Epigenome-wide association study of DNA methylation in maternal blood leukocytes with BMI in pregnancy and gestational weight gain.

OBJECTIVES: We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. METHODS: In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina's MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). RESULTS: We identified one CpG site significantly associated with GWG (p 5.8 × 10-8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10-8 to 2.1 × 10-10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10-8 to 0.04). CONCLUSIONS: We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits. GOV REGISTRATION NO: Not applicable.

Phenotypic and genotypic differences between Indian and Scandinavian women with gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. METHODS: Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). RESULTS: Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. CONCLUSIONS: Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.

A novel technique of Roux-en-Y gastric bypass reversal for postprandial hyperinsulinemic hypoglycaemia: A case report.

BACKGROUND: We describe an evaluation of the effects of partial Roux-en-Y gastric bypass (RYGB) reversal on postprandial hyperinsulinaemic hypoglycaemia, insulin and GLP-1 levels. CASE SUMMARY: A 37 year old man was admitted with neuroglycopenia (plasma-glucose 1.6mmol/l) 18 months after RYGB, with normal 72h fasting test and abdominal CT. Despite dietary modifications and medical treatment, the hypoglycaemic episodes escalated in frequency. Feeding by a gastrostomy tube positioned in the gastric remnant did not prevent severe episodes of hypoglycaemia. A modified reversal of the RYGB was performed. Mixed meal tests were done perorally (PO), through the gastrostomy tube 1 (GT1), 4 weeks (GT2) after placement and 4 weeks after reversal (POr), with assessment of glucose, insulin and GLP-1 levels. RESULTS: Plasma-glucose increased to a maximum of 9.6, 5.4, 6.5 and 5.8mmol/l at the PO, GT1, GT2 and POr tests respectively. The corresponding insulin levels were 2939, 731, 725 and 463pmol/l. A decrease of plasma-glucose followed: 2.2, 3.0, 3.9 and 2.9mmol/l respectively and insulin levels were suppressed at 150min: 45, 22, 21 and 14pmol/l, respectively. GLP-1 levels increased in the PO test (60min: 122pmol/l, 21 fold of basal), but was attenuated in the two latter tests (12-23pmol/l at 60min). CONCLUSIONS: Reduction of plasma-glucose, insulin and GLP-1 excursions and symptoms were seen after gastric tube placement and partial RYGB reversal. This attenuation of GLP-1 response to feeding could reflect an adaptation to nutrients.

Pain reduction after total laparoscopic hysterectomy and laparoscopic supracervical hysterectomy among women with dysmenorrhoea: a randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of total laparoscopic hysterectomy compared with laparoscopic supracervical hysterectomy for alleviating dysmenorrhoea. DESIGN: Randomised blinded controlled trial. SETTING: Norwegian university teaching hospital. SAMPLE: Sixty-two women with dysmenorrhoea. METHODS: Participants randomised to either total laparoscopic hysterectomy (n = 31) or laparoscopic supracervical hysterectomy (n = 31). MAIN OUTCOME MEASURES: The primary outcome measure, measured 12 months after intervention, was reduction of cyclic pelvic pain (visual analogue scale, 0-10). Secondary outcome measures included patient satisfaction (visual analogue scale, 0-10) and quality of life (Short Form 36, 0-100). RESULTS: The groups were comparable at baseline. There was no difference in self-reported dysmenorrhoea at 12 months (mean 0.8 [SD 1.6] versus 0.8 [SD 2.0], P = 0.94). There was no difference in patient satisfaction (mean 9.3 [SD 1.5] versus 9.1 [SD 1.2], P = 0.66) or quality of life (mean 81.6 [SD 17.8] versus 80.2 [SD 18.0], P = 0.69). CONCLUSION: Improvement in dysmenorrhoea and quality of life as well as patient satisfaction were comparable in the medium term when comparing total laparoscopic hysterectomy with laparoscopic supracervical hysterectomy.

Inhibition of phosphodiesterase-3 by levosimendan is sufficient to account for its inotropic effect in failing human heart.

