12 November 2018

The US Nurses’ Health Study is well placed to follow a large cohort of women over time and a recent publication from this study has linked menstrual cycle characteristics in adolescence and early adulthood with eventual early menopause [1]. In over 108,000 premenopausal women studied from a baseline age of 25–42 years, from the years 1989 to 2011, 2.6% of participants (n = 2794) underwent an early menopause (< 45 years) during follow-up. The authors of the paper reported that menarche at age 10 years (compared with 12 years) was a risk factor for early menopause, with a hazard ratio (HR) of 1.19 (95% CI 1.02–1.39). Other factors that were linked with an early menopause included cycle length < 25 days in early adulthood (18–22 years), with a HR of 1.71 (95% CI 1.47–1.96). Those with irregular cycles had a reduced risk of early menopause, HR 0.51 (95% CI 0.43–0.60), and women with a cycle length in early adulthood of ≥ 40 days had a similar reduction in risk of undergoing early menopause, HR 0.44 (95% CI 0.34–0.58). Hence it appears that factors that are associated with a higher frequency of ovulation at least early in reproductive life (and potentially throughout reproductive life if the pattern continues long term) may in fact be linked to an early menopause, with the reverse being true for those undergoing less frequent ovulation.

Comment

In most cases of premature or early menopause, a causative factor will not be found, which can be perplexing for women searching for answers for themselves and possibly also for their female children, who may also be at risk of undergoing menopause at a similar or even younger age. Hence the importance of research that attempts to find patterns or links that may point to markers that may be used to identify women at risk of undergoing an early or premature menopause.

Sonia Davison

Endocrinologist, Women’s Health Research Program, Monash University, Australia

12 November 2018

Women with osteoporosis commonly have other co-morbidities and are often on medications that may impact on bone health. Whilst considerable focus has been directed toward treatments with deleterious effects on bone, other non-osteoporosis medications may have favorable effects on bone turnover. This study in over 45,000 users of statins, compared to over 115,000 controls, included over 68,000 women, with an age range of 50–90 years [2]. Follow-up occurred over a 13-year period. 10% of the cohort overall developed osteoporosis: 6.8% of statin users and 11.3% of non-users, with a hazard ratio of developing osteoporosis in statin users of 0.52 (95% CI 0.49–0.54). When the individual statin products were examined, simvastatin, atorvastatin and rosuvastatin were all associated with a lower risk of developing osteoporosis (HR 0.85, 95% CI 0.76–0.94; HR 0.68, 95% CI 0.63–0.74; HR 0.43, 95% CI 0.36–0.52, respectively). No reduction in risk was seen for pravastatin, however: HR 0.89 (95% CI 0.76–1.05).

Comment

The authors highlighted the facts that statins augment osteoblast activity and inhibit osteoblast apoptosis and increase bone formation, in addition to sharing the same pathway as nitrogen-containing bisphosphonates. Furthermore, it has been reported that simvastatin has been shown to inhibit RANKL-induced osteoclast differentiation.

Sonia Davison

Endocrinologist, Women’s Health Research Program, Monash University, Australia

12 November 2018

This article examined the findings from 31 prospective cohort studies of women between 30 and 79 years and involved over 3.3 million women [3]. The authors reported that there was no relationship between BMI and breast cancer risk in premenopausal women; however, in postmenopausal women, breast cancer risk increased by 3.4% for every 1 kg/m2 increment in BMI. When exploring the relationship between BMI and breast cancer further, the authors reported a reduction in risk of breast cancer with increasing BMI in studies of European women (relative risk (RR) 0.79, 95% CI 0.70–0.88) but not in Asian or American women, or the group as a whole. However, in postmenopausal women, higher BMI was associated with higher risks of breast cancer in the group as a whole, Asian women (RR 2.10; 95% CI 1.64–2.69), US women (RR 1.29; 95% CI 1.14–1.46), women with estrogen receptor-positive breast cancer (RR 1.32; 95% CI 1.23–1.42) and those with no past hormone therapy use (RR 1.43; 95% CI 1.21–1.68), but interestingly no increase in risk with increasing BMI in European women (RR 1.19; 95% CI 0.98–1.43) or those with a past history of hormone therapy use (RR 0.94; 95% CI 0.63–1.40).

Comment

Increasingly cancer risk has been linked to lifestyle, and, whilst there are very clear links with regard to obesity and some cancers in women, such as endometrial cancer, the relationship between BMI per se and some cancers is yet to be fully defined. Fat is an endocrinologically active organ, especially with regard to estrogen, and hence a link between increased fat mass and hormonally linked cancers seems logical. These findings are interesting and point to the importance of lifestyle and metabolic factors in breast cancer risk, and also to the role of health practitioners in promoting general health measures such as achieving a healthy weight for height, as a cancer risk reduction strategy.

