EMAS position statement: Managing obese postmenopausal women

Introduction

Obesity is a public health problem, with overweight individuals representing approximately 20% of the adult world population. Postmenopausal status is associated with higher prevalence of obesity, as 44% of postmenopausal women are overweight, among whom 23% are obese. Obesity often co-exists with other diseases, the most important being diabetes mellitus, dyslipidemia and hypertension. Furthermore, obesity increases the risk of gynecologic cancer, cardiovascular disease, venous thromboembolism, osteoarthritis and chronic back pain.

Aim

To formulate a position statement on the management of the menopause in obese women.

Materials and methods

Literature review and consensus of expert opinion.

Results and conclusions

Obese women seeking hormone therapy should be evaluated for their individual baseline risk of developing breast cancer, cardiovascular disease and venous thromboembolism. These risks should be weighed against expected benefit from symptom relief, improved quality of life and osteoporosis prevention. The lowest effective estrogen dose should be used (CEE 0.300–0.400 mg or estradiol 0.5–1 mg orally daily or 25–50 μg estradiol transdermally). With regard to progestogens, although no RCT data exist, there are observational studies showing that micronized progesterone or dydrogesterone may have a better risk profile with respect to breast cancer risk. There are no RCT data comparing various progestogens with regard to VTE risk. There are observational data, however, suggesting that micronized progesterone or pregnane derivatives may be associated with a lower VTE risk in postmenopausal women taking HT compared to nonpregnane derivatives. There is a rationale in suggesting the use of transdermal HT in obese women, since this route of administration has been associated with a lesser risk of venous thromboembolism than oral therapy.     

Attitudes towards the menopause and hormone therapy over the turn of the century

Objective

To assess attitudes and beliefs about the menopausal transition in a population of peri- and postmenopausal women, and if these attitudes differed before and after publication of studies on risks and benefits with hormone therapy (HT).

Materials and methods

In 1999 and 2003 all women aged 53 and 54 years in the community of Linköping, Sweden, were sent a questionnaire about use of HT, menopausal status and attitudes regarding menopause and HT.

Results

Most women regarded menopause as a natural process characterized by both hormonal deficiency and aging and these views did not differ between 1999 and 2003. A majority of women thought that significant climacteric symptoms were a good reason to use HT, but not that women without symptoms should use HT. The fraction of women who supported HT use was, however, significantly lower in 2003 than in 1999. Most women agreed that menopause leads to increased freedom and that it is a relief not to have to think about contraception and pregnancies.

Conclusions

Most Swedish women had a mainly biological view on menopause but nevertheless they thought that only women with climacteric symptoms should use HT. Women's attitudes towards HT have changed after recent reports on risks from long-term use of HT whereas the attitudes towards the menopausal transition were stable. Other factors than attitudes towards menopause affect women's actual use of HT. Probably women's and health care provider's apprehension of the risk-benefit balance of HT use is one such factor.     

EMAS position statement: Managing the menopause in women with a past history of endometriosis

Introduction

Endometriosis is a common disease in women of reproductive age. The symptoms usually disappear after a natural or a surgical menopause. Estrogen-based hormone therapy is required in women with premature or early menopause until the average age of the natural menopause and should be considered in older women with severe climacteric symptoms. However use of hormone therapy raises concerns about disease recurrence with pain symptoms, need for surgery and possibly malignant transformation of residual endometriosis.

Aim

To formulate a position statement on the management of the menopause in women with a past history of endometriosis.

Materials and methods

Literature review and consensus of expert opinion.

Results and conclusions

The data regarding hormone therapy regimens are limited. However it may be safer to give either continuous combined estrogen–progestogen therapies or tibolone in both hysterectomised and nonhysterectomised women as the risk of recurrence may be reduced. The risk of recurrence with hormone therapy is probably increased in women with residual disease after surgery. Management of potential recurrence is best monitored by responding to recurrence of symptoms. Women not wanting estrogen or those who are advised against should be offered alternative pharmacological treatment for climacteric symptoms or skeletal protection if indicated. Herbal preparations should be avoided as their efficacy is uncertain and some may contain estrogenic compounds.     

EMAS position statement: Managing the menopause in women with epilepsy

Introduction

Epilepsy is a major public health problem worldwide which is clinically characterized by recurrent seizures.

