Introduction
Menopause is the cessation of the ovarian follicular activity followed by the termination of the menstrual cycle [1]. The age of menopause varies in different societies, but on average it occurs between 48 and 52 years old [2, 3]. The incidence and severity of menopausal symptoms vary between women and are affected by various factors such as genetics, environment, anthropometrics, lifestyle, and race. Menopause can cause a wide range of symptoms in different systems due to the decrease in estrogen during this period [4]. Vasomotor disorders [4], mood disorders [5], and urogenital atrophy [6] are among possible complications. Early menopause is also associated with an increased risk of osteoporosis [7], coronary artery disease, stroke, and death [8]. These factors can affect women’s health and quality of life. However, one of the most important symptoms of these patients is the symptoms related to metabolic disorders. Menopause can lead to an increase in total body fat and the distribution of body fat from the periphery to the trunk, resulting in visceral obesity [9, 10]. Abdominal obesity and estrogen reduction during menopause are associated with adverse metabolic changes such as insulin resistance, tendency to develop type 2 diabetes, and dyslipidemia [9, 11].
Due to the increase in the prevalence and occurrence of type 2 diabetes in recent decades, paying attention to possible risk factors of this disease has become very important [12]. The rate of disability- adjusted life years (DALYs) for women with T2DM increased by 34.2% from 2007 to 2017 [13]. Moreover, at least one of the T2DM risk factors, including hypertension (HTN), dyslipidemia, central obesity, and increased fasting glucose level, occurs in 50-80% of menopausal women [14]. Therefore, identifying potential risk factors for T2DM, such as menopause, is critical for early detection, prevention, and management. However, few studies have investigated the effect of menopause on the probability of type 2 diabetes. The results of these studies are conflicting. For example, some studies point to an increase in the probability of type 2 diabetes with a decrease in the age of menopause [15, 16]. However, other studies do no support such a relationship [17, 18]. Therefore, in this systematic review and meta-analysis, we will analyze the available studies on the relationship between the age of menopause and the risk of type 2 diabetes.
Methods
This systematic review and meta-analysis aimed to investigate the association of menopausal age and T2DM. This study adhered to the principles of Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA Checklist). The protocol of this study is available at the Open Science Framework (OSF) website (OSF: https://osf.io/26p38/).
Search strategy
We searched PubMed, Scopus, and Google Scholar databases to find all studies associated with menopause and type 2 diabetes up to January 24, 2024. We also manually checked the reference lists of relevant studies to ensure that all studies were found. The search strategy of this systematic review and meta-analysis is available in Table 1.
Study selection
Studies were reviewed for compliance with the inclusion criteria by two authors (A.A, R.HZ). Inclusion criteria included: 1) study design, prospective cohort, cross-sectional studies, case-control, and randomized controlled trials (RCTs); 2) participants were postmenopausal women (women who experienced natural or surgical menopause) without a history of type 2 diabetes at baseline; 3) reporting age of menopause; 4) type 2 diabetes diagnosis is confirmed through clinical or laboratory criteria; 5) studies should report sufficient data to calculate odds ratios (ORs) and 95% confidence intervals (95% CI) for the association between age at menopause and type 2 diabetes mellitus (T2DM).
Data extraction and quality assessment
Two separate reviewers (FAM and QB) extracted the necessary information based on the standard form. Information including author name, year, type of the study, sample size, and number of T2DM in each category of menopausal age was extracted from studies.
The quality assessment of the studies was performed by two reviewers (QB and AA) separately, and any disagreement was solved by discussion.
Statistical analysis
Data about the relationship between menopause and T2DM were extracted from included studies. Due to different outcome reporting, the age categories were unified into several groups: A) menopausal age > 45 vs. menopausal age < 45; B) menopausal age > 50 vs. menopausal age < 45, and C) menopausal age > 55 vs. menopausal age < 45. Moreover, surgical menopause (including oophorectomy and hysterectomy) vs. natural menopause constituted a separate category. Then, a meta-analysis was performed by calculating the ORs and 95% CIs using the random effect model and the DerSimonian-Laird method. Additionally, a forest plot was prepared to show the pooled effect size. We used leave-one-out analysis to ensure that the result did not have a great impact on any single study. Heterogeneity between included studies was evaluated using Cochran’s Q test and I2 statistic, and I2 > 50% was considered to indicate heterogeneity. Subgroup analyses were planned to explore potential sources of heterogeneity, including study design (cohort vs. cross-sectional), menopausal age categories (early vs. late), and geographic location. Interaction tests were performed to evaluate differences between subgroups.