Sonia Davison

Endocrinologist, Women’s Health Research Program, Monash University, Australia

The intuition of an association between sleep duration and mortality goes back to the 1970s. Since then, many prospective studies have suggested that short and long sleepers have an increased risk of all-cause and cause-specific mortality compared to subjects who sleep 7–8 hours per night. In the recent publication by Kabat and colleagues, data from the Women's Health Initiative (WHI) were used to examine sleep duration, insomnia, and use of sleep medications in relation to total and cause-specific mortality (cardiovascular, cancer, other) [1]. A total of 158,203 subjects in the combined clinical trial and observational study components of the WHI were included, among which a total of 30,400 deaths occurred, including 8857 cardiovascular disease (CVD) deaths, 9284 cancer deaths, and 11,928 other deaths over a median of 17.8 years. Sleep duration, sleep quality, assessed by the WHI Insomnia Rating Score, and use of sleep aids (alcohol or medication) were recorded at baseline and information on duration and quality of sleep was collected at multiple time points for most cohort members. Women with the lowest and highest number of hours of sleep per night (≤ 5 h or ≥ 9 h) had higher body mass index (BMI) and systolic blood pressure, higher levels of depression, use of sleep aids, fair-to-poor health, and a history of diabetes, CVD, or cancer. Moreover, they had lower levels of physical activity and were less likely to be white, to be college graduates, or to report ever use of hormone therapy. Women with insomnia had higher BMI, more pack-years of smoking, higher systolic blood pressure, higher proportions of use of sleep aids, higher proportions of diabetes, CVD, and/or cancer, and higher levels of depression. Short and long sleep durations measured at the baseline visit were associated with increased risk of total mortality, CVD mortality, and other mortality, but not with cancer mortality. Insomnia reported at baseline showed a weak inverse association with total and CVD mortality. Use of sleep aids was associated with increased risk of total mortality, CVD mortality, and other mortality. In time-dependent analysis, insomnia only showed a borderline positive association with cancer mortality. The association of short sleep duration with total mortality and CVD mortality was unchanged, while that with other mortality was strengthened and the association of long sleep duration with all four outcomes was strengthened. Use of sleep aids was positively associated with mortality.

A substantial contribution to the knowledge on the evolution of major chronic diseases in women has come from the Nurses' Health Study (NHS). With a new analysis of the data of over 90,000 female candidates during a 30-year timespan, researchers of the NHS aimed at examining cardiovascular disease risk in women with metabolic health, i.e. absence of diagnosed diabetes, hypertension and hypercholesterolemia, across different body mass index (BMI) categories [1]. Moreover, they verified the effect of the onset of metabolic disorders on cardiovascular risk in women who were healthy upon inclusion in the study [1]. BMI was defined as normal (18.5–24.9 kg/m²), overweight (BMI 25.0–29.9 kg/m²), and obese (BMI ≥ 30 kg/m²). Health status was assessed every 2 years based on questionnaires. Investigated outcomes were fatal and non-fatal myocardial infarction and stroke, as well as their combination as total cardiovascular disease. Results of the analysis showed that the risk of total cardiovascular disease was higher in women who were metabolically healthy overweight (hazard ratio (HR) 1.20) or obese (HR 1.39) than in women with metabolically healthy normal weight, but lower than that of women with pre-existing metabolic conditions across all BMI groups (HR 2.43 for normal weight, HR 2.61 for overweight, HR 3.15 for obese women). Metabolic health proved to be transient for most women as only 6% of obese, 7.9% of overweight and 15.4% of normal-weight subjects remained healthy over a 30-year follow-up. Women who converted to a metabolically unhealthy phenotype, especially those who developed diabetes (HR 1.29 for normal weight, HR 1.93 for overweight, HR 2.17 for obese women) or hypertension (HR 1.92 for normal weight, HR 1.87 for overweight, HR 2.03 for obese women), had a risk between that of women with stable metabolic health and that of women with pre-existing metabolic conditions; the risk was higher if these were long-standing. Incident hypercholesterolemia had a very slight effect on cardiovascular risk. In conclusion, the presence of metabolic disorders, especially hypertension and diabetes, confers the highest cardiovascular risk across all categories, which is proportional to BMI but also to their duration. Obesity, even in the absence of metabolic conditions, determines a cardiovascular risk which is higher than that for normal weight.

