Jan Roar Mellembakken

In vitro fertilization is a successful treatment in endometriosis-associated infertility

OBJECTIVE To assess success rates of IVF and intracytoplasmic sperm injection in women with various stages of endometriosis. DESIGN Retrospective cohort study. SETTING Reproductive medicine unit in a university hospital. PATIENT(S) Infertile women (n = 2,245) with various stages of endometriosis or tubal factor infertility. INTERVENTION(S) IVF or intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S) Dose of FSH, number of oocytes retrieved, fertilization rate, implantation rate, pregnancy rate (PR), live birth/ongoing PR. RESULT(S) Women with endometriosis had similar pregnancy and live birth/ongoing PR as did women with tubal factor infertility, but the American Society for Reproductive Medicine (ASRM) stage I and II endometriosis patients had a lower fertilization rate, and stage III and IV patients required more FSH and had fewer oocytes retrieved. Splitting the stage III and IV groups into patients with and without endometriomas showed that the endometrioma group required more FSH and had a significantly lower pregnancy and live birth/ongoing PR. CONCLUSION(S) With the exception of patients with endometrioma, infertile women with various stages of endometriosis have the same success rates with IVF and intracytoplasmic sperm injection as patients with tubal factor. This contrasts with the systematic review on which the European Society of Human Reproduction and Embryology bases its recommendations.

Chemokines and Leukocyte Activation in the Fetal Circulation During Preeclampsia

Preeclampsia is a potentially life-threatening disease for both mother and fetus. Endothelial dysfunction is pivotal in the pathogenesis of this disorder, possibly reflecting a state of persistent inflammation. In the present study, we examined whether signs of inflammation with production of chemokines and leukocyte activation were present in the fetal circulation during preeclampsia. Venous cord blood was sampled during cesarean sections from 36 neonates born after uncomplicated pregnancies and from 35 born after severe preeclamptic pregnancies with premature newborns. The expression of adhesion molecules on neutrophils and monocytes was analyzed by flow cytometry, and plasma levels of chemokines and soluble adhesion molecules were analyzed by enzyme immunoassay. Newborns of preeclamptic mothers had increased expression of CD15s (P =0.003), CD49d/CD29 (P =0.01/0.005), and CD31 (P =0.007) on neutrophils and CD15s (P <0.001), CD11c (P =0.009), and CD54 (P =0.001) on monocytes. This activation of neutrophils and monocytes was accompanied by raised plasma levels of the CXC chemokines interleukin-8 (P =0.007) and growth-related oncogene-&agr; (P =0.01) and decreased plasma levels of soluble E-selectin (P =0.001) and L-selectin (P =0.002). Although raised levels of adhesion molecules on leukocytes or decreased levels of soluble adhesion molecules in plasma were not related to prematurity or the degree of preeclampsia, raised interleukin-8 levels were found only in neonates of preeclamptic mothers with the highest blood pressures. Our findings suggest the activation of neutrophils and monocytes in the fetus during preeclampsia involving enhanced chemokine activation, possibly contributing to the fetal morbidity of this disorder.

Use of metformin before and during assisted reproductive technology in non-obese young infertile women with polycystic ovary syndrome: a prospective, randomized, double-blind, multi-centre study