BACKGROUND AND PURPOSE: Levosimendan is known as a calcium sensitizer, although it is also known to inhibit PDE3. We aimed to isolate each component and estimate their contribution to the increased cardiac contractility induced by levosimendan. EXPERIMENTAL APPROACH: Contractile force was measured in electrically stimulated ventricular strips from explanted failing human hearts and left ventricular strips from normal male Wistar rats. PDE activity was measured in a two-step PDE activity assay on failing human ventricle. KEY RESULTS: Levosimendan exerted a positive inotropic effect (PIE) reaching maximum at 10(-5) M in ventricular strips from failing human hearts. In the presence of the selective PDE3 inhibitor cilostamide, the PIE of levosimendan was abolished. During treatment with a PDE4 inhibitor and a supra-threshold concentration of isoprenaline, levosimendan generated an amplified inotropic response. This effect was reversed by ß-adrenoceptor blockade and undetectable in strips pretreated with cilostamide. Levosimendan (10(-6) M) increased the potency of ß-adrenoceptor agonists by 0.5 log units in failing human myocardium, but not in the presence of cilostamide. Every inotropic response to levosimendan was associated with a lusitropic response. Levosimendan did not affect the concentration-response curve to calcium in rat ventricular strips, in contrast to the effects of a known calcium sensitizer, EMD57033 [5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one]. PDE activity assays confirmed that levosimendan inhibited PDE3 as effectively as cilostamide. CONCLUSIONS AND IMPLICATIONS: Our results indicate that the PDE3-inhibitory property of levosimendan was enough to account for its inotropic effect, leaving a minor, if any, effect to a calcium-sensitizing component.

SERCA2 activity is involved in the CNP-mediated functional responses in failing rat myocardium.

BACKGROUND AND PURPOSES: Myocardial C-type natriuretic peptide (CNP) levels are increased in heart failure. CNP can induce negative inotropic (NIR) and positive lusitropic responses (LR) in normal hearts, but its effects in failing hearts are not known. We studied the mechanism of CNP-induced NIR and LR in failing hearts and determined whether sarcoplasmatic reticulum Ca(2+) ATPase2 (SERCA2) activity is essential for these responses. EXPERIMENTAL APPROACH: Contractility, cGMP levels, Ca(2+) transient amplitudes and protein phosphorylation were measured in left ventricular muscle strips or ventricular cardiomyocytes from failing hearts of Wistar rats 6 weeks after myocardial infarction. KEY RESULTS: CNP increased cGMP levels, evoked a NIR and LR in muscle strips, and caused phospholamban (PLB) Ser(16) and troponin I (TnI) Ser(23/24) phosphorylation in cardiomyocytes. Both the NIR and LR induced by CNP were reduced in the presence of a PKG blocker/cGMP analogue (Rp-8-Br-Pet-cGMPS) and the SERCA inhibitor thapsigargin. CNP increased the amplitude of the Ca(2+) transient and increased SERCA2 activity in cardiomyocytes. The CNP-elicited NIR and LR were not affected by the L-type Ca(2+) channel activator BAY-K8644, but were abolished in the presence of isoprenaline (induces maximal activation of cAMP pathway). This suggests that phosphorylation of PLB and TnI by CNP causes both a NIR and LR. The NIR to CNP in mouse heart was abolished 8 weeks after cardiomyocyte-specific inactivation of the SERCA2 gene. CONCLUSIONS AND IMPLICATIONS: We conclude that CNP-induced PLB and TnI phosphorylation by PKG in concert mediate both a predictable LR as well as the less expected NIR in failing hearts.

A comparison of oxycodone prolonged-release vs. oxycodone + naloxone prolonged-release after laparoscopic hysterectomy.

