Loes Jaspers

Efficacy and Safety of Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Women: A Systematic Review and Meta-analysis

IMPORTANCE In August 2015, the US Food and Drug Administration (FDA) approved flibanserin as a treatment for hypoactive sexual desire disorder (HSDD) in premenopausal women, despite concern about suboptimal risk-benefit trade-offs. OBJECTIVE To conduct a systematic review and meta-analysis of randomized clinical trials assessing efficacy and safety of flibanserin for the treatment of HSDD in women. DATA SOURCES Medical databases (among others, Embase, Medline, Psycinfo) and trial registries were searched from inception to June 17, 2015. Reference lists of retrieved studies were searched for additional publications. STUDY SELECTION Randomized clinical trials assessing treatment effects of flibanserin in premenopausal and postmenopausal women were eligible. No age, language, or date restrictions were applied. Abstract and full-text selection was done by 2 independent reviewers. DATA EXTRACTION AND SYNTHESIS Data were extracted by one reviewer and checked by a second reviewer. Results were pooled using 2 approaches depending on the blinding risk of bias. MAIN OUTCOMES AND MEASURES Primary efficacy outcomes included number of satisfying sexual events (SSEs), eDiary sexual desire, and Female Sexual Function Index (FSFI) desire. Safety outcomes included, among others, 4 common adverse events (AEs): dizziness, somnolence, nausea, and fatigue. RESULTS Five published and 3 unpublished studies including 5914 women were included. Pooled mean differences for SSE change from baseline were 0.49 (95% CI, 0.32-0.67) between 100-mg flibanserin and placebo, 1.63 (95% CI, 0.45-2.82) for eDiary desire, and 0.27 (95% CI, 0.17-0.38) for FSFI desire. The risk ratio for study discontinuation due to AEs was 2.19 (95% CI, 1.50-3.20). The risk ratio for dizziness was 4.00 (95% CI, 2.56-6.27) in flibanserin vs placebo, 3.97 (95% CI, 3.01-5.24) for somnolence, 2.35 (95% CI, 1.85-2.98) for nausea, and 1.64 (95% CI, 1.27-2.13) for fatigue. Womens mean global impression of improvement scores indicated minimal improvement to no change. CONCLUSIONS AND RELEVANCE Treatment with flibanserin, on average, resulted in one-half additional SSE per month while statistically and clinically significantly increasing the risk of dizziness, somnolence, nausea, and fatigue. Overall, the quality of the evidence was graded as very low. Before flibanserin can be recommended in guidelines and clinical practice, future studies should include women from diverse populations, particularly women with comorbidities, medication use, and surgical menopause.

Health in middle-aged and elderly women: a conceptual framework for ‘healthy menopause’

Middle-aged and elderly women constitute a large and growing proportion of the population. The peri and postmenopausal period constitutes a challenging transition time for womens health, and menopausal health is a crucial aspect in healthy and successful aging. Currently, no framework for the concept of healthy menopause exists, despite its recognized importance. Therefore, we aimed to: (i) characterize healthy menopause; (ii) identify aspects that contribute to it; and (iii) explore potential approaches to measure it. We propose healthy menopause as a dynamic state, following the permanent loss of ovarian function, which is characterized by self-perceived satisfactory physical, psychological and social functioning, incorporating disease and disability, allowing the attainment of a womans desired ability to adapt and capacity to self-manage. The concept of healthy menopause applies to all women from the moment they enter the menopausal transition, up until they reach early and late postmenopause and includes women with spontaneous, iatrogenic, and premature menopause. This conceptualization can be considered as a further step in the maintenance and improvement of health in menopausal women from different perspectives, foremost the womans own perspective, followed by the clinical, public health, and societal perspectives, and can be seen as a further step in delineating lines for future research. Furthermore, it could facilitate the improvement of adequate preventive and treatment strategies, guide scientific efforts, and aid education and communication to health care practitioners and the general public, allowing women the achievement of their potential and the fulfillment of their fundamental role in society.

