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Abstract

Menopause is a significant milestone for midlife women. The characteristic changes in sex hormones and associated symptoms mark a time of increased risk for chronic disease, most notably cardiovascular disease. The diabetes epidemic, combined with recent epidemiologic studies linking sex hormone profiles with incident diabetes risk, have recently raised the possibility that the menopause may increase diabetes risk as well. This report reviews studies of menopause and diabetes risk, as well as the potential mechanisms through which menopause might affect traditional and more novel diabetes risk factors. Diabetes risk appears to be more strongly linked with factors associated with chronological aging and sex hormones rather than changes in menopausal status per se. Strategies to reduce diabetes risk, namely lifestyle changes, hormone therapy and other pharmacologic interventions are also discussed vis à vis midlife women and menopause.

Keywords

diabetes endogenous sex hormones hormone therapy lifestyle behaviors menopause

Menopause is a natural milestone for midlife women and thus is a common occurrence. In 2010, over 23 million women in the USA were aged between 45 and 55 years [1], the typical age range for the menopausal transition [2]. The menopausal transition is characterized by a shift in women's sex hormone profile owing to permanent changes in ovarian function [3]. Such changes begin several years before the final menstrual period (FMP) and continue until several years afterwards [1]. This evolution is characterized by vasomotor symptoms [4], as well as increased risk of chronic disease, most notably coronary heart disease [5].

Midlife women have increased risk of Type 2 diabetes compared with younger women [6]. At least 1.85 million women of reproductive age (18–44 years) have diabetes, compared with approximately 3.8 million women aged 45–64 years [7]. Among women born in the year 2000, approximately one out of three will develop diabetes, with the most pronounced increases in risk occurring in midlife [7].

The concurrence of menopause and diabetes in midlife raises the question of whether menopause increases diabetes risk. In this review, the definition of menopause will be discussed. Next, Type 2 diabetes risk factors in midlife women, namely the link between menopause and these risk factors and the link between these risk factors and diabetes itself will be reviewed. These risk factors include unfavorable changes in endogenous sex hormones, adiposity and insulin resistance, as well as disorders of sleep and mood. Furthermore, the studies suggesting that menopause is associated with increased diabetes risk will be examined.

In the last section of this review, strategies that may alter diabetes risk in midlife women, including both premenopausal and postmenopausal women, are discussed. These strategies include hormone therapy (HT), lifestyle modification, and pharmacologic agents such as metformin.

Definitions of menopause

Menopause, specifically postmenopause, is defined as the lack of a spontaneous menstrual period for 12 months (i.e., amenorrhea for 1 year) [8]. ‘Perimenopause’ is defined as the time period preceding menopause where the menstrual cycle is changing, but 12 months without menses has not yet occurred. ‘Premenopause’ also describes the time leading up to the FMP, although it is also used to describe the time leading up to perimenopause [8]. Women who naturally achieve postmenopause can only be identified retrospectively. For example, a woman who has ceased menstruating for 6 months without gynecological procedures may have entered her postmenopause, although this cannot be confirmed unless she continues not to menstruate for another 6 months. Until then, she is technically in perimenopause.

Women have been classified as postmenopausal if they have no menses for several reasons (Table 1): naturally, through cessation of ovarian estradiol production or surgically, through removal of their uterus or both of their ovaries. The term ‘natural menopause’ is used to describe cessation of menses for 1 year if women have their uterus and at least part of one ovary. The term ‘surgical menopause’ has been used for women who have no menses due to surgery and has been used to refer to women who have had bilateral oophorectomy, hysterectomy or both [9]. Thus, what constitutes ‘surgical menopause’ in one study may not be equivalent to ‘surgical menopause’ in another study.

Table 1.

Definitions of menopause and range of hormone levels in the literature.

Term	Definition	Range of E2 (pg/ml)	Range of T (ng/dl)	Range of DHEA-S (ng/ml)	Range of SHBG (nmol/l)	Ref.
Premenopause	Menses within past year	40–82	18–40	576–1270	43–62	[19,107,108]
Natural menopause	Cessation of menses for 1 year in the presence of uterus and at least part of one ovary	10–21	24–35	529–708	35–52	[16,98,107 –111]
Surgical menopause
Hysterectomy	Removal of uterus	14	21	474	40	[16,108]
Bilateral oophorectomy	Removal of both ovaries	3–13	11–17	472–510	43	[16,108]

DHEA-S: Dehydroepiandrosterone-sulfate; E2: Estradiol; SHBG: Sex hormone binding globulin; T: Testosterone.

