Trond M. Michelsen

Bilateral oophorectomy before 50 years of age is significantly associated with the metabolic syndrome and Framingham risk score: A controlled, population-based study (HUNT-2)

OBJECTIVE Bilateral oophorectomy (BOE) is often recommended in order to prevent cancer at hysterectomy for non-malignant diseases and when familial risk of ovarian and breast cancer has been identified. Surgical menopause increases the risk of cardiovascular mortality, however, the intervening mechanisms are not clear. We compared the prevalence of the metabolic syndrome (MetS) and Framingham cardiovascular risk scores in women with BOE before 50 years of age to age-matched controls in a population-based study. METHODS 20,765 women aged 40-69 years were invited to a health study (HUNT-2 Norway 1995-97) and 17,650 (85%) attended. We compared 263 women with BOE before 50 years of age [63 with intact uterus (BO1 group), and 200 with hysterectomy also (BO2 group)] with 3 age-matched controls per case (n=789). Data on demographic, somatic, mental, and lifestyle variables, physical measurements and blood tests were obtained. RESULTS The BO1 and BO2 groups did not differ significantly regarding risk variables, and 4% had natural menopause. The combined BOE group had increased prevalence of MetS compared to controls according to the International Diabetes Federations definition (47% versus 36%; p=.001) and the revised NCEP ATP III definition (35% versus 25%; p=.002), which remained after adjustments (for reproductive, global health, and lifestyle variables). The prevalence of Framingham risk score > or =10% was higher in cases (22%) versus controls (15%) p=.005. CONCLUSION The higher prevalence of MetS and increased Framingham risk scores in women with bilateral oophorectomy before 50 years of age suggests that these women may be at higher risk of type 2 diabetes and cardiovascular disease compared to their counterparts in the general population.

Sexuality and fertility in women with Addison's disease

CONTEXT Females with primary adrenal insufficiency (Addisons disease) have reduced levels of circulating androgens, which are allegedly important for sexual functioning. OBJECTIVE The aim was to determine peripheral androgen status, sexual functioning, and birth rates in Addisons disease females. DESIGN In a postal survey, all 269 females in the Norwegian Addisons registry were invited to complete the Sexual Activity Questionnaire (SAQ) and registration of childbirths. Blood samples were analyzed for 5alpha-androstane-3alpha,17beta-diol-3-glucuronide (3alpha-Diol-G) and compared with blood donor levels. The SAQ scores were compared with 740 age-matched controls from the general population and 234 women subjected to risk-reducing salpingo-oophorectomy. Fertility was estimated as standardized incidence ratio for birth; the expected number of births was estimated from population statistics. RESULTS The SAQ was completed by 174 (65%) of the Addisons patients. Those not taking DHEA had significantly lower 3alpha-Diol-G levels than blood donors (mean, 0.53 vs. 2.2 ng/ml; P < 0.0001), whereas those on DHEA treatment had elevated levels (mean, 5.8 vs. 2.2 ng/ml; P = 0.002). The Addisons disease females were equally sexually active as the controls, but they reported significantly higher pleasure and less discomfort. They reported lower pleasure but less discomfort than the risk-reducing salpingo-oophorectomy women. The fertility was significantly reduced in females with Addisons disease; 54 children were born to mothers with established diagnosis (87.5 expected), yielding a standardized incidence ratio for birth of 0.69 (confidence interval, 0.52-0.86). CONCLUSION Despite androgen depletion, females with Addisons disease do not report impaired sexuality. The fertility is reduced after the diagnosis is made; the reasons for this remain unknown.

