Abstract
Objective
Postmenopausal women are at an increased risk of Cardiovascular Disease. We aimed to investigate whether this risk differed between individuals with a naturally occurring and other reasons for menopause within a large population-based Iranian sample.
Study Design
A total number of 1763 postmenopausal women (defined by amenorrhea for more than a year, or FSH > 30-40 mIU/ml), 900 of them with a natural menopause and 863 of them with other reasons for menopause caused by (hysterectomy without oophorectomy or one side oophorectomy, hysterectomy with oophorectomy or two side oophorectomy without hysterectomy) were recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorders (MASHAD) cohort study. Biochemical and hematological risk factors were measured in all the subjects and the data were analyzed by SPSS software version 20
Results
There was a significant difference in the presence of cardiovascular disease in the natural menopause group compared with other reasons for menopause group (p<0.05). There was also a meaningful difference between the prevalence of depression and anxiety in the natural menopause individuals compared with other reasons for menopause group (p<0.05).
Discussion
High prevalence of CVD, depression and anxiety in other reasons in menopause women were observed among Mashhad urban females. It should be considered as a noticeable message. Furthermore, studies are necessary to determine different parameters between evaluating CVD, depression and anxiety among menopauses women.
Author Contributions
Academic Editor: Kavitha Menon, Public Health Foundation of India| Indian Institute of Public Health Gandhinagar (IIPHG) Sardar Patel Institute Campus, Drive-In Road, Thaltej, Ahmedabad- 380 054, Gujarat, India.
Checked for plagiarism: Yes
Review by: Single-blind
Copyright © 2019 Susan Darroudi, et al.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Competing interests
The authors have declared that no competing interest exists.
Citation:
Introduction
Background
Menopause means the permanent cessation of menstruation due to loss of ovarian follicular function, which occurs at a mean age of 51 years normally. It is expected that a woman will spends almost a third of her life beyond the menopause. After the menopause, a marker of the end of a woman’s reproductive life, the amount of circulating estrogen falls significantly so the symptoms and disorders related to estrogen deficiency will appear1.
Menopause can occur before the median age of natural menopause (age 51 years) that called early menopause. It is may be occur due to medical or surgical interventions such as chemotherapy or surgical procedures such as oophorectomy2. Some epidemiological studies reported that women who undergo early menopause or premature menopause are under higher risk of all-causes mortalities. However, it is necessary to study more on this controversial issue3.
Menopause can increase the risk of cardiovascular diseases (CVD)4. CVD is the most important cause of mortality and morbidity worldwide5. Over the past decades the importance of CVD among women has been increased. Therefore, researchers have investigated whether there are gender differences in CVD risk. In the past two decades the epidemiological status of CVD has changed dramatically so, that it becomes the source of disease burden in women population6,7.
The importance of CVD among women has been highlighted over past decade, leading researchers to investigate the impact of gender differences in CVD risk factors. In some of these studies mentioned higher CVD risk in postmenopausal women but it is not certainly clear whether menopause is an issue of aging, estrogen deficiency or both6. Metabolic syndrome (MetS) is used to define the risk of cardiovascular diseases including obesity, dyslipidemia, hypertension and insulin resistance7. Some evidence shows a link between the menopause and some components of the MetS, but results have been inconsistent. There is a hypothesis that the menopause is associated with an increase in the risk of cardiovascular disease independent of normal aging8.
Objectives
In this study we want to explore the associations between normal and other reasons of menopause with CVD and lipid profile as a risk factor of CVD in a large population-based Iranian samples.
Materials and Methods
Population Study
In current cross-sectional study, 1556 postmenopausal women (with amenorrhea for more than a year by questioner or FSH > 30-40 mIU/ml )9, 783 of them include of natural menopause and 773 of them consist of other reason menopause (hysterectomy without oophorectomy or one side oophorectomy, hysterectomy with oophorectomy or two side oophorectomy without hysterectomy), were recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorders (MASHAD) Study using a cluster-randomized-assigned during 2007-2008, as described previously10. Inclusion criteria were no known history of infectious diseases, nor a family history of stroke, myocardial infarction. Informed consent was obtained from all individuals using approved protocols by the Ethics Committee of Mashhad University of Medical Sciences10.
Anthropometric and Biochemical Measurements
Anthropometric parameters, including height, body weight, body mass index (BMI) and hip circumference (WC and HC) were measured in all the subjected as previously described11,12, while systolic and diastolic blood pressures were measured by sphygmomanometers9,10,11. Lipid profile levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) , triglyceride (TG) and fasting blood glucose (FBG) and C-reactive protein (CRP), uric acid and LFT’s such as total and direct bilirubin, AST and ALT were measured by standard procedure as described previously13,14.