BACKGROUND: Targiniq®, an oxycodone prolonged-release (PR) formulation combined with the opioid antagonist naloxone PR, aims to prevent opioid-induced constipation without impairing the analgesic efficacy. This has been confirmed during prolonged use in chronic pain or cancer patients. The purpose of our study was to compare clinical effects of oxycodone PR with oxycodone PR + naloxone PR for short-term post-operative pain management. METHODS: This randomised, double-blind, prospective study included 85 women undergoing laparoscopic hysterectomy. The two groups received either oxycodone PR 10 mg or oxycodone PR 10 mg + naloxone PR 5 mg as pre-medication and twice daily for 3 days. As rescue analgesic, the patients received oxycodone intravenous during the first 24 h post-operatively and oxycodone tablets in the 24-72-h period. Constipation, other side effects, pain and satisfaction were registered during the first 7 post-operative days. RESULTS: Demographic, pre- and perioperative variables and the use of rescue analgesics were similar in the groups. There were no significant differences in variables related to constipation. In the oxycodone PR + naloxone PR group, 25% had no defecation during the first 72 h post-operatively, compared with 20% in the oxycodone PR group (mean 1.2 ± 1.1 vs. 2.1 ± 2.4 defecations). Other opioid-induced effects and side effects showed no significant differences. Only 7% were dissatisfied with their oral pain treatment. CONCLUSION: Addition of naloxone to oxycodone PR tablets in a pain regimen administered twice daily the first three post-operative days had no significant clinical effects on constipation or other variables during the first week after hysterectomy.

Nociceptive stimuli responses at different levels of general anaesthesia and genetic variability.

BACKGROUND: Changes in skin conductance (SC), clinical stress score (CSS), the bispectral index spectroscopy (BIS) index and the variation in the BIS index may be used to monitor responses to nociceptive stimuli. We wanted to examine these methods during noxious stimulation during general anaesthesia and if the responses were associated with variability in genes related to pain. METHODS: Sixty patients, given propofol to a BIS level of 40-50, were stimulated with standardised tetanic electrical stimuli during propofol infusion, plasma level of 3 µg/ml alone, or together with remifentanil target plasma level of 3 ng/ml or 10 ng/ml. The CSS, SC, BIS index and the variability of the BIS index were registered. The inter-individual variation in nociceptive responses was analysed for co-variation with genotypes of 89 single nucleotide polymorphisms from 23 candidate genes. RESULTS: During tetanic stimuli, CSS and SC increased significantly and were attenuated with increasing level of remifentanil, different from the BIS index and the variation in the BIS index. Polymorphisms in the P-glycoprotein (ABCB1), tachykinin 1 receptor (TACR1), dopamine receptor D3 (DRD3) and beta arrestin 2 (ARRB2) genes were associated with the co-variation in SC variables or CSS response or both during standardised nociceptive stimuli (P < 0.05). Because of no corrections for multiple testing, the genetic analyses are explorative, and associations must be tested in further studies. CONCLUSION: This exploratory study suggests genes that may be tested further with relation to nociceptive response during anaesthesia. SC and CSS may be useful tools for monitoring nociceptive response during general anaesthesia.

Correction of an unexpected increasing trend in glucose measurements during 7 years recruitment to a cohort study.

OBJECTIVES: To study an unexpected, significant increase in glucose measurements during 7 year recruitment to a cohort study. DESIGN AND METHODS: Measurements of quality control solutions and blood glucose in pregnant women were done by Accu-Chek Sensor glucometer. Time-trends were analysed by regression models and control charts. RESULTS: Cohort measurements were de-trended by weighted linear regressions based on independent control values. CONCLUSIONS: Biologically implausible trends in data can be corrected by using independent control values.

Overweight is associated with impaired beta-cell function during pregnancy: a longitudinal study of 553 normal pregnancies.

