Human endometrial adenocarcinoma cell lines HEC 1B and KLE secrete insulin-like growth factor binding protein-1 and contain IGF-I receptors.

The production of insulin-like growth factor binding proteins (IGFBP) with special reference to human IGFBP-1 was evaluated in five endometrial adenocarcinoma cell lines (HEC 1A, HEC 1B, KLE, RL952 and AN3CA) in continuous culture. Two of the cell lines (HEC 1B and KLE) produced immunoreactive IGFBP-1. The production was inhibited by clomiphene and progesterone, whereas estrogen, cortisol and insulin had no effect on IGFBP-1 secretion. The two cell lines which secreted immunoreactive IGFBP-1 also had IGF-I receptors, whereas the cell lines RL952 and AN3CA, not producing IGFBP-1, had no saturable IGF membrane binding sites. IGF-I receptor binding to HEC 1B and KLE cells was inhibited in the presence of purified IGFBP-1. In addition to IGFBP-1, the endometrial cancer cells secreted several other forms of IGFBPs as determined by cross-linking. Immunoprecipitation of IGF-BP complexes with a polyclonal antiserum against IGFBP-3 indicated that all cell lines secreted binding proteins antigenically related to IGFBP-3 with molecular weights ranging from 20 to 39 kDa.     

Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible endothelial cell mitogen and survival factor. Its receptor VEGFR-2 (KDR/Flk-1) mediates these effects. We studied the expression of VEGF and VEGFR-2 in ischemic human and rabbit skeletal muscle by immunohistochemistry and in situ hybridization. Human samples were obtained from eight lower limb amputations because of acute or chronic critical ischemia. In chronically ischemic human skeletal muscle VEGF and VEGFR-2 expression was restricted to atrophic and regenerating skeletal myocytes, whereas in acutely ischemic limbs VEGF and VEGFR-2 were expressed diffusely in the affected muscle. Hypoxia-inducible factor-1alpha was associated with VEGF and VEGFR-2 expression both in acute and chronic ischemia but not in regeneration. Hindlimb ischemia was induced in 20 New Zealand White rabbits by excising the femoral artery. Magnetic resonance imaging and histological sections revealed extensive ischemic damage in the thigh and leg muscles of ischemic rabbit hindlimbs with VEGF expression similar to acute human lower limb ischemia. After 1 and 3 weeks of ischemia VEGF expression was restricted to regenerating myotubes and by 6 weeks regeneration and expression of VEGF was diminished. VEGFR-2 expression was co-localized with VEGF expression in regenerating myotubes. Macrophages and an increased number of capillaries were associated with areas of ischemic muscle expressing VEGF and VEGFR-2. In conclusion, two patterns of VEGF and VEGFR-2 expression in human and rabbit ischemic skeletal muscle are demonstrated. In acute skeletal muscle ischemia VEGF and VEGFR-2 are expressed diffusely in the affected muscle. In chronic skeletal muscle ischemia and in skeletal muscle recovering from ischemia VEGF and VEGFR-2 expression are restricted to atrophic and regenerating muscle cells suggesting the operation of an autocrine pathway that may promote survival and regeneration of myocytes.     

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.     

Effects of ospemifene, a novel SERM, on vascular markers and function in healthy, postmenopausal women

OBJECTIVE: Ospemifene, a novel selective estrogen receptor modulator (SERM), shows promise for bone preservation in postmenopausal women. This study examined the effects of ospemifene on different vascular surrogate markers. DESIGN: A double-blinded study was conducted in 160 healthy, postmenopausal women who used, in a randomized order, ospemifene (at daily doses of 30, 60, or 90 mg) or placebo for 3 months. RESULTS: Although ospemifene caused falls from basal levels in total cholesterol, low-density lipoprotein cholesterol, oxidized low-density lipoprotein cholesterol, and a rise in high-density lipoprotein cholesterol, the only statistically significant difference between ospemifene and placebo was an increase of triglyceride levels (11.3%) in the 90-mg group. Ospemifene caused no significant effect on endothelial markers or homocysteine. Of the markers reflecting coagulation and fibrinolysis, plasma fibrinogen was significantly reduced in the 60- and 90-mg groups of ospemifene (8.7% and 8.5%, respectively) when compared with the placebo group. No changes were seen in generation of thrombin or degradation of crosslinked fibrin D-dimer. The uterine or carotid arteries and 24-h ambulatory blood pressure were not affected by ospemifene. Ospemifene caused no changes in basal insulin or in a 2-h glucose tolerance test, suggesting unaltered insulin sensitivity. CONCLUSIONS: Neutral effects of short-term use of ospemifene on vascular surrogate markers imply no effect for ospemifene on the risk for cardiovascular disorders in healthy, postmenopausal women.     

