Objective To investigate endometrial histopathology in a geographically defined population of women presenting with postmenopausal bleeding. Design Prospective study with collection of data during an 18–month period. Setting The health care county of Skaraborg, Sweden. Subjects Dilatation and curettage using general anaesthesia was performed on 457 postmenopausal women suffering from uterine bleeding. Women using hormone replacement therapy for climacteric complaints were not included in the investigation. Main outcome measures The frequency of bleeding was correlated to endometrial histopathology, and in relevant cases to pathological conditions in cervix and ovaries in a defined population of postmenopausal women. Results The incidence of postmenopausal bleeding decreased with increasing age while the probability of cancer as the underlying cause increased. The peak incidence of endometrial carcinoma was found in women between 65 and 69 years of age. Endometrial histopathology showed: atrophy (50%); proliferation (4%); secretion (1 %); polyps (9%); different degrees of hyperplasia (10 %); adenocarcinoma (8 %); not representative (14 %); other disorders (3 %). In six women a squamous carcinoma of the cervix was found, and eight proved to have ovarian tumours. Conclusions The histopathological finding of endometrial adenomatous hyperplasia or cancer in about 15% of the postmenopausal women with bleeding justifies a thorough examination. The probability of cancer as the underlying cause increased with age. The endometrium was atrophic in 50%. Eight women had ovarian tumours. These findings may imply that transvaginal ultrasound examination should be included in the evaluation of postmenopausal bleeding as occasionally endometrial biopsies of atrophic endometrium could be avoided and ovarian pathology detected.

Intrahepatic cholestasis of pregnancy (ICP) is characterized by troublesome maternal pruritus, elevated serum bile acids (>10 mol/L) and increased fetal risk. Recently we determined a cutoff level of serum bile acids, >40 mol/L, to be associated with impaired fetal outcome. We have now studied the effects of ursodeoxycholic acid (UDCA) and dexamethasone on pruritus, biochemical markers of cholestasis, and fetal complication rates in a double-blind, placebo-controlled trial. For this purpose, 130 women with ICP were randomly allocated to UDCA (1 g/day for three weeks), or dexamethasone (12 mg/day for 1 week and placebo during weeks 2 and 3), or placebo for 3 weeks. Pruritus and biochemical markers of cholestasis were analyzed at inclusion and after 3 weeks of treatment. Fetal complications (spontaneous preterm delivery; asphyxial events; and meconium staining of amniotic fluid, placenta, and membranes) were registered at delivery. An intention-to-treat analysis showed significant reduction of alanine aminotransferase (ALT) (P ‫؍‬ .01) and bilirubin (P ‫؍‬ .002) in the UDCA group only. In a subgroup analysis of ICP women with serum bile acids >40 mol/L at inclusion (n ‫؍‬ 34), UDCA had significant effects on pruritus (؊75%), bile acids (؊79%), ALT (؊80%), and bilirubin (؊50%) as well, but not on fetal complication rates. Dexamethasone yielded no alleviation of pruritus or reduction of ALT and was less effective than UDCA at reducing bile acids and bilirubin. In conclusion, 3 weeks of UDCA treatment improved some biochemical markers of ICP irrespective of disease severity, whereas significant relief from pruritus and marked reduction of serum bile acids were only found in patients with severe ICP. (HEPATOLOGY 2005;42:1399-1405

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Background: Intrahepatic cholestasis of pregnancy (ICP) is characterised by troublesome maternal pruritus, raised serum bile acid levels and increased fetal risk. Mutations of the ABCB4 gene encoding the hepatobiliary phospholipid transporter have been identified in a small proportion of patients with cholestasis of pregnancy. In a recent prospective study on 693 patients with cholestasis of pregnancy, a cut-off level for serum bile acid (>40 mmol/l) was determined for increased risk of fetal complications. Objectives: To investigate whether common combinations of polymorphic alleles (haplotypes) of the genes encoding the hepatobiliary ATP-binding cassette (ABC) transporters for phospholipids (ABCB4) and bile acids (ABCB11) were associated with this severe form of cholestasis of pregnancy. Methods: For genetic analysis, 52 women with bile acid levels >40 mmol/l (called cases) and 52 unaffected women (called controls) matched for age, parity and geographical residence were studied. Gene variants tagging common ABCB4 and ABCB11 haplotypes were genotyped and haplotype distributions were compared between cases and controls by permutation testing. Results: In contrast with ABCB11 haplotypes, ABCB4 haplotypes differed between the two groups (p = 0.019), showing that the severe form of cholestasis of pregnancy is associated with the ABCB4 gene variants. Specifically, haplotype ABCB4_5 occurred more often in cases, whereas haplotypes ABCB4_3 and ABCB4_7 were more common in controls. These associations were reflected by different frequencies of at-risk alleles of the two tagging polymorphisms (c.711A: odds ratio (OR) 2.27, p = 0.04; deletion intron 5: OR 14.68, p = 0.012). Conclusion: Variants of ABCB4 represent genetic risk factors for the severe form of ICP in Sweden.