Aim

The aim of this position statement is to provide evidence-based advice on management of the menopause in postmenopausal women derived from the limited data available.

Materials and methods

Literature review and consensus of expert opinion.

Results and conclusions

Women with epilepsy may undergo an earlier natural menopause, between 3 and 5 years depending on seizure frequency, but the data are limited. Data regarding the effects of the perimenopause and menopause on epilepsy are conflicting: some studies show an increased risk of seizures but others do not. With regard to hormone therapy (HT) one study has shown an increase in seizures with oral therapy with conjugated equine estrogens and medroxyprogesterone acetate, but no data are available for other regimens. Women starting HT should be closely monitored as their antiepileptic drug (AED) needs may change. As vitamin D and calcium metabolism can be affected by AEDS, supplements should be considered. Herbal preparations should be avoided as their efficacy is uncertain and they may interact with AEDs.     

EMAS position statement: Managing menopausal women with a personal or family history of VTE

Introduction

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a serious cardiovascular event whose incidence rises with increasing age.

Aims

To formulate a position statement on the management of the menopause in women with a personal or family history of VTE.

Material and methods

Literature review and consensus of expert opinion.

Results and conclusions

Randomized controlled trials have shown an increased risk of VTE in oral hormone therapy (HT) users. There are no randomized trial data on the effect of transdermal estrogen on VTE. Recent observational studies and meta-analyses suggest that transdermal estrogen does not increase VTE risk. These clinical observations are supported by experimental data showing that transdermal estrogen has a minimal effect on hepatic metabolism of hemostatic proteins as the portal circulation is bypassed. A personal or family history of VTE, especially in individuals with a prothrombotic mutation, is a strong contraindication to oral HT but transdermal estrogen can be considered after careful individual evaluation of the benefits and risks. Transdermal estrogen should be also the first choice in overweight/obese women requiring HT. Observational studies suggest that micronized progesterone and dydrogesterone might have a better risk profile than other progestins with regard to VTE risk. Although these findings should be confirmed by randomized clinical trials, they strongly suggest that both the route of estrogen administration and the type of progestin may be important determinants of the overall benefit-risk profile of HT.     

Menopause and modifiable coronary heart disease risk factors: A population based study

Objectives

The aim of our study was to determine the effect of the menopause on various coronary heart disease (CHD) risk factors and on the global risk of CHD in a population based sample of women, making the difference between menopause and age related effects.

Study design

The Third French MONICA cross-sectional survey on cardiovascular risk included 1730 randomly selected women, aged 35–64 years, representative from the general population.

Main outcome measures

Women were defined as post-menopausal (postM; n = 696), peri-menopausal (periM; n = 183) or pre-menopausal (preM; n = 659) based on the date of last menses. Socio-demographic, clinical and biological data were collected. Analyses of variance were used to compare means.

Results

PostM women had significantly higher age-adjusted levels of total cholesterol (6.0 mmol/L in postM vs. 5.7 mmol/L in preM, p < 0.05) and LDL cholesterol (3.9 mmol/L vs. 3.6 mmol/L, p < 0.05). There was no difference in HDL cholesterol or triglyceride levels, glycemia or blood pressure. Further adjustment on body mass index and hormonal treatments did not modify the results. No risk factor was significantly different between periM and postM. However, the Framingham 10-year risk of CHD was higher in postM, as compared with periM (5.1% vs. 5.0%, p < 0.05). In postM women, lipids and the Framingham risk were not associated with elapsed time since menopause.

Conclusions

The CHD risk increases during the sixth decade could be explained not only by estrogen deprivation but also by an effect on lipid profile, which is likely to occur in the peri-menopause period.     

Hormone therapy and coronary heart disease risk by vasomotor menopausal symptoms

Objectives

We examined whether the association between hormone therapy (HT) use and coronary heart disease (CHD) risk differed between women with and without vasomotor symptoms (VMS).

Study design

We used data from a Dutch (EPOS) and Swedish (WHILA) population-based sample of 8865 women, aged 46–64 years, and free of CHD, stroke, venous thrombosis/pulmonary embolism or cancer at baseline. Data on HT use, VMS and potential confounders were collected by questionnaires.

Main outcome measures

CHD endpoints, obtained via registries.

