Olavi Ylikorkala

Evidence of a state of increased insulin resistance in preeclampsia

Similarities in certain biochemical variables between preeclampsia and the insulin resistance syndrome imply a possible link between insulin resistance and preeclampsia. We measured insulin sensitivity by the minimal model technique between 29 and 39 weeks of gestation in 22 preeclamptic and 16 control women, whose glucose tolerance was first confirmed as normal by an oral glucose tolerance test. In addition, we measured the fasting levels of serum C-peptide, uric acid, lipids, and lipoproteins. Preeclamptic women showed a higher insulin response (P = .001) during the oral glucose tolerance test than the controls. Insulin sensitivity in preeclamptic women (1.11+/-0.15 x 10(-4) x min(-1) x microU/mL) was 37% lower (P = .009) than in control women (1.77+/-0.19 x 10(-4) x min(-1) x microU/mL). The free fatty acid (FFA) concentration in preeclamptic women (0.17+/-0.01 g/L, P = .0004) was 70% higher than in control women (0.10+/-0.01 g/L). Also, baseline serum levels of C-peptide, uric acid, and triglyceride were higher in preeclamptic women. Insulin sensitivity increased fourfold to fivefold within the first 3 postpartum months, but insulin sensitivity in preeclamptic women was still 26% lower (P = .04) than in control women. Preeclampsia is a state of increased insulin resistance, and it persists for at least 3 months after pregnancy. This may be a pathogenetic factor in preeclampsia and may contribute to the excess cardiovascular morbidity among women with prior preeclampsia.

A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients

OBJECTIVE Phytoestrogens are popular in treatment of menopause, although scientific evidence is insufficient as to their efficacy. We studied the effects of daily use of isoflavonoids on climacteric symptoms and quality of life in patients with a history of breast cancer. METHODS Sixty-two postmenopausal symptomatic women were randomized to use either phytoestrogen (tablets containing 114 mg of isoflavonoids) or a placebo for 3 months; the treatment regimens were reversed after a 2-month washout period. Fifty-six women completed the study. Menopausal symptoms were recorded on the Kupperman index and the visual analogue scale, and working capacity and mood changes were assessed via validated questionnaires. In addition, we followed the levels of phytoestrogens, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and sex hormone–binding globulin. Liver enzymes and creatinine were also assessed at each visit. RESULTS The phytoestrogen regimen raised the circulating levels of phytoestrogens (daidzein, genistein, equol) 19- to 106-fold. The Kupperman index was reduced by 4.2 ± 9.6 (mean ± standard deviation) (15.5%) during phytoestrogen use and similarly by 4.0 ± 8.1 (14.7%) during placebo use (P nonsignificant). The quality of life parameters (working capacity, mood changes) were unaffected by phytoestrogen. In addition, the phytoestrogen regimen caused no changes in FSH, LH, estradiol, or sex hormone-binding globulin. Phytoestrogen treatment was well tolerated and caused no changes in liver enzymes, creatinine, body mass index, or blood pressure. Of the 56 women, 25 (44.6%) preferred the phytoestrogen regimen, 15 preferred the placebo (26.8%), and 16 (28.6%) reported no preference (nonsignificant). CONCLUSION Pure isoflavonoids did not alleviate subjective menopausal symptoms in breast cancer patients.

Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population-based study.

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder, thought to be specific for pregnancy and to spontaneously resolve after delivery. Increased rates of gallstone formation and hepatitis C have previously been associated with ICP. However, there are no longitudinal studies to determine its significance as an indicator of subsequent liver or biliary diseases. In this retrospective cohort study with cases and controls we assessed the risk of liver and biliary diseases in 21,008 women, 10,504 with a history of ICP during the years 1972‐2000 (cases) and 10,504 with a normal pregnancy (controls). Cases and controls were matched for age, time of delivery, and place of delivery. The diagnoses of liver and biliary disease were traced from the Finnish Hospital Discharge Register with an almost 100% coverage. Several liver and biliary diseases were found to have a significantly higher incidence in patients with ICP than in controls. The rate ratio for hepatitis C was 3.5 (CI 1.6‐7.6; P < .001), for nonalcoholic liver cirrhosis 8.2 (CI 1.9‐35.5; P < .05), for gallstones and cholecystitis 3.7 (CI 3.2‐4.2; P < .001) and for nonalcoholic pancreatitis 3.2 (CI 1.7‐5.7; P < .001). In conclusion, there is an association of ICP with several liver and biliary diseases. Some patients with ICP are at risk of the subsequent development of cirrhosis and other severe chronic diseases. Contrary to what has been previously thought, follow‐up may need to be considered for these patients. (HEPATOLOGY 2006;43:723–728.)