Women who have undergone a hysterectomy and retain at least one ovary will have no menses, but these women may have hormonal profiles that are similar to the profiles of women who are naturally premenopausal, perimenopausal or postmenopausal. In several cohort studies, investigators have used clinical factors such as age to increase the odds that hysterectomized women will have ovaries functioning similarly to women in natural menopause. For example, in the Rancho Bernardo Study, the average age of natural menopause was 49 years in women without hysterectomy and therefore this cut-off was used to classify postmenopause in hysterectomized women [10]. In the Nurses' Health Study (NHS), the Women's Health Study and the Atherosclerosis Risk in Communities study [11], the usual age of natural menopause was approximately 55 years of age, and therefore this cut-off was used to classify postmenopause in hysterectomized women [11 –13]. In a final example, in the Women's Health Initiative (WHI), women were considered postmenopausal if they had no menses for 1 year or if they had a hysterectomy, even with the presence of one or more ovaries, regardless of age [14].

When possible, the menopause definition used in the review will be specified. Studies linking menopause and therapies for disease prevention and treatment enroll different subsets of women with menopause. Not all studies examine women with different types of menopause separately.

Diabetes risk factors in midlife

Midlife is a time of relative increase in androgenicity, adiposity and insulin resistance, sleep disturbance and depression, all of which are risk factors for diabetes. In the following paragraphs these risk factors, their prevalence during menopause, and the studies linking them with increased glucose and diabetes are further described.

Androgenicity

The most common and active androgens in perimenopausal women include testosterone (T), dehydroepiandrosterone (DHEA) or sulfated DHEA and other androgens such as androstenedione and their metabolites. The fraction of active T may be represented by the free androgen index, which represents the proportion of T not bound to sex hormone binding globulin (SHBG); free T level, which can be measured directly but with some difficulty; or bioavailable T level, which accounts for binding between T and albumin as well as SHBG. SHBG itself is a marker of androgenicity; as SHBG binds more avidly to T than to estradiol (E2), low SHBG levels reflect greater relative androgenicity and high SHBG levels reflect lesser androgenicity. The optimal representation of the androgenic state is somewhat controversial and there is a lack of consensus as to which assays and which androgen index should be used [15]. This is particularly true for postmenopausal women, who have low absolute levels of T and E2, and assays generally have lower precision at lower sex hormone levels.

Postmenopause is characterized by decreased estrogen levels and a relative increase in androgen levels compared with premenopause (Table 1). Table 1 displays the range of hormone levels in studies examining pre- and postmenopausal women by menopause type, including results from the Endogenous Breast Cancer Collaborative, a meta-analysis that pooled hormone levels from 13 studies of postmenopausal women [16]. Among women in natural menopause, the hormonal milieu is thought to change in response to the declining pool of ovarian follicles or ovarian reserve. Secretion of inhibin B, a peptide produced by ovarian antral follicles, decreases, and as a result follicle stimulating hormone (FSH) secretion by the pituitary gland increases [17]. Initially, E2 levels may actually increase as a result until follicles are depleted to the extent that the ovary no longer produces any estrogen [3]. However, in postmenopausal women, the ovaries continue to produce similar levels of T and approximately half of the levels of androstenedione compared with premenopausal women [18]. Thus, naturally postmenopausal women have a relatively androgenic hormonal milieu compared with premenopausal women, even though their absolute T levels may be slightly lower than premenopausal women.

Longitudinal studies of the menopausal transition support the concept of increased relative androgenicity due to a decline in estrogen levels over the transition. The Melbourne Women's Midlife Health Project followed Australian women between the ages of 45 and 55 years in order to characterize health changes occurring during menopause [19,20]. In the subgroup of women who were postmenopausal after 6 years, E2 levels began to decline approximately 4 years before the FMP with the most rapid declines occurring in the year before and year after the FMP [19,20]. Of note, T levels remained fairly stable while SHBG declined, perhaps owing to the negative feedback of lower E2 levels upon SHBG production. In the USA, the Study of Women's Health Across the Nation (SWAN) is an ongoing population-based, longitudinal cohort study designed to characterize biologic and symptomatic changes occurring during the menopausal transition [21]. Eligibility criteria were age 42–52 years at study entry, intact uterus and at least one ovary, no current estrogen use, and at least one menstrual period in the 3 months before screening. Beginning in 1994, women were enrolled at seven sites across the country and underwent period survey, anthropometric and serum collection. SWAN found similar changes in SHBG, T and E2 as the Melbourne study [22]; sulfated DHEA levels remained fairly constant across the transition [22]. Overall, the changes represent a shift to a more androgenic environment in postmenopause.

