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Introduction: While the associations of genetic, reproductive and environmental factors with the timing of natural menopause have been extensively investigated, few epidemiological studies have specifically examined their association with premature (<40 years) or early natural menopause (40-45 years)., Aim: The aim of this position statement is to provide evidence on the predictors of premature and early natural menopause, as well as recommendations for the management of premature and early menopause and future research., Materials and Methods: Literature review and consensus of expert opinion., Results and Conclusions: Strong genetic predictors of premature and early menopause include a family history of premature or early menopause, being a child of a multiple pregnancy and some specific genetic variants. Women with early menarche and nulliparity or low parity are also at a higher risk of experiencing premature or early menopause. Cigarette smoking (with a strong dose-response effect) and being underweight have been consistently associated with premature and early menopause. Current guidelines for the management of premature and early menopause mainly focus on early initiation of hormone therapy (HT) and continued treatment until the woman reaches the average age at menopause (50-52 years). We suggest that clinicians and health professionals consider the age at menopause of the relevant region or ethnic group as part of the assessment for the timing of HT cessation. In addition, there should be early monitoring of women with a family history of early menopause, who are a child of a multiple pregnancy, or who have had early menarche (especially those who have had no children). As part of preventive health strategies, women should be encouraged to quit smoking (preferably before the age of 30 years) and maintain optimal weight in order to reduce their risk of premature or early menopause., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Whether menopause increases the risk of type 2 diabetes mellitus (T2DM) independently of ageing has been a matter of debate. Controversy also exists about the benefits and risks of menopausal hormone therapy (MHT) in women with T2DM., Aims: To summarise the evidence on 1) the effect of menopause on metabolic parameters and the risk of T2DM, 2) the effect of T2DM on age at menopause, 3) the effect of MHT on the risk of T2DM, and 4) the management of postmenopausal women with T2DM., Materials and Methods: Literature review and consensus of experts' opinions., Results and Conclusion: Metabolic changes during the menopausal transition include an increase in and the central redistribution of adipose tissue, as well as a decrease in energy expenditure. In addition, there is impairment of insulin secretion and insulin sensitivity and an increase in the risk of T2DM. MHT has a favourable effect on glucose metabolism, both in women with and in women without T2DM, while it may delay the onset of T2DM. MHT in women with T2DM should be administered according to their risk of cardiovascular disease (CVD). In women with T2DM and low CVD risk, oral oestrogens may be preferred, while transdermal 17β-oestradiol is preferred for women with T2DM and coexistent CVD risk factors, such as obesity. In any case, a progestogen with neutral effects on glucose metabolism should be used, such as progesterone, dydrogesterone or transdermal norethisterone. Postmenopausal women with T2DM should be managed primarily with lifestyle intervention, including diet and exercise. Most of them will eventually require pharmacological therapy. The selection of antidiabetic medications should be based on the patient's specific characteristics and comorbidities, as well on the metabolic, cardiovascular and bone effects of the medications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Management of pelvic organ prolapse (POP) is a common and challenging task. Nowadays older women are more active than they were in the past, and the development of POP disrupts quality of life and impairs social and personal activities. The menopausal transition is a time of vulnerability, during which many women start experiencing symptoms and signs of POP. The role of hormonal changes or of hormonal therapies in influencing the development or progression of POP has been explored extensively. The management of POP requires considerable clinical skills. Correct diagnosis and characterization of the prolapse and an identification of the individual woman's most bothersome symptoms are the hallmark of appropriate initial management. Therapy is multimodal and often multidisciplinary, and requires a competence in pelvic medicine and surgery. The integration of hormonal, non-hormonal and surgical strategies is important and needs to be adjusted to changing circumstances on an individualized basis. When surgery is required, optimal management requires clinicians who are familiar with the advantages and disadvantages of all the available strategies and who are able to use these strategies in a tailored manner. Complex cases should be sent to specialist referral centers. Management of POP should be integrated into the practice of healthcare professionals dealing in menopause., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Postmenopausal osteoporosis is a highly prevalent disease. Prevention through lifestyle measures includes an adequate calcium intake. Despite the guidance provided by scientific societies and governmental bodies worldwide, many issues remain unresolved., Aims: To provide evidence regarding the impact of calcium intake on the prevention of postmenopausal osteoporosis and critically appraise current guidelines., Materials and Methods: Literature review and consensus of expert opinion., Results and Conclusion: The recommended daily intake of calcium varies between 700 and 1200mg of elemental calcium, depending on the endorsing source. Although calcium can be derived either from the diet or supplements, the former source is preferred. Intake below the recommended amount may increase fragility fracture risk; however, there is no consistent evidence that calcium supplementation at, or above, recommended levels reduces risk. The addition of vitamin D may minimally reduce fractures, mainly among institutionalised people. Excessive intake of calcium, defined as higher than 2000mg/day, can be potentially harmful. Some studies demonstrated harm even at lower dosages. An increased risk for cardiovascular events, urolithiasis and even fractures has been found in association with excessive calcium intake, but this issue remains unresolved. In conclusion, an adequate intake of calcium is recommended for general bone health. Excessive calcium intake seems of no benefit, and could possibly be harmful., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A vast majority of menopausal women suffer from vasomotor symptoms, such as hot flushes and night sweats, the mean duration of which may be up to 7-10 years. In addition to a decreased quality of life, vasomotor symptoms may have an impact on overall health. Vasomotor symptoms are associated with overactivity of the sympathetic nervous system, and sympathetic overdrive in turn is associated with metabolic syndrome, which is a known risk factor for cardiovascular disease. Menopausal hot flushes have a complex relationship to different features of the metabolic syndrome and not all data point towards an association between vasomotor symptoms and metabolic syndrome. Thus, it is still unclear whether vasomotor symptoms are an independent risk factor for metabolic syndrome. Research in this area is constantly evolving and we present here the most recent data on the possible association between menopausal vasomotor symptoms and the metabolic syndrome., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Context: There are conflicting data on postmenopausal hormone therapy (HT) and the risk of vascular dementia (VD) and Alzheimer's disease (AD)., Objective: We analyzed the mortality risk attributable to VD or AD in women with a history of HT use., Design, Patients, Interventions, and Main Outcome Measures: Finnish women (n = 489,105) using systemic HT in 1994 to 2009 were identified from the nationwide drug reimbursement register. Of these women, 581 died of VD and 1057 of AD from 1998 to 2009. Observed deaths in HT users with <5 or ≥5 years of exposure were compared with deaths that occurred in the age-standardized female population. Furthermore, we compared the VD or AD death risk of women who had started HT at <60 vs ≥60 years of age., Results: Risk of death from VD was reduced by 37% to 39% (<5 or ≥5 years of exposure) with the use of any systemic HT, and this reduction was not associated with the duration or type (estradiol only or estradiol-progestin combination) of HT. Risk of death from AD was not reduced with systemic HT use <5 years, but was slightly reduced (15%) if HT exposure exceeded 5 years. Age at systemic HT initiation (<60 vs ≥60 years) did not affect the death risk reductions., Conclusion: Estradiol-based HT use is associated with a reduced risk of death from both VD and AD, but the risk reduction is larger and appears sooner in VD than AD., (Copyright © 2017 by the Endocrine Society)