ASPREE (ASPirin in Reducing Events in the Elderly) was a randomized, placebo-controlled trial of aspirin (100 mg enteric coated daily) versus placebo in people aged 65 + years and free of cardiovascular events at recruitment. A total of 19,114 Australians and Americans, screened to confirm normal cognition and no prior cardiovascular event at study entry, were recruited and followed on average for 4.7 years. The first three outcome papers for the study have just been published on 16th September 2018 in the New England Journal of Medicine. The risk of death was greatest in the aspirin-treated group versus the placebo group: 12.7 events per 1000 person-years in the aspirin group and 11.1 events per 1000 person-years in the placebo group (hazard ratio 1.14; 95% confidence interval (CI), 1.01–1.29) [1]. The main contribution to the higher death rate in the aspirin group was cancer (hazard ratio 1.31, 95% CI 1.10–1.56). This was not confined to a specific cancer, although a higher rate of colon cancer was an important contributor (hazard ratio 1.77, 95% CI 1.02–3.06). Of note, intracranial bleeding was more likely with aspirin than with placebo (hazard ratio 1.50; 95% CI, 1.11–2.02), with no specific effect by subgroup analyses. The hazard ratio for a major secondary hemorrhage for women was 1.58 (95% CI 1.26–1.99). In addition, a cardioprotective effect was not seen (aspirin versus placebo hazard ratio, 0.89; 95% CI 0.77–to 1.03).

Comment

This large, robust, randomized, placebo-controlled clinical trial has clearly shown that aspirin, commenced at 65 + years, did not prevent cardiovascular disease or cancer, but unexpectedly was associated with increased total cancer risk and increased all-cause mortality. Furthermore, in a separate paper, concurrently published in the New England Journal of Medicine, aspirin was not associated with increased disability-free survival [2]. In women, past observational studies have suggested that aspirin and other anti-inflammatory drugs might protect women from breast cancer, with a risk reduction in the order of 10–20% [3]. This was not seen for the 10,783 female participants in ASPREE.

Ren and colleagues have undertaken a cross-sectional study of 8191 women (median age 56 years, interquartile range 47–65 years) recruited in rural China to determine the association between menopause and the likelihood of developing type 2 diabetes (T2D) [1]. The diagnosis of T2D in women was established by a fasting plasma glucose of 7.0 mmol/l or greater, and/or the use of insulin or an oral hypoglycemic agent and/or a self-reported history of diabetes (excluding type 1 diabetes, gestational diabetes mellitus, or diabetes due to other causes).

Of note, 38% of the women in the study were overweight, 22% were obese and 30% had hypertension. Only 7.8% reported a family history of T2D.

The study reported an overall prevalence of T2D of 13% amongst the included women. After adjusting for age, smoking, alcohol drinking, body mass index (BMI), age at menarche, systolic and diastolic blood pressures, and family history of diabetes, the risk of T2D was greater for women who were postmenopausal versus premenopausal women (adjusted odds ratio (AOR) 1.90, 95% CI 1.51–2.37). The strongest association between T2D and menopause in the adjusted model was for normal weight women (a BMI < 24 kg/m2), such that postmenopausal normal-weight women had a more than three-fold risk of having T2D versus premenopausal women (AOR 3.35, 95% CI 1.98–5.32). Age was a mediating factor in the apparent effect of menopause, but an effect of menopause persisted despite adjustment for age.

Review of North American Menopause Society ‘Guidelines for the Evaluation and Treatment of Perimenopausal Depression: Summary and Recommendations’

Endorsement by the IMS

Professor Wendy Wolfman

IMS Education Committee and Education Committee Members, Department of Obstetrics and Gynaecology, University of Toronto, Canada

The North American Menopause Society has developed an important guideline for the evaluation and treatment of perimenopausal depression [1]. This document, co-authored by an 11-member panel of experts and opinion leaders, who systematically reviewed the literature between 1980 and 2015 on depression and depressive symptoms, focuses on issues related specifically to perimenopause and postmenopausal women. The document reviews five relevant areas: epidemiology, clinical presentation, therapeutic effects of antidepressants and hormonal therapies as well as the efficacy of other therapies including psychotherapy, exercise and natural health products.

The IMS endorses this well-written comprehensive document that provides a summary and recommendations for improving the mental health of perimenopausal and menopausal women. Depressive symptoms are highly prevalent in at least 45% of perimenopausal women around the world. The paper confirms that the perimenopause is a time of vulnerability for the development of depression in women, particularly those who have had a prior episode of depression. The presentation may be complicated by perimenopausal symptomatology such as hot flushes, night sweats, sleep and sexual disturbances, weight changes and cognitive shifts. Evaluation involves identifying the menopausal stage and assessing psychiatric symptoms via validated screening tools. Proven therapeutic options include antidepressants such as SSRI and SNRI antidepressants, cognitive behavior therapy and other psychotherapies. For perimenopausal women, there is some evidence that estrogen therapy has antidepressant effects similar to antidepressant agents. However, estrogen alone is ineffective for depressive disorders in postmenopausal women. Estrogen may enhance the clinical response to antidepressants. This synergy needs to be evaluated in further research trials.