Androgen levels in women with various forms of ovarian dysfunction: associations with cardiometabolic features

STUDY QUESTION Are differences in androgen levels among women with various forms of ovarian dysfunction associated with cardiometabolic abnormalities? SUMMARY ANSWER Androgen levels differed substantially between women with and without ovarian dysfunction, and increased androgen levels were associated with impaired cardiometabolic features in all women irrespective of their clinical condition. WHAT IS KNOWN ALREADY Sex steroid hormones play important roles in the development of cardiovascular diseases (CVD). Extremes of low as well as high androgen levels have been associated with increased CVD risk in both men and women. STUDY DESIGN, SIZE, DURATION This cross-sectional study included 680 women with polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), natural post-menopausal women (NM), or regular menstrual cycles (RC) (170 women per group). PARTICIPANTS/MATERIALS, SETTING, METHODS Measurements of serum testosterone, androstenedione and dehydroepiandrosterone sulfate were performed using liquid chromatography-tandem mass spectrometry. Assessments were taken of body mass index (BMI), blood pressure, lipid profiles, glucose, insulin and SHBG, and the bioactive fraction of circulating testosterone was calculated using the free androgen index (FAI). MAIN RESULTS AND THE ROLE OF CHANCE PCOS women were hyperandrogenic [median FAI = 4.9 (IQR 3.6-7.4)], and POI women were hypoandrogenic [FAI = 1.2 (0.8-1.7)], compared with RC women [FAI = 1.7 (1.1-2.8)], after adjustment for age, ethnicity, smoking and BMI (P < 0.001). After adjustment for age, there were no significant differences in androgens between POI and NM (P = 0.15) women and between NM and RC (P = 0.27) women, the latter indicating that chronological aging rather than ovarian aging influences the differences between pre- and post-menopausal women. A high FAI was associated with elevated triglycerides (β log FAI for PCOS: 0.45, P < 0.001, POI: 0.25, P < 0.001, NM: 0.20, P = 0.002), insulin (β log FAI for PCOS: 0.77, POI: 0.44, NM: 0.40, all P < 0.001), HOMA-IR (β log FAI for PCOS: 0.82, POI: 0.46, NM: 0.47, all P < 0.001) and mean arterial pressure (β log FAI for PCOS: 0.05, P = 0.002, POI: 0.07, P < 0.001, NM: 0.04, P = 0.04) in all women; with increased glucose (β log FAI for PCOS: 0.05, P = 0.003, NM: 0.07, P < 0.001) and decreased high-density lipoprotein (β log FAI for PCOS: -0.23, P < 0.001, NM: -0.09, P = 0.03) in PCOS and NM women; and with increased low-density lipoprotein (β log FAI for POI: 0.083, P = 0.041) in POI women. Adjustment for BMI attenuated the observed associations. Associations between FAI and cardiometabolic features were the strongest in PCOS women, even after adjustment for BMI. LIMITATIONS, REASONS FOR CAUTION Associations between androgen levels and cardiometabolic features were assessed in PCOS, POI and NM women only, due to a lack of available data in RC women. Due to the cross-sectional design of the current study, the potential associations between androgen levels and actual future cardiovascular events could not be assessed. WIDER IMPLICATIONS OF THE FINDINGS This study affirms the potent effect of androgens on cardiometabolic features, indicating that androgens should indeed be regarded as important denominators of womens health. Future research regarding the role of androgens in the development of CVD and potential modulatory effects of BMI is required. STUDY FUNDING/COMPETING INTERESTS N.M.P.D. is supported by the Dutch Heart Foundation (grant number 2013T083). L.J. and O.H.F. work in ErasmusAGE, a center for aging research across the life course, funded by Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA. M.K. is supported by the AXA Research Fund. Nestlé Nutrition (Nestec Ltd), Metagenics Inc. and AXA had no role in the design and conduct of the study; the collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript. J.S.E.L. has received fees and grant support from the following companies (in alphabetical order): Ferring, Merck-Serono, Merck Sharpe & Dome, Organon, Schering Plough and Serono. In the last 5 years, B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Actavis, COGI, Euroscreen, Ferring, Finox, Genovum, Gedeon-Richter, Merck-Serono, OvaScience, Pantharei Bioscience, PregLem, Roche, Uteron and Watson laboratories. With regard to potential conflicts of interest, there is nothing further to disclose.

The association between vasomotor symptoms and metabolic health in peri- and postmenopausal women: A systematic review

The objective of this study was to systematically review studies describing the association between vasomotor symptoms and metabolic syndrome, type 2 diabetes and insulin resistance in peri- and postmenopausal women. A systematic search of studies was performed in EMBASE, MEDLINE, Web-of-science, Scopus, PubMed publisher, Cochrane Library, Google scholar. To identify studies eligible for inclusion, the following criteria were defined: randomised trials, cohort, case-control, and cross-sectional studies investigating the association between vasomotor symptoms and metabolic syndrome, type 2 diabetes and insulin resistance in peri- and postmenopausal women with natural menopause. Methodological quality was assessed using a modified NewCastle Ottawa Assessment Scale. After screening 2660 titles and abstracts, four studies, of which two cohort studies met the criteria of high methodological quality, were included in the review. Because of the heterogeneity and the limited number of studies, there is no sufficient evidence on the potential role of vasomotor symptoms in metabolic health. However, both high-quality cohort studies, with large study populations and adjustment for multiple confounding variables showed positive associations between vasomotor symptoms and insulin resistance and type 2 diabetes mellitus. These findings suggest that there is an association between vasomotor symptoms and metabolic health outcomes. To confirm this and to strengthen the evidence, more high quality longitudinal research on this topic is needed.