Objectives: The role of postmenopausal hormone therapy (HT) in the incidence of acute coronary syndrome (ACS) has been studied extensively, but less is known of the impact of HT on the mortality risk due to an ACS., Study Design and Main Outcome Measures: We extracted from a population-based ACS register, FINAMI, 7258 postmenopausal women with the first ACS. These data were combined with HT use data from the National Drug Reimbursement Register; 625 patients (9%) had used various HT regimens. The death risks due to ACS before admission to hospital, 2-28, or 29-365days after the incident ACS were compared between HT users and non-users with logistic regression analyses., Results: In all follow-up time points, the ACS death risks in HT ever-users were smaller compared to non-users. Of women with HT ever use, 42% died within one year as compared with 52% of non-users (OR 0.62, p<0.001). Most deaths (84%) occurred within 28days after the ACS, and in this group 36% of women with ever use of HT (OR 0.73, p=0.002) and 30% of women with ≥5year HT use (OR 0.54, p<0.001) died as compared to 43% of the non-users. Age ≤60 or >60 years at the HT initiation was accompanied with similar reductions in ACS mortality risk., Conclusions: Postmenopausal HT use is accompanied with reduced mortality risk after primary ACS., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Data are controversial on the impact of postmenopausal hormone therapy (HT) on breast cancer mortality. We analyzed nationwide Finnish data on breast cancer mortality risk in women using HT consisting of estradiol-only therapy (ET) or estrogen-progestogen therapy (EPT)., Methods: In total, 489,105 women using HT in 1994 to 2009, traced from the nationwide reimbursement register, were followed from the HT initiation (3.3 million cumulative exposure years) to breast cancer death (n = 1,578 women). The observed deaths were compared with those in the age-standardized background population., Results: The breast cancer mortality risk was reduced in all HT users with exposure for at most 5 years (standardized mortality ratio 0.56; CI 0.52-0.60), more than 5 to 10 years (0.46; 0.41-0.51), or more than 10 years (0.62; 0.56-0.68). A significantly larger risk reduction was detected in the 50 to 59 years age group (0.33; 0.29-0.37) compared with 60 to 69 (0.64; 0.59-0.70) or 70 to 79 (0.78; 0.69-0.87) years age groups. The death risk reductions in ET users tended to be larger in all age groups compared with EPT users, with a significant difference only in the 70 to 79 years age group (0.66; 0.57-0.76 vs 0.88; 0.77-1.00). The age at HT initiation, regardless whether ET or EPT, showed no association with breast cancer mortality., Conclusions: In the Finnish unselected population, breast cancer is fatal in 1 of 10 patients. Our data imply that this risk is prevalent in 1 of 20 patients with history of HT use. This is an important message for women considering or already using HT.

Context: The "window of opportunity hypothesis" refers to data indicating that conjugated equine estrogen alone or in combination with medroxyprogesterone acetate, if initiated before 60 years of age, protects the heart but endangers it if initiated later (Women's Health Initiative study). Less is known about the "window of opportunity hypothesis" with natural estradiol alone (ET) or with various progestins in combination with estradiol (EPT)., Objective: We related the death risk from coronary heart disease (CHD) in users of ET or EPT to the age at the initiation of therapy and to the progestin component of EPT. Design, Patients, Interventions, and Main Outcome Measures: Altogether, 498 105 women had used ET or EPT containing medroxyprogesterone acetate, norethisterone acetate, dydrogesterone, other progestins, or tibolone during 3.7 million person-years during 1994-2009. Women were followed from the therapy initiation to death, or to the end of year 2009. The risk of CHD death in hormone users was compared with that in the age-matched background population using standardized mortality ratio with 95% confidence intervals., Results: Age younger than 60 rather than older than 60 years at the initiation of ET (standardized mortality ratio, 0.53; 95% confidence interval, 0.47-0.59 vs 0.76; 0.71-0.82), EPT with norethisterone acetate (0.45; 0.41-0.49 vs 0.74; 0.67-0.81), or tibolone (0.35; 0.26-0.47 vs 1.01; 0.67-1.46) therapy lasting for less than 5 years was associated with significantly greater decreases in the CHD death risk. A similar tendency was also seen for other EPT groups and for longer use. In all hormone users, the CHD death risk was smaller the earlier the use of ET or EPT had started (P < .05); this phenomenon was unrelated to the progestin component of EPT., Conclusions: Estradiol-based hormone therapies are accompanied with larger CHD mortality risk reductions the earlier the therapies are initiated. The progestin component of EPT does not modify this "timing effect."

