Successful pregnancies after neonatal aortic thrombosis, childhood arterial repair, and a deficient pelvic vasculature.

Neonatal aortic bifurcation thrombosis can cause occlusion of iliac arteries causing abnormal pelvic vasculature and claudication in childhood. A bifurcation graft normalizes the perfusion of the legs but not of the pelvis. In a girl, this does not preclude successful pregnancies in adult life. It has not been reported before.

Heritability of endometriosis.

OBJECTIVE: To estimate the relative contribution of genetic influences and prevalence on endometriosis. DESIGN: Analysis of self-reported data from a nationwide population-based twin registry. SETTING: Not applicable. PATIENT(S): A total of 28,370 women, female monozygotic (MZ) or dizygotic (DZ) twins, who participated in either of two surveys (1998-2002 or 2005-2006). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Self-reported endometriosis, validated by medical records. RESULT(S): A history of endometriosis was reported by 1,228 female twins. The probandwise concordance was 0.21 for MZ and 0.10 for DZ twins. Higher within-pair (tetrachoric) correlation was observed among MZ (0.47) compared with DZ (0.20) twins. The best-fitting model revealed a contribution of 47% by additive genetic factors and the remaining 53% attributed to unique environmental effects. CONCLUSION(S): Our findings suggest both genetic and unique (nonshared) environmental influences on the complex etiology of endometriosis and support the hypothesis that genes have a strong influence on phenotypic manifestations of endometriosis.

Hormonal and surgical treatments for endometriosis and risk of epithelial ovarian cancer.

OBJECTIVE: Whether hormonal or surgical treatment of endometriosis is associated with risk of epithelial ovarian cancer. DESIGN: Nested case-control study. SETTING: Sweden. POPULATION: All women with a first-time discharge diagnosis of endometriosis in 1969-2007 were identified using the National Swedish Patient Register and constituted our study base. METHODS: By linkage to the National Swedish Cancer Register we identified all women diagnosed with epithelial ovarian cancer at least one year after the endometriosis diagnosis (cases). Two controls per case with no ovarian cancer before the date of cancer diagnosis of the case were randomly selected from the study base and matched for year of birth. Two-hundred-and-twenty cases and 416 controls entered the study. Information on hormonal and surgical treatments and other reproductive factors was extracted from medical records according to pre-specified protocols. Conditional logistic regression was used for all calculations. MAIN OUTCOME MEASURES: Crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) for all hormonal as well as surgical treatments. RESULTS: There was a significant association between one-sided oophorectomy, as well as for radical extirpation of all visible endometriosis, and ovarian cancer risk in both univariate analyses (crude OR 0.42, 95% CI 0.28-0.62 and OR 0.37, 95% CI 0.25-0.55, respectively) and multivariate analyses (adjusted OR 0.19, 95% CI 0.08-0.46 and OR 0.30, 95% CI 0.12-0.74, respectively). CONCLUSIONS: One-sided oophorectomy as well as radical extirpation of all visible endometriosis is protective against later development of ovarian cancer.

European content validation of the Self-Assessment Goal Achievement (SAGA) questionnaire in patients with overactive bladder.

INTRODUCTION AND HYPOTHESIS: The Self-Assessment Goal Achievement (SAGA) questionnaire is a patient-completed instrument designed to assess goal attainment in the behavioral or pharmacologic treatment of lower urinary tract symptoms (LUTS), including overactive bladder (OAB). The SAGA questionnaire allows patients to identify and rank the importance of treatment goals before treatment is initiated; the follow-up SAGA questionnaire quantifies the achievement of these patient-identified goals. The objective of this qualitative research was to confirm the content validity of the German, Spanish, Swedish, and English (UK) language versions of the SAGA questionnaire in patients with OAB with or without other LUTS. METHODS: The SAGA questionnaire was translated to each language in accordance with a well-established forward and backward harmonization method. Patient interviews were then conducted according to a cognitive debriefing methodology. Qualitative analysis of patients' input allowed assessment of content validity of each linguistically adapted SAGA questionnaire. RESULTS: All patients (n = 29; six to eight per targeted country) found the SAGA questionnaire easy to understand and to complete. Most patients completed the nine prespecified (fixed) treatment goals and were able to add up to five personal goals in the open-ended portion and rate each goal by importance. Differences were identified in how the various languages communicated some of the concepts assessed with the SAGA questionnaire. Rewording of the translated versions of the questionnaire was necessary in some cases. CONCLUSIONS: This linguistic content validation study in four European languages indicates that SAGA is a comprehensive, easy-to-understand, and relevant questionnaire for patient-completed evaluation of LUTS/OAB symptoms and treatment goal attainment.