Publication bias was evaluated through funnel plot, Egger’s test, and trim and fill analysis. All statistical analyses were performed using STATA version 17, and p-values < 0.05 were considered statistically significant.
Results
Study selection
Through a comprehensive search of three datasets, we found 345 relevant studies. We obtained three additional studies from the references list of previous meta-analyses. After removing duplicate studies, 286 studies remained. Then, 204 irrelevant studies were excluded through title and abstract screening. The full text of the remaining studies was evaluated, and 65 records were removed due to ineligibility with our inclusion criteria. Finally, 17 studies were included for systematic review and meta-analysis. The study selection procedure is shown in Figure 1.
Study characteristics
The selected studies were published between 2013 and 2022 and included a total of 421 801 menopausal woman participants, of whom 37 656 had T2DM. Geographical diversity was observed, with studies conducted in China [19–26], the USA [27, 28], Europe [16], Japan [29, 30], The Netherlands [31], France [32], Egypt [33], and ten different countries [34]. The studies employed different study designs, including cohort [16, 19–22, 27, 29–32, 34] and cross-sectional [23–25, 28, 33] studies (Fig. 2). The characteristic features of included studies are shown in Table 2.
Menopausal age was collected through self-reporting or medical documents in the natural and surgical menopause process, respectively. Additionally, T2DM was diagnosed through laboratory examination. Different studies reported their data in various categories. Therefore, we unified participant categories into three groups: A) menopausal age < 45 vs. menopausal age > 45; B) menopausal age < 45 vs. menopausal age > 50; and C) menopausal age < 45 vs. menopausal age > 55.
Menopausal age < 45 vs. menopausal age > 45
The combined analysis of 17 studies demonstrated a significant association between menopausal age and risk of T2DM. The calculated OR demonstrated that women with menopausal age > 45 showed a significant relation with T2DM development with an OR of 0.13 (95% CI: (0.04, 0.22), p < 0.01, indicating a 13% protective effect compared to menopausal age < 45. The studies demonstrated high heterogenicity, with an I2 of 84.57. The forest plot diagrams are presented in Figure 3.
Menopausal age < 45 vs. menopausal age > 50
A total of nine studies reported overall diabetic and non-diabetic cases with menopausal age greater than 50 years old. The pooled analysis revealed a substantial effect of menopausal age on T2DM development with an OR of 0.44 (95% CI: –1.12, 2.00), p > 0.05, I2 = 99.84% (Fig. 4).
Menopausal age < 45 vs. menopausal age > 55
The pooled analysis of 13 studies showed no significant effect of menopausal age on the risk of T2DM with an OR of 0.21 (95% CI: –1.39, 1.82), p > 0.05. Also, it showed strong heterogenicity, with an I2 of 99.85 (Fig. 5).
Surgical menopause vs. natural menopause
A total of 4 studies reported diabetes in surgical and natural menopause women separately. The surgical status showed an OR of 0.39 (95%CI: –0.13, 0.91), which was not statistically significant (Fig. 6).
Publication bias
We assessed publication bias using Egger’s test, funnel plot, and trim-and-fill analysis. The funnel plot (Fig. 7) exhibited a symmetrical pattern, indicating no publication bias. This result was supported by Egger’s test (p > 0.05) and trim-and-fill analysis (no imputed studies).
Discussion
This present meta-analysis unified the information of 17 studies with 421 801 menopausal women and 37 656 T2DM cases to evaluate the complex association between age at menopause and risk of developing T2DM. Merging data showed the multifactorial nature of this relationship, which needs further investigation. The syncretistic analysis showed that earlier menopausal age is significantly related to an increased risk of T2DM, while later menopausal age is associated with decreased risk of T2DM. This finding plays a critical role in our understanding of the association of hormonal alteration during menopause with the risk of metabolic disorders.
Our meta-analysis revealed a notable effect of menopausal age on the risk of T2DM development. Women with menopausal age higher than 45 have a 13% lower risk of developing T2DM. This effect increased to 44% for menopausal age more than 50. However, by increasing the age of menopause, this upward trend did not continue. Also, the probability of not developing diabetes was reduced to 21%, which still was higher than the menopausal age of > 45.
