Raloxifene is a nonsteroidal selective estrogen receptor modulator that has favorable effects on markers of cardiovascular risk and has been associated with a reduced risk of coronary heart disease (CHD) in postmenopausal women. Raloxifene also has antiestrogenic effects on the breast and in animals has suppressed the growth of estrogen-stimulated mammary cancers. The Raloxifene Use for The Heart (RUTH) trial was a randomized, double-blind, placebo-controlled study carried out at 177 sites in 26 countries. The 10,101 participants were women aged 55 and older who were at least 12 months postmenopausal and who either had established CHD or were at increased risk. They were assigned to receive either 60 mg raloxifene orally each day or a placebo. The 2 groups were similar in baseline characteristics except for slightly higher cardiovascular risk scores for women assigned to raloxifene. During a median follow up of 5.6 years, no significant differences were found with respect to deaths from coronary causes, nonfatal myocardial infarction, or hospital admission because of an acute coronary syndrome. Women with established CHD and those at increased risk for CHD had similar outcomes. For the primary coronary outcome, the results of as-treated analyses were comparable to those of intention-to-treat analyses. Raloxifene was associated with a decreased incidence of invasive breast cancer; the hazard ratio was 0.56 with a 95% confidence interval of 0.38 to 0.83. The absolute risk reduction for every 1000 women given raloxifene for 1 year was 1.2 cases for both invasive breast cancer and estrogen receptor-positive invasive breast cancer. Among secondary outcomes, the incidence of stroke did not differ significantly between the raloxifene and placebo groups, but fatal strokes were 49% more frequent in raloxifene-treated women. Venous thromboembolic events were 44% more frequent in the raloxifene group. Incidence rates of all breast cancers and of clinical vertebral fractures were lower in the raloxifene group. More than 90% of women in both groups reported adverse events. Rates of discontinuance because of side effects were 22% in the raloxifene group and 20% in the placebo group. Serum levels of low-density lipoprotein cholesterol declined in women given raloxifene but increased in placebo recipients. Levels of high-density lipoprotein cholesterol increased in both groups but more so in women treated with raloxifene. Raloxifene treatment, given for a median of over 5 years to postmenopausal women at increased risk of CHD, did not significantly alter CHD risk in the RUTH study. Its beneficial effects in lowering the risk of invasive breast cancer and vertebral fracture must be weighed against increased risks of fatal stroke and venous thromboembolism.

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Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women

Background: Stress is associated with an increased incidence of cardiovascular disease. The impact of chronic stress on cardiovascular risk has been studied by measuring cortisol in serum and saliva, which are measurements of only 1 time point. These studies yielded inconclusive results. The measurement of cortisol in scalp hair is a novel method that provides the opportunity to measure long-term cortisol exposure. Our aim was to study whether long-term cortisol levels, measured in scalp hair, are associated with cardiovascular diseases. Methods: A group of 283 community-dwelling elderly participants were randomly selected from a large population-based cohort study (median age, 75 y; range, 65-85 y). Cortisol was measured in 3-cm hair segments, corresponding roughly with a period of 3 months. Self-reported data concerning coronary heart disease, stroke, peripheral arterial disease, diabetes mellitus, and other chronic noncardiovascular diseases were collected. Results: Hair cortisol levels were significantly lower in women than in men (21.0 vs 26.3 pg/mg hair; P < .001). High hair cortisol levels were associated with an increased cardiovascular risk (odds ratio, 2.7; P = .01) and an increased risk of type 2 diabetes mellitus (odds ratio, 3.2; P = .04). There were no associations between hair cortisol levels and noncardiovascular diseases. Conclusions: Elevated long-term cortisol levels are associated with a history of cardiovascular disease. The increased cardiovascular risk we found is equivalent to the effect of traditional cardiovascular risk factors, suggesting that long-term elevated cortisol may be an important cardiovascular risk factor. Copyright

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High Long-Term Cortisol Levels, Measured in Scalp Hair, Are Associated With a History of Cardiovascular Disease