Results

252 CHD cases occurred during 10.3 years of follow-up. Neither for women with nor for women without flushing or (night) sweats ever HT use was associated with CHD risk, compared with never HT use. Among women with intense VMS, ever HT use borderline significantly decreased CHD risk compared with never HT use (HR 0.48 [95% CI 0.20–1.03]). Among women without intense VMS, ever HT use was associated with a borderline significant increased CHD risk (HR 1.28 [95% CI 0.96–1.70]; P for interaction = 0.02). However, after multivariate adjustment, as compared to never HT use, ever HT use was not associated with risk of CHD among women with or without intense VMS.

Conclusions

In both groups of women with and without VMS, HT use does not seem to be associated with the risk of CHD. Hence, our findings do not support the view that HT use increases the CHD risk among women with an indication, i.e. VMS, but this needs to be confirmed in specifically designed studies.     

Menopause: Knowledge,attitude and practice among Italian women

Objectives

Investigating women's knowledge, attitude and practice in relation to menopause and systemic hormone therapy (HT) through a sample survey implemented within the preliminary works for the Consensus Conference “Informing women on hormone replacement therapy” that took place in Turin in May 2008 [Available at www.partecipasalute.it. Last access 7/8/2008].

Methods

The survey involved representative samples of women 45–60 years from five Italian regions. Twenty trained interviewers distributed the questionnaires reaching participants at their homes. A total of 969 women were selected from electoral rolls. 720 of them completed the interview (74.3% response rate).

Results

Participants reported positive attitudes about menopause; more than 90% believed menopause is a normal phase in women's life and more than 40% stated it is a good experience for a woman. Nevertheless, more than half of the sample did not receive any information about menopause and possible therapies, and those who did, often rated it as poor and contrasting. Moreover, clinicians who prescribed HT reported advantages (94%) much more frequently than disadvantages (22%) and risks (39%) in relation to this treatment. Lack of knowledge was associated with women's low educational level and their no or scarce attitude to attend health services.

Conclusions

More and qualified information should be provided to support women in making informed choices in relation to menopause and the use of systemic HT. Therefore, actions’ should be carried out in order to strengthen the advisory role of clinicians and other sources of information, when taking care of women who may be using or thinking of using HT.     

Menopause and aging: Changes in the immune system—A review

Background

The higher risk of women developing autoimmune diseases suggests that immune system is mediated by sex steroids.

Objective

To review the effects of aging and menopause in immune system.

Methods

A systematic review of in vitro, animal and human studies involving aging and menopause and immune system was carried out. An electronic search based on Internet search engines, MEDLINE (1966–June 2010) and the Cochrane Controlled Clinical Trials Register was done.

Results

After crossing-cleaning the reference lists, a total of 688 studies dealing with immune system and menopause were identified. Of them, 30 were considered selectable. The concept of immunosenescence reflects changes in both cellular and serological immune responses throughout the process of generating specific response to foreign antigens. This may be related with a higher incidence of infectious and chronic diseases. After menopause, there is an increase in pro-inflammatory serum markers (IL1, IL6, TNF-alpha), an increase in response of the immune blood cells to these cytokines, a decrease in CD4 T and B lymphocytes and a decrease in the cytotoxic activity of NK cells. Additionally, IL-6 is a key factor in bone resorption and also seems to be associated with other diseases more common after menopause such as diabetes, atherosclerosis and cardiovascular disease.

Conclusions

Most of the studies suggested that in addition to age, in postmenopausal women, changes of the immune system have been attributed to estrogen deprivation. Furthermore, recent studies point out changes in immune response related to use or cessation of hormone replacement at menopause.     

Menopause with cardiovascular disease and its risk factors among rural Chinese women in Beijing: a population-based study

Objectives

This study was to explore the independent influence of menopause on cardiovascular disease (CVD) and its risk factors in rural Chinese females.

Study design

This cross-sectional population-based study enrolled 2245 premenopausal and 2498 postmenopausal women aged 40–59 years in Fangshan district, Beijing, China. Data was collected by face-to-face interview, physical examination and biochemical examination during 2009 and 2010. General liner models were employed to calculate age-adjusted means of cardiovascular risk factors (CRFs). The comparisons of CVD and it risk factors according to menopausal status, and calculation of adjusted odds ratios/coefficients and their 95% confidence intervals for the associations of quartiles of elapsed time since menopause and age at menopause with CVD and its risk factors was performed by multivariate logistic/liner regression models separately.