The correlation observed between the earlier onset of menopause (whether natural or surgical) and the risk of developing T2DM aligns with the findings of recent investigations. These findings suggest that a shorter period of exposure to endogenous estrogen may play a role in T2DM pathogenesis [35]. This relation corresponds with the recognized effect of ovarian hormones, especially estrogen, on the functioning of pancreatic beta cells and the maintenance of glucose homeostasis [36].
There are many disagreements among researchers that are worth investigating. Some studies did not report a significant relationship after adjusting confounding variables such as BMI, blood pressure, etc. [17, 18]. However, there are other studies that, similar to the results of our meta-analysis, have observed a positive relationship between early menopause and the risk of type 2 diabetes [15, 16]. This variation in the observed results indicates the complexity of this relationship and suggests that other factors may influence the observed associations.
One of the reasons for inconsistencies in the results may be the lack of a standard definition of surgical menopause in different studies. Surgical menopause includes various methods, including oophorectomy and hysterectomy [16], in which hormonal profiles can be significantly different [37, 38]. This variation in definitions of surgical menopause and differences in hormone levels can mask the true nature of the relationship between age at menopause and the risk of type 2 diabetes.
In addition, the menopause process is characterized by complex hormonal alterations. At first, there is an initial increase in estradiol secretion followed by a gradual decline, while blood testosterone levels remain relatively constant [39]. Also, the increase in androgenicity during menopause can be associated with a higher incidence of T2DM [40, 41]. These changes in women’s hormonal profiles can affect metabolic processes and potentially contribute to diabetes risk.
In addition, other changes occur in the human body with menopause. This includes an increase in fat mass, an increase in abdominal fat, and a decrease in body fat-free mass, resulting in metabolic changes, all of which can be risk factors for the development of T2DM [42]. Regular physical activity and lifestyle modification can act as factors that influence metabolic changes, weight gain, and alteration in body fat distribution after menopause [43]. For this reason, early menopausal women have more time exposed to these adverse changes, and the risk of T2DM is higher for them than for later menopause.
Our findings also raise interesting questions about the role of reproductive lifespan as a marker of lifetime estrogen exposure. Some experimental studies have shown that estrogen may have protective effects on insulin secretion, glucose metabolism, and diabetes risk [44, 45]. Therefore, assessment of reproductive lifespan, which accounts for the cumulative effect of estrogen exposure, may provide a more accurate understanding of the relationship between age at menopause and T2DM than age at menopause alone.
Another important consideration is the effect of postmenopausal obesity. Late menopause was associated with an increased risk of T2DM in non-obese subjects, while it was associated with a decreased risk in obese subjects [26]. Increased risk of diabetes after late menopause in non-obese women may be due to prolonged exposure to estradiol before menopause [46, 47]. This emphasizes the complex interplay between menopause, hormonal changes, and metabolic factors.
The effect of estrogen on glucose metabolism also appears to be multifaceted. Some evidence suggests a protective role of exogenous estrogen, particularly in glucose homeostasis [48]. Estrogen replacement in postmenopausal women causes lower incidence of T2DM [44, 45, 48]. Higher endogenous estrogen levels in postmenopausal women are associated with elevated glucose and insulin levels and an increased risk of diabetes [41, 47]. The complex relationship between estrogen and the risk of type 2 diabetes deserves further investigation.
Recent studies have shown that premature menopause is probably an indicator of premature aging. This is characterized by a decrease in the ability to repair and regenerate DNA. This happens both in the tissues of the reproductive system and in other tissues of the body. Thus, women who have a less efficient DNA repair system may be at risk of premature menopause and other chronic diseases, including diabetes [50–53].
The observed differences in the association between age at menopause and risk of T2DM across countries [32, 54] emphasize the need to consider diverse populations and their unique genetic and environmental backgrounds [35]. Social and environmental factors, such as education, smoking habits, and occupational status, can also influence age at menopause and potentially mediate the relationship with T2DM [25].
One of the complications of menopause is metabolic syndrome occurrence. This syndrome is associated with increased waist circumference, hyperglycemia, increased triglycerides, decreased HDL, and hypertension. These changes can increase the risk of diabetes in menopausal women. In addition, metabolic syndrome causes obesity by reducing metabolism and thus reducing calorie consumption. Also, this syndrome is associated with fat distribution in the abdominal area. All these factors contribute to the unique role of metabolic syndrome in the development of diabetes in postmenopausal women [55–58].
