Anneke A. Bouman

Oral, more than transdermal, estrogen therapy improves lipids and lipoprotein(a) in postmenopausal women: a randomized, placebo-controlled study.

Objective To assess the effects of low-dose oral and transdermal estrogen therapy on the lipid profile and lipoprotein(a) [Lp(a)] levels in healthy, postmenopausal women and to study the additional influence of gestodene administration. Design In a multicenter, randomized, double-blind, placebo-controlled study, 152 healthy, hysterectomized, postmenopausal women received daily either placebo (n = 49), 50 &mgr;g transdermal 17&bgr;-estradiol (tE2, n = 33), 1 mg oral 17&bgr;-estradiol (oE2, n = 37), or 1 mg oE2 combined with 25 &mgr;g gestodene (oE2 + G, n = 33) for 13 cycles of 28 days, followed by 4 cycles of placebo in each group. Fasting serum concentrations of total, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, triglycerides, and Lp(a) were measured at baseline and in cycles 4, 13, and 17. Results In cycle 13, a significant mean percentage decrease from baseline was found in all treatment groups compared with placebo in total cholesterol (tE2, −4.7%; oE2, −6.9%; oE2 + G, −10.5%) and LDL cholesterol (tE2, −5.8%; oE2, −12.6%; oE2 + G, −13.6%). For both oral groups, the reductions were already significant in cycle 4. None of the treatment groups showed a significant change in HDL cholesterol or triglycerides. In cycle 13, Lp(a) was decreased compared with placebo in the oE2 group (−6.6%) and the oE2 + G group (−8.2%). After washout, all observed changes had returned to baseline level, except for the decreases in total and LDL cholesterol in the oE2 + G group. Conclusions Oral E2 and E2 + G, and to a lesser extent transdermal E2, decreased total and LDL cholesterol. Lp(a) was lowered only by the oral treatments.

Continuously combined hormone replacement therapy and bone turnover: the influence of dydrogesterone dose, smoking and initial degree of bone turnover.

In this study we examined whether the effect of continuously combined hormone replacement therapy (HRT) on bone metabolism is influenced by dydrogesterone dose, smoking and initial degree of bone turnover. In a double-blind randomized study, 123 healthy postmenopausal women (mean age 51.7 years; range 30-61 years) received 17 beta-estradiol, 2 mg orally per day, continuously combined with either 2.5, 5, 10 or 15 mg of dydrogesterone daily. At baseline and at 3 and 6 months of therapy, bone formation was assessed by determining total alkaline phosphatase (TAP), bone-derived alkaline phosphatase (BAP), and the carboxy-terminal propeptide of collagen type I (PICP) in serum; bone resorption was assessed by the calcium/creatinine (Ca/Creat) and hydroxyproline/creatinine (Hp/Creat) ratio in 2-h fasting urine, and the serum carboxy-terminal pyridinolyne cross-linked telopeptide of collagen type I (ICTP). Dydrogesterone dose did not influence the effect of HRT on any of the bone markers. Combining the data of the four treatment groups, the decrease in each marker, compared to baseline values, was significant. However, in non-smokers, compared to smokers, after 6 months of therapy the decline in BAP and TAP was significantly more pronounced and the plasma estradiol level was significantly higher. For each bonemarker at baseline, women in the highest quartile, compared to women in the lowest quartile, showed a significantly stronger decrease in this marker in response to HRT. We conclude that dydrogesterone dose does not modify the effectiveness of replacement therapy. However, smoking and a low bone turnover at baseline may diminish its beneficial effect on bone.

Maternal and fetal plasma concentrations of endothelin, lipidhydroperoxides, glutathione peroxidase and fibronectin in relation to abnormal umbilical artery velocimetry

OBJECTIVE To study plasma concentrations of endothelin (ET), lipidhydroperoxides (LOOH), glutathione peroxidase (GSHpx) and fibronectin in relation to abnormal umbilical artery velocimetry. STUDY DESIGN Plasma concentrations of ET, LOOH, GSHpx and fibronectin were measured in fetal and maternal venous blood in: (i) a control group (n=10); (ii) in pregnancies complicated by intrauterine growth retardation (IUGR) (n=6) or preeclampsia (n=5) with positive end diastolic flow; and in (iii) pregnancies complicated by absent or reversed end diastolic (ARED) flow in the umbilical artery (n=18). All children were delivered by primary caesarean section. RESULTS The significantly highest maternal and fetal ET concentrations were found in plasma collected in pregnancies complicated by ARED flow in the umbilical artery. Maternal fibronectin levels were significantly raised in the ARED flow group. Maternal plasma ET levels were lowest in pregnancies complicated by IUGR. The maternal and fetal plasma concentrations of LOOH and GSHpx did not differ significantly between the groups. CONCLUSION Abnormal Doppler velocimetry, especially ARED flow is associated with elevated maternal and fetal plasma levels of ET. The exact mechanism causing the placental vasoconstriction is unknown yet, but oxidative stress seems not to be involved.

