Recent evidence exploring the associations between physical activity and menopausal symptoms in midlife women: perceived risks and possible health benefits

Although the health benefits of physical activity are well established, the prevalence of midlife women accumulating sufficient physical activity to meet current physical activity guidelines is strikingly low, as shown in United States (U.S.) based surveillance systems that utilize either (or both) participant-reported and device-based (i.e., accelerometers) measures of activity. For midlife women, these low prevalence estimates may be due, in part, to a general lack of time given more pressing work commitments and family obligations. Further, the benefits or “reward” of allocating limited time to physical activity may be perceived, by some, as too distant for immediate action or attention. However, shifting the health promotion message from the long term benefits of physical activity to the more short-term, acute benefits may encourage midlife women to engage in more regular physical activity. In this article, we review the latest evidence (i.e., past 5 years) regarding the impact of physical activity on menopausal symptoms. Recent studies provide strong support for the absence of an effect of physical activity on vasomotor symptoms; evidence is still inconclusive regarding the role of physical activity on urogenital symptoms (vaginal dryness, urinary incontinence) and sleep, but consistently suggestive of a positive impact on mood and weight control. To further advance this field, we also propose additional considerations and future research directions.


Introduction
The aging of the baby boomer cohort, born in the United States (U.S.) between mid-1946 and mid-1964 [1], has resulted in increased interest in strategies to optimize the health and well-being of midlife adults (ages 45 to 64 years). Indeed, research efforts specifically targeting midlife women, in particular, has increased exponentially in recent years. This interest may be due, in part, to the relatively recent recognition that sex differences exist, not only with regards to the incidence and/ or prevalence of various health outcomes, but also with the prevalence of health behaviors (e.g., not meeting physical activity guidelines) that increase one's disease and/or mortality risk.
Physical activity is a viable strategy to reduce the burden of chronic disease and disability. Strategies to increase physical activity at the individual-and population-level are particularly appealing given the strong evidence demonstrating the multiplicity of health benefits, including reduced risk of premature death, coronary heart disease (CHD), stroke, hypertension, hyperlipidemia, type 2 diabetes, metabolic syndrome, breast and colon cancer, and depression [2]. Further, since physical activity is a behavior and, thus, is modifiable, it is an excellent target for health promotion interventions focused on prevention.
Yet, despite the well-established health benefits of regular, habitual physical activity, few midlife women are accumulating sufficient levels to meet physical activity guidelines. Current U.S. based aerobic guidelines encourage: (1) ≥150 min per week of moderate intensity physical activity, (2) ≥75 min per week of vigorous intensity physical activity or (3) an equivalent combination of moderate and vigorous intensity physical activity (MVPA) [3]. The guidelines also recommend that adults participate in muscle-strengthening activities, across all major muscle groups, on ≥2 days per week. Based on 2013 Behavioral Risk Factor Surveillance System (BRFSS) data [4], 28.2 % (Standard Error (SE) ± 0.41) of women aged 45 to 54 years met the aerobic physical activity guidelines only, 6.0 % (SE ± 0.20) met muscle-strengthening guidelines only, and 14.8 % (SE ± 0.30) met both the aerobic and musclestrengthening guidelines. Among women aged 55 to 64 years, the prevalence estimates for meeting guidelines were similar: 28.5 % (SE ± 0.37), 5.6 % (SE ± 0.19), and 13.7 % (SE ± 0.26) met aerobic guidelines only, musclestrengthening guidelines only, or met both guidelines, respectively [4]. In the 2003-04 and 2005-06 cycles of the National Health and Nutrition Examination Survey (NHANES) [5], physical activity levels of a U.S. representative sample were also directly measured via accelerometers. The prevalence estimates for meeting physical activity guidelines were strikingly lower than those obtained in BRFSS using self-reported methods (as reported above). Using NHANES 2003-06 accelerometer data, only 26.7 % (SE ± 2.4) and 18.0 % (SE ± 2.6) of midlife women, aged 45-54 and 55 to 56 years, respectively, met aerobic guidelines. To be consistent with the wording of the 2008 Physical Activity Guidelines for Americans [3], meeting physical activity guidelines was defined as any accumulated time (minutes per day) spent above the moderateintensity threshold (1952 counts per minute [6]), and did not necessarily occur in prolonged activity bouts. It is important to note that these low prevalence estimates may be due, in part, to functional limitations that emerge during midlife. Previous studies have found that 20-40 % of midlife women reported moderate to severe physical limitations [7,8], which could serve as a significant barrier to engaging in sufficient, higher intensity physical activity to meet current physical activity guidelines.