BACKGROUND To study the effect of metformin before and during assisted reproductive technology (ART) on the clinical pregnancy rate (CPR) in non-obese women with polycystic ovary syndrome (PCOS). METHODS A multi-centre, prospective, randomized, double-blind study was conducted in eight IVF clinics in four Nordic countries. We enrolled 150 PCOS women with a body mass index <28 kg/m(2), and treated them with 2000 mg/day metformin or identical placebo tablets for ≥ 12 weeks prior to and during long protocol IVF or ICSI and until the day of pregnancy testing. The primary outcome measure was CPR. Secondary outcome measures included spontaneous pregnancy rates during the pretreatment period, and the live birth rate (LBR). RESULTS Among IVF treated women (n = 112), biochemical pregnancy rates were identical in both groups (42.9%), and there were no significant differences in the metformin versus the placebo group in CPR [39.3 versus 30.4%; 95% confidence interval (CI): -8.6 to 26.5]. The LBR was 37.5 versus 28.6% (95% CI: -8.4 to 26.3). However, prior to IVF there were 15 (20.3%) spontaneous pregnancies in the metformin group and eight (10.7%) in the placebo group (95% CI: -1.9 to 21.1; P = 0.1047). According to intention to treat analyses (n = 149); significantly higher overall CPR were observed in the metformin versus placebo group (50.0 versus 33.3%; 95% CI: -1.1 to 32.3; P = 0.0391). LBR was also significantly higher with use of metformin versus placebo (48.6 versus 32.0; 95% CI: 1.1 to 32.2; P = 0.0383). No major unexpected safety issues or multiple births were reported. More gastrointestinal side effects occurred in the metformin group (41 versus 12%; 95% CI: 0.15 to 0.42; P < 0.001). CONCLUSIONS Metformin treatment for 12 weeks before and during IVF or ICSI in non-obese women with PCOS significantly increases pregnancy and LBRs compared with placebo. However, there was no effect on the outcome of ART per se. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00159575.

Increased systemic activation of neutrophils but not complement in preeclampsia

Objective To investigate whether neutrophils and systemic complement are activated in pregnancies complicated by preeclampsia more than in normal pregnancies. Methods We measured native complement components and activation products in plasma by enzyme immunoassays in 19 women with uncomplicated pregnancies, 15 with preeclampsia before cesarean deliveries, and 16 nonpregnant women. Neutrophil activation was measured by specific enzyme immunoassays for myeloperoxidase and lactoferrin. Results Myeloperoxidase was significantly higher in women with preeclampsia (197 μg/L, 95% confidence interval [CI] 94, 646) than in women with uncomplicated pregnancies (124 μg/L, 95% CI 70, 289; P = .009), whereas lactoferrin did not differ between groups. C4 was decreased in preeclamptic women (0.16 g/L, 95% CI 0.07, 0.48) compared with women with uncomplicated pregnancies (0.21, 95% CI 0.10, 0.30, P < .001). There were no differences for the other native complement components. There was a significant decrease in C1rs-C1 inhibitor, 13 AU/mL (95% CI 9, 34) versus 19 (95% CI 13, 38) (P ≤ .001) in normal pregnant women compared with nonpregnant women. There also was an increase in C3, C4, C9 (data not shown), C4bp, 132% (95% CI 94%, 161%) versus 91% (95% CI 57%, 128%); C3bc (7.4 AU/mL, 95% CI 4.2, 10.7) versus 4.8 AU/mL (95% CI 3.2, 7.3) and C4bc (8.6 AU/mL, 95% CI 5.7, 14.0) versus 3.5 AU/mL (95% CI 2.2, 6.7) in normal pregnant women compared with nonpregnant women (P ≤ .001). Conclusion Neutrophil activation in preeclampsia was shown by systemic increases in myeloperoxidase. Except for a decrease in C4, systemic complement activation could not be detected in preeclampsia.

IgVH gene analysis suggests that peritoneal B cells do not contribute to the gut immune system in man

The contribution of peritoneal B cells to the intestinal lamina propria plasma cell population is well documented in mice, but unknown in humans. We have analyzed immunoglobulin (Ig) genes of human peritoneal B cells, because such genes show distinctive characteristics in mucosal B cells, particularly highly mutated variable regions. Here, we report the characteristics of variable regiongenes used by IgM, IgA and IgG in peritoneal cells. We focused on the properties of IgVH4–34 to allow comparisons of like‐with‐like between different isotypes and cells from different immune compartments. We observed that the IgM genes were mostly unmutated, and that the mutated subset had less mutations than would be expected in a mucosal B cell population. Likewise, the IgVH4–34 genes used by IgA and IgG from peritoneal B cells had significantly lower numbers of mutations than observed in the mucosal counterparts. Other trends observed, while not reaching statistical significance, followed the trend of peripheral B cells. The peritoneal B cell population had more IgA1 than IgA2 sequences, and there was no dominance of JH4 in the IgA from peritoneum or spleen, in contrast to the mucosal sequences. Overall, this study suggested that human peritoneal B cell are either peripheral or mixed in origin; they are unlikely to represent an inductive compartment for the mucosal B cell system.