Results

After adjustment for age and other confounders, no statistically significant association of menopause with CVD was observed in our participants; however, dyslipidemia prevalence and levels of waist-to-hip ratio, triglycerides, total cholesterol and low-density lipoprotein cholesterol were presented higher in postmenopausal group, compared to the premenopausal one (P < 0.05). Compared to women who had been menopausal for less than1 year, those with the elapsed time since menopause of 2–3 years had higher CHD prevalence, higher triglycerides level and lower high-density lipoprotein cholesterol level (P < 0.05).

Conclusions

Postmenopausal women in rural China had worse CRFs profile than the premenopausal ones, which implied menopause might aggravate the CRFs epidemic beyond effects of aging, and would increase the CVD burden during and after their middle ages.     

Menopausal hormone therapy and risk of lung cancer—Systematic review and meta-analysis

Objectives

Lung cancer rates increase among women in many regions of the world. To explore whether menopausal hormone therapy (MHT) plays a role.

Methods

We conducted a systematic search of the literature and performed meta-analyses of cohort studies (C), case–control studies (CC), randomized controlled trials (RCTs), and cancer registry studies (CR) to analyse the impact of estrogen therapy (ET), estrogen/progestin therapy (EPT) and any hormone therapy (HT) on lung cancer risks. We explored associations between ever-use of therapies and risks, analysed annual changes of risk, and the impact of therapies on histological subtypes. We calculated summary odds ratios, relative risks, 95% confidence intervals (CI; fixed-effects model), and assessed heterogeneity across studies. Eighteen studies were eligible (9 CC, 4 C, 3 RCT, 2 CR).

Results

We found a significant increase of risk – 76.2% – in non-smoking women with adenocarcinoma (CI 1.072–2.898) reporting ever-use of HT. Estrogen plus progestin therapy does not change the risk; however, the pooled analysis of 2 RCTs points at an increased risk (RR 1.359; CI 1.031–1.791). Our further results should be interpreted with caution as significances were found in analyses only when smoking and non-smoking women, various hormone regimens, or histological subtypes, respectively, were pooled.

Conclusions

Dedicated studies designed to more adequately delineate the role of MHT are necessary to substantiate whether use of MHT is a risk factor for this or other types of lung cancer.     

Premature menopause or early menopause: Long-term health consequences

Objective

To review and summarize current evidence on the health consequences of premature menopause and early menopause.

Methods

We reviewed existing literature and combined graphically some results from the Mayo Clinic Cohort Study of Oophorectomy and Aging.

Results

Premature menopause or early menopause may be either spontaneous or induced. Women who experience premature menopause (before age 40 years) or early menopause (between ages 40 and 45 years) experience an increased risk of overall mortality, cardiovascular diseases, neurological diseases, psychiatric diseases, osteoporosis, and other sequelae. The risk of adverse outcomes increases with earlier age at the time of menopause. Some of the adverse outcomes may be prevented by estrogen treatment initiated after the onset of menopause. However, estrogen alone does not prevent all long-term consequences, and other hormonal mechanisms are likely involved.

Conclusions

Regardless of the cause, women who experience hormonal menopause and estrogen deficiency before reaching the median age of natural menopause are at increased risk for morbidity and mortality. Estrogen treatment should be considered for these women, but may not eliminate all of the adverse outcomes.     

Degree and correlates of cardiac knowledge and awareness among cardiac inpatients

Objective

To investigate the degree of CHD awareness as well as symptom, risk factor, and treatment knowledge in a broad sample of cardiac inpatients, and to examine its sociodemographic, clinical and psychosocial correlates.

Methods

1308 CHD inpatients (351 [27.0%] female), recruited from 11 acute care sites in Ontario, participated in this cross-sectional study. Participants were provided with a survey which included a knowledge questionnaire among other measures, and clinical data were extracted from medical charts.

Results

855 (68.8%) respondents cited heart disease as the leading cause of death in men, versus only 458 (37.0%) in women. Participants with less than high school education (p < .001), an annual family income less than $50,000CAD (p = .022), low functional capacity (p = .042), who were currently smoking (p = .022), who had no family history of heart disease (p < .001), and who had a perception of low personal control (p = .033) had significantly lower CHD knowledge.