Previous studies have suggested that another barrier to engaging in sufficient physical activity is a "lack of time" [9][10][11]. This is certainly a tangible barrier for midlife women given that during this stage of adulthood, women often find themselves "sandwiched" between caring for both dependent children and aging parents [12]. In addition, many midlife women are working outside the home; according to 2013 BRFSS data [4], 56.6 % (SE ± 0.46) and 43.1 % (SE ± 0.41) women aged 45 to 54 and 55 to 64 years, respectively, reported being employed for wages. Additionally, self-employment was reported in 8.6 % (SE ± 0.28) and 7.1 % (SE ± 0.21) of women aged 45 to 54 years and 55 to 64 years, respectively. Work demands and family obligations, therefore, frequently compete with the desire for leisure time activities such as physical activity, given the limited amount of time (i.e., leisure time) available during a day.
Principles of behavioral economics posit that decisions about being physically active involve trade-offs relative to fixed resources [13]. Thus, allocating time to recreational physical activity, given other competing demands, may be perceived as a "risk" for midlife women. However, individuals may undertake this risk, if the perceived "rewards" are sufficiently adequate and/or valued. The risk of developing the top three leading causes of death in women (i.e., coronary heart disease, cancer, and stroke) [14] increases with age, with risk escalating after age 65 [15,16]. While midlife women are at immediate risk for developing these conditions, they may not perceive that a reduction in disease risk, that may be manifested in the future, is an adequate reward given the immediate risk of needing to allocate ≥ 30 min per day for physical activity in their already full schedules.
One potential strategy to alter the risk/benefit ratio and increase the prevalence of midlife women meeting physical activity guidelines may be to target health promotion messages centered on the benefit of physical activity for more acute health outcomes or concerns, such as a reduction in-or relief from-menopausal symptoms. A 2005 review paper by Woods and Mitchell [17] summarized the prevalence of menopausal symptoms from published community-based longitudinal studies of the menopausal transition by Staging Reproductive Aging Workshop (STRAW) criteria, whenever possible. The prevalence of reported vasomotor symptoms ranged from 6 to 13 % in the late reproductive phase to as high as 79 % among postmenopausal women. The prevalence of reported vaginal dryness ranged from 3 % of women in the reproductive stage to 47 % among women who were 3 years postmenopausal. According to data from the Study of Women's Health Across the Nation (SWAN), Sampselle et al. [18] found that 57 % of study participants reported urinary incontinence with 15 % reporting it as moderate and 10 % as severe. The prevalence of reported sleep disturbances ranged from 31 % of women in the reproductive phase to 45 % among women who are 3 years postmenopausal. With regards to reported depressed mood symptoms, the prevalence estimates ranged from 19 to 29 %. Several other longitudinal investigations have reported significant increases in mean body weight and other markers of adiposity (e.g., waist circumference and fat mass) during the menopausal transition [19][20][21][22]. In addition to the moderate to high prevalence of reported menopausal symptoms in mid-life women, other studies [23,24] suggest that these symptoms may persist for a substantial portion of the menopausal transition. For example, a recent (2015) longitudinal SWAN analysis found that vasomotor symptoms persisted for a median duration of 7.4 years [25], and even longer among some demographic groups such as Black women.
Therefore, if women were convinced that physical activity would improve their most salient and disturbing symptoms, they might accept the "risk" of allocating valuable time to be physically active in exchange for the "reward" of symptom relief. They would also, as a secondary, longer-term reward, gain additional benefit in relation to chronic disease and disability prevention. The purpose of this paper is to evaluate whether this health promotion message is tenable by reviewing the recent literature (i.e., past 5 years) reporting on the effect of physical activity on menopausal symptoms. The selection of menopausal symptoms included in this review were based on the prevalence estimates reported by Woods et al. [17] We also provide commentary on the strengths and limitations of the existing research, and propose future research directions.