Sustained fertility from 22 to 41 years of age in women with polycystic ovarian syndrome

BACKGROUND Subfertility due to chronic anovulation is common in women with polycystic ovary syndrome (PCOS) and is often treated with IVF. Women with PCOS have an increased ovarian follicle and oocyte count, increased ovarian reserve and/or a slower rate of follicle atresia. If so, one would expect women with PCOS to display a delayed reduction in fertility with advancing age as compared with eumenorrheic women. METHODS To test this hypothesis, we compared oocyte count and live birth rates among two groups undergoing IVF, 500 women with PCOS and 500 eumenorrheic women with infertility due to tubal factor only. RESULTS Across the age range of 22-41 years, oocyte count and live birth rates remained stable in women with PCOS. In the eumenorrheic comparison group, these parameters decreased significantly with age. CONCLUSIONS Women with PCOS display sustained fertility with advancing age as compared with infertile eumenorrheic women.

Characterization of the vasodilatatory response to serotonin in human umbilical arteries perfused in vitro. The influence of the endothelium

In most preparations of human cord arteries perfused in vitro, infusion of 10(-7) M of serotonin leads to a biphasic pressure response starting with a transient minor vasodilatation followed by a dominant vasoconstriction. In some preparations, however, the vasoconstrictive part of the response with this dose of serotonin is less pronounced or completely absent, whereas the dilatation is stronger and more prominent. The present study deals exclusively with experiments on cord arteries displaying the latter type of serotonin reactivity, and was undertaken in order to characterize the relaxing effect of serotonin, and in particular, the role of the endothelial layer. This was accomplished by studying the response pattern before and after treatment with different drugs or removal of the endothelium. The vasodilatatory action of serotonin was found to be abolished following treatment with methysergide, significantly reduced after denudation (P <0.05), slightly reduced after exposure to methylene blue or N omega-nitro-L-arginine methyl ester (L-NAME) (non-significantly), but not affected by indomethacin. The results suggest that the relaxing effect is mediated by specific serotonin receptors and that endothelium-derived substances, possibly including nitric oxide, are involved.

Mitotically active cellular luteinized thecoma of the ovary and luteinized thecomatosis associated with sclerosing peritonitis: case studies, comparison, and review of the literature.

In this study, we distinguish two clinical and pathological entities that are similarly named: luteinized thecoma and luteinized thecoma associated with sclerosing peritonitis. Ovarian luteinized thecoma lacks definitive criteria for malignancy. Based on our case study of a mitotically active neoplasm without nuclear atypia in which the patient was living and well 19 years after operation and comparison with prior studies of luteinized thecoma and the closely related entity of cellular fibroma, we propose presumptive criteria for malignancy for this rare neoplasm. Increased mitotic activity in luteinized thecoma without significant nuclear atypia is not an indication of malignant behavior, and such cases should therefore be referred to as mitotically active cellular luteinized thecoma. We also contrast neoplasms in the luteinized thecoma category with the entity originally reported as luteinized thecoma associated with sclerosing peritonitis. In the latter, the ovarian stromal proliferations are typically bilateral, can have an exceedingly high mitotic rate as was seen in our illustrative case, often incorporate non-neoplastic ovarian structures at their periphery, and are responsive to medical therapy. In our patient with sclerosing peritonitis, both the ovarian masses and peritoneal sclerosis underwent complete regression following treatment with gonadotropin-releasing hormone agonist and high doses of steroids, and an ovarian biopsy taken 2 months after therapy showed a histologically normal ovary. The patient subsequently became pregnant and delivered a normal infant. This is, to our knowledge, the first case of successful medically conservative treatment of a young patient with this entity that led to complete relief of symptoms and allowed preservation of fertility. Because recent observations support the non-neoplastic nature of the ovarian stromal proliferations, we advocate use of the previously proposed term luteinized thecomatosis associated with sclerosing peritonitis for this entity.