Importance Nearly half of postmenopausal women report bothersome vulvovaginal symptoms, but few data support the efficacy of 2 commonly recommended treatments. Objective To compare the efficacy of a low-dose vaginal estradiol tablet and a vaginal moisturizer, each vs placebo, for treatment of moderate-to-severe postmenopausal vulvovaginal symptoms. Design, Setting, and Participants This 12-week multicenter randomized clinical trial enrolled postmenopausal women with moderate to severe symptoms of vulvovaginal itching, pain, dryness, irritation, or pain with penetration. Interventions Vaginal 10-μg estradiol tablet (daily for 2 weeks, then twice weekly) plus placebo gel (3 times a week) (n = 102) vs placebo tablet plus vaginal moisturizer (n = 100) vs dual placebo (n = 100). Main Outcomes and Measures The main outcome was decrease in severity (0-3) of most bothersome symptom (MBS) between enrollment and 12 weeks. Additional measures included a composite vaginal symptom score, Female Sexual Function Index (FSFI) score (2-36), modified Female Sexual Distress Score–Revised item 1, treatment satisfaction and meaningful benefit, Vaginal Maturation Index, and vaginal pH. Results The 302 women had a mean (SD) age of 61 (4) years and were primarily white (267 [88%]), college educated (200 [66%]), and sexually active (245 [81%]). Most women (294 [97%]) provided data for the primary analysis. The most commonly reported MBS was pain with vaginal penetration (182 [60%]), followed by vulvovaginal dryness (63 [21%]). Mean baseline MBS severity was similar between treatment groups: estradiol, 2.4 (95% CI, 2.3 to 2.6); moisturizer, 2.5 (95% CI, 2.3 to 2.6); placebo, 2.5 (95% CI, 2.4 to 2.6). All treatment groups had similar mean reductions in MBS severity over 12 weeks: estradiol, −1.4 (95% CI, −1.6 to −1.2); moisturizer, −1.2 (95% CI, −1.4 to −1.0); and placebo, −1.3 (95% CI, −1.5 to −1.1). No significant differences were seen between estradiol ( P  = .25) or moisturizer ( P  = .31) compared with placebo. Mean total FSFI improvement was similar between estradiol (5.4; 95% CI, 4.0 to 6.9) and placebo (4.5; 95% CI, 2.8 to 6.1) ( P  = .64), and between moisturizer (3.1; 95% CI, 1.7 to 4.5) and placebo ( P  = .17). Conclusions and Relevance Our results suggest that neither prescribed vaginal estradiol tablet nor over-the-counter vaginal moisturizer provides additional benefit over placebo vaginal tablet and gel in reducing postmenopausal vulvovaginal symptoms. Trial Registration clinicaltrials.gov Identifier:NCT02516202

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Efficacy of Vaginal Estradiol or Vaginal Moisturizer vs Placebo for Treating Postmenopausal Vulvovaginal Symptoms: A Randomized Clinical Trial.

There is a new appreciation of the perimenopause - defined as the early and late menopause transition stages as well as the early postmenopause - as a window of vulnerability for the development of both depressive symptoms and major depressive episodes. However, clinical recommendations on how to identify, characterize and treat clinical depression are lacking. To address this gap, an expert panel was convened to systematically review the published literature and develop guidelines on the evaluation and management of perimenopausal depression. The areas addressed included: 1) epidemiology; 2) clinical presentation; 3) therapeutic effects of antidepressants; 4) effects of hormone therapy; and 5) efficacy of other therapies (eg, psychotherapy, exercise, and natural health products). Overall, evidence generally suggests that most midlife women who experience a major depressive episode during the perimenopause have experienced a prior episode of depression. Midlife depression presents with classic depressive symptoms commonly in combination with menopause symptoms (ie, vasomotor symptoms, sleep disturbance), and psychosocial challenges. Menopause symptoms complicate, co-occur, and overlap with the presentation of depression. Diagnosis involves identification of menopausal stage, assessment of co-occurring psychiatric and menopause symptoms, appreciation of the psychosocial factors common in midlife, differential diagnoses, and the use of validated screening instruments. Proven therapeutic options for depression (ie, antidepressants, psychotherapy) are the front-line treatments for perimenopausal depression. Although estrogen therapy is not approved to treat perimenopausal depression, there is evidence that it has antidepressant effects in perimenopausal women, particularly those with concomitant vasomotor symptoms. Data on estrogen plus progestin are sparse and inconclusive.

Guidelines for the evaluation and treatment of perimenopausal depression: summary and recommendations.

Folic acid is a member of the B-vitamin family and is essential for amino acid metabolism. Adequate intake of folic acid is vital for metabolism, cellular homeostasis, and DNA synthesis. Since the initial discovery of folic acid in the 1940s, folate deficiency has been implicated in numerous disease states, primarily those associated with neural tube defects in utero and neurological degeneration later in life. However, in the past decade, epidemiological studies have identified an inverse relation between both folic acid intake and blood folate concentration and cardiovascular health. This association inspired a number of clinical studies that suggested that folic acid supplementation could reverse endothelial dysfunction in patients with cardiovascular disease (CVD). Recently, in vitro and in vivo studies have begun to elucidate the mechanism(s) through which folic acid improves vascular endothelial function. These studies, which are the focus of this review, suggest that folic acid and its active metabolite 5-methyl tetrahydrofolate improve nitric oxide (NO) bioavailability by increasing endothelial NO synthase coupling and NO production as well as by directly scavenging superoxide radicals. By improving NO bioavailability, folic acid may protect or improve endothelial function, thereby preventing or reversing the progression of CVD in those with overt disease or elevated CVD risk.