Measurements of Hematological Markers
Hematological factors, including white blood cell (WBC), red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), platelet count (PLT), platelet distribution width (PDW) were measured in all the subjects, as described previously15
Clinical Evaluation of Depression and Anxiety
Depression Inventory (BDI) and Beck Anxiety Inventory (BAI)16,17were completed by all participants18. The BDI and BAI consist of 21 multiple-choice items, with each item having four options ranked according to severity. A score of 0 to 3 is assigned to each item and the aggregate score is calculated to determine the severity of depression and anxiety18.
Statistical Analysis
Data were analyzed using SPSS-18 software (SPSS Inc., IL, and USA). The normality of distribution was evaluated using Kolmogorov–Smirnov test. Descriptive statistics including mean ± standard deviation was considered for normally distributed variables or median ± interquartile range for variables that were not normally distributed. For normally distributed variables, Student’s t-test was applied to compare clinical and baseline demographics characteristics between groups. The Mann-Whitney U test was used for continuous variables and non-normally distributed variables. For categorical parameters, Chi-square or Fisher exact tests were used. All the analyses were two-sided and p value < 0.05 was considered as significant.
Results
Anthropometric Characteristics and the Presence of Dyslipidemia According to Menopause status
Clinical and demographic characteristics of participants are presented in Table 1. Among the subjects 1763, 900 (50.3%) had a natural menopause and 863 (49.7%) subjects had other reasons for the menopause. The mean age was 54.32±3.88 and 48.12±7.06 years for natural menopause and other reasons for the menopause respectively (Table 1).
Our results demonstrated that the mean of BMI was significantly higher in other reasons of menopause than natural menopause status (p< 0.05). But WC was significantly lower in other reasons of menopause than natural menopause (p< 0.05). Also, there were not significant differences between two groups in HC, mid upper circumference, systolic and diastolic blood pressure (p>0.05).
According to our findings the levels of LDL, BUN, creatinine, AST were significantly higher in the natural menopause group, whereas uric acid and hs-CRP were meaningfully lower in natural menopause group compared with the group of other reasons for the menopause (p< 0.05). But no statistically differences were found in HC, MC, SBP, DBP, glucose, triglyceride, HDL, total and direct bilirubin, and ALT between natural menopause groups and other reasons for menopause groups (Table 1). Moreover, depression and anxiety score in other reasons of menopause group were significantly higher than natural menopause groups.
Table 1. Anthropometrics and clinical characteristic according to Menopause status| Natural menopause | Other reasons for menopause | p-value | |
| N | 900 | 863 | |
| Age (years) | 54.32±3.88 | 48.12±7.06 | < 0.001 |
| BMI (Kg/m2) | 28.0±4.8 | 29.4±4.9 | 0.007 |
| Waist circumference (cm) | 101.4±12.6 | 95.7±12.8 | < 0.001 |
| Hip circumference (cm) | 104.87±9.89 | 106.04±10.63 | 0.2 |
| Mid upper circumference (cm) | 30.50±3.71 | 31.25±5.51 | 0.094 |
| Systolic blood pressure (mmHg) | 128.7±22.3 | 122.8±19.6 | 0.76 |
| Diastolic blood pressure (mmHg) | 81.7±11.5 | 79.6±11.7 | 0.63 |
| FBG (mg/dl) | 98.91±48.28 | 96.13±36.39 | 0.27 |
| Uric acid (mg/dl) | 4.41±1.31 | 4.49±1.25 | 0.007 |
| Cholesterol (mg/dl) | 206.99±41.38 | 198.05±40.02 | 0.9 |
| Triglyceride (mg/dl) | 127(92-179) | 125(91-173) | 0.9 |
| HDL (mg/dl) | 46.6±9.9 | 47.2±10.5 | 0.13 |
| LDL (mg/dl) | 127.9±37.8 | 112.2±39.5 | <0.001 |
| hs-CRP (mg/l) | 1.98(1.18-4.19) | 2.41(1.25-5.76) | 0.02 |
| BUN (mg/dl) | 13.65±4.55 | 11.95±4.09 | <0.001 |
| Creatinine (mg/dl) | 0.83±0.27 | 0.79±0.20 | 0.014 |
| Total Bilirubin (mg/dl) | 0.43±0.24 | 0.41±0.18 | 0.26 |
| Direct Bilirubin (mg/dl) | 0.29±0.14 | 0.26±0.12 | 0.076 |
| AST (mg/dl) | 25.18±16.08 | 22.39±10.93 | 0.003 |
| ALT (mg/dl) | 16.61±13.37 | 16.59±10.53 | 0.9 |
| Depression score | 14.43 | 15.53 | 0.029 |
| Anxiety score | 12.46 | 13.92 | 0.006 |
Comparison of Hematological Parameters Between Groups
We also compared the level of different hematological parameters of the participants between natural menopause group and other reasons of menopause group. Results presented in Table 2 clearly defined that individuals with a natural menopause had a significantly higher level of MCHC and platelets than the other groups (p<0.05). In contrast, the level of WBC was lower in the natural menopause group (p<0.05) (Table 2). But there were no expressive differences between groups with regard to RBC, HCT, Hb, MCV, MCH, RDW, PDW and MPV.
