The menopausal hot flush: a review.

The hot flush is the most characteristic and often the most distressing symptom of the menopause. It is a unique feature and yet the mechanism and health implications are still not fully understood. This review summarizes some of the current thoughts on factors contributing to flushing, the physiological, vascular and neuroendocrine changes associated with flushing and the possible cardiovascular and other health implications for women experiencing hot flushes. Therapy is not discussed.

Personal opinion: Treatment of vulvovaginal atrophy--are hidden interests and misinformation preventing better management?

Menopausal women very often complain of vulvovaginal atrophy (VVA)-related symptoms, which mainly include dryness, irritation, dyspareunia and pain. The ideal therapeutic approach is to use systemic or intravaginal estrogen, which has proved to be effective. However, because of safety concerns that were raised after the publication of the Women's Health Initiative data, non-estrogenic and non-hormonal therapies for VVA have been developed and heavily promoted. Many menopause specialists believe that the flow of information on the newer products indicated for VVA seems to include an inaccurate message, which downgrades the use of estrogenic preparations and upgrades modern non-estrogenic therapies. Both media and medical sources have created an atmosphere of exaggerated worries over intravaginal estrogen therapies, which are not substantiated by hard clinical facts.

An International Menopause Society study of climate, altitude, temperature (IMS-CAT) and vasomotor symptoms in urban Indian regions.

OBJECTIVE: To examine the relationships between climate (season, temperature, humidity), lifestyle, health, mood and beliefs and experience of hot flushes and night sweats amongst mid-aged women living in eight urban Indian centers. METHODS: A total of 717 peri- and postmenopausal women, aged 45-55 years, from urban centers in different regions of India were included. Data were collected during both summer and winter months. Participants completed questionnaires eliciting information about sociodemographics, hot flushes (prevalence, frequency and problem-rating), health and lifestyle (body mass index, diet, exercise, alcohol use), mood (Women's Health Questionnaire) and attributions and beliefs (Menopause Representations Questionnaire). RESULTS: The prevalence of vasomotor symptoms was low, with 34% of the sample reporting hot flushes and/or night sweats. Seasonal variation in temperature was not associated with hot flush prevalence, frequency or problem rating. Hot flush prevalence was mainly associated with higher anxiety and intake of spicy foods, frequency with (older) age and (more) frequent exercise, while hot flushes were more problematic for women who reported poorer general health and more negative beliefs about menopause. CONCLUSIONS: In this study of Indian women, seasonal temperature variation did not appear to influence hot flush reporting. Health, mood, beliefs and lifestyle factors appear to explain some, but not all, of the variance in experience of menopausal symptoms.

IMS study of climate, altitude, temperature and vasomotor symptoms in the United Arab Emirates.

OBJECTIVE: To examine the relationships between temperature, season (summer versus winter), lifestyle, health, mood, beliefs, and experience of hot flushes and night sweats (HFNS), amongst mid-aged women living in the United Arab Emirates (UAE). METHODS: The UAE climate is hyper-arid, being a hot desert climate, with warm winters and hot summers. A total of 372 peri- and postmenopausal women, aged from 45 to 55 years, from urban UAE regions were included. Data were collected during both summer and winter months. Participants completed questionnaires eliciting information about sociodemographics, HFNS (prevalence, frequency and problem-rating), health and lifestyle (body mass index (BMI), diet, exercise), mood (Women's Health Questionnaire) and menopause attributions and beliefs (Menopause Representations Questionnaire). RESULTS: HFNS were currently being experienced by 46.5% of women, with an average weekly frequency of five and problem-rating of 5.7/10. Seasonal variation in temperature was not associated with prevalence, frequency or problem-rating. Hot flush prevalence was associated with poor health, life satisfaction, mood, employment, lower BMI and diet. Higher frequency was associated with higher BMI and more years since the last period. HFNS were more problematic mainly for women who reported lower life satisfaction and held more negative beliefs about the menopause. CONCLUSIONS: In this UAE study, temperature and seasonal temperature variation did not appear to influence HFNS-reporting, but health, life satisfaction, BMI, beliefs and lifestyle factors partially explained women's experiences of menopausal symptoms. A qualitative study might provide further information about the meanings of HFNS and menopause amongst UAE women.

Risks and benefits of hormone therapy: has medical dogma now been overturned?