The hormonal milieu probably differs between menopause types (Table 1). Among women who have had their ovaries removed, overall androgen levels are lower than in women in natural menopause, but these women are still androgenic compared with premenopause, owing to continued androgen production by the adrenal glands and lack of estrogen production by the ovaries [10]. Among women who retain their ovaries but have undergone hysterectomy, T levels are slightly lower than in women in natural menopause for unclear reasons, possibly related to unintentional ovarian necrosis during hysterectomy [10].

Hypothetically, menopause could increase glucose levels through greater relative androgenicity. Several types of studies support this supposition. First, greater androgens are associated with higher levels of glucose and insulin in premenopausal women with polycystic ovarian syndrome [23]. Second, exogenous methyltestosterone leads to increased insulin resistance and increased glucose levels in clamp studies [24]. Third, epidemiologic studies in premenopausal women and postmenopausal women show associations between a single measure of SHBG or a single measure of T with glucose [25 –27].

Adiposity & insulin resistance

Obesity or a BMI >35 kg/m² is common in midlife women. Between 2005 and 2008, 37% of non-Hispanic white women, 52% of African–American women and 38% of Mexican–American women aged 40–59 years were obese [28]. During the same time period, the prevalence of obesity in 20–39 year old women was 29% in non-Hispanic whites, 47% of African–Americans and 38% of Mexican–Americans, underscoring the higher prevalence of obesity in midlife women than in younger women [28]. These data also underscore how obesity may increase more dramatically for non-Hispanic whites at midlife whereas African–Americans and Mexican–Americans may transition at younger ages.

Changes in adiposity may be affected by menopause type. In the SWAN, Sutton-Tyrrell et al. found that women undergoing a natural menopausal transition did not have an increased risk of obesity due to menopause per se, although their risk increased with age [9]. However, women who had undergone surgical menopause (in this case, meaning hysterectomy and/or oophorectomy) had a significant increase in odds for obesity compared with premenopausal women [9]. Of note, these odds were increased both in women who had and had not undergone oophorectomy.

In addition to overall body mass, central or visceral adipose deposition increases in midlife, as measured by waist circumference or waist:hip ratio [8,27,28]. The hypothesis that the relative androgenicity of menopause could lead to relatively greater visceral fat is supported by small randomized studies of exogenous estrogen and progesterone therapy. These studies noted that women who used and did not use exogenous estrogen had similar increases in body weight and fat mass, but the waist:hip ratio increased in nonhormone users [29].

Observational studies of the association between endogenous hormones and visceral adiposity also suggested that bioavailable T levels were directly related to visceral adiposity on CT scan [30]. In the SWAN, increases in the free androgen index and decreases in SHBG over time were strongly associated with both incident obesity as well as severe obesity [9]. The Melbourne Women's Midlife Health Project and the SWAN longitudinal reports both confirmed that incremental increases in adiposity, either by waist circumference or BMI, increased in women who underwent the transition naturally [9,31,32]. However, these changes occurred gradually over time rather than more suddenly around the FMP, suggesting that the adiposity changes that occur with menopause were primarily due to chronological rather than ovarian aging. Therefore, menopause may increase the risk of visceral rather than subcutaneous fat deposition. The increases in central or total body fat due to ovarian age or menopause compared with chronological age were relatively small, even as the associations between sex hormones and obesity were strong [9].

Obesity, weight gain and visceral weight gain are clearly established risk factors for diabetes in midlife women [33,34]. Adiposity may increase risk through several mechanisms, including insulin resistance. Insulin resistance and its associated glucose intolerance are strong predictors of Type 2 diabetes [35]. A comprehensive review of the mechanisms of insulin resistance and diabetes risk is beyond the scope of this report, but briefly, the insulin resistance observed in Type 2 diabetes is thought to occur in those who are susceptible to the disease through genetic factors when compounded with obesity [36 –38]. A meta-analysis of six prospective studies found that adults with glucose intolerance, in turn, had a high-risk of progression to diabetes, approximately 57 per 1000 person-years [35]. Between population-based surveys of adults occurring between 1988 to 1994 and 1999 to 2006, fasting insulin levels, a proxy for insulin resistance, were significantly higher in the later time period [39]. This suggests that the prevalence of insulin resistance in the population as a whole was increasing in conjunction with obesity. In the SWAN, insulin seemed to increase linearly through the transition, at approximately 3% per year, rather than abruptly around the FMP, suggesting that insulin sensitivity was more strongly related to chronological aging rather than ovarian aging [40].