Associations of Steroid Sex Hormones and Sex Hormone-Binding Globulin with the Risk of Type 2 Diabetes in Women: a Population-Based Cohort Study and Meta-Analysis.

It remains unclear whether endogenous sex hormones (ESH) are associated with risk of type 2 diabetes (T2D) in women. Data of 3,117 postmenopausal women participants of the Rotterdam Study were analyzed to examine whether ESH and sex hormone–binding globulin (SHBG) were associated with the risk of incident T2D. Additionally, we performed a systematic review and meta-analysis of studies assessing the prospective association of ESH and SHBG with T2D in women. During a median follow-up of 11.1 years, we identified 384 incident cases of T2D in the Rotterdam Study. No association was observed between total testosterone (TT) or bioavailable testosterone (BT) with T2D. SHBG was inversely associated with the risk of T2D, whereas total estradiol (TE) was associated with increased risk of T2D. Similarly, in the meta-analysis of 13 population-based prospective studies involving more than 1,912 incident T2D cases, low levels of SHBG and high levels of TE were associated with increased risk of T2D, whereas no associations were found for other hormones. The association of SHBG with T2D did not change by menopause status, whereas the associations of ESH and T2D were based only in postmenopausal women. SHBG and TE are independent risk factors for the development of T2D in women.

Sex Steroids, Sex Hormone-Binding Globulin and Cardiovascular Health in Men and Postmenopausal Women: The Rotterdam Study

CONTEXT The concept of cardiovascular health was recently introduced. Sex steroids and sex hormone-binding globulin (SHBG) influence different health domains, but no studies assessed their role in cardiovascular health. OBJECTIVE To assess the association between estradiol (E2), testosterone (T), SHBG, and free androgen index (FAI) with cardiovascular health. DESIGN, SETTING, AND PARTICIPANTS Analyses included 1647 men (68.6 y) and 1564 naturally postmenopausal women (69.6 y) with available data on sex steroids and cardiovascular health from the population-based Rotterdam Study. EXPOSURES E2, T, SHBG, and FAI. OUTCOME To define cardiovascular health, 7 metrics including 3 health factors (total cholesterol, fasting glucose, and blood pressure) and 4 health behaviors (physical activity, smoking, body mass index, and diet) were adopted. Three category levels of each metric were added up to a total score ranged 0-14. Logistic regression was performed to explore the association between E2, T, SHBG, and FAI and optimal cardiovascular health (OCH) (score of 11-14). RESULTS OCH was reached by 153 men (9.3%) and 162 women (10.4%). The prevalence of OCH was higher in the lowest tertile of E2 (38.9%), and of T (43.8%), and the highest tertile of SHBG (48.1%) in women, and the highest tertile of T (43.1%) and SHBG (47.1%) in men. After adjustment for confounders, OCH was associated with lower T (odds ratio and 95% confidence interval, 0.69 [0.48-1.00]) and lower FAI (0.43 [0.32-0.57]) and higher levels of SHBG (4.55 [2.99-6.94]) among women and with higher levels of SHBG (2.56 [1.45-4.49]) in men. CONCLUSIONS OCH was associated with sex steroids and with SHBG in both men and women. The complexity and temporality of the interrelation between sex steroids, SHBG, and cardiovascular health requires further investigation.

Estrogen receptor β actions in the female cardiovascular system: A systematic review of animal and human studies

Five medical databases were searched for studies that assessed the role of ERβ in the female cardiovascular system and the influence of age and menopause on ERβ functioning. Of 9472 references, 88 studies met our inclusion criteria (71 animal model experimental studies, 15 human model experimental studies and 2 population based studies). ERβ signaling was shown to possess vasodilator and antiangiogenic properties by regulating the activity of nitric oxide, altering membrane ionic permeability in vascular smooth muscle cells, inhibiting vascular smooth muscle cell migration and proliferation and by regulating adrenergic control of the arteries. Also, a possible protective effect of ERβ signaling against left ventricular hypertrophy and ischemia/reperfusion injury via genomic and non-genomic pathways was suggested in 27 studies. Moreover, 5 studies reported that the vascular effects of ERβ may be vessel specific and may differ by age and menopause status. ERβ seems to possess multiple functions in the female cardiovascular system. Further studies are needed to evaluate whether isoform-selective ERβ-ligands might contribute to cardiovascular disease prevention.