Objective: Menopausal hot flushes are associated with elevated activity of the sympathetic nervous system and may be related to increased risk for cardiovascular events. Sympathetic activation may trigger severe arrhythmias by modulating cardiac repolarization. The aim of this study was to evaluate the impact of hot flushes on cardiac repolarization in postmenopausal women with and without hot flushes., Methods: We assessed 150 recently postmenopausal healthy women-72 with hot flushes and 78 without hot flushes. They underwent 24-hour electrocardiographic recording, comprising a total of over 10,000,000 QT-interval measurements. The cardiac repolarization was assessed by measuring QT-intervals, heat rate dependence of QT-end intervals, and T-waves., Results: The maximal QT-end interval was shorter in women with hot flushes compared with those without hot flushes (481 ± 64 ms vs 493 ± 50 ms; P = 0.046). There were no differences between the rate dependence of QT-end intervals and T-wave measures between the groups. During the night-time hot flush period, we detected a steeper rate-dependence of QT-end intervals and a longer maximal T-peak-T-end interval (117 ± 54 ms vs 111 ± 56 ms; P < 0.001) compared with the control period., Conclusions: Women with hot flushes did not have clinically significant differences in ambulatory cardiac repolarization measurements compared with asymptomatic women. However, a sudden sympathetic surge occurring during the night-time hot flush may have direct effects on cardiac repolarization.

Study Question: Does the use of post-menopausal vaginal estradiol (VE) affect the mortality risk for coronary heart disease (CHD) and stroke., Summary Answer: The use of VE reduces the risk for cardiovascular mortality., What Is Known Already: A growing number of women use VE for post-menopausal genitourinary symptoms. Although this therapy is intended to have only local effects, estrogen is absorbed into the blood circulation and thus VE use may also have systemic effects., Study Design, Size, Duration: We studied a nationwide cohort in Finland 1994-2009 during which post-menopausal women (n = 195 756) initiated the use of VE (age [mean ± SD] 65.7 ± 10.9 years). Follow-up data gathered 1.4 million women-years and we assessed the mortality risk due to CHD (n= 9656) or stroke (n = 4294)., Participants/materials, Setting, Methods: The mortality risk in VE users was compared with that in the age-matched background population (standardized mortality ratio; [SMR]; 95% confidence interval) and related to various durations of exposure to VE (1 to ≤3, >3 to ≤5, >5 to ≤10 and >10 years)., Main Results and the Role of Chance: The use of VE was accompanied by decreases in the risk for CHD and stroke death. The risk reduction for CHD death was highest for >3 to ≤5 years exposure (SMR 0.64; 0.57-0.70) and for stroke for >5 to ≤10 years exposure (SMR 0.64; 0.57-0.72). The risk reductions for both CHD and stroke mortality were detected in all age groups with the highest risk reduction being in women aged 50-59 years (SMR 0.43; 0.19-0.88 and SMR 0.21; 0.06-0.58, respectively)., Limitations, Reasons for Caution: Our series lack a placebo arm and thus, may harbor a healthy woman bias. Moreover, data on clinical variables such as weight, smoking, blood pressure and family background were unobtainable for this study. Women using both VE and systemic hormone therapy (HT) were included in the comparator background population. This should not cause any significant error because the proportion of women using VE or other HT was modest (<10% in age-matched population) and because the use of systemic HT also reduces death risks in the same population. Our data cannot be directly applied for local regimens containing conjugated equine estrogens, because they are absorbed differently and may show effects that differ from those of estradiol., Wider Implications of the Findings: In 1000 women using VE for up to 10 years, a maximum of 24 fewer CHD deaths and 18 fewer stroke deaths is likely to occur., Study Funding/competing Interests: This work was supported by unrestricted grants from the Päivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, Finska Läkaresällskapet, the Orion Farmos Research Foundation, the Paavo Nurmi Foundation and a special governmental grant for health sciences research. The funding sources had no role in the study design, data handling or manuscript preparation. EPID Research is a company that performs financially supported studies for several pharmaceutical companies. Dr Korhonen, Dr Hoti and MSc Vattulainen, employed by Epid Research, report financial activities from several other pharmaceutical companies outside the submitted work. Dr Mikkola has been a speaker and/or received consulting fees from Mylan and Novo Nordisk. Dr Tuomikoski has been a speaker and/or received consulting fees from Orion and Mylan. The remaining authors report no conflict of interest., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Context: Current guidelines recommend annual discontinuation of postmenopausal hormone therapy (HT) to evaluate whether a woman could manage without the treatment. The impact of HT on cardiovascular health has been widely studied, but it is not known how the withdrawal of HT affects cardiovascular risk., Objective: We evaluated the risk of cardiac or stroke death after the discontinuation of HT. Design, Patients, Interventions, and Main Outcome Measures: Altogether 332 202 Finnish women discontinuing HT between 1994 and 2009 (data from National Reimbursement register) were followed up from the discontinuation date to death due to cardiac cause (n = 3177) or stroke (n = 1952), or to the end of 2009. The deaths, retrieved from the national Cause of Death Register, were compared with the expected number of deaths in the age-standardized background population. In a subanalysis we also compared HT stoppers with HT users., Results: Within the first posttreatment year, the risk of cardiac death was significantly elevated (standardized mortality ratio; 95% confidence interval 1.26; 1.16-1.37), whereas follow-up for longer than 1 year was accompanied with a reduction (0.75; 0.72-0.78). The risk of stroke death in the first posttreatment year was increased (1.63; 1.47-1.79), but follow-up for longer than 1 year was accompanied with a reduced risk (0.89; 0.85-0.94). The cardiac (2.30; 2.12-2.50) and stroke (2.52; 2.28-2.77) death risk elevations were even higher when compared with HT users. In women who discontinued HT at age younger than 60 years, but not in women aged 60 years or older, the cardiac mortality risk was elevated (1.94; 1.51-2.48)., Conclusions: Increased cardiovascular death risks question the safety of annual HT discontinuation practice to evaluate whether a woman could manage without HT.