Linguistic validation of translation of the Self-Assessment Goal Achievement (SAGA) questionnaire from English.

BACKGROUND: A linguistic validation of the Self-Assessment Goal Achievement (SAGA) questionnaire was conducted for 12 European languages, documenting that each translation adequately captures the concepts of the original English-language version of the questionnaire and is readily understood by subjects in the target population. METHODS: Native-speaking residents of the target countries who reported urinary problems/lower urinary tract problems were asked to review a translation of the SAGA questionnaire, which was harmonized among 12 languages: Danish, Dutch, English (UK), Finnish, French, German, Greek, Icelandic, Italian, Norwegian, Spanish, and Swedish. During a cognitive debriefing interview, participants were asked to identify any words that were difficult to understand and explain in their own words the meaning of each sentence in the questionnaire. The qualitative analysis was conducted by local linguistic validation teams (original translators, back translator, project manager, interviewer, and survey research expert). RESULTS: Translations of the SAGA questionnaire from English to 12 European languages were well understood by the participants with an overall comprehension rate across language of 98.9%. In addition, the translations retained the original meaning of the SAGA items and instructions. Comprehension difficulties were identified, and after review by the translation team, minor changes were made to 7 of the 12 translations to improve clarity and comprehension. CONCLUSIONS: Conceptual, semantic, and cultural equivalence of each translation of the SAGA questionnaire was achieved thus confirming linguistic validation.

A prospective observational study of the effects of treatment with extended-release tolterodine on health-related quality of life of patients suffering overactive bladder syndrome in Sweden.

OBJECTIVE: Overactive bladder (OAB) is a chronic condition that has a profound impact on health-related quality of life (HRQoL). This study measured changes in bother of OAB symptoms and self-perceived HRQoL over 6 months in patients treated with extended-release (ER) tolterodine in a naturalistic setting. MATERIAL AND METHODS: This was a prospective, single-cohort observational study of patients diagnosed with OAB, naïve to antimuscarinic treatment and prescribed tolterodine ER for the first time. Patients were asked to complete the Overactive Bladder Questionnaire (OAB-q) containing a symptom bother scale (0-100) and an HRQoL scale (0-100), which measures coping, social interaction, concern and sleep, at baseline and after 3 and 6 months. RESULTS: In total, 235 patients (211 women and 24 men), with a mean age of 61 years (30-87), were recruited. The numbers of patients who completed the OAB-q were 220 and 169 at 3 and 6 months, respectively. The mean reductions in the symptom bother score from baseline were 19.6 and 19.3 at 3 and 6 months, respectively. Significant improvement (p < 0.0001) was seen in all HRQoL subscale scores. The proportion of responders who met the minimally important difference (change in the score of 10 or more units between baseline and 6 months) was 64% for the symptom bother score and 34-60% for the total HRQoL and subscale scores. CONCLUSIONS: OAB patients beginning treatment with tolterodine ER reported clinically significant improvement in OAB symptoms and self-perceived HRQoL over the 6 months of this observational study. The rate of discontinuation from treatment was 49%.

Effects of anti-TNF-mAb treatment on pregnancy in baboons with induced endometriosis.