Metabolic syndrome after risk-reducing salpingo-oophorectomy in women at high risk for hereditary breast ovarian cancer: A controlled observational study

Surgical menopause may increase the risk of cardiovascular diseases (CVDs). The aim of this study was to determine the risk of metabolic syndrome in women who had undergone risk-reducing salpingo-oophorectomy (RRSO) because of increased risk of hereditary breast ovarian cancer (HBOC). A sample of 326 (65% of invited) women at risk of HBOC who had undergone RRSO was compared to 679 women from the general population. Mean follow-up after surgery was 6.5 years (standard deviations [SD] 4.4). RRSO was significantly associated with metabolic syndrome according to the 2005 National Cholesterol Education Program Adult Treatment Panel III criteria (odds ratio [OR] 2.46 [95% confidence interval (CI) 1.63, 3.73]) and according to the International Diabetes Federation criteria (OR 2.49 [CI 1.60, 3.88]), as were increasing age and body mass index (BMI). RRSO in women at risk of HBOC is significantly associated with the metabolic syndrome, and the follow-up after RRSO should take these findings into consideration.

A controlled study of mental distress and somatic complaints after risk-reducing salpingo-oophorectomy in women at risk for hereditary breast ovarian cancer

OBJECTIVES Risk-reducing salpingo-oophorectomy (RRSO) provides effective protection against ovarian cancer in BRCA mutation carriers and in women at risk for hereditary breast ovarian cancer, but little is known about non-oncologic morbidity after the procedure. We explored mental distress and somatic complaints in women after RRSO compared to controls from the general population. METHODS 503 women from hereditary breast ovarian cancer families who had undergone RRSO after genetic counseling received a mailed questionnaire. 361 (71%) responded and 338 (67%) delivered complete data (cases). Controls were five randomly allocated age-matched controls per case (N=1690) from the population-based Norwegian Nord-Trøndelag Health Study (HUNT-2). RESULTS Mean age of cases and controls was 54.6 years at survey. Mean time since surgery was 5.3 years (median 6.0). Compared to controls, the RRSO group had more palpitations (p=0.02), constipation (p=0.01), pain and stiffness (p=0.02), osteoporosis (p=0.02) and musculoskeletal disease (p=0.01) even after adjustments for demographic factors including use of hormonal replacement therapy. The RRSO group had lower levels of depression (p<0.001) and total mental distress (p=0.002) compared to controls. In multivariate linear regression analyses, RRSO was associated with lower levels of depression (p<0.001) and total mental distress (p=0.002). CONCLUSIONS In this controlled observational study, we found more somatic morbidity such as osteoporosis, palpitations, constipation, musculoskeletal disease and pain and stiffness but lower levels of mental distress among women who had undergone RRSO compared to controls.

Fatigue and quality of life after risk-reducing salpingo-oophorectomy in women at increased risk for hereditary breast-ovarian cancer

Background: Risk-reducing salpingo-oophorectomy (RRSO) is the safest intervention for prevention of ovarian cancer in women at increased risk for hereditary breast-ovarian cancer. Little is known about other effects of RRSO. The objective of this study was to investigate quality of life (QoL) and fatigue in a sample of women who had RRSO for increased cancer risk and to compare the findings with those of age-matched controls from the general population (NORM). Materials and Methods: In a cross-sectional follow-up mailed questionnaire design, 301 (67%) of 450 invited Norwegian women with RRSO attended. The questionnaire contained measures of QoL, fatigue, anxiety/depression, and body image, and questions about demography, lifestyle, and morbidity. The findings were compared with those of the NORM. Results: For RRSO women, mean age at survey was 53.7 years (SD, 9.2), mean age at RRSO was 48.4 years (SD 8.4), and median follow-up time was 5.0 years (range, 1-15 years). No clinically significant differences were observed between RRSO and NORM for any of the QoL or fatigue dimensions. In subgroup analyses of the RRSO group, no clinically significant differences in QoL and fatigue were observed between those who had surgery before or after age 50 years, or between BRCA1/2 carriers and women with unknown mutation statuses. Women who had cancer (32%), however, showed clinically significant lower levels of QoL and more fatigue than women without cancer. Conclusions: Women who had RRSO showed similar levels of QoL and fatigue as NORM. Women who had cancer before RRSO had lower levels of QoL and more fatigue.