Furthermore, the etiology of T2DM is multifactorial, with genetic, lifestyle, and environmental factors all contributing [32]. These factors could vary by ethnicity and potentially influence the associations we observed. Diet can help determine BMI and body fat distribution. This effect is not only related to the amount of food consumed, but also the composition of food plays an important role. A diet containing large amounts of fat, red meat, and sweets can contribute to obesity and diabetes. Fruits and vegetables, by contrast, have a protective effect [59–62].
Due to the observed protective effect of higher menopause age on type 2 diabetes, women with menopause age below 45 years need more preventive measures than women with higher menopause age. As mentioned before, type 2 diabetes is a multifactorial disease, and one of the modifiable factors in the etiology of this disease is the diet of people.
In a study, Jin et al. investigated the effect of diet on the risk of type 2 diabetes in 11 000 postmenopausal women. They used an empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores. The high level of these criteria indicated a hyper-insulinemic and hyper-proinflammatory diet. Finally, it was observed that the diet with a higher EDIH and EDIP score was associated with an increased risk of type 2 diabetes [63]. The EDIH and (EDIP) scores measure the protein C and inflammatory markers, respectively. These substances play a role in the etiology of several chronic diseases, including T2DM [64, 65].
Another study by Vitale et al. investigated the effect of micronutrients on metabolic parameters in postmenopausal women. In this study, the participants were treated with calcium, vitamin D, isoflavone, and insulin for 12 months versus placebo. Finally, it was observed that the amount of HDL in the case group was significantly higher compared to the placebo group [66]. The importance of increasing HDL in this study is shown by the observation that a lower HDL level is associated with an increased T2DM risk [67, 68]. Therefore, increasing the level of HDL serum through modifying the diet with calcium, vitamin D, and isoflavone can help prevent diabetes in postmenopausal people.
This meta-analysis displays several remarkable strengths. Primarily, we conducted a comprehensive and complete search to identify all relevant articles related to this topic and defined specific criteria to select the best research. Furthermore, during the data extraction process, we collected the most adjusted model data to minimize the potential confounding variables. Additionally, it is worth mentioning that the included studies contain investigations on both natural and surgical menopause, thereby enhancing the depth and extent of this meta-analysis.
Nonetheless, our study contains certain limitations. Included studies utilized self-reported data to determine menopausal age, which leads to concerns about potential recall bias. Nevertheless, prior investigations have demonstrated the reasonable reliability of this data collection method [69, 70]. Moreover, we performed leave-one-out analysis to ensure the reliability of our results, the outcome of which did not change significantly. This supports the robustness of our meta-analysis.
Conclusions
In conclusion, this present meta-analysis emphasizes the importance of the complex relationship between earlier menopausal age and the risk of T2DM development. It is necessary to investigate the confounding variables of this association, such as hormonal, genetic, and lifestyle factors. Future investigations must focus on the underlying mechanistic pathways. Understanding these mechanisms will help us with preventive strategies and interventions in post-menopausal women.
Acknowledgements
We would like to express our gratitude to all the authors whose studies have been included in the analysis.
Disclosures
1. Institutional review board statement: Not applicable.
2. Assistance with the article: None.
3. Financial support and sponsorship: None.
4. Conflicts of interest: None
References
1. Liu J, Jin X, Liu W, et al. The risk of long-term cardiometabolic disease in women with premature or early menopause: a systematic review and meta-analysis. Front Cardiovasc Med 2023; 10: 1131251. doi: 10.3389/fcvm.2023.1131251.
2.
Tom SE, Mishra GD. A life course approach to reproductive aging. In: Current Topics in Menopause. Bantham Books 2013.
3.
Schoenaker DA, Jackson CA, Rowlands JV, et al. Socioeconomic position, lifestyle factors and age at natural menopause: a systematic review and meta-analyses of studies across six continents. Int J Epidemiol 2014; 43: 1542-1562.
4.
Davis SR, Lambrinoudaki I, Lumsden M, et al. Menopause. Nat Rev Dis Primers 2015; doi: 10.1038/nrdp.2015.4.
5.
Vivian-Taylor J, Hickey M. Menopause and depression: is there a link? Maturitas 2014; 79: 142-146.
6.