In summary, adiposity and insulin resistance may have stronger links with chronological aging rather than ovarian aging, but the prevalence of both conditions is high in midlife women and increased compared with younger ages. These risk factors are essential precursors of Type 2 diabetes.

Sleep disturbances

Sleep disturbances, that is insomnia or sleep arousal, are common in midlife [41]. In the SWAN cohort, 28% of premenopausal women and 34% of early perimenopausal women reported sleep difficulties, defined as staying asleep as opposed to waking early or difficulty falling asleep [38]. After adjustment for age, postmenopausal women had more than twice the odds of difficulty falling asleep or waking up several times during the night than premenopausal women. Frequent awakening was also more pronounced among women in surgical menopause (bilateral oophorectomy) compared with premenopause (odds ratio: 2.52; 95% CI: 1.73–3.67) than women who were in natural menopause compared with premenopause (odds ratio: 2.24; 95% CI: 1.79–2.80) [38].

Menopause may cause sleep difficulty for several reasons. Hot flashes lead to a fivefold increase in the odds of falling asleep or waking up several times [38]. In addition, mood disorders are more common among women who have sleep difficulties and are also linked with the transition [42]. These are discussed further in the next section. Fluctuations in FSH may also contribute to sleep difficulties, although the mechanisms are unclear. In the SWAN, both higher FSH levels and more rapid FSH changes were associated with more difficulty sleeping, although other sex hormone levels including E2, T and DHEAS were not linked with sleep after adjustment for FSH [43].

Sleep duration is a risk factor for diabetes. Among women in the NHS, women with particularly long (>9 h per day) and short (<5 h per day) sleep durations had an increased risk of diabetes [44]. The association decreased after adjustment for BMI, suggesting that sleep restriction could lead to weight gain [44]. Other analyses found that the U-shaped relationship between sleep duration and diabetes and impaired glucose intolerance persisted even after adjustment for BMI or waist circumference [45 –47]. The mechanisms through which sleep might increase diabetes risk are unknown. Sleep deprivation may increase sympathetic tone, which may depress pancreatic function [48]. More sleep may decrease evening cortisol levels [49], which may in turn increase insulin resistance. Sleep deprivation or longer sleep length may also reflect sleep-disordered breathing, which apart from obesity may increase diabetes risk [50]. It is also possible that sleep fragmentation could be undiagnosed diabetes manifesting in fatigue, as the relationship between glucose and sleep was significant among adults with diabetes but not among adults without diabetes [50]. Diabetes may affect central control of ventilation, as diabetes increases the odds of period breathing [51]. The intermittent hypoxia associated with sleep apnea increased the odds for incident diabetes among middle-aged men and women [52 –54]. The stressors associated with intermittent hypoxia are similar to those hypothesized for sleep restriction (i.e., stress related) [52,53].

Depression

Mood disorders are common in midlife women, and their prevalence increases compared with the reproductive years. In the SWAN, almost a quarter of women had significant depressive symptoms at baseline, as represented by a high score (>16) on the Center for Epidemiologic Studies Depression Scale (CES-D) [42]. As women progressed through the transition, women had increasing odds of a high CES-D score, with the odds of a high score in postmenopause of 1.79 compared with premenopause. Greater levels of T, but not E2 or FSH, were also associated with more severe depressive symptoms [42]. In a separate study, the investigators found that women were two-to-four-times more likely to have a major depressive episode when they were perimenopausal or early postmenopausal compared with premenopausal, even after consideration of other contributors to depression including vasomotor symptoms, change in hormone levels, or upsetting life events [55].

Depression predicts incident diabetes, in part because depressed persons tend to engage in less exercise, consume more calories and smoke more often [56]. As a result, depressed women also tend to weigh more [57]. The medications used to treat diabetes may further exacerbate weight gain and poor lifestyle behaviors [58]. Finally, people with lower socioeconomic status tend to have more depressive symptoms and also to be at greater diabetes risk [58]. Large prospective studies suggest that depression may predict diabetes independently of these risk factors [59]. Aside from lifestyle behaviors and BMI, the mechanisms are not clear. Depression and depressive symptoms can represent dysfunction of the hypothalamic–pituitary–adrenocortical axis and sympathetic nervous system, which coregulate glucose [60].

Does menopause itself increase diabetes risk?

Owing to the increase in androgenicity, adiposity, sleep disturbance and depression in midlife, and their association with menopausal sex hormone changes, it is logical that glucose levels would also increase. However, the studies comparing diabetes risk in premenopause and postmenopause and across the transition have not found a strong association between menopause status per se, glucose and diabetes risk.