Conclusions

Awareness of CHD is not optimal, especially among women, South Asians, and those of low socioeconomic status. CHD patients have a moderate level of disease knowledge overall, but greater education is needed.

Practice implications

Tailored educational approaches may be necessary for those of low socioeconomic status, particularly with regard to the nature of CHD, tests and treatments.     

The effect of hormone therapy on serum melatonin concentrations in premenopausal and postmenopausal women: A randomized,double-blind,placebo-controlled study

Objectives

Melatonin levels decrease physiologically with age, and possibly with the transition to menopause. The plausible influence of hormone therapy (HT) on melatonin is poorly understood. The aim of this randomized, placebo-controlled, double-blind trial was to investigate the effect of HT administration on serum melatonin concentrations in late premenopausal and postmenopausal women.

Study design

Analyses were carried out among 17 late premenopausal and 18 postmenopausal healthy women who participated in a prospective HT study in Finland. Serum melatonin was sampled at 20-min (21:00–24:00 h; 06:00–09:00 h) and 1-h (24:00–06:00 h) intervals at baseline and after 6 months with HT or placebo.

Main outcome measures

Melatonin levels and secretion profile after 6 months of HT compared to placebo.

Results

Mean melatonin levels, mean melatonin exposure level (area under curve, AUC) and mean duration of melatonin secretion did not differ after 6 months with HT vs. placebo, irrespectively of the reproductive state. However, in postmenopausal women the melatonin peak time (acrophase) was delayed by 2.4 h (2 h 21 min) on average after 6 months with HT vs. placebo (p < 0.05). No interaction between time and group was detected when melatonin level was modelled before or after treatment.

Conclusions

Administration of HT to postmenopausal women alters melatonin peak time, but not melatonin levels. Further research on larger clinical samples is needed to better understand the effects of HT on melatonin profile.     

Use of calcium supplements and the risk of coronary heart disease in 52–62-year-old women: The Kuopio Osteoporosis Risk Factor and Prevention Study

Background

To analyse prospectively the effect of calcium or calcium + D supplementation on coronary heart disease (CHD) in 52–62-year-old women.

Methods and results

10,555 52–62-year-old women from the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) who did not have CHD at baseline were followed for nearly 7 years in 1994–2001. Information about use of calcium supplements and health events was obtained from two repeated questionnaires in 1989 and 1994. Information about causes of death during the follow-up was obtained from the Statistics Finland. Information about CHD and other disease morbidity before and during the follow-up was obtained from the Registry of Specially Refunded Drugs of the Finnish Social Insurance Institution (SII). Cox's proportional-hazards models were used to estimate the risk of CHD morbidity related to the use of calcium supplements. At baseline, 2723 women reported current use of calcium or calcium + D supplementation. During the follow-up, CHD was diagnosed in 513 women. Compared to non-users of calcium/calcium + D supplements, the multivariate adjusted hazard ratio (HR) of CHD was 1.24 (95% CI 1.02–1.52) in women who used these supplements. The multivariate adjusted HR for CHD morbidity in postmenopausal women who used calcium/calcium + D supplements was 1.26 (95% CI 1.01–1.57).

Conclusions

Calcium or calcium + D supplementation appears to increase the risk of CHD among women before old age.     

Problem based learning in chronic disease management: A review of the research

Objective

To determine whether problem based learning (PBL) is an effective educational strategy in chronic disease management.

Methods

The databases CINAHL, EMBASE, HealthStar, Medline and PubMed were searched for articles which focused on PBL and patient education or patient learning.

Results

Individual studies using PBL as an intervention with chronic disease management reflect significant changes in cognitive and clinical outcomes among individuals experiencing diabetes, asthma, arthritis and coronary artery disease.

Conclusion

There is a need for more well designed studies that assess the impact of PBL on self-care management of a variety of chronic diseases.

Practice implications

There is some evidence that PBL is effective in promoting self-care with individuals experiencing diabetes, arthritis, asthma and coronary artery disease.     