Increased incidence of retching and vomiting during periovulatory phase after middle ear surgery

Purpose  

To assess the effect of the menstrual cycle on post-operative retching and vomiting (R& V) after middle ear surgery, and the efficacy of prophylaxis against R& V in female patients with transdermal scopolamine during either general or local anaesthesia and with intravenous ondansetron during general anaesthesia.     

Soluble 34K binding protein inhibits the binding of insulin-like growth factor I to its cell receptors in human secretory phase endometrium: evidence for autocrine/paracrine regulation of growth factor action

The human secretory phase endometrium synthesizes and secrets a 34K insulin-like growth factor (IGF)-binding protein designated placental protein 12. We now report that membrane preparations of human endometrium possess IGF receptors that complete with the soluble binding protein for binding to IGF-I. Multiplication-stimulating activity and insulin were 1% and 0.1% as potent as recombinant (Thr59)IGF-I in inhibiting the binding of [125I](Thr59)IGF-I to endometrial membranes. Scatchard plots for the IGF-I binding data were curvilinear, and the apparent affinities [Ka = 1.4 +/- 0.2 ( +/- SEM) X 10(9) M-1] for (Thr59)IGF-I (high affinity site) did not change during the menstrual cycle. Affinity cross-linking of [125I](Thr59)IGF-I to endometrial membranes revealed two major bands with mol wt of 130K and 260K on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions. The 130K band is consistent with the alpha-subunit of the type I IGF receptor. The 260K band is either the type II IGF receptor or represents cross-linking (dimer) of two alpha-subunits of the type I receptor. A less intense band at about 40K was also seen in all membrane preparations. It comigrated with the cross-linked purified 34K binding protein. The band was more intensely labeled when the tracer was cross-linked to proteins in the cytosol fractions of late secretory phase endometria. By specific RIA, the 34K binding protein was detected in the cytosol of late secretory phase endometria only. Newly synthesized binding protein, which contaminated membrane preparations, caused an apparent increase in the binding of (Thr59)IGF-I to the membranes prepared from late secretory phase endometria when studied by competitive binding assay. In contrast, purified binding protein prevented the binding of [125I](Thr59)IGF-I to membrane receptors, as confirmed by affinity cross-linking. These results suggest that the 34K IGF-binding protein, secreted by the human endometrium in a cyclic fashion, has a significant role in inhibiting the receptor binding and, thus, the possible biological action of IGF-I in the endometrium in an autocrine/paracrine manner.     

Placental protein 12 (PP12): factors affecting levels in late pregnancy

The circulating concentration of placental protein 12 was measured by radioimmunoassay in 109 pregnant women. The effect on the serum PP12 level of temperature, repeat freezing and thawing, and day-to-day and diurnal variation were assessed and the post partum changes of levels were studied. On average, PP12 levels in plasma are about one-half of those in serum in the same individual. PP12 immunoreactivity is destroyed by heating but not by repeated freezing and thawing. Changes in serum PP12 levels at various times of day showed a significant and consistent diurnal variation (F = 7.21; d.f.24; 96; P less than 0.001). The peak mean (+/- s.e.m.) value at 0800 h (80.8 +/- 8.7 ng/ml) was 41 per cent higher than the 24-h mean (P less than 0.05), and the nadir concentration at 1400 h (40.4 +/- 5.4 ng/ml) was 29 per cent lower than the 24-h mean (P less than 0.025). There is also considerable day-to-day variation (up to 72 per cent) in serum PP12 levels. If serum samples are taken at 0700 h, there is a slight negative correlation between PP12 concentration and placental weight (P less than 0.05), but not between PP12 level and birthweight of the child. In term pregnancy, the levels taken at 0700 h are higher (163.7 +/- 12.4 ng/ml) than at 0900 to 1300 h (115.7 +/- 11.4 ng/ml, P less than 0.001). The PP12 level is not affected by labour.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum prolactin levels and immunohistochemical localization of prolactin in trophoblastic disease

The circulating levels of chorionic gonadotropin, pregnancy specific beta-I-glycoprotein, prolactin and oestradiol were estimated by radioimmunoassay in 219 serum samples from 18 patients with choriocarcinoma and 45 samples from 8 patients with hydatidiform mole. Prolactin and oestradiol concentrations were higher in samples which also contained trophoblastic markers. This difference was also seen in patients with choriocarcinoma and it was not due to chemotherapy, since the difference between hCG positive and hCG negative samples was maintained during chemotherapy. Prolactin was found by immunoperoxidase technique in the syncytiotrophoblast of normal placenta throughout gestation, and also in hydatidiform mole, invasive mole and choriocarcinoma. It is suggested that the malignant syncytiotrophoblast may contribute to circulating prolactin levels either by direct secretion of prolactin or by oestrogen stimulation of the pituitary.