Objective: Data on the health benefits and risks of postmenopausal hormone therapy (HT) are derived mainly from the use of conjugated equine estrogens. Estradiol-based regimens may have a different risk-benefit profile. We evaluated the risk of death caused by coronary heart disease (CHD), stroke, or any disease among users of estradiol-based HT regimens in a nationwide study in Finland., Methods: A total of 489,105 women who used HT from 1994 to 2009 (3.3 million HT exposure years), as indicated in the nationwide reimbursement register and the national Cause of Death Register, were followed. A total of 28,734 HT users died during follow-up; among the deaths, 3,843 were caused by CHD and 2,464 were caused by stroke. Mortality risk in HT users with varying duration of exposure (≤1 y, >1 to 3 y, >3 to 5 y, >5 to 10 y, or >10 y) was compared with that in an age-matched background population., Results: Risk of CHD death was significantly reduced by 18% to 54% in HT users and was positively related to HT exposure time. Risk of stroke death was also reduced by 18% to 39%, but this reduction was not clearly related to HT exposure time. Risk of all-cause mortality was reduced in HT users by 12% to 38%, almost in linear relationship with duration of exposure. All these risk reductions were comparable in women initiating HT before age 60 years and women initiating HT at age 60 years or older., Conclusions: In absolute terms, the risk reductions mean 19 fewer CHD deaths and 7 fewer stroke deaths per 1,000 women using any HT for at least 10 years.

Objective: The Women's Health Initiative (WHI) study clarified the indications and contraindications for postmenopausal hormone therapy (HT). We studied the impact of the WHI results on the risk of fatal stroke in HT users in Finland., Study Design: Retrospective analysis setting: Nationwide registers on postmenopausal HT use and causes of death between 1995 and 2009., Population: Women ≥40 years (n=290,272) using systemic estradiol-based postmenopausal HT., Methods: Follow-up started from the first HT purchase during the pre-WHI era (1995-2001) and post-WHI era (2002-2009)., Main Outcome Measures: Stroke deaths in HT users were compared with that in the age-matched background population and expressed as standardized mortality ratio (SMR) with 95% confidence intervals., Results: Overall, 311 HT users died due to stroke. The exposure to HT ≤1 year was associated with a similarly reduced 22% (0.67-0.91) risk of stroke death in the pre-WHI era and in the post-WHI era 27% (0.55-0.94). The risk reductions for HT exposure of 1-8 years in the pre-WHI era (47%, 0.42-0.65) did not differ from that in the post-WHI era (32%, 0.48-0.94). The discontinuation of HT was accompanied by a significant 33% (1.02-1.72) increase in stroke death risk in the pre-WHI era and a non-significant 32% (0.84-1.99) increase in the post-WHI era within the first post-treatment year, but no longer after 1-8 years., Conclusions: The change in prescribing policy after the WHI study did not affect the risk of fatal stroke in Finnish HT users., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To study the possible association between menopausal hot flushes and bone mineral density., Design: Observational study., Setting: University clinic., Population: Healthy women (n = 143) with or without hot flushes, 6-36 months postmenopausal after participating in a 6-month hormone therapy trial., Methods: The women prospectively recorded the number and severity of hot flushes for 2 weeks. Bone mineral density in lumbar and hip bones was measured with dual-energy X-ray absorptiometry at recruitment and reassessed in 114 women approximately 6.2 years later., Main Outcome Measures: Hot flushes and bone mineral density., Results: At recruitment, hot flushes were absent in 22 women, mild in 32, moderate in 28, and severe in 61. Lumbar bone mineral densities in non-flushing women (1.130 ± 0.022 g/cm(2) ; mean ± SEM), and in those with mild (1.088 ± 0.024 g/cm(2) ), moderate (1.082 ± 0.030 g/cm(2) ) or severe (1.102 ± 0.019 g/cm(2) ) hot flushes did not differ, nor were there differences in hip bone mineral densities between the four study groups. During the follow-up, lumbar bone mineral density decreased by a mean of 0.4 ± 0.1% a year in women not using hormone therapy, and increased by 0.1 ± 0.2% a year in hormone therapy users (p = 0.019). The respective non-significant changes in left and right total hip bone mineral densities were - -0.6 ± 0.01 and -1.0 ± 0.1 for the non-users, and -0.4 ± 0.1 and -0.6 ± 0.2 for hormone therapy users. These changes in bone mineral density bore no relation to the hot flush status at baseline., Conclusion: In recently menopausal women, hot flushes do not appear to determine bone mass density., (© 2014 Nordic Federation of Societies of Obstetrics and Gynecology.)

Hormone therapy is the most effective treatment for sweating and hot flashes, which are the most common symptoms of the menopause. The initiation of therapy for a healthy female of 50 to 59 years usually entails more health benefits than adverse effects, and there is no absolute upper limit for the duration of the treatment. It remains to be evaluated yearly whether the need or prerequisites for continuation of the treatment still exist. If the use of hormone therapy is not desired, alleviation of hot flashes and sweating can be attempted with life style modifications and other remedies.