Happiness, rather than depression, is associated with sexual behaviour in partnered older adults

Background The relation between positive psychological well-being (PPWB) and sexual behaviour is understudied in older adult groups. Objective To examine the relation between PPWB (positive affect and life satisfaction) and sexual behaviour (sexual activity and physical tenderness) in older adults, and whether it is independent from depressive symptoms and uniform across older age groups. Design Cross-sectional. Setting Community-dwelling adults aged 65 years or older, Rotterdam, The Netherlands. Methods Sexual behaviour, the Cantril Self-Anchoring Striving Scale, the Center for Epidemiological Studies Depression (CES-D) scale and partner status were assessed in 2,373 dementia-free older adults from the Rotterdam Study. Results For partnered participants, greater positive affect and life satisfaction was associated with more sexual activity and physical tenderness. Although CES-D was negatively associated with sexual behaviour within partnered older adults, there was no association between the negative affect sub-scale and sexual behaviour. The relations were independent of depressive symptoms, physical health and chronic disease status and were observed for both sexes at all older ages. For unpartnered participants, greater life satisfaction and was associated with more physical tenderness. There was low prevalence of sexual behaviour in unpartnered participants, limiting further stratification. Conclusion Greater PPWB was associated with more sexual behaviour in partnered, community-dwelling older adults. We are the first to demonstrate that sexual behaviour is associated with PPWB, rather than lack of depressive symptoms; and that the association was present at all ages for partnered older adults. Limited conclusions can be drawn for unpartnered older adults as their sexual behaviour was infrequent.

Design of a frailty index among community living middle-aged and older people: The Rotterdam study

OBJECTIVES To design a frailty index (FI) and evaluate three methods to handle missing data. Furthermore, we evaluated its construct (i.e., skewed distribution, correlation with age and sub-maximum score) and criterion validity (based on mortality risk). STUDY DESIGN We included 11,539 participants (45± years) from a population-based cohort in the Netherlands. Frailty was measured with a FI, which we constructed based on the accumulation of 45 health-related variables, related to mood, cognition, functional status, diseases and conditions, biomarkers, and nutritional status. A total FI-score was calculated by averaging the scores of the deficits, resulting in a score between 0 and 1, with higher scores indicating increasing frailty. Mean imputation, single- and multiple imputation were applied. MAIN OUTCOME MEASURE Mortality data were obtained by notification from the municipal administration. Median follow-up time was 9.5 years, during which 3902 (34%) participants died. RESULTS The median FI for the full population was 0.16 (IQR=0.11-0.23). The distribution of the FI was slightly right-skewed, the absolute maximum score was 0.78 and there was a strong correlation with age (Pearson correlation=0.52;95%CI=0.51-0.54). The adjusted HR per unit increase in FI-score on mortality was 1.05 (95%CI=1.05-1.06). Multiple imputation seemed to provide more robust results than mean imputation. CONCLUSION Based on our results we advise to the use of at least 30 deficits from different health domains to construct a FI if data are not imputed. Future research should use the continuous nature of the FI to monitor trajectories in frailty and find preventive strategies.

Maternal weight status, diet, and supplement use as determinants of breastfeeding and complementary feeding: a systematic review and meta-analysis

CONTEXT Infant feeding practices are influenced by maternal factors. OBJECTIVE The aim of this review is to examine the associations between maternal weight status or dietary characteristics and breastfeeding or complementary feeding. DATA SOURCES A systematic literature search of the Embase, Cochrane Library, Google Scholar, MEDLINE, PubMed, and Web of Science databases was performed. STUDY SELECTION Interventional and cohort studies in healthy mothers and infants that reported on maternal weight status, diet, or supplement use were selected. DATA EXTRACTION Outcomes assessed included delayed onset of lactogenesis; initiation, exclusivity, duration, and cessation of breastfeeding; and timing of complementary feeding. DATA ANALYSIS Eighty-one studies were included. Maternal underweight, diet, and supplement use were not associated with infant feeding practices. Obese women had a relative risk of failure to initiate breastfeeding (risk ratio [RR] = 1.23; 95%CI, 1.03-1.47) and a delayed onset of lactogenesis (RR  =  2.06; 95%CI, 1.18-3.61). The RR for breastfeeding cessation was 1.11 (95%CI, 1.07-1.15) per increase in category of body mass index. CONCLUSIONS Prevention of obesity in women of reproductive age, as well as counseling of obese women after delivery, could be targeted to improve infant feeding practices.