with menorrhagia, secretory phase endometrium exhibited more proliferative activity than in women without menorrhagia. No significant differences were found in the immunoreactivity of the oestrogen or progesterone receptors in women either with or without menorrhagia suggesting that, in addition to endocrine hormones, other factors are involved in the regulation of endometrial proliferation and menstrual blood loss. A total of 35 women were treated with LNG-IUS. After 6 months use of an LNG-IUS, the immunoreactivity of both epithelial and stromal progesterone receptors, as well as those of epithelial Ki-67 declined, and no differences were detectable between the women in the menorrhagia and control groups. Breakthrough bleeding remained a problem for nine (26%) LNG-IUS users, with no association with the pre-treatment amount of bleeding. No significant differences were found in the parameters studied between the women with and without breakthrough bleeding 6 months after insertion of an LNG-IUS.

Insulin-like growth factors and insulin-like growth factor binding proteins in the endometrium. Effect of intrauterine levonorgestrel delivery.

Insulin-like growth factor (IGF) system is one of the growth factor systems that are believed to modulate steroid hormone actions in the endometrium through autocrine/paracrine mechanisms. IGF-I and IGF-II stimulate proliferation and differentiation, and maintain differentiated cell functions in several cell types in vitro. Endometrial stromal cells produce IGF-I and IGF-II as well as the high affinity IGF-binding proteins (IGFBP), whereas epithelial cells and, in a lesser amount, stromal cells contain cell membrane receptors for IGF. Oestrogen stimulates IGF-I gene expression, and IGF-II gene expression is associated with endometrial differentiation. The mRNA of six high affinity IGFBPs, which can modulate IGF actions, are expressed in human endometrium. The most abundant IGFBP in human endometrium is IGFBP-1, which is secreted by predecidualized/decidualized endometrial stromal cells in late secretory phase and during pregnancy. The primary negative regulator of IGFBP-1 production is insulin. IGFBP-1 competes with type I IGF receptor for binding of IGF in the endometrium and in cultured human trophoblastic cells. IGF-I mRNA is suppressed and mRNA encoding IGF-II and IGFBP-1 are consistently up-regulated in decidualized endometrium in women treated with the intrauterine levonorgestrel system (LNG-IUS). Strong cytoplasmic staining for IGFBP-1 was detected in decidualized endometrium in women using LNG-IUS for contraception or for endometrial protection during post-menopausal oestrogen replacement therapy. Simultaneously, oestrogen receptors were present, while progesterone receptors were hardly detectable in the endometrium by immunohistochemistry. The latter findings suggest that suppression of IGF-I action by IGFBP-1 may be one of the molecular mechanisms accounting for progestagenic and anti-oestrogenic effects of LNG-IUS in the endometrium. Consequently, examination of local IGF-I, IGF-II and IGFBP-1 expression might provide additional information when evaluating the effect of different progestins on the endometrium at the molecular level.

Insulin-like growth factors in obstetrics.

Data from a number of studies reported during the past two decades indicate that the insulin-like growth factor (IGF) system, including IGF-I and IGF-II, their receptors and six high-affinity binding proteins, is involved in the control of foetal and placental growth and development. Recent studies that addressed the role of the IGF system in pregnancy and the clinical usefulness of IGF and IGF-binding protein measurements in obstetrics are reviewed and discussed.

Markers of collagen metabolism and insulin-like growth factor binding protein-1 in term infants.

AIM: To study the relation between fetal growth and markers of collagen metabolism and insulin-like growth factor binding protein-1 (IGFBP-1) in term infants. METHODS: Cord vein plasma was obtained from 67 term infants of gestational age 37.1-41.7 weeks (39 appropriate for gestational age (AGA), 11 large for gestational age (LGA; relative birth weight >/= 2.0 SD), and 17 small for gestational age (SGA; relative birth weight 0.05). CONCLUSIONS: In the term fetus, collagen metabolism is primarily dependent on maturity and not on intrauterine growth status, whereas IGFBP-1 reflects intrauterine growth independently of maturity.