Nappi R, Kokot-Kierepa M. Vaginal Health: Insights, Views & Attitudes (VIVA) – results from an international survey. Climacteric 2012; 15: 36-44.
7.
Shuster LT, Rhodes DJ, Gostout BS, et al. Premature menopause or early menopause: long-term health consequences. Maturitas 2010; 65: 161-166.
8.
Wellons M, Ouyang P, Schreiner PJ, et al. Early menopause predicts future coronary heart disease and stroke: the Multi-Ethnic Study of Atherosclerosis. Menopause 2012; 19: 1081-1087.
9.
Tchernof A, Després JP. Pathophysiology of human visceral obesity: an update. Physiol Rev 2013; 93: 359-404.
10.
Davis SR, Castelo-Branco C, Chedraui P, et al. Understanding weight gain at menopause. Climacteric 2012; 15: 419-429.
11.
Barton M. Cholesterol and atherosclerosis: modulation by oestrogen. Curr Opin Lipidol 2013; 24: 214-220.
12.
Ogurtsova K, da Rocha Fernandes JD, Huang Y, et al. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract 2017; 128: 40-50.
13.
GBD 2017 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018; 392: 1859-1922.
14.
OlaOlorun FM, Shen W. Menopause. Oxford University Press 2020.
15.
Malacara JM, Huerta R, Rivera B, et al. Menopause in normal and uncomplicated NIDDM women: physical and emotional symptoms and hormone profile. Maturitas 1997; 28: 35-45.
16.
Brand JS, van der Schouw YT, Onland-Moret NC, et al. Age at menopause, reproductive life span, and type 2 diabetes risk: results from the EPIC-InterAct study. Diabetes Care 2013; 36: 1012-1019.
17.
Di Donato P, Giulini NA, Modena AB, et al.; Gruppo di Studio Progetto Menopausa Italia. Risk factors for type 2 diabetes in women attending menopause clinics in Italy: a cross-sectional study. Climacteric 2005; 8: 287-293.
18.
Luborsky J, Meyer P, Sowers MF, et al. Premature menopause in a multi- ethnic population study of the menopause transition. Hum Reprod 2003; 18: 199-206.
19.
Shen L, Song L, Li H, et al. Association between earlier age at natural menopause and risk of diabetes in middle-aged and older Chinese women: The Dongfeng-Tongji cohort study. Diabetes Metab 2017; 43: 345-350.
20.
Wang M, Gan W, Kartsonaki C, et al. Menopausal status, age at natural menopause and risk of diabetes in China: a 10-year prospective study of 300,000 women. Nutr Metab (Lond) 2022; 19: 7.
21.
Yang A, Liu S, Cheng N, et al. Reproductive factors and risk of type 2 diabetes in an occupational cohort of Chinese women. J Diabetes Complications 2016; 30: 1217-1222.
22.
Zhang L, Bao L, Li Y, et al. Age at menopause, body mass index, and risk of type 2 diabetes mellitus in postmenopausal Chinese women: The Henan Rural Cohort study. Nutr Metab Cardiovasc Dis 2020; 30: 1347-1354.
23.
Li Y, Zheng H, Tian L, et al. Mediatory role of abdominal obesity in the association of early menopause with diabetes among middle-aged and older Chinese women. Menopause 2020; 27: 1037-1041.
24.
Qiu C, Chen H, Wen J, et al. Associations between age at menarche and menopause with cardiovascular disease, diabetes, and osteoporosis in Chinese women. J Clin Endocrinol Metab 2013; 98: 1612-1621.
25.
Yu Y, Li Y, Jiang Y, et al. Association between reproductive factors and type 2 diabetes: a cross-sectional study. Int J Environ Res Public Health 2022; 19: 1019.
26.
Jiang J, Cui J, Wang A, et al. Association between age at natural menopause and risk of type 2 diabetes in postmenopausal women with and without obesity. J Clin Endocrinol Metab 2019; 104: 3039-3048.
27.
LeBlanc ES, Kapphahn K, Hedlin H, et al. Reproductive history and risk of type 2 diabetes mellitus in postmenopausal women: findings from the Women’s Health Initiative. Menopause 2017; 24: 64-72.
28.
Xing Z, Kirby RS, Alman AC. Association of age at menopause with type 2 diabetes mellitus in postmenopausal women in the United States: National Health and Nutrition Examination Survey 2011-2018. Prz Menopauzalny 2022; 21: 229-235.