Potential biological mechanisms: physical activity and menopausal symptoms
Physical activity has both acute and chronic physiological and psychological effects, many of which could help to alleviate menopausal symptoms and other complaints of midlife women. Even though the specific etiology of vasomotor symptoms remains unclear, hot flashes and night sweats are the result of neuroendocrine processes at the level of the hypothalamus [60]. One hypothesis for how physical activity might alleviate vasomotor symptoms is through the impact of physical activity on neurotransmitters (e.g., β-endorphins) which regulate thermoregulation [61]. Similarly, physical activity, which increases sympathetic nervous system activity, could alleviate the vaginal dryness which results from the declines in circulating estrogen characteristic of menopause [62] by increasing sexual arousal and lubrication [63]. However, it is unclear if this is an acute effect of physical activity or if the increased lubrication persists at rest. The benefit of physical activity for reduced risk of urinary incontinence is likely mediated through obesity. Previous studies have indicated that obesity is a risk factor for urinary incontinence and studies have shown that weight loss can result in urinary incontinence remission [64]. The mechanisms by which physical activity may improve sleep quality include associated reductions in anxiety and depression. More directly, physical activity has been shown to promote increases in slow wave sleep, which is indicative of good sleep quality. Physical activity may also impact sleep through favorable influences on circadian functioning [65]. As reported by Dugan et al., the proposed biological mechanisms supporting the beneficial role of physical activity for preventing or reducing depression include: reduced inflammation, increased neurotransmitter (i.e., dopamine and serotonin) levels, and increased endorphin secretion [46]. Finally, physical activity contributes to prevention of weight gain and promotion of weight loss and reduces risk of adiposity-related outcomes because physical activity is a key component of total energy expenditure (i.e.,~20 % of total energy expenditure) [66]. Table 1 summarizes the recent evidence examining the association between physical activity and vasomotor symptoms, including hot flashes and night sweats. In a 15-day longitudinal study, Elavsky et al. [41] found an acute bout of exercise (30 min of moderate intensity exercise) decreased subjective and objectively determined hot flashes, but had no impact on night sweats. Also, daily physical activity estimates (detected via accelerometry during the 15-day observation period) were not associated with reported hot flash frequency, although less fit participants reported more hot flashes on days when they engaged in more activity than usual. In another longitudinal study by Elavsky and colleagues [42], participants concurrently wore an accelerometer and reported daily hot flashes via an electronic personal digital assistant for 30 consecutive days. Statistically significant                There was a significant decrease in body weight, BMI, and body fat percentage from baseline to 6-months x a Physical activity dose reflective of 2008 Physical Activity Guidelines for Americans [3] same-day and cross-lagged (previous day's physical activity compared to hot flashes the next day) associations were highly variable in both magnitude and direction. Three recent prospective cohort studies have also been conducted, including one showing a null association [43], another showing an increased risk of hot flashes among women classified as active [44], and the third reporting significantly fewer hot flashes in women classified in the highest active group (i.e., maintained or increased to >60 min per day over 12-weeks) [45]. A non-randomized intervention study also reported a significant decrease in reported hot flashes and night sweats following a 6-month aerobic program [50], and the same general finding was seen in a small randomized control trial of Turkish women (n = 42) [51]. In contrast, the evidence from the majority of randomized controlled trials, including results from the 2 × 3 Factorial Menopause Strategies: Finding Lasting Answers for Symptoms & Health (MsFLASH) Study, shows no association between physical activity and vasomotor symptoms [54,56]. For MsFLASH, women were recruited from three sites: Indianapolis, IN, Oakland, CA, and Seattle, WA and were randomized (3:3:4) to 12 weeks of exercise, yoga, or usual activity and further randomized to (1:1) to omega-3 fish oil or a placebo. Women in the yoga group performed one, 90 min session of supervised yoga per week and 20 min of unsupervised yoga on all other days. The exercise group participated in an individualized, supervised aerobic program (3 times per week, 40-60 min per session) with a progressively increasing energy expenditure goal. During month 1, the prescribed workload was 50-60 % of heart rate reserve. In months 2 and 3, heart rate reserve was increased to 60-70 % heart rate reserve [55]. Activity modes included: treadmill, elliptical trainer, or stationary bike. Heart rate and perceived exertion was recorded every 5-10 min by trained supervisors [56]. The usual activity group were instructed to follow their usual activity patterns and were asked to not begin a yoga or new exercise program [55,56]. Reed et al. [55] reported that after the 12-week program, the yoga group had significant improvements in reported vasomotor symptoms, obtained via the 29-item Menopausal Quality of Life Questionnaire (MENQOL), when compared to the usual activity group. However, when the frequency and intensity of vasomotor systems were obtained using more sophisticated daily diaries, yoga had no effect on the vasomotor symptoms when compared to the usual activity group [54]. This null association was also found when comparing the reported frequency and burden of vasomotor symptoms via daily diaries between the exercise and usual activity groups [56]. This evidence from the more rigorous RCT studies largely supports the 2014 Cochrane Report by Daley et al. [67], which concluded there was insufficient evidence to demonstrate that physical activity is an effective treatment for management of vasomotor symptoms.