Increased leptin concentration in preterm infants of pre-eclamptic mothers.

AIM: To study the effect of maternal pre-eclampsia on cord plasma leptin concentrations in preterm infants. METHODS: Leptin concentration was analysed in cord plasma of 74 preterm infants, gestational age 24 to 32 weeks. Of these, 14 were born to pre-eclamptic mothers, in 10 intrauterine growth retardation (IUGR) was present, and 59 had been exposed antenatally to corticosteroids. RESULTS: The mean (SD) concentration of cord plasma leptin was 1.31 (0.88) microg/l. A significant correlation was found between leptin concentration and gestational age (r = 0.336; p = 0.0037). Leptin levels were higher in infants of pre-eclamptic mothers (p = 0.0007), in those with IUGR (p = 0.0005), and in infants exposed antenatally to corticosteroids (p = 0.02). In multiple regression analysis, leptin was associated with gestational age and maternal pre-eclampsia (both p < 0.05), but not with antenatal corticosteroids. CONCLUSIONS: Increased fetal leptin in maternal pre-eclampsia may reflect a physiological adaptation to fetal stress such as hypoxia.

Induction of endometrial plasminogen activator-inhibitor 1: a possible mechanism contributing to the effect of intrauterine levonorgestrel in the treatment of menorrhagia.

OBJECTIVE: To elucidate molecular mechanisms accounting for excessive menstrual blood loss, and to present the therapeutic effect of an intrauterine levonorgestrel system (LNG-IUS) in menorrhagia. DESIGN: A multicenter study comparing hysterectomy with the LNG-IUS in treating menorrhagia. SETTING: A university hospital. PATIENT(S): Women with (n = 27) and without (n = 14) menorrhagia, and women with uterine fibroids but undetermined menstrual blood loss (n = 35). INTERVENTION(S): An LNG-IUS was inserted into the uterine cavity in 11 women with menorrhagia and six women experiencing normal menstrual blood loss. MAIN OUTCOME MEASURE(S): Expression of the messenger ribonucleic acid (mRNA) of tissue-type plasminogen activator (t-PA) and that of a specific PA inhibitor type 1 (PAI-1) in endometrial tissue samples, as evaluated with the use of Northern blot analysis. RESULT(S): t-PA mRNA was expressed in the endometrium throughout the menstrual cycle, with no statistically significant difference between a proliferative (n = 30) and a secretory endometrium (n = 40), or between women experiencing normal menstrual blood loss (n = 14) and those with menorrhagia (n = 27). The levels of t-PA mRNA in menstrual phase samples (n = 6) were significantly higher than those in proliferative or secretory endometrium. PAI-1 mRNA was detected in the endometrium during menstruation only. Both t-PA mRNA and PAI-1 mRNA were expressed in all endometrial samples (n = 17) obtained 6 months after an LNG-IUS was inserted, regardless of the menstrual cycle phase. The relative levels of both types of mRNA were significantly higher in LNG endometrium than in proliferative or secretory endometrium, but levels did not differ from those in menstrual-phase endometrium. CONCLUSION(S): The mean (+/-SD) levels of t-PA mRNA and PAI-1 mRNA in the endometrium of women with and without menorrhagia did not differ, suggesting that the PA system is not the major determinant of menstrual blood loss. However, continuous induction of PAI-1 may contribute to the therapeutic effect of LNG-IUS in treating menorrhagia.

Serum insulin-like growth factor binding protein-1 at 16 weeks and subsequent preeclampsia.