29.
Heianza Y, Arase Y, Kodama S, et al. Effect of postmenopausal status and age at menopause on type 2 diabetes and prediabetes in Japanese individuals: Toranomon Hospital Health Management Center Study 17 (TOPICS 17). Diabetes Care 2013; 36: 4007-4014.
30.
Lee JS, Hayashi K, Mishra G, et al. Independent association between age at natural menopause and hypercholesterolemia, hypertension, and diabetes mellitus: Japan nurses’ health study. J Atheroscler Thromb 2013; 20: 161-169.
31.
Muka T, Asllanaj E, Avazverdi N, et al. Age at natural menopause and risk of type 2 diabetes: a prospective cohort study. Diabetologia 2017; 60: 1951-1960.
32.
Tatulashvili S, Gusto G, Cosson E, et al. Gonadal hormonal factors before menopause and incident type 2 diabetes in women: a 22-year follow-up of 83 799 women from the E3N cohort study. J Diabetes 2021; 13; 330-338.
33.
Seddek MY, El-Sayed MS, Rezq AY. Relation between age at menopause, reproductive life span and type 2 diabetes. Int J Adv Res 2016; 4: 281-294.
34.
Pandeya N, Huxley RR, Chung HF, et al. Female reproductive history and risk of type 2 diabetes: a prospective analysis of 126 721 women. Diabetes Obes Metab 2018; 20: 2103-2112.
35.
Appiah D, Winters SJ, Hornung CA. Bilateral oophorectomy and the risk of incident diabetes in postmenopausal women. Diabetes Care 2014; 37: 725-733.
36.
Bailey C, Ahmed-Sorour H. Role of ovarian hormones in the long-term control of glucose homeostasis: effects on insulin secretion. Diabetologia 1980; 19: 475-481.
37.
Kim C. Does menopause increase diabetes risk? Strategies for diabetes prevention in midlife women. Womens Health 2012; 8: 155-167.
38.
Howard BV, Kuller L, Langer R, et al. Risk of cardiovascular disease by hysterectomy status, with and without oophorectomy: the Women’s Health Initiative Observational Study. Circulation 2005; 111: 1462-1470.
39.
Guthrie JR, Dennerstein L, Taffe JR, et al. The menopausal transition: a 9-year prospective population-based study. The Melbourne Women’s Midlife Health Project. Climacteric 2004; 7: 375-389.
40.
Burger HG, Dudley EC, Cui J, et al. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab 2000; 85: 2832-2838.
41.
Kalyani RR, Franco M, Dobs AS, et al. The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. J Clin Endocrinol Metab 2009; 94: 4127-4135.
42.
Szmuilowicz ED, Stuenkel CA, Seely EW. Influence of menopause on diabetes and diabetes risk. Nat Rev Endocrinol 2009; 5: 553-558.
43.
Sternfeld B, Bhat AK, Wang H, et al. Menopause, physical activity, and body composition/fat distribution in midlife women. Med Sci Sports Exerc 2005; 37: 1195-1202.
44.
Kanaya AM, Herrington D, Vittinghoff E, et al. Glycemic effects of postmenopausal hormone therapy: the heart and estrogen/progestin replacement study: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003; 138: 1-9.
45.
Bonds DE, Lasser N, Qi L, et al. The effect of conjugated equine oestrogen on diabetes incidence: the Women’s Health Initiative randomised trial. Diabetologia 2006; 49: 459-468..
46.
Golden SH, Dobs AS, Vaidya D, et al. Endogenous sex hormones and glucose tolerance status in postmenopausal women. J Clin Endocrinol Metab 2007; 92: 1289-1295.
47.
Ding E, Song Y, Manson JE, et al. Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study. Diabetologia 2007; 50: 2076-2084.
48.
Godsland I. Oestrogens and insulin secretion. Diabetologia 2005; 48: 2213-2220.
49.
Margolis K, Bonds DE, Rodabough RJ, et al. Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia 2004; 47: 1175-1187.
50.
Day FR, Ruth KS, Thompson DJ, et al. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nat Genet 2015; 47: 1294-1303.
51.
Laven JS, Visser JA, Uitterlinden AG, et al. Menopause: genome stability as new paradigm. Maturitas 2016; 92: 15-23.
52.
Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature 2009; 461: 1071-1078.
53.