Objective: Because premenstrual symptoms in fertile age resemble menopausal symptoms, many women with premenstrual symptoms fear that they have an increased risk for developing vasomotor symptoms in menopause. We investigated the impact of premenstrual symptoms on the occurrence and severity of menopausal vasomotor symptoms and quality of life., Methods: One hundred fifty recently postmenopausal healthy women recorded hot flashes prospectively (23, none; 34, mild; 30, moderate; 63, severe), and their quality of life was assessed using the Women's Health Questionnaire. We measured the occurrence of premenstrual symptoms in fertile age using the Premenstrual Symptoms Screening Tool and calculated a premenstrual score reflecting symptom severity., Results: One hundred seven women (89.2%) reported premenstrual symptoms (median score, 7.0; range, 0-38), which had impaired work efficiency or social relations in 64 women (53.3%). The occurrence of premenstrual symptoms was similar in women with and without hot flashes of different magnitudes, as the mean (SEM) premenstrual score was 7.8 (1.4) for no hot flashes, 5.0 (1.0) for mild hot flashes, 7.7 (1.3) for moderate hot flashes, and 9.4 (1.2) for severe hot flashes (P = 0.10). The severity of premenstrual symptoms failed to correlate with the severity of postmenopausal hot flashes (r = 0.087, P = 0.346). A history of premenstrual symptoms was associated with impaired memory and concentration capacity (r = -0.448, P < 0.001), depressive mood (r = -0.263, P = 0.02), sleep problems (r = -0.282, P = 0.01), and feeling less attractive (r = -0.260, P = 0.02) during the first menopausal years., Conclusions: The occurrence of premenstrual symptoms in fertile age is associated with impaired quality of life, but not hot flashes, in recently postmenopausal women.

Objective: To assess whether coronary heart disease mortality in Finnish hormone therapy (HT) users differed before and after 2002 when the Women's Health Initiative study was published., Methods: The risks of coronary heart disease death in HT users in relation to the age-matched background population were compared between the pre- (1995-2001) and post- (2002-2009) Women's Health Initiative eras. We used a nationwide register on HT (ie, estradiol with or without progestin) reimbursement and linked them to causes of death in 290,272 women aged 40 years or older., Results: Exposure to HT for 1 year or less was accompanied by a 29% reduction (0.71; 0.63-0.80; three per 10,000 fewer deaths) and an exposure of 1-8 years with a 43% reduction (0.57; 0.48-0.66; three per 10,000 fewer deaths) in the risk of coronary heart disease death in the pre-Women's Health Initiative era. In the post-Women's Health Initiative era, HT use of 1 year or less was associated with an 18% reduction (0.82; 0.76-1.00; one per 10,000 fewer deaths) and an exposure of 1-8 years with a 54% reduction (0.46; 0.32-0.64; two per 10,000 fewer deaths) in coronary heart disease mortality. Discontinuation of HT was associated with an increased risk of cardiac death of 42% (1.42; 1.17-1.71; seven per 10,000 extra deaths) in the pre-Women's Health Initiative era and 31% (1.31; 0.92-1.82; two per 10,000 extra deaths) in the post-Women's Health Initiative era during the first posttreatment year. This risk increase vanished in further follow-up during both eras., Conclusion: Changes in HT use after the Women's Health Initiative failed to affect coronary heart disease mortality of HT users in this nationwide study.

Objective: We assessed the impact of hot flashes and various forms of hormone therapy on health-related quality of life and sexual well-being in recently postmenopausal women., Methods: We prospectively interviewed 150 healthy women about hot flashes and health-related quality of life (using the Women's Health Questionnaire and the McCoy Female Sexuality Questionnaire), menopause-related symptoms, and general health. The women were classified into those with (n = 72) and without (n = 78) hot flashes and treated for 6 months with transdermal estradiol (1 mg/d), oral estradiol (2 mg/d) with or without medroxyprogesterone acetate (5 mg/d), or placebo., Results: At baseline, hot flashes contributed most strongly to poor sleep (correlation coefficient r = -0.525, P < 0.0001), somatic symptoms such as muscle pains (r = -0.348, P < 0.0001), menstrual cycle-resembling complaints (r = -0.304, P < 0.0001), anxiety and fears (r = -0.283, P < 0.0001), decreased memory and concentration (r = -0.279, P = 0.001), and sexual behavior (r = -0.174, P = 0.035). The different hormone therapy regimens alleviated hot flashes equally effectively and were therefore combined into a single group for further analysis. In women with baseline flashes, hormone therapy use significantly improved the scores for sleep (0.787 [0.243] vs 0.557 [0.249], hormone therapy vs placebo, P = 0.001, at 6 mo), memory and concentration capacity (0.849 [0.228] vs 0.454 [0.301], P < 0.0001, at 6 mo), and anxiety and fears (0.942 [0.133] vs 0.826 [0.193], P = 0.005, at 6 mo). Hormone therapy use showed no significant impact on these variables in women without baseline flashes., Conclusions: Hot flashes contribute differently to various variables affecting health-related quality of life shortly after menopause. Estradiol or an estradiol-medroxyprogesterone acetate combination similarly alleviates hot flashes and improves health-related quality of life in relation to elimination of hot flashes. Hormone therapy use does not confer any detectable quality-of-life benefit over placebo in women without disturbing baseline flashes.

In women, cardiovascular disease (CVD) accounts for about half of all deaths in Western countries. It is generally accepted that endogenous estrogen protects premenopausal women from CVD. However, whether postmenopausal hormone therapy (HT) confers cardiovascular benefit or harm remains controversial. One of the most pronounced factors modifying the cardiovascular effects of HT is age or time since menopause at the initiation of HT. Recently also the impact of hot flushes on CVD risk and the outcomes of HT has gained attention. This review summarizes the newest data regarding HT and CVD in recently postmenopausal women aged 50-59 years in light of the results from older HT trials. The aim is to help clinicians counsel their patients regarding the individual risks and benefits associated with HT use in this age group, where HT use is most prevalent.