OBJECTIVE: To determine whether serum concentrations of insulin-like growth factor-binding protein-1 (IGFBP-1), a major decidual protein, at 16 weeks' gestation differ between women who later develop pregnancy-related hypertension and normotensive women. METHODS: Concentrations of IGFBP-1 were measured using immunoenzymometric assay in serum samples collected for alpha-fetoprotein (AFP) and free beta subunit of hCG (free beta-hCG) determinations in a Down syndrome screening program at 16 weeks' gestation in a population-based cohort of 1049 nulliparous women. After exclusion of subjects with multiple pregnancies, insulin-dependent diabetes, major fetal malformations, and incomplete data, 917 subjects remained eligible. RESULTS: The mean levels (+/- standard deviation) of IGFBP-1 were significantly lower in 34 women who later developed preeclampsia (73 +/- 43 microg/L, P < .01) and in 80 women with White A diabetes (84.7 +/- 53 microg/L, P < .01) compared with controls (103 +/- 58 microg/L). In seven women with White A diabetes and subsequent preeclampsia IGFBP-1 levels were especially low (41 +/- 34 microg/L). The concentrations of AFP and free beta-hCG in the subgroups with hypertensive disorders were not significantly different from those of normotensive women. CONCLUSION: Decreased IGFBP-1 levels at 16 weeks' gestation in women who develop preeclampsia might indicate impaired decidual function. Hyperinsulinemia, a known risk factor for preeclampsia, might contribute to decreased concentrations of serum IGFBP-1. However, due to low sensitivity, assay of serum IGFBP-1 was not clinically valuable for predicting preeclampsia.

Phosphorylated isoforms of insulin-like growth factor binding protein-1 in the cervix as a predictor of cervical ripeness.

OBJECTIVE: To study the isoforms of insulin-like growth factor binding protein-1 (IGFBP-1) in cervical secretion and to evaluate whether their assessment could serve in prediction of cervical ripeness at term. METHODS: We measured the concentrations of IGFBP-1 in cervical swab samples of 64 women scheduled for labor induction by amniotomy or cervical ripening with prostaglandin E2 gel. Two immunoenzymometric assays were used: a previously described assay 1, which detects the nonphosphorylated and lesser phosphorylated isoforms, and a novel assay 2, which detects the lesser and highly phosphorylated isoforms of IGFBP-1. A set of 39 amniotic fluid (AF) samples also was analyzed to compare the phosphorylation status of IGFBP-1 in cervical secretion with that in AF. RESULTS: In all cervical samples, IGFBP-1 concentration was higher by assay 2 than by assay 1, whereas in all AF samples, the results were the opposite. Initially, the median IGFBP-1 concentration in the ripe cervices (Bishop scores 6 or greater; n = 29) was approximately four times as high as that in the unripe cervices (Bishop scores 5 or less; n = 35). The cervical IGFBP-1 concentrations increased eight-fold in 6 hours after the first application of PGE2. CONCLUSION: Phosphorylated isoforms of IGFBP-1, different from those in AF, are present in the cervical secretion of women with intact fetal membranes and reflect cervical ripeness. A bedside test for those IGFBP-1 isoforms might help in predicting amenability for labor induction.

The association between c-fos and c-jun expression and estrogen and progesterone receptors is lost in human endometrial cancer.

In normal human endometrium, expressions of the proto-oncogenes c-fos and c-jun parallel. We have previously shown that the expression of c-jun is related to proliferation and estrogen receptor (ER) status in endometrial epithelial cells. In this study, we analyzed endometrial cancer tissues for c-fos and c-jun messenger RNA (mRNA) expression by Northern blotting. Proto-oncogene expression was compared with ER and progesterone receptor (PR) status and with the proliferation marker Ki-67, as well as with histological grade and the use of hormone-replacement therapy (HRT). Messenger RNA for c-fos was detected in 35 of 37 cancer tissues and mRNA for c-jun in 37 of 40 tissue samples studied. No correlation was observed between the relative mRNA levels of c-fos and c-jun, suggesting distinct control mechanisms, if any, in endometrial cancer. In contrast to normal endometrium, there was no correlation between the proto-oncogene expression and Ki-67, ER or PR immunoreactivity. Neither were there any correlations between c-fos or c-jun expression and the histological grade of the tumor or preceding HRT. Our results reveal the loss of association between proto-oncogene expression and ovarian steroid receptors or cell proliferation in malignant endometrium. This gives further support to the hypothesis that alterations in estrogen and progesterone signalling pathways are involved in the pathogenesis of endometrial cancer.