Fructose content of low calorie diets: effect on cardiometabolic risk factors in obese women with polycystic ovarian syndrome: a randomized controlled trial

We aimed to examine whether a whole-grain crispbread (CB) low-fructose, low-calorie diet (LCD) might be superior to a traditional LCD based on fructose-rich liquid meal replacements (LMRs) with respect to improvement of various cardiometabolic risk factors and reproductive hormones. Parallel-group randomised controlled clinical trial. Morbidly obese women with polycystic ovarian syndrome (PCOS) were randomised to either an 8-week CB-LCD or LMR-LCD (900–1100 kcal/day, fructose 17 g/day or 85 g/day). A total of 51 women completed the study. Body weight, fat mass and waist circumference reduced by mean (s.d.) 10.0 (4.8) kg, 7.4 (4.2) kg and 8.5 (4.4) cm, with no significant differences between groups. Total-cholesterol, HDL-cholesterol and Apo-A1 were significantly reduced within both groups (all P values <0.01), with no significant between-group differences. The triacylglycerol and LDL-cholesterol levels were reduced within the LMR group only, with no significant between-group differences. Blood pressure and most measures of glucose metabolism improved significantly in both diet groups, with no significant between-group difference. Uric acid levels rose by 17.7 (46.4) and 30.6 (71.5) μmol/l in the CB and LMR group, respectively, with no significant difference between groups. Gastrointestinal discomfort was significantly and equally reduced in both intervention groups. Free testosterone index was reduced in both groups, with no significant difference between groups. Morbidly obese women with PCOS who underwent either an 8-week low or high-fructose LCD-diet had similar changes in various cardiometabolic risk factors and reproductive hormones. Registration at ClinicalTrials.gov: NCT00779571.

The prevalence of Type 2 diabetes is not increased in normal-weight women with PCOS

STUDY QUESTION Is oral glucose tolerance test (OGTT) needed in all women with polycystic ovary syndrome (PCOS)? SUMMARY QNSWER OGTT is not routinely needed in women with PCOS and BMI < 25 kg/m2. WHAT IS KNOWN ALREADY PCOS is associated with insulin resistance and increased prevalence of prediabetes and Type 2 diabetes (T2D) which is closely linked to obesity and possibly age, ethnicity and PCOS phenotype. Several guidelines recommend OGTT upon diagnosis of PCOS and during follow-up. STUDY DESIGN, SIZE, DURATION A Nordic cross-sectional study including 876 women. PARTICIPANTS/MATERIALS, SETTING, METHODS The 876 Nordic women with PCOS, aged 14-57 years, were examined for T2D and prediabetes (impaired glucose tolerance [IGT] or impaired fasting glucose (IFG) by OGTT. MAIN RESULT AND THE ROLE OF CHANCE Of all study subjects 3% (23/876) had T2D, 23% (204/876) prediabetes and 74% (649/876) had normal glucose tolerance (NGT). Increased BMI and waist circumference were significantly (P < 0.001) associated with prevalence of prediabetes and T2D. No normal-weight woman (BMI < 25 kg/m2) was diagnosed with T2D. The prevalence of BMI ≥ 25 kg/m2 was 66% (578/ 876). 91% of women (21/23) with T2D had BMI ≥ 30 kg/m2. Testosterone levels and PCOS phenotype did not predict 2-h glucose levels during OGTT after adjustment for BMI and age. LIMITATIONS, REASONS FOR CAUTION The present study included cross-sectional data and prospective studies are needed to confirm our results. These results may not apply to populations of other ethnic origin. WIDER IMPLICATIONS OF THE FINDINGS Routine OGTT may not be indicated in normal-weight women with PCOS. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER N/A.