In one SWAN report by Matthews et al., changes in glucose over the 5 years before the FMP and in the 5 years after the FMP were examined in the subset of women without hysterectomy, oophorectomy or estrogen use [40]. While insulin increased in a linear fashion 2.8% per year, fasting glucose actually decreased linearly 2.2% per year, suggesting that menopause was not linked to increased glucose at the time of the transition. Moreover, since insulin increased in a linear fashion and did not change dramatically around the FMP [32,40], changes in insulin sensitivity were more strongly related to chronological aging rather than ovarian aging. Another SWAN report which also examined women who underwent natural menopause found that menopausal declines in SHBG and increases in bioavailable (although not total) T were associated with odds of metabolic syndrome. While this would be consistent with the hypothesis that menopause increases diabetes risk [32], the increased odds of metabolic syndrome was due primarily to detrimental changes in the nonglucose components of the metabolic syndrome (namely, triglycerides and high-density lipoprotein cholesterol) rather than glucose levels themselves.

Similarly, in other studies of menopause and diabetes risk, no statistically significant association between menopause and diabetes risk has been observed. In a report by Soriguer and colleagues, no significant risk of diabetes was found in postmenopause compared with premenopause [61]. No specification was made regarding surgical versus natural menopause. Mishra and colleagues also found no association between menopause status or type of menopause with diabetes risk [62]. Surgical menopause was defined as hysterectomy with or without oophorectomy, so that women in ‘surgical menopause’ could have retained both ovaries, which may have led to significant overlap in hormone profiles between women in ‘natural’ versus ‘surgical’ menopause.

We compared diabetes risk in premenopausal women and postmenopausal women participating in the Diabetes Prevention Program (DPP) [63]. The DPP was a randomized, controlled trial, which assigned glucose intolerant participants to placebo versus metformin versus a lifestyle change intervention, where the goal was loss of 7% of the baseline weight. Among women assigned to the placebo group, women in natural menopause had a similar hazard of progressing to diabetes compared with premenopausal women after adjustment for age (hazard ratio: 0.88; 95% CI: 0.44–1.75) (Figure 1). Similarly, women with bilateral oophorectomy or surgical menopause had a similar hazard of diabetes compared with premenopausal women after adjustment for age (hazard ratio: 1.06; 95% CI: 0.59–1.90) (Figure 1) [63].

Figure 1.

Diabetes hazard ratio and 95% CI in premenopausal versus postmenopausal women not using hormone therapy in the Diabetes Prevention Program. The light bar indicates women randomized to lifestyle intervention, the shaded bar indicates women randomized to metformin and the dark bar indicates women randomized to placebo. Each bar compares the risk of diabetes in postmenopausal women to premenopausal women (comparison group), with women in natural menopause illustrated on the left and women with bilateral oophorectomies illustrated on the right. A hazard ratio >1 indicates that the hazard of diabetes was greater in postmenopausal women than premenopausal women in the randomization arm.

In summary, midlife women are at significant diabetes risk due to the high prevalence of excess adiposity, insulin resistance and disorders that contribute separately to diabetes risk such as sleep disorders and depression. The evidence linking menopausal-specific changes in sex hormones and diabetes is less compelling than evidence linking chronological aging and diabetes.

Strategies for diabetes risk reduction during the perimenopause & postmenopause

Since menopause is a universal milestone for women, the presentation for management of menopausal symptoms can afford an opportunity to reduce diabetes risk as well. In the following paragraphs we discuss strategies that reduce diabetes risk or are associated with reduced glucose levels. These strategies include lifestyle changes, HT consisting primarily of exogenous estrogen, and other pharmacologic therapies. While the effectiveness of these strategies has been examined for midlife women in general, interventions have usually not examined whether effectiveness differs by menopausal status.

Lifestyle

The benefits of physical activity and weight loss upon diabetes risk have been extensively supported in prospective studies. For midlife women, physical activity ameliorates the increases in weight that usually occur during midlife [64]. In the SWAN, women tended to have weight gains over the transition, as mentioned earlier: over 3 years of follow-up mean weight increased by 2.1 kg (standard deviation: 4.8 kg) or 3.0% of total weight, while mean waist circumference also increased by 2.2 cm (standard deviation: 5.4 cm) or 2.8% total waist circumference [64]. However, if women increased their exercise intensity, they had decreases in weight of 0.32 kg (p < 0.01) and stable waist circumference. Such activity included routine activity such as walking and biking for transportation, as well as more vigorous activity such as sports [64]. Increased physical activity and subsequently lower weight independently decreased diabetes risk in the NHS [65,66]. Sedentary behaviors such as television watching also increase diabetes risk independently of exercise levels; even among women in the lowest tertile of physical activity (<7.7 metabolic equivalent-hours per week), hours of television viewed was still associated with greater diabetes risk [67,68].