Introduction: Sex-related physiological differences result in different expressions of diseases for men and women. Data are contradicting regarding the increase in the female risk for cardiovascular disease (CVD) at mid-life. Thus, we studied possible sex differences in age-adjusted mortality for CVD and non-vascular diseases stratifying our findings by specific age groups., Methods: Over one million deaths (1 080 910) reported to the Finnish nationwide Causes of Death Register in 1986-2009 were analyzed. A total of 247 942 male deaths and 278 752 female deaths were of CVD origin, the remaining deaths were non-vascular. The annual mortality rates were calculated per 100 000 mid-year population, separately for men and women in 5-year age categories., Results: The age-standardized risk of death from CVD was 80% higher for men (442/100 000) than for women (246/100 000). After age 45-54 the male CVD mortality rate elevated parallel to the non-vascular mortality, whereas in women the CVD mortality elevated considerably more rapidly than the non-vascular mortality from age 60 years onwards., Conclusions: Heart disease mortality in men accelerates at a relatively young age, but in women the risk shows a steep increase at approximately 60 years of age. These data emphasize the need to identify and prevent risk factors for CVD, especially in women in their mid-life years.

Objective: Recent data have indicated that menopausal hot flashes may be a determinant for cardiovascular health. Therefore, we studied the impact of hot flashes on insulin resistance, one of the most powerful markers of cardiovascular health, in recently postmenopausal women., Methods: We studied 143 recently postmenopausal (amenorrhea 6-36 mo) healthy and normal-weight women without previous hormone therapy use. The women prospectively recorded the number and severity of hot flashes for 2 weeks, and a validated total symptom score, the hot flash weekly weighted score, was calculated for each woman. Insulin resistance was assessed from fasting blood levels of glucose and insulin with the homeostasis model assessment., Results: In 12 women, the assessment of insulin (n = 11) or glucose (n = 1) failed, and they were excluded from further analysis. Thus, hot flashes were absent in 19, mild in 32, moderate in 27, and severe in 53 women. The levels of glucose or insulin, or HOMA showed no differences between these groups, nor was insulin resistance related to the number or severity of hot flashes or to the levels of C-reactive protein or sex hormone-binding globulin. Overall, insulin resistance showed a positive association with body mass index (mean difference, 0.058; 95% CI, 0.015-0.102; P = 0.009) and a negative association with level of estradiol (mean difference, -0.002; 95% CI, -0.003 to -0.001; P = 0.009)., Conclusions: Insulin resistance may not be involved in hot flash-related changes in cardiovascular health. However, because of the small sample size, these findings need to be interpreted with caution.

Objectives: To compare the responses of heart rate and blood pressure to various autonomic tests in women with and without pre-treatment hot flushes during estradiol and estradiol+medroxyprogesterone acetate (MPA) use., Study Design and Main Outcome Measures: Hundred and fifty recently postmenopausal women (72 with and 78 without hot flushes) were randomized to receive transdermal estradiol (1mg/day), oral estradiol (2 mg/day) alone or in combination with MPA (5mg/day), or placebo for six months. Cardiovascular responsiveness was comprehensively assessed with controlled and deep breathing, active orthostatic test, Valsalva maneuver and handgrip test., Results: Hot flushes were accompanied with a significant reduction (-2.2±0.7 vs. 1.3±1.1 beats/min, p=0.03) in resting heart rate during estradiol-only treatment; the route of estradiol administration was no factor in this regard. This effect was attenuated by the addition of MPA to oral estradiol. Hot flushes were also associated with reduced maximal heart rate in response to handgrip during the use of estradiol-only therapy (-2.2±1.3 vs. 2.8±1.5 beats/min, p=0.038); again, the MPA addition eliminated this effect. Hot flushes were accompanied with lowered resting but augmented blood pressure responses to handgrip test during all hormone regimens, whereas in women without hot flushes estradiol-only regimen tended to elevate diastolic resting blood pressure., Conclusions: Hot flushes appear as determinants for cardiovascular responses to hormone therapy. Estradiol-only therapy causes beneficial changes in cardiovascular regulation in flushing women, and these are blunted, in part, by the addition of MPA., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: The aim of the study was to compare the responses of heart rate variability (HRV) with hormone therapy in recently postmenopausal women with and without vasomotor hot flashes., Methods: Seventy-two women with and 78 women without hot flashes were randomized to receive transdermal estradiol gel (1 g/day), oral estradiol alone (2 mg/day), oral estradiol combined with medroxyprogesterone acetate (MPA; 5 mg/day), or placebo for 6 months. Time- and frequency-domain measures of HRV were assessed using 24-hour electrocardiographic recordings at baseline and after hormone therapy., Results: At baseline, the cardiac variables were similar in women with and without hot flashes. In women with hot flashes, the mean 24-hour heart rate and nighttime heart rate showed a tendency toward reduction in estradiol-only users compared with those taking placebo and those taking estradiol combined with MPA. In women with hot flashes, oral estradiol versus transdermal estradiol reduced nighttime HRV in the time domain (triangular index, -27 ± 36 vs +8 ± 36, P = 0.042). In women without hot flashes, the use of oral estradiol with MPA reduced time-domain HRV (SD of all normal-to-normal intervals; -11 ± 13 ms, P = 0.048, and square root of the mean of the sum of the squares of differences between adjacent normal-to-normal intervals; -6 ± 8 ms, P = 0.036). The women with hot flashes had more supraventricular ectopic beats when using oral estradiol with MPA than when using oral estradiol only (71 ± 128 vs 12 ± 11, P = 0.018)., Conclusions: Oral estrogen, especially when combined with MPA, may have adverse effects on HRV in women with and without hot flashes, whereas transdermal estradiol showed no such effects. Furthermore, women with hot flashes receiving oral estrogen combined with MPA are possibly more prone to cardiac arrhythmias than are women using estrogen only.