Physical activity and vaginal dryness
As shown in Table 2, the recent evidence from crosssectional studies examining the association between physical activity and vaginal dryness is mixed [33,34], while a prospective cohort study [45] of Brazilian women by de Azevedo Guimaraes and colleagues found no association between habitual physical activity and vaginal dryness. Similarly, a non-randomized intervention study found no pre-to post-exercise program difference in vaginal dryness after 6-months [50]. Yet, in a randomized controlled trial of Finnish women [53] the prevalence of vaginal dryness decreased pre-to post intervention following a 6-month, unsupervised aerobic training program (4 times per week, 50 min per session at 64-80 % of maximal heart rate) in the treatment group versus control. Table 3 presents the evidence regarding the association between physical activity and urinary symptoms, including incontinence. In the prospective cohort study of Brazilian women by de Azevedo Guimaraes et al., women classified in the highest active group (maintained or increased to >60 min per day), reported less instances of leaking urine than those classified as low or moderately active at the 12-week follow-up [45], and in the nonrandomized intervention study by Karacan [50], there was a reduction in urinary symptoms following a 6-month aerobic exercise program. However, in the Finnish randomized controlled study, there was no change in urinary symptoms as a result of a 6-month aerobic exercise program [53]. When interpreting these findings it is important to note that associations were not adjusted for change in body weight, which is unfortunate given the proposed underlying biological mechanism between physical activity and urinary incontinence.

Sleep quality and disturbances
Cross-sectional studies have generally shown better sleep quality and/or fewer sleep disturbances among physically active women (Table 4); this association was also shown in the non-randomized intervention study by Karacan [50] and has been largely confirmed in recent evidence from randomized controlled trials. Utilizing data from the Dose-response to Exercise in postmenopausal Women (DREW) Study [58], participants randomized to any of the three exercise groups reported improvements in sleep quality when compared to the control group. Further, a dose-response effect was shown with reported sleep quality across the exercise groups, with the magnitude of the effect increasing with each increase in exercise dose. The exercise intervention arms were designed specifically to reflect 50 %, 100 % or 150 % of the National Institutes of Health (NIH) Consensus Panel physical activity recommendations [68]. Further, the odds of reporting a significant sleep disturbance were also lower with a dose response relation in all exercise groups compared to the controls. The beneficial effect of physical activity on sleep quality was also shown in two additional randomized control studies, including the Finnish study [59] and the MsFLASH trial [56]. The Advisory Committee for the development of the 2008 Physical Activity Guidelines for Americans [2], concluded that the evidence supporting the benefit of physical activity for improved sleep quality was moderate. These findings will likely provide additional support for the next iteration of the Guidelines.