The NHS has also provided a wealth of information regarding dietary risk factors for diabetes in midlife women [69]. Nurses had lower diabetes risk if they consumed diets high in cereal fiber and polyunsaturated fat, low in trans-fat and glycemic load, as well as half an alcoholic beverage per day [69]. Other foods that may increase diabetes risk include both processed and unprocessed red meats and sugar-sweetened beverages, such as soft drinks [70,71]. Conversely, greater low-fat dairy, coffee, caffeine and nut consumption may decrease diabetes risk in women if total energy intake remains stable [72 –74].

These strong prospective cohort data are supported by the randomized studies supporting decreased caloric intake and consumption of healthy calories along with greater physical activity. Three randomized, controlled trials enrolled midlife women for the purpose of diabetes reduction. The first, the Da Qing Study, enrolled 557 middle-aged women and men with impaired glucose tolerance and followed them for 6 years [75]. Participants were assigned to a control group or one of three interventions: dietary therapy, physical activity or a combination of the two. The cumulative incidence of diabetes was 68, 44, 41 and 46%, respectively, with a significant difference between each of the intervention groups and the control group, but no significant difference between each of the intervention groups [75]. The next randomized trial to be conducted was the Finnish Diabetes Prevention Study [76]. Women participating in this study, most of whom were middle-aged, also had impaired glucose tolerance and were also overweight. If randomized to the intervention, participants received dietary counseling aimed towards reduction of total caloric content, particularly saturated fat content and increased fiber intake, along with 30 min of exercise per day. After 3 years, participants in the intervention group had a cumulative incidence of diabetes of 14 versus 6% in the control group (p < 0.05), even though less than half of the participants in the intervention group achieved their weight loss goals [76].

The most recent study was the aforementioned DPP, which enrolled 3819 adults, approximately two-thirds of whom were women, and the majority of whom were middle-aged. Women participating in this study also had impaired glucose tolerance and were overweight, and if randomized to lifestyle change, were given weight loss targets, dietary counseling for calorie reduction and healthy calorie consumption, and moderate physical activity goals [77]. Participants randomized to lifestyle intervention had a significantly lower cumulative incidence of diabetes than participants randomized to placebo, 4.8 versus 11 cases per 100 person-years [77]. The effectiveness of lifestyle intervention was similar between men and women [77]. When we compared the effectiveness of lifestyle among premenopausal women compared with postmenopausal women in the DPP, we found that the effectiveness of lifestyle change for diabetes prevention was similar between women who were and were not postmenopausal (Figure 1) [63], with a suggestion that lifestyle may have been particularly effective among women with bilateral oophorectomies compared with premenopausal women.

HT

Use of exogenous estrogens lowers fasting glucose levels in premenopausal [78] and postmenopausal women [79 –83]. Among postmenopausal women, secondary analyses of randomized trials of estrogen replacement [79 –83] have consistently shown that oral estrogens, with or without progestins, have favorable effects on fasting glucose and at least one report has suggested that exogenous estrogen also decreases the incidence of diabetes by self-report [84]. However, in another randomized trial of estrogen with or without a progestin in postmenopausal women, exogenous estrogen decreased fasting but increased postchallenge glucose [82]. The progestin did not significantly modify the association between HT and glucose.

Exogenous estrogens may reduce abdominal fat and insulin resistance [83]. In some studies, decreases in glucose and diabetes risk persisted after adjustment for adiposity, suggesting that exogenous estrogen reduced hepatic gluconeogenesis or hepatic insulin resistance [79,82,84,85]. A meta-analysis of randomized trials and HT, found that HT led to reduced insulin resistance and reductions in fasting glucose, although postprandial glucose levels were not obtained frequently enough to report [83]. Effects tended to be greater with oral agents compared with transdermal agents, most notably for lipids.