BACKGROUND: In an integrated overview of the benefits and risks of menopausal hormone therapy (HT), the Women's Health Initiative (WHI) investigators have claimed that their 'findings … do not support use of this therapy for chronic disease prevention'. In an accompanying editorial, it was claimed that 'the WHI overturned medical dogma regarding menopausal [HT]'. OBJECTIVES: To evaluate those claims. METHODS: Epidemiological criteria of causation were applied to the evidence. RESULTS: A 'global index' purporting to summarize the overall benefit versus the risk of HT was not valid, and it was biased. For coronary heart disease, an increased risk in users of estrogen plus progestogen (E + P), previously reported by the WHI, was not confirmed. The WHI study did not establish that E+ P increases the risk of breast cancer; the findings suggest that unopposed estrogen therapy (ET) does not increase the risk, and may even reduce it. The findings for stroke and pulmonary embolism were compatible with an increased risk, and among E+ P users there were credible reductions in the risk of colorectal and endometrial cancer. For E+ P and ET users, there were credible reductions in the risk of hip fracture. Under 'worst case' and 'best case' assumptions, the changes in the incidence of the outcomes attributable to HT were minor. CONCLUSIONS: Over-interpretation and misrepresentation of the WHI findings have damaged the health and well-being of menopausal women by convincing them and their health professionals that the risks of HT outweigh the benefits.

Are progestins really necessary as part of a combined HRT regimen?

For many years it has been perceived wisdom that hormone replacement therapy for women with a uterus should include a progestin to prevent the proliferative effects of estrogen on the endometrium and endometrial cancer. But, with the reports from the Women's Health Initiative (WHI) and Million Women Study indicating that such regimens are associated with an increased risk of breast cancer, whereas unopposed estrogen may not increase this risk, or even reduce it, it is pertinent to reassess the merits of adding a progestin. In addition, the suggestion from the WHI that the effects of estrogen and progestins are a 'class effect' are clearly inaccurate, as there is particular evidence from the French E3N cohort studies of differential effects of progestins, with progesterone and dydrogesterone additions showing no increase in risk of breast cancer. The data are presented but an answer to the posed question remains unclear and as usual dependent on the circumstances and views of each individual woman and her medical adviser.

The International Menopause Study of Climate, Altitude, Temperature (IMS-CAT) and vasomotor symptoms.

OBJECTIVE: To examine the relationship between climate (including altitude, temperature, humidity and annual range of temperature) and experience of hot flushes and night sweats amongst Spanish-speaking mid-aged women living in five urban centers. METHODS: A total of 896 peri- and postmenopausal women from centers in Chile (Santiago de Chile), Ecuador (Guayaquil and Quito), Panama (Panama City) and Spain (Madrid) completed questionnaires eliciting information about sociodemographics, hot flushes (prevalence, frequency and problem-rating), health and lifestyle (body mass index, diet, exercise, alcohol use) and mood (Women's Health Questionnaire). RESULTS: There was a wide range of altitude and temperature in the participating centers. Of the sample, 58.5% (524/896) were currently experiencing vasomotor symptoms. Prevalence was associated with higher temperatures, while hot flushes were more frequent and problematic for women living in higher temperature and lower altitudes. Hot flush variables were not associated with seasonal variation in temperature. When health and lifestyle variables were included as covariates in regression analyses, prevalence was best predicted by age (younger), poor general health, more depressed mood and anxiety; hot flush frequency by anxiety, temperature, life satisfaction (lower), age (higher), regular strenuous exercise (more strenuous exercise more frequent), and a diet including regular hot spicy food intake. Hot flush problem-rating was best predicted by anxiety, life satisfaction, altitude (lower more problematic), any regular exercise (more exercise less problematic), and depressed mood. CONCLUSIONS: In this study of Spanish-speaking women, those living in countries with higher temperatures and lower altitudes reported more frequent and problematic hot flushes.

Quality of life and the role of menopausal hormone therapy.

The quality of life of countless menopausal women world-wide has been significantly diminished following the sensationalist reporting of the Women's Health Initiative (WHI) and the resulting 50% or more decline in the use of hormone replacement therapy (HRT) over the subsequent 10 years. Quality of life is difficult to measure as there are so many contributing factors and a large number of different instruments, some of which assess general health and only a few which specifically include symptoms related to menopause. HRT improves quality of life of symptomatic menopausal women and some studies of the effects of HRT provide reliable evidence on quality of life other than reduction in vasomotor symptoms. Until there is a better understanding of the minimal risks of HRT for the majority of women, too many will continue to suffer a reduced quality of life unnecessarily.

Menopausal hot flushes and night sweats: where are we now?