OBJECTIVE: Hormonal suppressive therapy is not effective for endometriosis-associated subfertility and can even prevent conception. Medical inhibition of TNFalpha, which has been shown to improve conception, is effective in the prevention and treatment of endometriosis in baboons. DESIGN: Prospective, placebo-controlled fertility trial. SETTING: Animal research and laboratory facility. ANIMAL(S): Sixteen adult female baboons with induced endometriosis. INTERVENTION(S): All animals received a single IV dose of the anti-TNFalpha monoclonal antibody c5N (n = 9) or placebo (n = 7) at four different time points. The animals were then exposed to timed mating up to nine completed cycles or until pregnancy was achieved. MAIN OUTCOME MEASURE(S): Pregnancy rate (PR), cycle fecundity rate (CFR), time to pregnancy (TTP), and cumulative pregnancy rate (CPR). RESULT(S): Inhibition of TNFalpha did not result in a significant improvement in PR (100% c5N vs. 86% placebo), CFR (18% c5N vs. 30% placebo), median TTP (5 cycles c5N vs. 2 cycles placebo), or CPR (100% c5N vs. 80% placebo). The duration of the menstrual cycle was unchanged in both groups before and after the study. Two nonpregnant baboons in the c5N-group died during the study. CONCLUSION(S): Medical inhibition of TNFalpha allowed for normal conception but did not improve fecundity in baboons with induced endometriosis when compared with placebo. Larger studies with clinically available TNFalpha blockers in baboons with moderate to severe endometriosis are needed to further test the potential of these agents in the prevention or treatment of endometriosis-associated subfertility.

Expression of human endogenous gammaretroviral sequences in endometriosis and ovarian cancer.

Endogenous retroviruses (ERVs) probably originate from ancient germ cell infections by exogenous retroviruses. A high expression of retroviruses in reproductive tissue increases the risk of viral transmission to germ line cells. We therefore investigated the expression of human ERVs (HERVs) in normal endometrium, endometriosis, normal ovaries, and ovarian cancer. Four real-time PCRs (QPCRs) for HERV-E, HERV-I/T, HERV-H, and HERV-W, respectively, and an expression control gene were used. HERV-E RNA expression was significantly higher in endometriotic tissue (average, SD) than in normal endometrium (average, SD), both measured as ratios versus control gene expression and as. HERV-E and HERV-W RNA were higher in normal ovarian tissue than in ovarian cancer. This illustrates that HERV expression is not automatically higher in malignant tissues. The other HERV PCRs did not show expression patterns as distinctive as HERVE and HERV-W in the two kinds of reproductive tissue. A small number of candidate HERV-E loci from which the transcription took place were identified by sequencing of amplimers. The role of HERV-E and HERV-W in endometriosis merits further investigation.

Subcutaneous injection of depot medroxyprogesterone acetate compared with leuprolide acetate in the treatment of endometriosis-associated pain.

OBJECTIVE: To compare the efficacy and safety of SC depot medroxyprogesterone acetate (DMPA-SC 104) with that of leuprolide acetate in treatment of endometriosis. DESIGN: Phase 3, multicenter, randomized, evaluator-blinded, comparator-controlled trial. SETTING: Clinical trial sites in Canada and United States. PATIENT(S): Two hundred seventy-four women with surgically diagnosed endometriosis. INTERVENTION(S): Intramuscular injections of DMPA-SC (104 mg) or leuprolide acetate (11.25 mg), given every 3 months for 6 months, with 12 months of posttreatment follow-up. MAIN OUTCOME MEASURE(S): Reduction in five endometriosis symptoms or signs (dysmenorrhea, dyspareunia, pelvic pain, pelvic tenderness, pelvic induration); change in bone mineral density (BMD), hypoestrogenic symptoms, bleeding, and weight. RESULT(S): The depot medroxyprogesterone acetate given SC was statistically equivalent to leuprolide in reducing four of five endometriosis symptoms or signs at the end of treatment (month 6) and in reducing all five symptoms after 12 months' follow-up (month 18). Patients in the DMPA-SC 104 group showed significantly less BMD loss than did leuprolide patients at month 6, with scores returning to baseline at 12 months' follow-up. No statistically significant differences in median weight changes were observed between groups. Compared with leuprolide, DMPA-SC 104 was associated with fewer hypoestrogenic symptoms but more irregular bleeding. CONCLUSION(S): Efficacy of DMPA-SC 104 was equivalent to that of leuprolide for reducing endometriosis-associated pain, with less impact on BMD and fewer hypoestrogenic side effects but more bleeding.