Psychological distress: depression and anxiety
As shown in Table 5, the majority of the recent evidence in midlife women supports an inverse association between physical activity and depressive symptoms, including anxiety. Indeed of six recent cross-sectional studies [27,30,31,[35][36][37], only one study [35] found no difference in depressive symptoms by regular exercise status (≥3 times per week). In the prospective cohort study of Brazilian women, de Azevedo Guimaraes et al. [45], found improved psychological symptoms after 12-weeks in the high active group. This was also shown in an analysis of SWAN participants. Here, those classified as meeting physical activity guidelines had a lower odds of depression than inactive participants and this finding persisted over 10 years [46]. Karacan [50] also reported a reduction in psychological symptoms, including depressive mood, irritability, and anxiety after 3 and 6 months of participation in an aerobic exercise program. There was also a statistically significant reduction in exhaustion from baseline to 3 and 6 months. Of the four studies detailing findings from randomized controlled studies, all demonstrated a beneficial effect of physical activity for psychological symptoms including depressive symptoms [51,56,57], mood swings [53], and anxiety symptoms [57] when compared to a control [51,53,57] or usual activity group [56]. However, the impact of the physical activity intervention on depressive symptoms did not reach statistical significance in the MsFLASH Study [56] due to a more conservative alpha level to account for multiple comparisons (α = p < 0.028). These findings generally support the conclusions of the 2008 Physical Activity Guidelines for Americans [2] Advisory Committee that rated the evidence pertaining to the benefit of physical activity for reduced risk of depression as strong. Table 6 outlines the recent evidence including three prospective cohort studies [47][48][49] and one non-randomized intervention study [50], supporting an inverse association between physical activity and weight gain Cross-sectional studies were not included in this review because the outcome was weight change or weight loss over time,. In a study by Choi and colleagues [47], 346 participants from the Biobehavioral Health in Diverse Midlife Women Study, the 2-year change in physical activity was categorized as increase, decrease, or maintained. Participants who increased physical activity levels had significantly less weight gain and less of an increase in waist circumference when compared to those who decreased physical activity levels, after controlling for age, initial physical activity and relevant outcome value (both p < 0.05  [49], the associations between physical activity groups (sedentary, low-, moderate-, and high-active) and weight change were examined by age group (50-59 years, 60-69 years, and 70-79 years). Interestingly, Sims et al., reported that among the youngest age group, women in the moderate activity group experienced a significant weight loss [−0.30 (95 % CI: −0.53, −0.07) compared to the sedentary group. Yet, in women aged 70-79 years, higher physical activity was associated with the attenuation of the expected age-related weight loss due to loss of lean mass observed in this age group [0.34 (95 % CI: 0.04, 0.63). Authors posit that this attenuation in weight loss was due to the retention of lean muscle mass rather than a loss in adipose tissue [49]. Finally, Karacan [50] reported a significant decrease in body weight, body mass index (BMI), and body fat percentage (via skinfolds) after a 6-month supervised, aerobic-based physical activity program. However, these associations were not adjusted for potential confounders or other covariates. These findings generally support the conclusions of the 2008 Physical Activity Guidelines for Americans [2] Advisory Committee that rated the evidence supporting the benefit of physical activity for the prevention of weight gain and promotion of weight loss as strong, particularly when combined with reduced dietary intake. There is also currently moderate to strong evidence to support the inverse association between physical activity and abdominal adiposity.

Conclusions
The recent evidence, accumulated over the past 5 years, regarding the association between physical activity and hormone-related (i.e., primary) menopausal symptoms in midlife women generally mirrors previous research in this area in that the evidence remains either null or inconclusive. However, with more general health outcomes that result from biological aging, including poor sleep quality, increased depressive symptoms, and weight gain, the evidence supporting the beneficial effect of physical activity is quite conclusive. For primary menopausal symptoms, the inconsistencies across studies may be due to differences in targeted study populations. (i.e., study eligibility based on general age range, reflecting midlife versus menopausal status) as well as measurement strategies used to assess physical activity and menopausal symptom outcomes. Further, many studies did not examine and/or report the observed physical activitymenopausal symptom associations by menopausal status. This is particularly important given that the prevalence and severity of reported symptomology varies by menopausal status, as reported by Woods et al. [17]. Finally, for studies including a physical activity intervention component, there have also been distinct differences in the specific targets in terms of prescribed activity mode (i.e., aerobic versus resistance), frequency, intensity, and duration.