OBJECTIVE: To monitor beta-cell function and insulin sensitivity longitudinally in a large cohort of pregnant women to elucidate mechanisms that influence glycemic control in pregnancy. DESIGN AND METHODS: Five hundred and fifty-three pregnant Scandinavian women underwent 75 g oral glucose tolerance test (OGTT) at weeks 14-16 and 30-32. Insulin sensitivity (Matsuda index) and beta-cell function (ratio of AUC(insulin) to AUC(glucose), AUC(ins/glc)) were calculated from 520 complete tests, and subsequently beta-cell function was adjusted for insulin sensitivity, rendering an oral disposition index (DI(o)). RESULTS: Eleven women (2.1%) had gestational diabetes mellitus (GDM1) at weeks 14-16, and 49 (9.4%) at weeks 30-32 (GDM2), which is higher than that previously reported in this region. In the subdivision of OGTT, more overweight (body mass index>25) was found in glucose-intolerant groups (glucose-tolerant women (normal glucose tolerance, NGT) 38 versus GDM2 women 58 and GDM1 women 82%, P<0.005). In early pregnancy, insulin sensitivity was lowest in GDM1, intermediate in GDM2, and highest in NGT. In late pregnancy, insulin sensitivity decreased in all groups, most in gestational diabetes. beta-cell function demonstrated minor shifts during pregnancy, but when adjusted for decreasing insulin sensitivity, DI(o) levels fell by 40% (P<0.001). DI(o) was significantly attenuated relative to glucose intolerance (GDM1 25% and GDM2 53%) during pregnancy. In overweight women, DI(o) levels were lower throughout pregnancy (P<0.001 versus normal weight women), this reduction was significant (P<0.01) in both NGT (21-25%) and GDM2 subjects (26-49%). CONCLUSION: beta-cell function adjusted for insulin sensitivity (DI(o)) deteriorated during pregnancy in both glucose-tolerant and glucose-intolerant women. The failure to compensate the decrease in insulin sensitivity was accentuated in overweight women.

A combination of misoprostol and estradiol for preoperative cervical ripening in postmenopausal women: a randomised controlled trial.

OBJECTIVE: To compare the impact of 1000 microg of self-administered vaginal misoprostol versus self-administered vaginal placebo on preoperative cervical ripening after 2 weeks of pretreatment with estradiol vaginal tablets in postmenopausal women prior to day-care operative hysteroscopy. DESIGN: Randomised, double-blind, placebo-controlled sequential trial. SETTING: Norwegian university teaching hospital. POPULATION: Sixty-seven postmenopausal women referred for day-care operative hysteroscopy. METHODS: The women were randomised to receive either 1000 microg of self-administered vaginal misoprostol or self-administered vaginal placebo on the evening before day-care operative hysteroscopy. All women had administered a 25-microg vaginal estradiol tablet daily for 14 days prior to the operation. PRIMARY OUTCOME: preoperative cervical dilatation at hysteroscopy. SECONDARY OUTCOMES: difference in dilatation at recruitment and before hysteroscopy, number of women who achieved a preoperative cervical dilatation of 5 mm or more, acceptability, complications and adverse effects. RESULTS: The mean cervical dilatation was 5.7 mm (SD, 1.6 mm) in the misoprostol group and 4.7 mm (SD, 1.5 mm) in the placebo group, the mean difference in cervical dilatation being 1.0 mm (95% CI, 0.2-1.7 mm). Self-administered vaginal misoprostol of 1000 microg at home on the evening before day-care hysteroscopy is safe and highly acceptable, although a small proportion of women experienced lower abdominal pain. CONCLUSIONS: One thousand micrograms of self-administered vaginal misoprostol, 12 hours prior to day-care hysteroscopy, after 14 days of pretreatment with vaginal estradiol, has a significant cervical ripening effect compared with placebo in postmenopausal women.

Beneficial effects of K-ATP channel openers in diabetes: an update on mechanisms and clinical experiences.

Stresses associated with the diabetic state participate in the demise of beta-cells and therapies that eliminate or reduce such stresses are much needed. K-ATP channel openers, of which diazoxide is the most studied, are potentially useful because experimental studies show that they can counteract chronic over-stimulation of beta-cells and protect against toxic conditions, including relative hypoxia. Several mechanisms may underlie the beneficial effects of diazoxide; these may include both indirect (counteracting over-stimulation) and direct mitochondrial effects. Side effects of diazoxide have limited its use in human trials. We have tested lower doses than previously of diazoxide and thereby largely eliminated side effects. In this setting, we demonstrate positive effects on beta-cell function in type 2 diabetic patients who were simultaneously treated with bedtime insulin. However, such effects were absent in insulin-naïve patients. In newly diagnosed type 1 diabetic patients, a 6-month intervention with diazoxide failed to result in better preservation of beta-cell function. K-ATP channel openers have a potential to improve beta-cell function in subgroups of type 2 diabetes patients. Analogues of diazoxide with more potency in relation to side effects would heighten the possibilities for K-ATP channel openers to be of therapeutic use in type 1 diabetes.