Susceptibility Loci for Preeclampsia on Chromosomes 2p25 and 9p13 in Finnish Families

Preeclampsia is a common, pregnancy-specific disorder characterized by reduced placental perfusion, endothelial dysfunction, elevated blood pressure, and proteinuria. The pathogenesis of this heterogeneous disorder is incompletely understood, but it has a familial component, which suggests that one or more common alleles may act as susceptibility genes. We hypothesized that, in a founder population, the genetic background of preeclampsia might also show reduced heterogeneity, and we have performed a genomewide scan in 15 multiplex families recruited predominantly in the Kainuu province in central eastern Finland. We found two loci that exceeded the threshold for significant linkage: chromosome 2p25, near marker D2S168 (nonparametric linkage [NPL] score 3.77; P=.000761) at 21.70 cM, and 9p13, near marker D9S169 (NPL score 3.74; P=.000821) at 38.90 cM. In addition, there was a locus showing suggestive linkage at chromosome 4q32 between D4S413 and D4S3046 (NPL score 3.13; P=.003238) at 163.00 cM. In the present study the susceptibility locus on chromosome 2p25 is clearly different (21.70 cM) from the locus at 2p12 found in an Icelandic study (94.05 cM) and the locus at 2q23 (144.7 cM) found in an Australian/New Zealand study. The locus at 9p13 has been shown to be a candidate region for type 2 diabetes in two recently published genomewide scans from Finland and China. The regions on chromosomes 2p25 and 9p13 may harbor susceptibility genes for preeclampsia.

Polycystic ovaries and levels of gonadotrophins and androgens in recurrent miscarriage: prospective study in 50 women

Objective To compare the serum levels of gonadotrophins and androgens, as well as ovarian morphology, in 50 women with a history of recurrent miscarriage and in 20 healthy controls.

Breast cancer risk in postmenopausal women using estradiol-progestogen therapy.

OBJECTIVE: To estimate the risk for breast cancer in Finnish women using postmenopausal estradiol (E2)–progestogen therapy. METHODS: All Finnish women over 50 years using E2–progestogen therapy for at least 6 months in 1994–2005 (N=221,551) were identified from the national medical reimbursement register and followed up for breast cancer incidence (n=6,211 cases) through the Finnish Cancer Registry to the end of 2005. The risk for breast cancer in E2–progestogen therapy users was compared with that in the general population. RESULTS: The standardized incidence ratio for all types of breast cancer was not elevated within the first 3 years of use, but it rose to 1.31 (95% confidence interval 1.20–1.42) for the use from 3–5 years and to 2.07 (1.84–2.30) with 10 or more years of use. Exposure to sequential progestogen for 5 years or more was accompanied with a lower risk elevation (1.78, 1.64–1.90) than exposure to continuous use (2.44, 2.17–2.72). Oral and transdermal use of E2–progestogen therapy was associated with comparable risk elevations for breast cancer. The use of norethisterone acetate was accompanied with a higher risk after 5 years of use (2.03, 1.88–2.18) than that of medroxyprogesterone acetate (1.64, 1.49–1.79). The risk of lobular breast cancer increased sooner than that for ductal cancer and was detectable for E2–progestogen therapy use less than 3 years (1.35, 1.18–1.53). There was no excess risk of breast cancer with distant metastases among E2–progestogen therapy users. CONCLUSION: The use of E2–progestogen therapy is associated with an increased risk for breast cancer after 3 years of use. The risk is lower for sequential than for continuous use, but comparable for oral and transdermal use. The risk elevation may not be uniform for all progestogens. LEVEL OF EVIDENCE: II

Factors associated with fear of delivery in second pregnancies

OBJECTIVE To identify factors associated with fear of childbirth during and after first labor. METHODS We analyzed first deliveries of 100 primiparas who reported severe fear of vaginal childbirth during their second pregnancies and 200 age- and parity-matched controls who reported no later fear of delivery. The main outcome measures were previous miscarriages, participation in birth-education classes, support during labor, length of first delivery, pain relief, obstetric complications, welfare of the newborn, and time between deliveries. RESULTS The prevalence of emergency cesarean (adjusted odds ratio [OR] 26.9, confidence interval [CI] 11.9, 61.1) and vacuum extraction (adjusted OR 4.5, CI 2.2, 9.3) during first delivery was much higher in subjects than controls. Labor lasted longer in cases than in controls during the first (10.5 hours versus 7.8 hours, P = .016) and second stages (62 minutes versus 47 minutes, P = .002). They received epidural analgesia more often, but its timing and the amount used were not different between groups. Of the group with fear, 44% could not define any specific cause for fear and regarded the entire delivery as frightening. CONCLUSION Emergency cesarean and vacuum extraction during first deliveries were associated with secondary fear of delivery. Emergency obstetric procedures cannot be avoided, so prevention of fear might require more education on causes and consequences of cesarean or vacuum extraction, eg, in birth classes and at postpartum visits.