Nitric oxide may serve as one cofactor for human papillomavirus (HPV)-induced development of cervical cancer. Therefore, we first assessed the levels of cervical fluid nitric oxide metabolite (NOx) in 283 women with and without high-risk (hr) HPV. The NOx level in women with hr HPV (48.4 μmol/L [95% CI: 39.4-56.6], n = 199) was higher (p < 0.001) than that in women without hr HPV (24.6 μmol/L [95% CI: 19.1-38.7], n = 84). Second, we evaluated if cervical fluid NOx levels could predict the persistence of hr HPV. Therefore, we followed up 113 women with detectable hr HPV without any treatment for 12 mo and repeated hr HPV test. High-risk HPV persisted in 72 women (64%) and disappeared in 41 women (36%). The median basal levels of NOx were higher (p = 0.02) in women with persistent hr HPV (56.9 μmol/L [95% CI: 48.7-81.0]) compared to those with eradicated hr HPV (37.7 μmol/L [95% CI: 27.0-58.0]). The NOx level higher than the 75th percentile (>87.0 μmol/L) predicted hr HPV persistence (OR = 4.1 [95% CI: 1.3-13.1]). This cutoff level of NOx showed 33% sensitivity and 90% specificity in predicting the persistence of hr HPV, but it failed to predict cytological progression or regression in 12 mo. In conclusion, high cervical fluid NOx appears to be connected to the persistence of hr HPV, but the low predictive capacity of NOx prevents its clinical use at this phase., (Copyright © 2010 UICC.)

Hot flushes are complained of by approximately 75% of all postmenopausal women, and hormone therapy (HT) is the most effective way to alleviate them. Hot flushes are characterized by altered vascular function and sympathetic nervous system activity. Hot flushes occurred more often in women attending large, non-randomized observational studies (e.g. Nurses' Health Study), where HT use protected against cardiovascular disease (CVD). However, they were absent (or mild) in randomized HT trials where HT use was accompanied with an elevated risk for CVD. Hot flushes, if a factor for cardiovascular health, could partly explain the conflict between observational and randomized trials. Several cross-sectional studies imply that hot flushes are detrimental to the cardiovascular system. However, the data are not uniform, and hot flushes were recalled retrospectively or during HT use. In our prospective study hot flushes were accompanied with a vasodilatory effect during endothelial testing, and this was related to the severity of hot flushes. Night-time hot flushes were followed with transient rises in ambulatory blood pressure (BP). However, no effect of hot flushes on diurnal BP was detected. The use of estradiol showed no harmful effects on endothelial function in women with hot flushes, but in non-flushing women oral, but not transdermal, estradiol led to vasoconstrictive changes. Estradiol complemented with medroxyprogesterone acetate eliminated the vasoconstrictive effect of sole oral estradiol. Thus, both oral and transdermal estradiol are applicable in flushing women, whereas a transdermal route should be favored in non-flushing women if used e.g. for bone protection.

Objectives: During menopausal transition autonomic balance is known to shift towards sympathetic dominance, but the role of vasomotor hot flushes in this phenomenon is not understood. We compared cardiovascular autonomic responsiveness between women with and without hot flushes., Study Design and Main Outcome Measures: One hundred fifty recently postmenopausal healthy women with varying degree of hot flushes (none, mild, moderate, severe) underwent comprehensive cardiovascular autonomic nervous testing (controlled and deep breathing, active orthostatic test, Valsalva manoeuvre and handgrip test) assessing both sympathetic and parasympathetic activity. The responses of heart rate, heart rate variability and blood pressure in these tests were evaluated., Results: Responses in heart rate showed differences between the study groups only in the Valsalva manoeuvre where the tachycardia ratio in all symptomatic women was lower (p=0.041) than in women without hot flushes. Neither change in the heart rate variability analyses nor the blood pressure responses were affected by hot flush status. However, there was a non-significantly higher maximum systolic (140 (112-182)mmHg vs. 135 (102-208)mmHg) and diastolic blood pressure (94 (72-112)mmHg vs. 90 (66-122)mmHg) following the handgrip test in women without hot flushes vs. all the symptomatic women., Conclusions: Menopausal hot flushes seem to be associated with a possibly increased sympathetic preponderance without an effect on parasympathetic activity in cardiovascular autonomic responses. This may imply a potentially negative impact on cardiovascular health in women experiencing hot flushes., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Blood pressure (BP) is one of the most powerful determinants of cardiovascular risk in women. This risk may differ between post-menopausal women with and without vasomotor hot flushes, possibly indicating different vascular responses to hormone therapy (HT). Thus, we compared in a clinical trial the effect of HT on ambulatory BP in normotensive, recently post-menopausal women with or without severe hot flushes., Methods: A total of 147 women recorded prospectively their hot flushes for 2 weeks; 70 women were symptomatic (>or=7 moderate/severe hot flush episodes/day), whereas 77 women were defined as asymptomatic (

Background: Menopausal hot flushes may be a marker for a difference in vascular function. We studied the associations between hot flushes of varying severity and ambulatory blood pressure (BP) and heart rate (HR)., Methods: A total of 147 women with onset of menopause within the preceding 6-36 months reported no hot flushes (n = 23) or mild (n = 33), moderate (n = 30), or severe (n = 61). Ambulatory BP and HR were registered for 24 hours. The variables, analyzed separately for day-time and night-time, were compared among the four study groups., Results: Hot flushes failed to show any relationship to mean day- or night-time BP, nocturnal dipping of BP, or HR. However, severe night-time hot flushes were accompanied by elevations in systolic BP (4.1 +/- 10.5 mmHg, P = 0.061), diastolic BP (3.1 +/- 6.8 mmHg, P = 0.032), and heart rate (3.0 +/- 7.2 beats/minute, P = 0.043)., Conclusion: Hot flushes are not associated with ambulatory BP or heart rate in normotensive, recently post-menopausal women, although severe night-time hot flush episodes are followed by significant elevations in BP and heart rate. The latter may be of clinical significance.