Activation of muscarinic receptors elicits inotropic responses in ventricular muscle from rats with heart failure through myosin light chain phosphorylation.

BACKGROUND AND PURPOSE: Muscarinic stimulation increases myofilament Ca(2+) sensitivity with no apparent inotropic response in normal rat myocardium. Increased myofilament Ca(2+) sensitivity is a molecular mechanism promoting increased contractility in failing cardiac tissue. Thus, muscarinic receptor activation could elicit inotropic responses in ventricular myocardium from rats with heart failure, through increasing phosphorylation of myosin light chain (MLC). EXPERIMENTAL APPROACH: Contractile force was measured in left ventricular papillary muscles from male Wistar rats, 6 weeks after left coronary artery ligation or sham surgery. Muscles were also frozen, and MLC-2 phosphorylation level was quantified. KEY RESULTS: Carbachol (10 micromol.L(-1)) evoked a positive inotropic response only in muscles from rats with heart failure approximating 36% of that elicited by 1 micromol.L(-1) isoproterenol (20 +/- 1.5% and 56 +/- 6.1% above basal respectively). Carbachol-evoked inotropic responses did not correlate with infarction size but did correlate with increased left ventricular end diastolic pressure, heart weight/body weight ratio and lung weight, primary indicators of the severity of heart failure. Only muscarinic receptor antagonists selective for M(2) receptors antagonized carbachol-mediated inotropic effects with the expected potency. Carbachol-evoked inotropic responses and increase in phosphorylated MLC-2 were attenuated by MLC kinase (ML-9) and Rho-kinase inhibition (Y-27632), and inotropic responses were abolished by Pertussis toxin pretreatment. CONCLUSION AND IMPLICATIONS: In failing ventricular muscle, muscarinic receptor activation, most likely via M(2) receptors, provides inotropic support by increasing MLC phosphorylation and consequently, myofilament Ca(2+) sensitivity. Enhancement of myofilament Ca(2+) sensitivity, representing a less energy-demanding mechanism of inotropic support may be particularly advantageous in failing hearts.

Flow differences between endometrial polyps and cancer: a prospective study using intravenous contrast-enhanced transvaginal color flow Doppler and three-dimensional power Doppler ultrasound.

OBJECTIVES: To evaluate whether assessment of blood flow by transvaginal color Doppler and three-dimensional power Doppler imaging, enhanced by intravenous contrast, may be useful in the differentiation between benign endometrial polyps and endometrial cancer. METHODS: A prospective study was performed comparing 17 women with benign endometrial polyps and 17 women with endometrial cancer. Transvaginal color Doppler and three-dimensional power Doppler angiography were performed before and after injection of intravenous contrast. The pulsatility index (PI) and the resistance index (RI) of the polyp feeding vessel or central vessel in malignant lesions, as well as the power Doppler endometrial flow indices vascularization index (VI), flow index (FI) and vascularization flow index (VFI), were calculated before and after enhancement by contrast, and compared between the two groups of women. RESULTS: PI (mean difference +/- SD, 0.68 +/- 0.22; 95% CI, 0.23-1.13; P = 0.004) and RI (mean difference +/- SD, 0.16 +/- 0.08; 95% CI, 0.00-0.32; P = 0.045) were significantly lower in vessels of malignant tumors than in those of benign endometrial polyps after enhancement by intravenous contrast. No significant differences in PI, RI, VI, FI or VFI before enhancement by contrast, or in VI, FI or VFI after enhancement by contrast, were detected between women with endometrial polyps and those with endometrial cancer. CONCLUSIONS: Transvaginal color Doppler examination enhanced by intravenous contrast may help to discriminate between benign endometrial polyps and cancer. Larger studies are required to confirm these findings.

5-HT4-elicited positive inotropic response is mediated by cAMP and regulated by PDE3 in failing rat and human cardiac ventricles.