OBJECTIVE: An overview of the current knowledge on the etiology and treatment of vasomotor symptoms in postmenopausal women. MATERIALS AND METHODS: Acknowledged experts in the field contributed a brief assessment of their areas of interest which were combined and edited into the final manuscript. RESULTS: Women around the world experience vasomotor symptoms as they enter and complete the menopause transition. Vasomotor symptoms, specifically hot flushes, are caused by a narrowing of the thermoneutral zone in the brain. This effect, although related to estrogen withdrawal, is most likely related to changes in central nervous system neurotransmitters. Peripheral vascular reactivity is also altered in symptomatic women. Estrogen replacement therapy is the most effective treatment for hot flushes. Of the other interventions investigated, selective serotonin and selective norepinephrine reuptake inhibitors and gabapentin show efficacy greater than placebo. Objective monitoring of hot flushes indicates a robust improvement with hormone replacement therapy but little to no change with placebo. These data suggest that the subjective assessment of responses to therapy for vasomotor symptom results in inaccurate data. Hot flushes have recently been associated with increased cardiovascular risks and a lower incidence of breast cancer, but these data require confirmation. CONCLUSIONS: Vasomotor symptoms are experienced by women of all ethnic groups. They are caused by changes in the central nervous system associated with estrogen withdrawal and are best treated with estrogen replacement therapy. Objective monitoring of hot flushes indicates that placebo has little to no effect on their improvement. Subjective assessments of hot flushes in clinical trials may be inaccurate based on objective measurement of the frequency of hot flushes. Based on preliminary reports, women experiencing hot flushes have an increased risk of cardiovascular disease and a reduced incidence of breast cancer.

Recommendations for the management of postmenopausal vaginal atrophy.

Unlike hot flushes and night sweats which resolve spontaneously in time, atrophic symptoms affecting the vagina and lower urinary tract are often progressive and frequently require treatment. The prevalence of vaginal dryness increases as a woman advances through the postmenopausal years, causing itching, burning and dyspareunia, and sexual activity is often compromised. But, despite the various safe and effective options, only a minority (about 25% in the Western world and probably considerably less in other areas) will seek medical help. Some of this reluctance is due to the adverse publicity for hormone replacement therapy (HRT) over recent years that has suggested an increased risk of breast cancer, heart disease and stroke. But, regardless of whether these scares are justified, local treatment of vaginal atrophy is not associated with these possible risks of systemic HRT. Other reasons for the continued suffering in silence may be cultural and an understandable reluctance to discuss such matters, particularly with a male doctor, but the medical profession must also take much of the blame for failing to enquire of all postmenopausal women about the possibility of vaginal atrophic symptoms. Vaginal dryness can be helped by simple lubricants but the best and most logical treatment for urogenital atrophy is to use local estrogen. This is safe, effective and with few contraindications. It is hoped that these guidelines and recommendations, produced to coincide with World Menopause Day 2010, will help to highlight this major cause of distress and reduced quality of life and will encourage women and their medical advisers all over the world to seek and provide help.

Testosterone treatment of HSDD in naturally menopausal women: the ADORE study.

OBJECTIVE: To evaluate the efficacy and safety of a transdermal testosterone patch (TTP, 300 microg/day) in naturally menopausal women with hypoactive sexual desire disorder (HSDD). METHODS: A total of 272 naturally menopausal women, predominantly not using hormone therapy, were randomized in this 6-month, placebo-controlled, double-blind, multicenter study to receive twice weekly either TTP or an identical placebo. Efficacy endpoints measured were the 4-week frequency of satisfying sexual episodes (SSE) using the Sexual Activity Log, the sexual desire domain of the Profile of Female Sexual Function and distress by the Personal Distress Scale. Safety was assessed by adverse events, laboratory parameters and hormone levels. RESULTS: The TTP group demonstrated significant improvements in SSE (p = 0.0089) as well as in sexual desire (p = 0.0007) and reduced personal distress (p = 0.0024) versus placebo at 6 months (intent-to-treat analysis, n = 247). The results were significant for all three endpoints in the subgroup (n = 199) not using hormone therapy. Similar numbers of women treated with placebo and TTP discontinued (n = 39, 27.5% vs. n = 26, 20%), reported adverse events (including application site reactions) (n = 101, 71.1% vs. n = 81, 62.3%) and withdrew due to adverse events (n = 20, 14.1% vs. n = 9, 6.9%). No clinically relevant changes were noted in laboratory parameters. Serum free and total testosterone levels increased from baseline in the TTP group (geometric means 5.65 pg/ml and 67.8 ng/dl, respectively, at week 24) within the physiological range; no changes were seen in estradiol and sex hormone binding globulin levels. CONCLUSIONS: TTP was effective in treating HSDD and improving sexual function in this study of naturally menopausal women with and without concurrent hormone therapy.