EMAS position statement: Managing women with premature ovarian failure

Introduction

Premature ovarian failure (also known as premature menopause) is defined as menopause before the age of 40. It can be “natural” or “iatrogenic” such as after bilateral oophorectomy. It may be either primary or secondary. In the majority of cases of primary POF the cause is unknown. Chromosome abnormalities (especially X chromosome), follicle-stimulating hormone receptor gene polymorphisms, inhibin B mutations, enzyme deficiencies and autoimmune disease may be involved. Secondary POF is becoming more important as survival after treatment of malignancy through surgery, radiotherapy and chemotherapy continues to improve.

Aim

To formulate a position statement on the management of premature ovarian failure.

Materials and methods

Literature review and consensus of expert opinion.

Results and conclusions

Diagnosis should be confirmed with an elevated FSH greater than 40 IU/L and an estradiol level below 50 pmol/L in the absence of bilateral oophorectomy. Further assessment should include thyroid function tests, autoimmune screen for polyendocrinopathy, karyotype (less than 30 years of age) and bone mineral density. Untreated early ovarian failure increases the risk of osteoporosis, cardiovascular disease, dementia, cognitive decline and Parkinsonism. The mainstay of treatment is hormone therapy which needs to be continued until the average age of the natural menopause. With regard to fertility, while spontaneous ovulation may occur the best chance of achieving pregnancy is through donor oocyte in vitro fertilization. It is essential that women are provided with adequate information as they may find it a difficult diagnosis to accept. It is recommended that women with POF are seen in a specialist unit able to deal with their multiple needs.     

Influence of menopause on biochemical markers of endothelial dysfunction—A case–control pilot study in North Indian population

Objective

Menopause, an estrogen deficient state, is known to increase the cardiovascular risk. Lipid changes accompanying menopause account for only few cases of coronary artery disease (CAD). Endothelium-dependent nitric oxide-mediated vasodilatory mechanisms are also known to play a role in development of coronary artery disease, but studies in menopausal women are very few. This study was hence undertaken to see if nitric oxide (NO)–cyclic guanidine monophosphate (c-GMP) pathway is influenced by menopause.

Design

This study was a hospital-based case–control study involving 100 women in age group 40–55 years. Of these, 50 women were postmenopausal and 50 were premenopausal. Women with known risk factors for CAD were excluded. Fasting blood samples from these women were collected and analyzed for estradiol levels, lipid profile, apolipoprotein B, plasma nitric oxide, c-GMP and platelet nitric oxide using standard kits and reagents. Statistical analysis was done on SPSS and two-tailed p-value <0.05 was considered significant.

Result

Postmenopausal women had significantly lower estradiol, plasma NO, and c-GMP levels as compared to premenopausal women (p < 0.05). Cholesterol, low-density lipoprotein (LDL) cholesterol and apolipoprotein B (apo-B) levels were higher and HDL levels were lower in postmenopausal as compared to premenopausal women (p < 0.05). Plasma NO showed a significant positive correlation with estradiol, HDL levels and negative correlation with apo-B levels.

Conclusion

Menopause tends to downregulate NO–c-GMP pathway resulting in endothelial dysfunction. The mechanism may be directly through estrogen receptors or indirectly through potentiation of dyslipidemia.     

Cigarette smoking and age of menopause: a large prospective study

Objectives

One of the possible consequences of tobacco consumption is that it contributes to an earlier age of menopause, though the causal relationship is yet to be confirmed. This study aimed to examine the prospective association between smoking and earlier age of menopause in a cohort of middle age Australian women after adjustment for a number of potential confounders.

Study design

21-Year follow-up of a cohort prospective study, Brisbane, Australia.

Main outcome measures

Age of menopause measured at the 21-year follow-up. Smoking and menopausal status were assessed by self-report. Other covariates were measured prospectively in the previous follow-ups.

Results

This study is based on 3545 women who provided data on their menopausal status at the 21-year follow-up of the study, and prospective as well as concurrent data on smoking. In univariate analysis tobacco smoking during the reproductive life course, socio-economic status and gravidity were significantly associated with earlier age of menopause. In multivariate analyses women who smoked cigarettes were more likely to experience earlier menopause than non-smokers. Compared to current smokers, risk of early menopause was significantly lower in those women who quit smoking in the past.

Conclusions

The data suggest that the impact of smoking is independent of other covariates associated with both smoking and age of menopause. The findings raise the possibility that effective quit smoking interventions may lead to a later age of menopause, and reduce the risk of adverse health consequences of early menopause.