Objective: Menopausal hot flashes may affect vascular function and perhaps explain conflicting data on cardiovascular disease (CVD) between observational and randomized hormone therapy (HT) studies. We prospectively assessed hot flash status in recently postmenopausal women and related it to a number of biochemical vascular surrogate markers for CVD., Methods: Healthy, nonsmoking women (n = 150) exhibiting a broad range (no, mild, moderate, severe) of hot flashes and an onset of menopause within the previous 0.5 to 3 years were studied with laboratory tests for lipids, lipoproteins, apolipoproteins, high-sensitivity C-reactive protein, and sex hormone-binding globulin., Results: Apart from marked differences in hot flashes, the groups showed comparable levels of estrone, estradiol, or free estradiol index. The levels of total cholesterol (3.7-9.1 mmol/L) were similar between the groups (P = 0.744), and hypercholesterolemia (>6.5 mmol/L) was encountered equally often (P = 0.699). No difference was seen in high-, low-, or very low-density lipoproteins, triglycerides, apolipoprotein A-1, apolipoprotein B (or their ratio), or lipoprotein(a) between the groups. The levels of sex hormone-binding globulin and high-sensitivity C-reactive protein correlated negatively with each other (r = -0.204; P = 0.013) but showed no dependence on hot flashes (P = 0.531 and P = 0.215, respectively)., Conclusions: No baseline difference in lipid or nonlipid CVD risk factors was observed between women with hot flashes (potential HT users) and women with no or mild hot flashes (potential HT nonusers). This may imply that hot flash status per se cannot explain the difference between observational and randomized trials.

Objective: To compare the vascular responses to hormone therapy in women with and without hot flushes., Methods: We randomly assigned 143 healthy, recently postmenopausal women (mean age 52.4+/-0.2 years, time since menopause 19.5+/-0.9 months) with intolerable hot flushes (more than seven moderate/severe episodes per day) or tolerable hot flushes (fewer than three mild episodes per day) to receive 1 mg of transdermal estradiol gel, oral estradiol (2 mg) with and without daily medroxyprogesterone acetate, or placebo for 6 months. Vascular function was assessed by pulse-wave analysis and endothelial function testing with nitroglycerin and salbutamol challenges., Results: Hot flushes did not affect the changes in arterial or aortic stiffness or endothelial function in response to various forms of hormone therapy. However, in women with tolerable hot flushes, oral estradiol caused a decrease of 13.2% (P=.028) in the time to the first systolic peak (dependent on the rapid phase of ventricular ejection) after nitroglycerin. In addition, the time to the reflected wave (dependent on pulse-wave velocity) after nitroglycerin was decreased by 8.4% (P=.018). These effects were not seen in women with intolerable hot flushes or with the other treatment regimens., Conclusion: Women without troublesome hot flushes are susceptible to unfavorable vascular effects after oral estrogen treatment, resulting in less compliant vasculature., Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00668603., Level of Evidence: I.

Objective: Observational studies indicate that postmenopausal hormone therapy (HT) prevents cardiovascular disease, but randomized clinical trials have not confirmed this effect. Hot flushes were more likely to be present in women starting HT in observational studies, whereas these symptoms were mild or absent among women attending randomized clinical trials. We hypothesized that vascular function may differ in women with and without vasomotor hot flushes., Methods: One hundred forty-three recently postmenopausal women showing a broad range of variation in hot flushes were studied with radial artery tonometry. Pulse wave analyses were assessed at baseline and after nitroglycerin and salbutamol challenges. Wilcoxon signed rank test was used for paired comparisons after challenges with nitroglycerin and salbutamol., Results: Neither baseline arterial stiffness nor endothelial function differed between women without or with mild, moderate, or severe hot flushes. However, after nitroglycerin challenge, the time to the onset of the reflected wave (dependent on pulse wave velocity) was 9.5% longer (P=.014), and the time to the first systolic peak (dependent on the rapid phase of ventricular ejection) was 13.9% longer (P=.025) in women with severe hot flushes as compared with asymptomatic women., Conclusion: Women with severe vasomotor hot flushes show greater vascular responsiveness to nitroglycerin than women without hot flushes. This may partially explain the conflicting data between observational and randomized HT studies., Clinical Trial Registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00668603, Level of Evidence: II.

Objective: Intrahepatic cholestasis of pregnancy predisposes women to liver disorders years after affected pregnancy. We compared the basal levels and responses of hyaluronic acid, a marker of liver fibrosis, and liver transaminases to postmenopausal hormone therapy in women with (n = 20) and without (n = 20) a history of intrahepatic cholestasis of pregnancy., Study Design: This was a randomized, double-blind, placebo-controlled, crossover trial., Results: Basal levels of hyaluronic acid were similar in both groups. Two weeks of oral estradiol 2.0 mg/day led to significant but similar (10.9% to 15.4%) rises in hyaluronic acid in both groups. Increasing the dose of oral estradiol to 4.0 mg/day resulted in normalization of the levels, whereas the addition of medroxyprogesterone acetate led to falls (11.0% to 10.7 %) in hyaluronic acid. Transdermal estradiol 50 microg led to a rise (3.2 %) in hyaluronic acid only in the control group. Other liver markers were normal at baseline and during hormone therapy., Conclusion: Normal basal levels and/or normal responses of hyaluronic acid and other liver markers to hormone therapy in women with previous intrahepatic cholestasis suggest that this therapy does not predispose these women to liver diseases.