Some of the limitations of the document identified by the IMS reviewers included little mention of effects of other hormones on depression such as thyroid and adrenal hormones, and only a small mention of testosterone [2,3]. A section on directions for future research would have been useful in the document. For instance, comment could have been made about very important recent genetic research and its impact on depression, as noted in the recent review on gene polymorphisms and the risk of depression in menopausal women [4]. Also, there is currently a deficiency in the literature comparing doses, types, vehicles and timing of hormone therapies with regard to outcomes of depression. More research is needed to address the etiology and management of premature ovarian insufficiency-related depression as well as the synergistic effects of psychoactive medication with hormone therapies. These areas may prove to be relevant to address in future research recommendations.

In conclusion, we endorse this excellent guideline. We believe it validates the alterations in mental well-being that occur during the menopause transition, with the goal of improving the health of women around the globe.

As the world-wide population ages, it is projected that the number of persons living with osteoporosis will also increase. Osteoporosis is usually asymptomatic until a fracture occurs, and preventing osteoporotic fractures is the main goal of an osteoporosis screening strategy. Osteoporosis justifies a screening program because it is an important public health problem and effective treatments are available.

The objectives of bone mineral density (BMD) measurements are to provide diagnostic criteria, prognostic information on the probability of future fractures, and a baseline status to follow the evolution of the disease. Dual-energy X-ray absorptiometry (DXA) is the most widely used bone densitometric technique for this purpose.

All the major societies recommend the evaluation of risk factors for osteoporosis in women after the age of 50 years. There is also agreement that DXA-based screening is indicated after the age of 65 in all women not tested previously, and for all men 70 years and older. In the younger population, women less than 65 and men less than 70 years old, BMD assessment is only recommended when risk factors for low bone mass are present. These recommendations are included in the guidelines and consensus for women by the International Menopause Society and the North American Menopause Society and for both genders in the guidelines from the National Osteoporosis Foundation [2], the American College of Obstetrics and Gynecology, the International Society for Clinical Densitometry, the International Osteoporosis Foundation, the Endocrine Society [3] and the American Academy of Family Physicians. The American Association of Clinical Endocrinologists also recommends evaluating all women 50 years and older for osteoporosis risk and considering DXA testing based on clinical fracture risk profile.

The US Preventive Services Task Force (USPSTF) has recently published recommendations on screening for osteoporosis, to prevent bone fractures in adults, based on the revision of evidence on screening and treatment of osteoporotic fractures in men and women [1]. The screening population was postmenopausal women and older men with no known previous osteoporotic fracture and no known co-morbid conditions or medication use associated with secondary osteoporosis.

Professor Rod Baber is Clinical Professor of Obstetrics and Gynaecology, Faculty of Medicine and Health, The University of Sydney, Australia, the Editor-in-Chief of the Society’s journal, Climacteric, and Past President of the International Menopause Society.

I’ve been reading

I’ve been reading The Immortal Life of Henrietta Lacks by Rebecca Skloot. This book describes the sad tale of an African American woman who died of cervical cancer but whose donation of cells (unbeknown to her) prior to her death established the HeLa cell line, the oldest and still most commonly used immortal human cell line. Scientists are estimated to have grown over 20 tonnes of cells from HeLa for multiple scientific purposes, the first of which was the development of the Salk Polio vaccine. This prize-winning book is notable for its reflections on ethics as well as its ability to explain scientific processes to non-scientific readers.

I’m researching

We are about to start a mixed-methods multi-ethnic study on women’s experience of menopause and aging, in collaboration with The University of Tasmania.

My team

My team is small but busy, comprising three consultant gynecologists with a particular interest in menopause, menstrual disorders, reproductive endocrinology and infertility, and psychosocial issues. We also have two research fellows and, most importantly, our Nurse coordinator without whom nothing would happen.

An anecdote

When I was a young research fellow, I presented a free communication at an international meeting on research that I had done with my boss. In the audience was one of my boss’s mortal enemies who, in question time, did his best to discredit everything I had said. After the session, as I sat shell-shocked in the auditorium, the chair of the session reminded me that ‘if you swim with sharks you must expect to get bitten’. It taught me not to take these things too personally or too seriously. It’s sometimes just part of a game.

An interesting case

All of our referrals are tertiary and all are ‘interesting’, but I think those which challenge me most are the women who need ongoing care after surviving hormone-dependent cancers. These women need a ‘conductor of the orchestra’ to balance the views, wishes and priorities of all the different health-care professionals involved in their ongoing care.