Mid-Aged Health in Women from the Indian Subcontinent (MAHWIS): a further quantitative and qualitative investigation of experience of menopause in UK Asian women, compared to UK Caucasian women and women living in Delhi.

OBJECTIVES: We previously found differences in experience of menopausal symptoms between a migrated Asian sample of women from the Indian subcontinent living in the UK (UKA), and matched samples of UK Caucasian women (UKC) and Asian women living in Delhi, India (DEL). This study aims to explain these differences using quantitative and qualitative methods. METHODS: A total of 153 peri- and postmenopausal women aged 45-55 years (52 UKA, 51 UKC and 50 DEL) were interviewed about their experience of menopause, lifestyle and health. The current study combines a quantitative analysis of potential predictors (sociodemographic variables, mood, lifestyle, ethnicity, country of residence and religion) of vasomotor symptoms and a qualitative thematic content analysis of descriptions of experience of menopause. RESULTS: Country of residence and anxiety best predicted vasomotor symptoms, while religion, ethnicity, age of menopause and lifestyle factors did not. Within the UK Asian sample, poor general health, anxiety and less acculturation were predictors of vasomotor symptoms. Qualitative analyses revealed cultural differences in symptoms and beliefs about the menopause. CONCLUSIONS: These results challenge assumptions about migrated Asian populations living in western cultures and the qualitative data provides information that might increase understanding of the experience and meanings of menopause amongst migrated Asian communities.

Effects of menopausal status on circulating calcitonin gene-related peptide and adipokines: implications for insulin resistance and cardiovascular risks.

OBJECTIVES: To determine, first, the effects of menopausal status on circulating calcitonin gene-related peptide (CGRP) levels and, second, the correlation between circulating CGRP levels and biomarkers for cardiovascular disease. METHODS: Cross-sectional study of healthy premenopausal and postmenopausal women volunteers and women admitted for elective benign abdominal surgery in a district general hospital. All women were non-smokers, had no history of endocrinological problems and were not receiving any hormone therapy. Fasting blood samples (premenopausal (n = 45): follicle stimulating hormone (FSH) < 20 IU/l, estradiol (mean +/- SEM) 440.33 +/- 51.82 pmol/l; postmenopausal women (n = 28): FSH > 20 IU/l, estradiol 93.79 +/- 17.40 pmol/l) were analyzed for CGRP, resistin, leptin, adiponectin, insulin and lipids using ELISA and immunoassays. RESULTS: Mean circulating CGRP levels were higher in the postmenopausal women compared with premenopausal women (pre: 41.79 +/- 9.01 pg/ml, post: 138.14 +/- 45.75 pg/ml; p = 0.047). Among women who were experiencing hot flushes, the postmenopausal women had significantly higher CGRP levels than the premenopausal women (pre: 21.98 +/- 4.95 pg/ml, post: 171.08 +/- 61.80 pg/ml; p = 0.028). Serum CGRP levels positively correlated with serum insulin levels (r = 0.652, p = 0.016) and HOMA index (r = 0.54, p < 0.001). CONCLUSION: These data show that circulating CGRP levels are influenced by menopausal status and suggest additional mechanisms through which increased risk of hyperinsulinemia and cardiovascular disease may arise in postmenopausal women.

17Beta-estradiol and anti-estrogen ICI:compound 182,780 regulate expression of lipoprotein lipase and hormone-sensitive lipase in isolated subcutaneous abdominal adipocytes.