Currently, HT use in the perimenopause is recommended primarily for vasomotor symptom relief [86,87]. Estrogens, prescribed with progestins for protection against endometrial cancer if women have a uterus, are thought to improve quality of life primarily among women with severe hot flashes [88]. The small increases in cardiovascular events and breast cancer observed in randomized studies of conjugated estrogen and progestin; for example, the WHI [89] and the Heart Estrogen–Progestin Replacement Study [90] have generally precluded HT use for preventive purposes only. However, among women with severe vasomotor symptoms, HT may provide some relief of sleep and mood disturbances, and thus is not contraindicated in the short-term among women without a history of thromboembolic events or malignancy [88]. In addition, the WHI and the Heart Estrogen–Progestin Replacement Study examined women with a more distant FMP. In these studies, the majority of women were over 63 and 67 years of age, respectively. Thus, it is possible that earlier replacement during the transition rather than after the transition might prove to be less risky for thromboembolic events and breast cancer [91], as well as more beneficial for other outcomes such as glucose. Two trials are currently underway (the Kronos Early Estrogen Prevention Study and the Early versus Late Intervention Trial with Estradiol) that examine the benefits of exogenous estrogen and progestin in the perimenopausal population rather than in women with a more distant FMP [92].

Other pharmacologic interventions

Medications can also lower diabetes risk. Metformin reduces weight and is also thought to reduce hepatic gluconeogenesis and improve hepatic sensitivity [93]. In the DPP, participants randomized to the metformin arm had a 31% reduction compared with placebo. Of note, lifestyle reduced the risk of diabetes by 39% compared with metformin [77]. When we examined the response to metformin by menopausal status, we found no significant difference between premenopausal and postmenopausal women (Figure 1) [63]. While there were no major side effects or hospitalizations with metformin, more participants who were randomized to metformin had gastrointestinal side effects compared with those randomized to placebo (77.8 vs 30.7 per 100 person-years). Cost–effectiveness analyses have suggested that metformin is most practical in participants less than 65 years of age owing to its smaller margin of effectiveness compared with lifestyle intervention [94].

Acarbose is an α-glucosidase inhibitor, which also reduces diabetes risk in midlife adults. In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus, participants had a 25% risk reduction in diabetes after 3 years. However, side effects were common and gastrointestinal side effects led to drop in approximately 44% of the acarbose group versus 14% of the placebo group [95], making this therapy somewhat less practical. Orlistat, a gastrointestinal lipase inhibitor, reduces dietary fat absorption. In a meta-analysis of orlistat trials [96], participants randomized to orlistat lost more weight than those randomized to placebo and also had a lower cumulative incidence of diabetes (3.0 vs 7.6%). Although side effects were not commented upon in this study, the drug is also somewhat notorious for gastrointestinal side effects, which can include steatorrhea.

Conclusion

Midlife women undergoing menopause experience significant endogenous hormone shifts that impact their health status and quality of life, as well as advance their societal roles beyond the reproductive phase. While menopause plays a key role in the lives of midlife women, the hormonal changes that characterize menopause are not the strongest determinants of diabetes risk. Rather, the midlife increases in adiposity and insulin resistance and comorbidities such as depression and sleep disorders have strong relationships with chronological aging. The increased diabetes risk associated with these factors can be reduced through lifestyle changes, and, for the women experiencing significant vasomotor symptoms, exogenous HT. For women with significant glucose intolerance and who are overweight, medications such as metformin may offer additional benefit.

Future perspective

Prospective studies of the sex hormone changes that occur during menopause and their link with changing cardiovascular risk factors have suggested that menopausal changes, per se, do not necessarily increase women's diabetes risk. However, multiple questions regarding the mechanisms of diabetes risk in midlife women remain. The role of endogenous sex hormones in determining glucose levels in both healthy premenopausal women and postmenopausal women, apart from adiposity and insulin, remains unclear. Genome-wide association studies combined with traditional epidemiologic analysis suggest that women's sex hormone profiles, and specifically their SHBG levels apart from menopause, may yet be a significant determinant of elevated glucose levels [25]. However, owing to the lack of randomized studies, the role of sex hormones as an independent mediator of diabetes risk, apart from traditional diabetes risk factors, is not clear. Observational studies [27,97,98] have shown that a single measurement of elevated T, elevated E2 or lower SHBG are associated with a greater fasting glucose level. However, it is unclear whether this association is due to common mediators such as adiposity [99 –101] or elevated insulin levels [102], both of which are associated with endogenous sex hormones as well as with glucose. In addition, previous work has rarely examined postchallenge glucose, which may have different associations with endogenous sex hormones than fasting plasma glucose [97]. Further examination of associations between endogenous sex hormone levels with pre- and postchallenge glucose is needed, before and after adjustment for insulin sensitivity and adiposity.