Role of folic acid in nitric oxide bioavailability and vascular endothelial function.

Objectives: This study aimed to determine the frequency of dysmenorrhea, as identified by different definitions, in a population of young women, and to investigate factors associated with this complaint. Materials and methods: A final group of 408 young women completed a self-assessment questionnaire. This was a cross-sectional analytical study. Results: Menstrual pain was reported by 84.1% of women, with 43.1% reporting that pain occurred during every period, and 41% reporting that pain occurred during some periods. Women with menstrual pain had an earlier menarche (P = 0.0002) and a longer menstrual flow ( P = 0.006), and this group was characterized as having a higher prevalence of smokers (P = 0.031) and a lower prevalence of hormonal contraception users (P = 0.015). Pain intensity was correlated (r = 0.302, P , 0.0001) positively with menstrual flow length (CR = 0.336), history of abortions (CR = 3.640), and gynecological pathologies (CR = 0.948), and negatively with age at menarche (CR = -0.225), use of hormonal contraception (CR = -0.787), and history of gynecological surgery (CR = -2.115). Considering the parameters of menstrual pain, a need for medication, and inability to function normally (absenteeism from study or social activities) alone or together, the prevalence of dysmenorrhea is 84.1% when considering only menstrual pain, 55.2% when considering the association between menstrual pain and need for medication, 31.9% when considering the association between menstrual pain and absenteeism, and 25.3% when considering the association between menstrual pain, need for medication, and absenteeism (P , 0.0001). The probability of having more severe dysmenorrhea is directly related to pain intensity as measured by a visual analog scale, but does not coincide with it. Conclusion: Menstrual pain is a very common problem, but the need for medication and the inability to function normally occurs less frequently. Nevertheless, at least one in four women experiences distressing menstrual pain characterized by a need for medication and absenteeism from study or social activities.

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Prevalence of menstrual pain in young women: what is dysmenorrhea?

Objective:Vasomotor symptoms may increase the risk for cardiovascular diseases through still elusive mechanisms. Increased cortisol release may favor atherosclerosis. In this study, we tested whether vasomotor and psychological symptoms are associated with an increase in cortisol levels.Meth

Increased cortisol level: a possible link between climacteric symptoms and cardiovascular risk factors

Objective:The progestin dienogest (DNG) given alone effectively reduces pelvic pain of women with endometriosis. It is not clear whether the same occurs when DNG is associated with estradiol (E2).Design:Patient preference prospective observational study.Setting:Outpatient centre of university hospital.Patients:40 patients with endometriosis and menstrual pain.Interventions:24-week treatment with a quadriphasic association of E2 valerate (E2V) and DNG or a nonsteroidal anti-inflammatory drug (NSAID) to be used only in case of pain (ketoprofene 200-mg tablets).Main Outcome Measures:Menstrual pain and, when present, intermenstrual pain, and dyspareunia were investigated by means of a 10-cm visual analogue scale (VAS). Quality of life was investigated by the short form 36 (SF-36) of the health-related quality of life questionnaire.Results:Final study group consists of 34 patients, 19 in the E2V/DNG group and 15 in the NSAID group. After 24 weeks, no significant modification of menstrual pain, intermenstrual p...

Pelvic pain and quality of life of women with endometriosis during quadriphasic estradiol valerate/dienogest oral contraceptive: a patient-preference prospective 24-week pilot study.

The most bothersome symptom of vaginal atrophy: Evidence from the observational AGATA study

Women with chronic pelvic pain (CPP) frequently suffer from mood disturbances and reduced quality of life. Whether pain improvement ameliorates mood and quality of life is still unclear, and it was...

Anjeza Xholli

Papers

Prevalence of menstrual pain in young women: what is dysmenorrhea?

Increased cortisol level: a possible link between climacteric symptoms and cardiovascular risk factors

Pelvic pain and quality of life of women with endometriosis during quadriphasic estradiol valerate/dienogest oral contraceptive: a patient-preference prospective 24-week pilot study.

The most bothersome symptom of vaginal atrophy: Evidence from the observational AGATA study

Chronic pelvic pain improvement: impact on quality of life and mood.