Advances in the management of endometriosis: an update for clinicians.

Endometriosis is a chronic and recurrent disease characterized by the presence and proliferation of endometrial tissue outside the uterine cavity, which occurs in approximately 10% of women of reproductive age. In this estrogen-dependent disorder, lesions become inactive and gradually undergo regression during states of ovarian down-regulation, such as amenorrhoea or menopause. The impact of endometriosis includes impaired fertility potential, as well as symptoms of dysmenorrhoea, dyspareunia and chronic non-menstrual pain, all of which adversely affect quality of life. Management of endometriosis focuses on pain relief and includes medical and surgical treatment. Pharmacologic therapies currently in use include combination oral contraceptives (COCs), danazol, GnRH analogues and progestins. Although some agents show efficacy in relieving pain, all differ in their side effects, making it difficult to achieve a balance between efficacy and safety. Efficacy has been demonstrated with danazol or GnRH analogues; however, treatment is limited to 6 months because of significant metabolic side effects. Alternatives for longer-term management of symptoms include add-back therapy with GnRH analogues, COCs or progestins. Newer options for treatment of endometriosis include depot medroxyprogesterone acetate subcutaneous injection, as well as several agents under investigation that may prove to have therapeutic potential.

ESHRE guideline for the diagnosis and treatment of endometriosis.

The objective was to develop recommendations for the diagnosis and treatment of endometriosis and its associated symptoms. A working group was convened comprised of practising gynaecologists and experts in evidence-based medicine from Europe, as well as an endometriosis self-help group representative. After reviewing existing evidence-based guidelines and systematic reviews, the expert panel met on three occasions for a day during which the guideline was developed and refined. Recommendations based solely on the clinical experience of the panel were avoided as much as possible. The entire ESHRE Special Interest Group for Endometriosis and Endometrium was given the opportunity to comment on the draft guideline, after which it was available for comment on the ESHRE website for 3 months. The working group then ratified the guideline by unanimous or near-unanimous voting; finally, it was approved by the ESHRE Executive Committee. The guideline will be updated regularly, and will be made available at http://www.endometriosis.org/guidelines.html with hyperlinks to the supporting evidence, and the relevant references and abstracts. For women presenting with symptoms suggestive of endometriosis, a definitive diagnosis of most forms of endometriosis requires visual inspection of the pelvis at laparoscopy as the 'gold standard' investigation. However, pain symptoms suggestive of the disease can be treated without a definitive diagnosis using a therapeutic trial of a hormonal drug to reduce menstrual flow. In women with laparoscopically confirmed disease, suppression of ovarian function for 6 months reduces endometriosis-associated pain; all hormonal drugs studied are equally effective although their side-effects and cost profiles differ. Ablation of endometriotic lesions reduces endometriosis-associated pain and the smallest effect is seen in patients with minimal disease; there is no evidence that also performing laparoscopic uterine nerve ablation (LUNA) is necessary. In minimal-mild endometriosis, suppression of ovarian function to improve fertility is not effective, but ablation of endometriotic lesions plus adhesiolysis is effective compared to diagnostic laparoscopy alone. There is insufficient evidence available to determine whether surgical excision of moderate-severe endometriosis enhances pregnancy rates. IVF is appropriate treatment especially if there are coexisting causes of infertility and/or other treatments have failed, but IVF pregnancy rates are lower in women with endometriosis than in those with tubal infertility. The management of severe/deeply infiltrating endometriosis is complex and referral to a centre with the necessary expertise is strongly recommended. Patient self-help groups can provide invaluable counselling, support and advice.

Basal release of urokinase plasminogen activator, plasminogen activator inhibitor-1, and soluble plasminogen activator receptor from separated and cultured endometriotic and endometrial stromal and epithelial cells.