While HT is much less commonly prescribed now than in the past, as it is linked with adverse cardiovascular outcomes, HT prescription for symptom relief remains common. In addition, it is still undecided whether earlier initiation of HT might provide some benefit for chronic disease prevention. Thus, it is important to determine how HT affects longer-term carbohydrate metabolism, particularly upon 2-h glucose and in perimenopausal women. It is also important to examine how HT might interact with other therapies to alter women's diabetes risk. Among DPP women randomized to lifestyle change, we found that women who had undergone bilateral oophorectomy and used HT actually had lower diabetes risk than premenopausal women, possibly through the mutually beneficial effects of lifestyle and HT upon sex hormones and glucose [63]. Among postmenopausal women using exogenous estrogen, the association between other interventions, such as lifestyle or pharmacologic agents such as metformin, with sex hormone changes has not been studied. It is possible that these interventions could minimize the unfavorable effects of exogenous estrogens upon postchallenge glucose. However, it is also possible that exogenous hormones could potentiate the favorable impact of lifestyle change upon fasting but still lead to detrimental increases in postchallenge glucose.

Along similar lines, pharmacologic therapies such as metformin may affect sex hormone levels as well as glucose. How these agents might affect women's transition through menopause and how menopause might interact with these drugs upon glucose have not been studied in healthy women. Studies to date have primarily focused upon premenopausal women with polycystic ovarian syndrome, but analyses examining postmenopausal women have not been conducted.

The vast majority of studies have commented upon sex hormone profiles in natural menopause, but women undergoing hysterectomy or bilateral oophorectomy have not been as well studied. These procedures are not uncommon: in the USA; approximately 600,000 hysterectomies are performed per year [103]. Of the 93,676 postmenopausal women participating in the WHI observational study, 14,254 had a history of hysterectomy and bilateral oophorectomy, and 11,194 had hysterectomy alone for benign reasons [104]. In this study, no adverse risks with surgery were found, but diabetes was not examined. In the NHS, bilateral oophorectomy was associated with a greater risk of cardiovascular disease as well as cancer and total mortality, and diabetes was not reported upon [105]. Since women undergoing oophorectomy often use HT, it is important to study the effects of HT as well as endogenous sex hormones with glucose.

Finally, on a practical note, the effectiveness of randomized interventions for diabetes prevention is established, but the best way of disseminating these interventions is not. Using the menopause as a ‘teachable’ moment during which women can implement healthy lifestyle behaviors and therapies that minimize both menopausal symptoms and diabetes risk has not been studied. However, many women undergoing menopause have frequent contact with the healthcare system during this time for management of their symptoms [106]. These contacts have not been explored as an opportunity for further chronic disease management.

Executive summary

Diabetes risk factors in midlife

The transition to natural menopause is characterized by increased relative androgenicity, even though their absolute testosterone levels are fairly stable.

The ovaries continue to produce testosterone in postmenopause at approximately half of the levels in premenopause. Thus, women with bilateral oophorectomy will have a less androgenic milieu than women who undergo natural menopause.

Both adiposity and insulin resistance increase in midlife and both are associated with chronological aging and, to a lesser extent, with ovarian aging.

Sleep disturbances are common in perimenopausal women owing to hot flashes, coexisting mood disorders and fluctuations in follicle stimulating hormone levels, and both short and long sleep duration predict diabetes risk.

Mood disorders, particularly depressive symptoms, are common in perimenopausal women and increase diabetes risk through detrimental effects on activity and weight and perhaps independently.

Does menopause itself increase diabetes risk?

Longitudinal studies suggest that adiposity and insulin levels increase during the transition, but changes in glucose levels are less marked.

Neither natural nor surgical menopause per se has been reported to have strong associations with diabetes risk.

Strategies for diabetes risk reduction during the perimenopause & postmenopause

Women who are physically active during the transition can stabilize and even decrease their weight.

Specific dietary changes, particularly reduction in calories, red meat consumption, sugar-sweetened beverages, trans-fats, increases in fiber, nuts and caffeine, and alcohol within moderation may help reduce diabetes risk.

Estrogen therapy with progestin if women have a uterus can decrease fasting glucose, although currently, hormone therapy is recommended primarily for women who have severe vasomotor symptoms.

Metformin, acarbose and orlistat may reduce diabetes risk in glucose intolerant women, although gastrointestinal side effects can limit their use.

Footnotes

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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Does Menopause Increase Diabetes Risk? Strategies for Diabetes Prevention in Midlife Women

Abstract

Keywords

Definitions of menopause

Diabetes risk factors in midlife

Androgenicity

Adiposity & insulin resistance

Sleep disturbances

Depression

Does menopause itself increase diabetes risk?

Strategies for diabetes risk reduction during the perimenopause & postmenopause

Lifestyle

HT

Other pharmacologic interventions

Conclusion

Future perspective

Footnotes

References