Shimizu I, Yoshida Y, Suda M, et al. DNA damage response and metabolic disease. Cell Metab 2014; 20: 967-977.
54.
Nguyen C, Pham NM, Nguyen QV, et al. Menopausal status and type 2 diabetes: a nationwide epidemiological survey in Vietnam. Public Health 2016; 138: 168-169.
55.
Kaya C, Cengiz H, Yeşil A, et al. The relation among steroid hormone levels, lipid profile and menopausal symptom severity. J Psychosom Obstet Gynecol 2017; 38: 284-291.
56.
Cengiz H, Kaya C, Caypinar SS, et al. The relationship between menopausal symptoms and metabolic syndrome in postmenopausal women. J Obstet Gynaecol 2019; 39: 529-533.
57.
Dobrowolski P, Prejbisz A, Kuryłowicz A, et al. Metabolic syndrome – a new definition and management guidelines: a joint position paper by the Polish Society of Hypertension, Polish Society for the Treatment of Obesity, Polish Lipid Association, Polish Association for Study of Liver, Polish Society of Family Medicine, Polish Society of Lifestyle Medicine, Division of Prevention and Epidemiology Polish Cardiac Society, “Club 30” Polish Cardiac Society, and Division of Metabolic and Bariatric Surgery Society of Polish Surgeons. Arch Med Sci 2022; 18: 1133-1156.
58.
Amihăesei IC, Chelaru L. Metabolic syndrome a widespread threatening condition; risk factors, diagnostic criteria, therapeutic options, prevention and controversies: an overview. Rev Med Chir Soc Med Nat Iasi 2014; 118: 896-900.
59.
Goss AM, Goree LL, Ellis AC, et al. Effects of diet macronutrient composition on body composition and fat distribution during weight maintenance and weight loss. Obesity (Silver Spring) 2013; 21: 1139-1142.
60.
Panagiotakos DB, Tzima N, Pitsavos C, et al. The relationship between dietary habits, blood glucose and insulin levels among people without cardiovascular disease and type 2 diabetes; the ATTICA study. Rev Diabet Stud 2005; 2: 208-215.
61.
Amin TT, Al-Sultan AI, Ali A. Overweight and obesity and their association with dietary habits, and sociodemographic characteristics among male primary school children in Al-Hassa, Kingdom of Saudi Arabia. Indian J Community Med 2008; 33: 172-181.
62.
Villegas R, Shu XO, Gao YT, et al. Vegetable but not fruit consumption reduces the risk of type 2 diabetes in Chinese women. J Nutr 2008; 138: 574-580.
63.
Jin Q, Shi N, Aroke D, et al. Insulinemic and inflammatory dietary patterns show enhanced predictive potential for type 2 diabetes risk in postmenopausal women. Diabetes Care 2021; 44: 707-714.
64.
Kim JD, Kang SJ, Lee MK, et al. C-peptide-based index is more related to incident type 2 diabetes in non-diabetic subjects than insulin-based index. Endocrinol Metab (Seoul) 2016; 31: 320-327.
65.
Namazi N, Anjom-Shoae J, Najafi F, et al. Pro-inflammatory diet, cardio-metabolic risk factors and risk of type 2 diabetes: A cross-sectional analysis using data from RaNCD cohort study. BMC Cardiovasc Disord 2023; 23: 5.
66.
Vitale SG, Caruso S, Rapisarda AMC, et al. Isoflavones, calcium, vitamin D and inulin improve quality of life, sexual function, body composition and metabolic parameters in menopausal women: result from a prospective, randomized, placebo-controlled, parallel-group study. Prz Menopauzalny 2018; 17: 32-38.
67.
Wilson PW, Meigs JB, Sullivan L, et al. Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study. Arch Intern Med 2007; 167: 1068-1074.
68.
Waldman B, Jenkins AJ, Davis TME, et al. HDL-C and HDL-C/ApoA-I predict long-term progression of glycemia in established type 2 diabetes. Diabetes Care 2014; 37: 2351-2358.
69.
Den Tonkelaar I. Validity and reproducibility of self-reported age at menopause in women participating in the DOM-project. Maturitas 1997; 27: 117-123.
70.
Must A, Phillips SM, Naumova EN, et al. Recall of early menstrual history and menarcheal body size: after 30 years, how well do women remember? Am J Epidemiol 2002; 155: 672-679.