Faecal immunochemical test accuracy in patients referred for surveillance colonoscopy: a multi-centre cohort study

BackgroundGiven the increasing burden on colonoscopy capacity, it has been suggested that faecal immunochemical test (FIT) results could guide surveillance colonoscopy intervals. Against this background, we have evaluated the test accuracy of single and double FIT sampling to detect colorectal cancer (CRC) and/or advanced adenomas in an asymptomatic colonoscopy-controlled high-risk population.MethodsCohort study of asymptomatic high-risk patients (personal history of adenomas/CRC or family history of CRC), who provided one or two FITs before elective colonoscopy. Test accuracy of FIT for detection of CRC and advanced adenomas was determined (cut-off level 50 ng/ml).Results1,041 patients provided a FIT (516 personal history of adenomas, 172 personal history of CRC and 353 family history of CRC). Five CRCs (0.5%) and 101 advanced adenomas (9.7%) were detected by colonoscopy. Single FIT sampling resulted in a sensitivity, specificity, PPV and NPV for CRC of 80%, 89%, 3% and 99.9%, respectively, and for advanced adenoma of 28%, 91%, 24% and 92%, respectively. Double FIT sampling did not result in a significantly higher sensitivity for advanced neoplasia. Simulation of multiple screening rounds indicated that sensitivity of FIT for advanced adenoma could reach 81% after 5 screening rounds.ConclusionsIn once-only FIT sampling before surveillance colonoscopy, 70% of advanced neoplasia were missed. A simulation approach indicates that multiple screening rounds may be more promising in detecting advanced neoplasia and could potentially alleviate endoscopic burden.

Similar fecal immunochemical test results in screening and referral colorectal cancer

AIM To improve the interpretation of fecal immunochemical test (FIT) results in colorectal cancer (CRC) cases from screening and referral cohorts. METHODS In this comparative observational study, two prospective cohorts of CRC cases were compared. The first cohort was obtained from 10 322 average risk subjects invited for CRC screening with FIT, of which, only subjects with a positive FIT were referred for colonoscopy. The second cohort was obtained from 3637 subjects scheduled for elective colonoscopy with a positive FIT result. The same FIT and positivity threshold (OC sensor; ≥ 50 ng/mL) was used in both cohorts. Colonoscopy was performed in all referral subjects and in FIT positive screening subjects. All CRC cases were selected from both cohorts. Outcome measurements were mean FIT results and FIT scores per tissue tumor stage (T stage). RESULTS One hundred and eighteen patients with CRC were included in the present study: 28 cases obtained from the screening cohort (64% male; mean age 65 years, SD 6.5) and 90 cases obtained from the referral cohort (58% male; mean age 69 years, SD 9.8). The mean FIT results found were higher in the referral cohort (829 ± 302 ng/mL vs 613 ± 368 ng/mL, P = 0.02). Tissue tumor stage (T stage) distribution was different between both populations [screening population: 13 (46%) T1, eight (29%) T2, six (21%) T3, one (4%) T4 carcinoma; referral population: 12 (13%) T1, 22 (24%) T2, 52 (58%) T3, four (4%) T4 carcinoma], and higher T stage was significantly associated with higher FIT results (P < 0.001). Per tumor stage, no significant difference in mean FIT results was observed (screening vs referral: T1 498 ± 382 ng/mL vs 725 ± 374 ng/mL, P = 0.22; T2 787 ± 303 ng/mL vs 794 ± 341 ng/mL, P = 0.79; T3 563 ± 368 ng/mL vs 870 ± 258 ng/mL, P = 0.13; T4 not available). After correction for T stage in logistic regression analysis, no significant differences in mean FIT results were observed between both types of cohorts (P = 0.10). CONCLUSION Differences in T stage distribution largely explain differences in FIT results between screening and referral cohorts. Therefore, FIT results should be reported according to T stage.

S1123 Double Versus Single Sampling of Fecal Immunochemical Tests for Colorectal Cancer Screening; Added Value or Added Costs?

Background Fecal immunochemical tests (FITs) are state of the art in colorectal cancer(CRC) screening. Sensitivity of a single FIT for advanced neoplasia is around 50%. Theoretically, as blood loss from colon tumors can be intermittent, sensitivity of FITs could improve by double sampling. This study aims to compare the sensitivity of single FIT sampling and double FIT sampling at different cut-off values, for the detection of advanced neoplasia. Methods All subjects (≥18 years) scheduled for elective colonoscopy in three participating centers in the Amsterdam area were asked to perform FITs (OC sensor®) on two consecutive days. FIT results were compared with colonoscopy and histology as gold standard. Test performance of single FIT was compared to the sensitivity of double FIT sampling. Double FIT sampling was considered positive if one of both FITs was higher than the cut-off value. Test performances were evaluated at cut-off values ranging from 50-150ng/ml (incremental steps of 25ng/ml). Results Of 1105 subjects who performed two FITs and underwent total colonoscopy, 140 (9,4%) had advanced neoplasia (AN), of which 34 were CRC and 106 were advanced adenomas (AA). Of the CRC cases, 70% were Dukes stage A or B (stage unknown in 2). Positivity rates for single FIT ranged from 11-17%, and for double FIT from 14-23%. At the same cut-off value for positivity, sensitivity of double FIT sampling was higher than sensitivity of single FIT sampling. For any particular specificity (e.g. 90%), the sensitivity of double FIT was slightly higher than that of single FIT at a lower cut-off value (see table), but these differences were not statistically significant. Conclusions Two fold sampling of FIT does increase sensitivity for advanced neoplasia. However, at a given specificity, sensitivity of double sampling is comparable to single sampling at a lower cutoff value. Sensitivity and specificity of single and double FIT testing for the detection of advanced neoplasia