BACKGROUND AND PURPOSE: The left ventricle in failing hearts becomes sensitive to 5-HT parallelled by appearance of functional G(s)-coupled 5-HT(4) receptors. Here, we have explored the regulatory functions of phosphodiesterases in the 5-HT(4) receptor-mediated functional effects in ventricular muscle from failing rat and human heart. EXPERIMENTAL APPROACH: Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats. Contractility was measured in left ventricular papillary muscles of rat, 6 weeks after surgery and in left ventricular trabeculae from explanted human hearts. cAMP was quantified by RIA. KEY RESULTS: In papillary muscles from postinfarction rat hearts, 5-HT(4) stimulation exerted positive inotropic and lusitropic effects and increased cAMP. The inotropic effect was increased by non-selective PDE inhibition (IBMX, 10 microM) and selective inhibition of PDE3 (cilostamide, 1 microM), but not of PDE2 (EHNA, 10 microM) or PDE4 (rolipram, 10 microM). Combined PDE3 and PDE4 inhibition enhanced inotropic responses beyond the effect of PDE3 inhibition alone, increased the sensitivity to 5-HT, and also revealed an inotropic response in control (sham-operated) rat ventricle. Lusitropic effects were increased only during combined PDE inhibition. In failing human ventricle, the 5-HT(4) receptor-mediated positive inotropic response was regulated by PDEs in a manner similar to that in postinfarction rat hearts. CONCLUSIONS AND IMPLICATIONS: 5-HT(4) receptor-mediated positive inotropic responses in failing rat ventricle were cAMP-dependent. PDE3 was the main PDE regulating this response and involvement of PDE4 was disclosed by concomitant inhibition of PDE3 in both postinfarction rat and failing human hearts. 5-HT, PDE3 and PDE4 may have pathophysiological functions in heart failure.

Long-term outcomes following laparoscopic supracervical hysterectomy.

OBJECTIVE: Evaluation of long-term outcomes following laparoscopic supracervical hysterectomy (LSH). DESIGN: Retrospective postal questionnaire. SETTING: Norwegian university teaching hospital. POPULATION: A total of 315 consecutive patients. METHODS: A questionnaire sent to all patients who underwent a LSH during 2004 and 2005. MAIN OUTCOME MEASURES: Persistent vaginal bleeding and pelvic pain, patient acceptability of such symptoms and patient satisfaction following LSH. RESULTS: A total of 240 women (78%) completed the questionnaire. About 24% reported experiencing vaginal bleeding up to 3 years following their hysterectomy, although this was rated as minimal in 90% of cases, resulting in a mean bothersome score of 1.1 (SD 2.0) on a 10-point visual analogue scale (VAS). Women operated on by less experienced surgeons were more likely to report vaginal bleeding following surgery (P = 0.02). About 74% of women reported having menstrual pain prior to surgery, with a mean score of 6.8 (SD 2.1) (10-point VAS). Up to 3 years following surgery, 38% continued to experience menstrual pain, although this was significantly less intense with a mean score of 3.5 (SD 2.2) (P < 0.01). While all women reported a decrease in the amount of pain experienced following the hysterectomy, those having a hysterectomy because of endometriosis reported significantly higher levels of menstrual/cyclical pain after surgery compared with women who had a hysterectomy for other reasons (P < 0.01). Ninety per cent of women reported being satisfied with their surgery. CONCLUSION: Although vaginal bleeding and pelvic pain are frequently observed following LSH, these symptoms are significantly reduced and patient satisfaction is high.

Does self-administered vaginal misoprostol result in cervical ripening in postmenopausal women after 14 days of pre-treatment with estradiol? Trial protocol for a randomised, placebo-controlled sequential trial.