Sexual activity and functioning after risk-reducing salpingo-oophorectomy: Impact of hormone replacement therapy

OBJECTIVE To examine sexual activity and functioning in women after risk-reducing salpingo-oophorectomy (RRSO) compared with the general population (NORM). METHODS Retrospective cohort study. 294 women who underwent RRSO and 1228 women from the NORM group provided written information based on mailed questionnaires. Sexual pleasure and discomfort scores and frequency of sexual activity were evaluated using the Sexual Activity Questionnaire. RESULTS The RRSO group reported less sexual pleasure (10.5 vs. 11.9, P=0.009), more discomfort (1.9 vs. 0.83, P<0.001), and less frequent sex than did the controls. Significant associations were observed between a lower pleasure score and being in the RRSO group, older age, history of cancer, low body image, high level of role functioning, and low level of global quality of life (QoL). Further, significant associations were detected between more discomfort and being in the RRSO group, older age, history of cancer, poor body image, and low level of global QoL. Hormone replacement therapy (HRT) use had no impact on pleasure or discomfort score in regression analyses among all the sexually active women. However, in subanalyses of the RRSO group, users of systemic HRT reported less discomfort (1.2 vs. 2.4, P=0.001) than did the nonusers. CONCLUSIONS After RRSO, women reported significantly less sexual pleasure, more discomfort, and less frequent sex compared with the controls. In the RRSO group, systemic HRT users reported less discomfort than did the nonusers. Health care providers should be attentive to these issues when counseling before and after prophylactic surgery.

Gynecologic Oncology Training Systems in Europe A Report From the European Network of Young Gynaecological Oncologists

Objective: The objectives of the study were to highlight some of the differences in training systems and opportunities for training in gynecologic oncology across Europe and to draw attention to steps that can be taken to improve training prospects and experiences of European trainees in gynecologic oncology. Methods: The European Network of Young Gynaecological Oncologists national representatives from 34 countries were asked to review and summarize the training system in their countries of origin and fulfill a mini-questionnaire evaluating different aspects of training. We report analysis of outcomes of the mini-questionnaire and subsequent discussion at the European Network of Young Gynaecological Oncologists national representatives Asian Pacific Organization for Cancer Prevention meeting in Istanbul (April 2010). Results: Training fellowships in gynecologic oncology are offered by 18 countries (53%). The median duration of training is 2.5 years (interquartile range, 2.0-3.0 years). Chemotherapy administration is part of training in 70.5% (24/34) countries. Most of the countries (26/34) do not have a dedicated national gynecologic-oncology journal. All trainees reported some or good access to training in advanced laparoscopic surgical techniques, whereas 41% indicated no access, and 59% some access to training opportunities in robotic surgery. European countries were grouped into 3 different categories on the basis of available training opportunities in gynecologic oncology: well-structured, moderately structured, and loosely structured training systems. Conclusions: There is a need for further harmonization and standardization of training programs and structures in gynecologic oncology across Europe. This is of particular relevance for loosely structured countries that lag behind the moderately structured and well-structured ones.

Placental glucose transfer: A human in vivo study

Objectives The placental transfer of nutrients is influenced by maternal metabolic state, placenta function and fetal demands. Human in vivo studies of this interplay are scarce and challenging. We aimed to establish a method to study placental nutrient transfer in humans. Focusing on glucose, we tested a hypothesis that maternal glucose concentrations and uteroplacental arterio-venous difference (reflecting maternal supply) determines the fetal venous-arterial glucose difference (reflecting fetal consumption). Methods Cross-sectional in vivo study of 40 healthy women with uncomplicated term pregnancies undergoing planned caesarean section. Glucose and insulin were measured in plasma from maternal and fetal sides of the placenta, at the incoming (radial artery and umbilical vein) and outgoing vessels (uterine vein and umbilical artery). Results There were significant mean (SD) uteroplacental arterio-venous 0.29 (0.23) mmol/L and fetal venous-arterial 0.38 (0.31) mmol/L glucose differences. The transplacental maternal-fetal glucose gradient was 1.22 (0.42) mmol/L. The maternal arterial glucose concentration was correlated to the fetal venous glucose concentration (r = 0.86, p<0.001), but not to the fetal venous-arterial glucose difference. The uteroplacental arterio-venous glucose difference was neither correlated to the level of glucose in the umbilical vein, nor fetal venous-arterial glucose difference. The maternal-fetal gradient was correlated to fetal venous-arterial glucose difference (r = 0.8, p<0.001) and the glucose concentration in the umbilical artery (r = −0.45, p = 0.004). Glucose and insulin concentrations were correlated in the mother (r = 0.52, p = 0.001), but not significantly in the fetus. We found no significant correlation between maternal and fetal insulin values. Conclusions We did not find a relation between indicators of maternal glucose supply and the fetal venous-arterial glucose difference. Our findings indicate that the maternal-fetal glucose gradient is significantly influenced by the fetal venous-arterial difference and not merely dependent on maternal glucose concentration or the arterio-venous difference on the maternal side of the placenta.