930 Comparing Three Different Strategies of Double Sampling by Fecal Immunochemical Tests for Detection of Advanced Colorectal Neoplasm's

Background Fecal Immunochemical Tests (FITs) are widely used for Colorectal Cancer (CRC) screening. Some sampling schemes use one-day FIT testing, whereas others use twoday FIT testing. Data on sensitivity and specificity of two-day FIT testing are lacking. This study aims to compare the difference in sensitivity and specificity of three different strategies of two-day FIT sampling, at different cut-off values. Methods In three hospitals in the Amsterdam area, all subjects ≥18 years who were referred for elective colonoscopy were asked to perform a FIT (OC sensor®) on two consecutive days. Colonoscopy and histology were considered as gold standard. Two-day FIT sampling was defined positive in three different ways: 1) when at least one of two FITs was above the cut-off value (FIT+), 2) when both FITs were above the cut-off value(FIT++), and 3) when the geometric mean of two FITs was above the cut-off value (FITmean). Test performance of all three strategies was evaluated at cut-off values of 50, 75 and 100ng/ml. Results In 1105 subjects with complete colonoscopy, 140 (9,4%) AN were found (34 CRCs and 106 advanced adenomas). Of the CRC cases, 70% were Dukes stage A or B (stage unknown in 2). Positivity rates for FIT+ ranged from 16-23%, for FIT++ from 10-13% and for FITmean from 13-17% (see table). At any cut-off level, FIT++ resulted in the lowest and FIT+ in the highest sensitivity. FIT++ showed a higher specificity than both other strategies (see table). Conclusions The most sensitive strategy in two-day FIT sampling is defining the test positive when at least one of both FITs passes the cut off (FIT+), whereas the highest specificity is obtained when both FITs need to be positive for calling the tests positive (FIT++). At all cut-off values, FITmean offers substantially better specificity than FIT+, while sensitivity is substantially higher than FIT++. Sensitivity and specificity of three methods to use two-day FIT sampling for the detection of advanced neoplasia

The Role of Serum Iron Levels in Diagnosing Hypertensive Disorders in Pregnancy

Objective: The clinical use of serum iron in the assessment of 46 patients of mixed parity with hypertensive pregnancies was compared to other laboratory parameters and the possible relationship between maximum serum iron levels and pregnancy outcome was assessed.Methods: Serum iron concentrations measured in 46 women admitted because of pregnancy-induced hypertensive disorders were related to pregnancy outcome and compared to a control group consisting of 128 normotensive women with uncomplicated pregnancies.Results: Serum iron levels were significantly higher and birth weights were significantly lower in patients with established preeclampsia (PE) as compared to patients with gestational hypertension (GH) or normotensive control women.Conclusions: Both serum uric acid as well as serum iron correlate positively with the presence of hypertensive disorders in pregnancy, however, unlike serum uric acid, serum iron was shown (a) to be significantly different between the GH and the PE groups, and (b) to corre...

Effects of continuously combined hormone replacement therapy on the biochemical markers of bone turnover

PHOSPHATE METABOLISM IN MINERAL MATRIX OF INTACT BONES DURING FRACTURE }IEAL1NG. A. Avrunin. N. Koruilov. Russian Research Institute of Traumatology and Orthopaedics named after R. Vredcn, St. Petersburg, Russia. The formation and turnover of mineral matrix of intact bones in the procoss of isolated fracture healing occurs with circascptanc periodicity (Avrunin et al., 1988, 1991, 1992, 1994). The purpose of the study was to estimate the changes in mineral metabolism in intact boncs during fracture healing. In 174 male rats weighing 180220 g with a transverse fracture of the right femur fixed with an intramedullary nail thc phosphate content in the nfincrai matrix of samples of humeral, tibial and left femoral shafts was estimated by Fiske and Seborrow methods, as well as the spced of their exchange between the blood and the bone judged by the partial reactivity of n p labelled phosphates. The animals were examined every day during 2 months after the trauma. The mathematical models of each parameter dynamics were obtained, it was found out that the phosphate content and the spced of their metabolism varied with a circaseptanc periodicity around the trend with a changing direction. The analysis of trend dynanfics showed that there was the greatest intcrorganal discoordination of metabolism during the first 12 day after the fracture, from the 13th till the 17th day a change in the bone turnover was fouud, and from the 18th to the 30th day the increase of the phosphate content and the spccd of their exchange were observed. ,From the 31st to the 39th day a new change in the metabolism occured which was characterized by the reduction of the phosphate content and the speed of their metabolism till the end of the study. So the 12th, 17th, 30th, 39th days wcrc critical terms of mineral metabolism changes in the bone system.