Clinical presentation and risk factors of placental abruption

Background. To study the risk factors of placental abruption during the index pregnancy. Methods. One hundred and ninety‐eight women with placental abruption and 396 control women were identified among 46,742 women who delivered at a tertiary referral university hospital between 1997 and 2001. Clinical variables were compared between the groups. Multivariate logistic regression analysis was applied to identify independent risk factors. The clinical manifestations of placental abruption were also studied. Results. The overall incidence of placental abruption was 0.42%. The independent risk factors were maternal (adjusted OR 1.8; 95% CI 1.1, 2.9) and paternal smoking (2.2; 1.3, 3.6), use of alcohol (2.2; 1.1, 4.4), placenta previa (5.7; 1.4, 23.1), pre‐eclampsia (2.7; 1.3, 5.6), and chorioamnionitis (3.3; 1.0, 10.0). Vaginal bleeding (70%), abdominal pain (51%), bloody amniotic fluid (50%), and fetal heart rate abnormalities (69%) were the most common manifestations. Neither bleeding nor pain was present in 19% of the cases. Overall, 59% had preterm labor (OR 12.9; 95% CI 8.3, 19.8), and 91% were delivered by cesarean section (34.7; 20.0, 60.1). Of the newborns, 25% were growth restricted. The perinatal mortality rate was 9.2% (OR 10.1; 95% CI 3.4, 30.1). Retroplacental blood clot was seen by ultrasound in 15% of the cases. Conclusions. Maternal alcohol consumption and smoking, and smoking by the partner turned out to be independent risk factors for placental abruption. Smoking by both partners multiplied the risk. The liberal use of ultrasound examination contributed little to the management of women with placental abruption.

Breast Cancer Risk in Postmenopausal Women Using Estrogen-Only Therapy

OBJECTIVE: To evaluate whether the risk of estrogen-only therapy on breast cancer varies by dose, constituent, and route of administration. METHODS: All Finnish women older than age 50 years using oral or transdermal estradiol (n=84,729), oral estriol (n=7,941), or vaginal estrogens (n=18,314) for at least 6 months during 1994–2001 were identified from the national medical reimbursement register. They were followed for breast cancer with the aid of the Finnish Cancer Registry to the end of 2002. RESULTS: Altogether, 2,171 women with breast cancer were identified. The standardized incidence ratio of breast cancer with systemic estradiol for less than 5 years was 0.93 (95% confidence interval 0.80–1.04), and for estradiol use for 5 years or more, 1.44 (1.29–1.59). Oral and transdermal estradiol was accompanied by a similar risk of breast cancer. The risk was most prominent with the dose greater than 1.9 mg/d orally; whereas the risk associated with transdermal route was not dose-dependent. The standardized incidence ratio for the lobular type of breast cancer (1.58) was slightly higher than that for the ductal type (1.36). The use of estradiol was associated with both localized breast cancer (1.45; 1.26–1.66) and cancer spread to regional nodes (1.35; 1.09–1.65). The incidence of carcinoma in situ (n=32) was increased (2.43; 1.66–3.42) among estradiol users. CONCLUSION: Estradiol for 5 years or more, either orally or transdermally, means 2–3 extra cases of breast cancer per 1,000 women who are followed for 10 years. Oral estradiol use for less than 5 years, oral estriol, or vaginal estrogens were not associated with a risk of breast cancer. LEVEL OF EVIDENCE: II-2

Prostacyclin and thromboxane in diabetes.

Concentrations of the stable antiaggregatory prostacyclin metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and of the proaggregatory thromboxane A2 metabolite thromboxane B2 were measured by radioimmunoassay in plasma from 53 diabetics. In 33 of these patients the ability of platelets to produce thromboxane B2 during spontaneous clotting was also studied. Plasma 6-keto-PGF1 alpha concentrations were higher (p less than 0.05) in the diabetics (mean 107.7 +/- SE 7.6 ng/l) than in non-diabetic controls matched for age and sex (87.5 +/- 4.7 ng/l), and diabetics with microangiography (n = 28) and higher (p less than 0.01) concentrations (124.3 +/- 10.8 ng/l) than those without microangiography (n = 25; 89.2 +/- 9.3 ng/l). Plasma thromboxane B2 concentrations were also higher (p less than 0.01) in the diabetics (mean 218.5 +/- SE 25.3 ng/l) than in the controls (127.7 +/- 9.8 ng/l), but this increase was not related to microangiography. The ability of platelets to generate thromboxane B2 did not differ between the diabetics (181.4 +/- 16.4 microgram/l) and controls (195.8 +/- 11.8 microgram/l). Platelets of diabetics with microangiopathy or taking oral hypoglycaemic agents (n = 19), however, produced decreased amounts of thromboxane B2 during clotting. Plasma concentrations of 6-keto-PGF1 alpha and thromboxane B2 were not related to concentrations of glucose, haemoglobin A1, high-density lipoprotein cholesterol, cholesterol, triglycerides, magnesium, or creatinine. These results suggest that in diabetics with microangiopathy a balance between prostacyclin and thromboxane A2 is shifted to dominance by prostacyclin.