Coronary heart disease risk profile in women who underwent salpingo-oophorectomy to prevent hereditary breast ovarian cancer

Introduction: We examined coronary heart disease risk profile in women from hereditary breast ovarian cancer families who had undergone risk-reducing salpingo-oophorectomy and compared the results to that of controls from the general population. Methods: A sample of 326 (65% of invited) women with previous risk-reducing salpingo-oophorectomy after genetic counseling provided data and blood samples (cases). Controls were 1630 age-matched women from a Norwegian population-based health study. We examined the coronary heart disease risk profile and the Framingham risk score in both groups. Results: The cases had a lower mean (SD) Framingham total score compared to the controls (12.9 [5.1] vs 14.5 [5.2]; P = 0.02). Except for a wider waist circumference, the cases had a more favorable coronary heart disease risk profile including more physical activity, lower levels of total cholesterol, higher levels of high-density lipoprotein cholesterol, lower systolic blood pressure, and lower body mass index compared with the controls. In multivariate logistic regression analyses, the risk-reducing salpingo-oophorectomy group was inversely associated with a Framingham 10-year risk score of 5% or higher (odds ratio, 0.49; 95% confidence interval, 0.34-0.71; P < 0.001). Lower levels of education, not having paid work, a history of stroke, and a wider waist circumference were significantly associated with a Framingham risk score higher than 10% in the total sample. Conclusions: Self-selection of women seeking risk-reducing salpingo-oophorectomy, changes in lifestyle after surgery, and survival bias may explain that the women who underwent risk-reducing salpingo-oophorectomy had a more favorable coronary heart disease risk profile compared with the controls. Longitudinal studies are needed to further clarify the associations observed in this cross-sectional study.

Association between Hysterectomy with Ovarian Preservation and Cardiovascular Disease in a Norwegian Population-Based Sample

Background/Aims: Some previous studies have reported that hysterectomy predicts increased prevalence of cardiovascular diseases, but the findings are disputed. We aimed to examine associations between hysterectomy and cardiovascular disease in a Norwegian cross-sectional health study. Methods: The data were obtained from the population-based cross-sectional Nord-Trøndelag Health Study (The HUNT-2 Study). Of 46,709 invited females, 35,280 (76%) participated; 939 (3%) reported hysterectomy without oophorectomy (exposed women). Each exposed woman was age-matched with four randomly chosen women (n = 3,756) without hysterectomy or oophorectomy. Oophorectomy and hysterectomy status was self-reported by the women. Hazard ratio for cardiovascular diseases was calculated by Cox regression analyses with hysterectomy as a time-dependent covariate. Results: Median time since hysterectomy was 14 years (range 0–56 years). We calculated a significantly larger cumulative probability of cardiovascular diseases after hysterectomy with a hazard ratio of 1.92, 95% CI (1.51–2.38) after adjustments for cardiovascular risk factors (diabetes, age, use of hormonal replacement therapy and positive family history of myocardial infarction). Conclusion: Women had a significantly increased risk of cardiovascular diseases after hysterectomy compared to age-matched controls. Studies with longitudinal design and confirmed medical outcome data are needed.