We sought to investigate the influence of 17beta-estradiol (E(2)) on key enzymes of lipogenesis and lipolysis in subcutaneous (SC) abdominal adipocytes isolated from women. In addition, we wished to determine the influence of an anti-estrogen, ICI:compound 182,780 (anti-E), known to act via the estrogen receptor (ER), alone and in combination with E(2). Adipose tissue was obtained from 17 women undergoing elective surgery, with a mean age of 47 years (range, 34 to 62), mean weight of 65.4 kg (range, 58.1 to 75.0), and mean body mass index (BMI) of 25 kg/m(2) (range, 22 to 27). Isolated adipocytes were treated with varying doses of E(2), anti-E, or E(2) in combination with anti-E 10(-8) mol/L for 48 hours. Following treatment, proteins were extracted and the effects on lipogenesis and lipolysis were assessed, using Western blotting to determine the relative expression of the key enzymes of these processes, lipoprotein lipase (LPL; 56 kd), and hormone-sensitive lipase (HSL; 84 kd), respectively. Glycerol release into the medium was also measured as an index of lipolytic activity. The protein expression studies demonstrated that E(2) altered expression of LPL relative to control, with the highest dose significantly reducing LPL expression and the lower doses significantly increasing LPL expression (mean protein expression relative to control +/- SE): E(2) 10(-12) mol/L, 1.79 +/- 0.16 (P <.001); E(2) 10(-7) mol/L, 0.56 +/- 0.08 (P <.05). In contrast, HSL expression was increased relative to control at the higher doses of E(2) but was not significantly altered relative to control at the lower doses: E(2) 10(-12) mol/L, 1.02 +/- 0.14 (P >.05); E(2) 10(-7) mol/L, 1.55 +/- 0.17 (P <.01). Anti-E 10(-8) mol/L alone reduced LPL protein expression relative to control (P <.05) and increased HSL protein expression relative to control (P >.05). In combination with E(2) 10(-7) mol/L, anti-E 10(-8) mol/L did not abrogate the inhibitory effect on LPL expression relative to control (P <.05). Furthermore, E(2) 10(-7) mol/Lin combination with anti-E 10(-8) mol/L, displayed a stimulatory effect on HSL expression relative to control (P <.01). Glycerol release studies following the higher doses of E(2), and also following E(2) 10(-7) mol/L in combination with anti-E 10(-8) mol/L, provided support for the HSL protein expression studies. We conclude that the highest concentration of E(2) (10(-7) mol/L) significantly reduced LPL expression relative to control, while the lower concentrations significantly increased LPL expression relative to control. The highest concentration of E(2) also significantly increased both HSL expression and glycerol release relative to control. The effects of anti-E suggest that the in vitro effects of E(2) on lipogenesis and lipolysis occur, at least in part, through a receptor-mediated pathway. In addition, as recently observed in other tissues, ICI:compound 182,780 does not appear to behave as a pure anti-estrogen in isolated human adipocytes.

Pregnancy associated alpha2-glycoprotein in post-menopausal women receiving hormone replacement therapy.

Serum pregnancy associated alpha2-glycoprotein (P.A.G.) concentrations were measured in a group of post-menopausal women receiving hormone replacement therapy. The P.A.G. concentrations increased from a mean basal level of 48.1 mug/ml (range 20.6--104.4 mug/ml) to a maximum after six months therapy of 359 mug/ml (range 82--1290 mug/ml). This represents a mean increase of 647%. Two months after cessation of therapy the P.A.G. concentrations decreased but the mean level (60.3 mug/ml) was still significantly higher than the pre-treatment level. There was a significant correlation between the pre-treatment P.A.G. concentrations and the levels after six months of therapy. These findings may be of relevance to the use of P.A.G. determinations in the monitoring of malignant disease.

HRT in women with diabetes--review of the effects on glucose and lipid metabolism.

Hormone replacement therapy (HRT) is prescribed less frequently to women with diabetes. In this article, we review the effects of HRT on glucose metabolism and plasma lipids in women with type 2 diabetes. Current evidence is reassuring about the effects of HRT in women with diabetes, although as in all women, HRT should be prescribed on an individual basis with appropriate consideration given to advantages and disadvantages of therapy.

Thermography of menopausal hot flushes.

The skin temperature changes associated with menopausal hot flushes have been examined by thermography on a small group of patients. The subjective sensation of heat during a flush seems to be out of proportion to the actual skin temperature increase which was only about 1 degrees C on the face, neck and upper chest during this study. The increased temperature on the cheeks often persisted for several minutes after the symptoms of the flush had subsided, whereas sweating on the forehead produced a more rapid local cooling effect. Sequential temperature changes were portrayed by using an AGA Thermovision Model 680 Medical System with a colour isotherm attachment. This study provided colourful objective evidence that the symptoms of menopausal flushing is associated with an increase of skin temperature which may be monitored by thermography.

Effect of transdermal oestradiol on the haemostatic balance of menopausal women.

OBJECTIVE: To determine the effect of transdermal oestrogen replacement therapy on the haemostatic balance of menopausal women. DESIGN: Open, parallel group, prospective study. SETTING: Three hospital-based menopause clinics. SUBJECTS: Fifty-two postmenopausal women receiving transdermal hormone replacement therapy (Estrapak 50) for 6 months. Comparison group of 48 untreated postmenopausal women studied in parallel. MAIN OUTCOME MEASURES: Changes in platelet number, plasma concentrations of coagulation factors and their natural inhibitors, fibrinolytic activity, and rheological parameters. RESULTS: Estrapak 50 had no significant thrombophilic effect on any of the outcome measures. CONCLUSION: The haemostatic balance and thus the risk of thrombosis would not appear to be upset by this dose of transdermal oestrogen.