While it is intuitive that physical activity measurement strategies may vary across studies due to differences in the target population (e.g., race and cultural differences, menopausal status), a preponderance of studies included in this review utilized physical activity questionnaires with unreported and/or unknown measurement properties. This is despite recently published evaluation studies demonstrating the test-retest reliability and validity of physical activity questionnaires designed specifically for midlife women [69]. It is well-established that physical activity behaviors in women are quite different than in men and can vary by activity domain and/or preferred activity type [70]. For example, midlife women may accumulate the majority of their daily physical activity in domestic pursuits (e.g., caretaking) and walking or yoga during leisure-time. Therefore, it is critically important that, whenever possible, physical activity questionnaires used in this population are structured to elicit the most accurate information (i.e., reliable and valid) on the types of physical activities that are most pertinent to midlife women. This practice was implemented in a few studies included in this review that utilized more established questionnaires including, the International Physical Activity Questionnaire (IPAQ), Kaiser Physical Activity Survey (KPAS), or Modifiable Activity Questionnaire (MAQ) was used. A few additional studies included in this review used accelerometers, with known measurement properties, to quantify the physical activity exposure [41,42].
Another weakness is that several observational studies included in this review, classified participants into physical activity groups in analyses, and did not provide details on the threshold limits used to distinguish groups. While these categories, distinguishing non-exerciser from exerciser or low and moderate active from high active, may have acceptable internal study validity, the categorization is a substantial limitation to interpreting overall study findings within the context of the entire body of literature relevant to physical activity and menopausal symptoms during midlife. Further, the practice of utilizing cut-point thresholds that are not meaningful from a clinical or public health standpoint may increase the likelihood for potential misclassification bias of the physical activity exposure and also lead to spurious findings.
Since there is currently a lack of evidence regarding the specific dose of physical activity that confers menopausal symptom risk reduction, threshold values used for analysis should be based on meaningful categories that reflect current physical activity recommendations for general health benefit [3]. This same practice should also be applied when designing physical activity interventions. The specific physical activity targets or components of interventions should allow participants to accumulate at least 150 min of moderate intensity physical activity per week to reflect current physical activity guidelines [3]. However, it is important to note that midlife women may also have pre-existing disease or disability that may preclude their ability to fully meet recommended physical activity levels. For these women, even low to moderate increases in daily physical activity may be beneficial to health, which is also noted in the 2008 Physical Activity Guidelines for Americans [3]. Further, the intervention should include activity modes or types that are common and acceptable among midlife women, including brisk walking or bicycling. These intervention specific details should be included in the methods section of all peer-reviewed publications to facilitate the interpretation of the study findings. The MsFLASH [54][55][56] and DREW studies [58] provide excellent examples of how best to implement these recommendations when designing and/or reporting findings from physical activity intervention studies.
In summary, the recent evidence has not provided much clarity regarding the role of physical activity with menopausal symptoms in mid-life women beyond what was already known [67]. Yet, the evidence supporting the beneficial role of physical activity for more general health outcomes, including sleep quality, psychological distress, and weight gain, is quite conclusive. Given the considerable prevalence of sleep disturbances [71], depressive symptoms [72,73], and overweight/obesity [74] in midlife women, health care and physical fitness professionals should encourage their patients or clients to engage in regular physical activity levels to reduce risk of these important health outcomes. For some midlife women, this may be sufficient "reward" to overcome the "risk" of allocating sufficient time, in an already busy schedule, to be physically active. In addition, midlife is a particularly vulnerable period when individuals are at immediate risk for disability, and there is moderate to strong evidence to support the beneficial role of physical activity for optimizing functional health and reducing risk of falls among older adults [3]. However, midlife women initiating a new exercise program should strive to make small, incremental increases in physical activity levels over time to reduce risk of acute musculoskeletal injuries, including sprains and strains [3]. Finally, while the evidence is still accumulating regarding the role of physical activity for specific menopausal symptoms, health care professionals should periodically remind midlife women that they will experience a reduced lifetime risk of chronic disease and disability development if they remain physically active as they age.