OBJECTIVE: To investigate whether separated and cultured endometriotic and endometrial stromal and epithelial cells release urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and soluble plasminogen activator receptor (suPAR) antigens in vitro. DESIGN: In vitro study. SETTING: University hospital clinic. PATIENT(S): Regularly menstruating women with and without endometriosis. INTERVENTION(S): Tissue samples were collected at surgery performed for clinical reasons. MAIN OUTCOME MEASURE(S): The antigen concentrations of uPA, PAI-1, and suPAR in culture medium were assayed by enzyme-linked immunosorbent assay. RESULT(S): Both stromal and epithelial cells from endometriotic and endometrial tissue released the three types of antigens, but the release of PAI-1 was significantly higher from stromal cells in the three types of tissue than from epithelial cells. Furthermore, the release of PAI-1 was significantly higher from endometriotic cells than from endometrial stromal cells. CONCLUSION(S): This study has demonstrated the basic capacity of separated epithelial and stromal cells from all three types of tissue to release uPA, PAI-1, and suPAR without any paracrine influence, as in vivo. The higher release of PAI-1 from endometriotic stromal cells might have importance for the invasive growth.

Impact of epidermal growth factor and transforming growth factor beta-1 on the release of fibrinolytic factors from cultured endometrial and ovarian endometriotic stromal cells.

We have investigated whether there are any differences in the release of urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) from cultured endometrial and endometriotic stromal cells, and whether the release is regulated by epidermal growth factor (EGF) or transforming growth factor beta1 (TGFbeta1). The cells were isolated from endometriomas and endometrium from women with and without endometriosis. After treatment with EGF or TGF and in untreated controls, incubated media collected at 0, 24, 48 and 72 h were analyzed by ELISA. Stromal cells from all three types of tissues released uPA and PAI-1, but the soluble receptor of uPA was not measurable in any group. The basal release of uPA and PAI-1 from endometriotic cells was higher than from endometrial cells. The uPA release in endometriotic cells was reduced with and without the addition of EGF (p < 0.05) or TGFbeta1 (p < 0.05). EGF increased the release of PAI-1 from stromal cells from women without endometriosis (p < 0.05) but decreased the release of PAI-1 from stromal cells from endometriotic women (p < 0.05). TGFbeta1 increased the release of PAI-1 from endometriotic cells (p < 0.05) but had no effect in endometrial cells.

Effects of hormones on uPA, PAI-1 and suPAR from cultured endometrial and ovarian endometriotic stromal cells.

PROBLEM: To investigate whether endometriotic stromal cells release the urokinase plasminogen activator, soluble urokinase plasminogen activator receptor and plasminogen activator inhibitor-1. If so, to establish if there are any differences between endometrial stromal cells from women with and without endometriosis, and whether the release is hormonally regulated. METHOD: Biopsies were obtained from endometriotic tissue and from endometrium from women with and without endometriosis. Stromal cells were isolated, incubated and treated with estradiol-17beta, progesterone or raloxifen. Incubation media collected at 0, 24, 48 and 72 h were analyzed by enzyme-linked immunosorbent assay. RESULTS: All these types of stromal cells released the urokinase plasminogen activator, soluble urokinase plasminogen activator receptor and urokinase plasminogen inhibitor-1. There was a significantly higher release of urokinase plasminogen inhibitor-1 and lower release of urokinase plasminogen activator and soluble urokinase plasminogen activator receptor in endometriotic cells. The release of urokinase plasminogen activator from endometrial stromal cells decreased during the study period both in control cultures and in cultures treated with progesterone or estradiol-17beta, but not in cultures treated with raloxifen nor in endometriotic cultures. The given hormones did not influence the release of the soluble urokinase plasminogen activator receptor. Progesterone significantly increased the urokinase plasminogen inhibitor-1 release in endometrial cells from both patient categories, and raloxifen significantly reduced the urokinase plasminogen inhibitor-1 release from stromal cells from both tissue categories from endometriotic patients. Estradiol-17beta had no effect. CONCLUSIONS: This study shows that stromal cells from endometrium and endometriotic tissues release the urokinase plasminogen activator, soluble urokinase plasminogen activator receptor and urokinase plasminogen inhibitor-1. The release is partly hormonally regulated, but differently in endometriotic than in endometrial cells.