OBJECTIVE: To compare the impact of 1000 micrograms of self-administered vaginal misoprostol versus self-administered vaginal placebo on preoperative cervical ripening after pre-treatment with estradiol vaginal tablets at home in postmenopausal women prior to day-care operative hysteroscopy. DESIGN: Randomised double-blind placebo-controlled sequential trial. The boundaries for the sequential trial were calculated on the primary outcomes of a difference of cervical dilatation > or = 1 millimetre, with the assumption of a type 1 error of 0.05 and a power of 0.95. SETTING: Norwegian university teaching hospital. POPULATION: Postmenopausal women referred for day-care operative hysteroscopy. METHODS: The women were randomised to either 1000 micrograms of self-administered vaginal misoprostol or self-administered vaginal placebo the evening before day-care operative hysteroscopy. All women had administered a 25-microgram vaginal estradiol tablet daily for 14 days prior to the operation. MAIN OUTCOME MEASURES: Preoperative cervical dilatation (difference between misoprostol and placebo group, primary outcome), difference in dilatation before and after administration of misoprostol or placebo, number of women who achieve a preoperative cervical dilatation > or = 5 millimetres, acceptability, complications and side effects (secondary outcomes). RESULTS: Intra-operative findings and distribution of cervical dilatation in the two treatment groups: values are given as median (range) or n (%). Difference in dilatation before and after administration of misoprostol and placebo: values are given as median (range) of intraindividual differences. Percentage of women who achieve a cervical dilatation of > or = 5 mm, percentage of women who were difficult to dilate. Acceptability in the two treatment groups: values are given as completely acceptable n (%), fairly acceptable n (%), fairly unacceptable n (%), completely unacceptable n (%). Pain in the two treatment groups: pain was measured with a visual analogue scale ranging from 0 (no pain) to 10 (unbearable pain): values are given as median (range). Occurrence of side effects in the two treatment groups. Values are given as n (%). Complications given as n (%). FUNDING SOURCES: No pharmaceutical company was involved in this study. A research grant from the regional research board of Northern Norway has been awarded to finance Dr K.S.O.'s leave from Hammerfest hospital as well as travel expenses between Hammerfest and Oslo, and research courses. The research grant from Prof B.I.N. (Helse Øst) funded the purchase of estradiol tablets, the manufacturing costs of misoprostol and placebo capsules from the hospital pharmacy, as well as the costs incurred for preparing the randomisation schedule and distribution of containers containing capsules to hospital. Prof B.I.N.'s research grant also funded insurance for the study participants. CONCLUSIONS: Estimated completion date 31 December 2008.

Differential impact of conventional and low-dose oral hormone therapy, tibolone and raloxifene on mammographic breast density, assessed by an automated quantitative method.

OBJECTIVE: To evaluate impact of different postmenopausal hormone therapy (HT) regimens and raloxifene on mammographic breast density. DESIGN: Open, randomised, comparative clinical trial. SETTING: Women were recruited through local newspapers and posters. They were examined at the Departments of Haematology, Gynaecology, and Radiology in a University Hospital. POPULATION: A total of 202 healthy postmenopausal women between the age of 45 and 65 years. METHODS: Women were randomly assigned to receive daily treatment for 12 weeks with tablets containing low-dose HT containing 1 mg 17 beta-estradiol + 0.5 mg norethisterone acetate (NETA) (n = 50), conventional-dose HT containing 2 mg 17 beta-estradiol and 1 mg NETA (n = 50), 2.5 mg tibolone (n = 51), or 60 mg raloxifene (n = 51). Mammographic density was determined at baseline and after 12 weeks by an automated technique in full-field digital mammograms. MAIN OUTCOME MEASURES: Mammographic density was expressed as volumetric breast density estimations. RESULTS: Mammographic breast density increased significantly and to a similar degree in both the conventional- and low-dose HT groups. A small reduction in mammographic breast density was seen in the raloxifene group, whereas those allocated to tibolone treatment only showed minor changes. CONCLUSIONS: Our findings demonstrated a significant difference in impact on mammographic breast density between the regimens. Although these results indicate a differential effect of these regimens on breast tissue, the relation to breast cancer risk remains unresolved.

Comparison of self-administered vaginal misoprostol versus placebo for cervical ripening prior to operative hysteroscopy using a sequential trial design.

OBJECTIVE: To compare the impact of 1000 micrograms of self-administered vaginal misoprostol versus self-administered vaginal placebo at home on preoperative cervical ripening in both premenopausal and postmenopausal women before operative hysteroscopy. DESIGN: Two separate but identical parallel, randomised, double-blind, placebo-controlled sequential trials, one in premenopausal women and one in postmenopausal women. The boundaries for the sequential trials were calculated on the primary outcomes of a difference of cervical dilatation > or = 1 mm, with the assumption of a type 1 error of 0.05 and a power of 0.95. SETTING: Norwegian university teaching hospital. SAMPLE: Eighty-six women referred to outpatient operative hysteroscopy. METHODS: The women were randomised to either 1000 micrograms of self-administered vaginal misoprostol or self-administered vaginal placebo the evening before outpatient operative hysteroscopy. MAIN OUTCOME MEASURES: Preoperative cervical dilatation (primary outcome), number of women who achieve a preoperative cervical dilatation > or = 5 mm, acceptability, complications and adverse effects (secondary outcomes). RESULTS: In premenopausal women, the mean cervical dilatation was 6.4 mm (SD 2.4) in the misoprostol group and 4.8 mm (SD 2.0) in the placebo group, the mean difference in cervical dilatation being 1.6 mm (95% CI 0.5-2.7). Among the premenopausal women receiving misoprostol, 88% achieved a cervical dilatation of > or = 5 mm compared with 65% in the placebo group. Twelve percent of the women who received misoprostol were difficult to dilate compared with 32% who received placebo. Dilatation was also quicker in the misoprostol group. Misoprostol had no effect on cervical ripening in postmenopausal women compared with placebo, and 43% of the women were difficult to dilate. The trials were terminated after analysis of 21 postmenopausal women and 65 premenopausal women after reaching a conclusion on the primary outcome with only 28% of the number of women needed in a fixed sample size trial. Three of 45 women who received misoprostol experienced severe lower abdominal pain, and there was an increased occurrence of light preoperative bleeding in the misoprostol group. Most women did not experience misoprostol-related adverse effects. The majority (83% of premenopausal and 76% of postmenopausal women) found self-administered vaginal misoprostol at home to be acceptable. There were two serious complications in the premenopausal misoprostol group: uterine perforation with subsequent peritonitis and heavy postoperative bleeding requiring blood transfusion, but these were not judged to be misoprostol related. Complications were otherwise comparatively minor and distributed equally between the two dosage groups. CONCLUSIONS: One thousand micrograms of self-administered vaginal misoprostol 12 hours prior to operative hysteroscopy has a significant cervical ripening effect compared with placebo in premenopausal but not in postmenopausal women. Self-administered vaginal misoprostol of 1000 micrograms at home the evening before operative hysteroscopy is safe and highly acceptable, although a small proportion of women experienced severe lower abdominal pain. There is a risk of lower abdominal pain and light preoperative bleeding with this regimen, which is very cheap and easy to use.

Comparison of self-administered vaginal misoprostol versus placebo for cervical ripening prior to operative hysteroscopy using a sequential trial design.

OBJECTIVE: To compare the impact of 1000-microgram self-administered vaginal misoprostol versus self-administered vaginal placebo at home on preoperative cervical ripening in both premenopausal and postmenopausal women prior to outpatient resectoscopy. DESIGN: Randomised, double-blind, placebo-controlled sequential trial. SETTING: Norwegian university teaching hospital. SAMPLE: Premenopausal and postmenopausal women referred to outpatient resectoscopy. METHODS: The women were randomised to either 1000 micrograms of self-administered vaginal misoprostol or self-administered vaginal placebo the evening before outpatient resectoscopy. MAIN OUTCOME MEASURES: Preoperative cervical dilatation, acceptability and complications. RESULTS: (a) Intraoperative findings and distribution of cervical dilatation in the two treatment groups. Values are given as median (range) or n (%). (b) Acceptability in the two treatment groups. Values are given as completely acceptable, n (%); fairly acceptable, n (%); fairly unacceptable, n (%) and completely unacceptable, n (%). (c) Pain in the two treatment groups. Pain was measured with a visual analogue scale score, scale ranges from 0 (no pain) to 10 (unbearable pain). Values are given as median (range). (d) Occurrence of adverse effects in the two treatment groups. Values are given as n (%). (e) Complications, given as n (%).