Table 2. CBC markers according to Menopause status| Natural menopause | Natural menopause | p-value | |
| WBC | 5.86±1.44 | 5.91±1.43 | 0.34 |
| RBC | 4.72±0.4 | 4.72±0.41 | 0.97 |
| HGB | 13.39±1.08 | 13.13±1.31 | 0.07 |
| HCT | 40.28±3.45 | 39.95±3.12 | 0.08 |
| MCV | 84.37±5.36 | 84.79±5.73 | 0.6 |
| MCH | 28.32±2.11 | 27.92±2.46 | 0.42 |
| MCHC | 33.15±1.25 | 32.87±1.4 | 0.001 |
| PLT | 239.78±61.26 | 235.30±59.16 | 0.004 |
| RDW | 41.57±2.98 | 41.36±2.88 | 0.094 |
| PDW | 12.87±2.03 | 12.94±1.93 | 0.46 |
| MPV | 10.09±1.07 | 10.14±0.92 | 0.27 |
Logistic regression analysis was performed to determine the odds ratio (OR) of the association between demographic, biochemical and hematological (Table 3). Results obtained from univariate analysis demonstrated that BMI, WC, LDL, BUN, creatinine, AST and MCHC are associated with menopause, but when multivariate analysis was done with entering age and all factors in table to model, BMI, WC, BUN, uric acid, AST, MCHC and platelets are an independent predictive risk factor for menopause (Table 3).
Table 3. Association between demographic, biochemical and hematological parameters with menopause#.| Odds Ratio (95% CI) | ||
| Univariate | Multivariatea | |
| BMI | 1.027(1.008-1.047)** | 1.14(1.08-1.2)*** |
| Waist circumference | 0.963(0.955-0.97)*** | 0.928(0.91-0.947)*** |
| Uric acid | 1.047(0.974-1.124) | 1.268(1.096-1.467)** |
| LDL | 0.991(0.988-0.993)*** | 0.998(0.994-1.002) |
| BUN | 0.888(0.861-0.916)*** | 0.94(0.897-0.985)** |
| Creatinine | 0.331(0.193-0.566)** | 1.3(0.492-3.45) |
| AST | 0.976(0.965-0.988)** | 0.984(0.969-0.999)* |
| MCHC | 0.819(0.76-0.88)*** | 0.775(0.677-0.888)*** |
| PLT | 0.999(0.997-1.0) | 0.997(0.994-1)* |
Metabolic Syndrome
In this study, we investigated metabolic syndrome in natural menopause individuals compared to other reasons of menopause groups (Table 4). Our results demonstrated that 56.5% of natural menopause groups and 43.5% of other reasons of menopause groups at the risk of metabolic syndrome. Using the Chi-square for comparison, we shows significant differences risk of metabolic syndrome between natural menopauses individuals compared to other reasons of menopause groups (p< 0.001). According to logistic regression, our results suggested the association of metabolic syndrome with menopause status, but when data were adjusted for age in multivariate analysis, we did not found significant differences between metabolic syndrome and menopause status (Table 5).
Diabetes
In this study, we investigated diabetes in the natural menopause individuals compared with other reasons of menopause groups (Table 4). Our results demonstrated that 60.2% of natural menopause groups and 39.8% of other reasons of menopause groups at risk of diabetes. Using the Chi-square for comparison, there were significant differences risk of diabetes between natural menopause individuals compared with other reasons of menopause group (p<0.001). By using logistic regression, our results suggested the association of diabetes with menopause status in univariate analysis, but when data were adjusted for age in multivariate analysis, we did not found meaningful differences between diabetes and menopause status (Table 5).
CVD
We have investigated the risk of cardiovascular disease in two groups (Table 4). Our results demonstrated that 44.1% and 55.9% of natural menopause groups and other reasons of menopause groups respectively had cardiovascular disease. (History of MI, Angina or Stroke). Using the Chi-square for comparison, we found significant differences risk of cardiovascular disease between natural menopause individuals compared with other reasons of menopause groups (p<0.001). By using logistic regression, our results suggested that there is an association in CVD with menopause in univariate analysis, when data were adjusted for age in multivariate analysis, our result strongly showed association between CVD and menopause (Table 5).
Depression and Anxiety
Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were used for classification individuals to four groups, no (<13), mild (13-19), moderate (20-28) and severe (29-63) for depression and no (<9), mild (10-16), moderate (17-29) and severe (30-63) for anxiety. Our results showed that 21.9%, 19.7% and 10.1% of women with the other reasons of menopause had mild, moderate and severe depression, respectively (Table 4). Also, our findings showed that 35.6%, 26.0% and 8.5% of women with the other reasons of menopause had mild, moderate and severe anxiety, respectively (Table 4). Using the Chi-square for comparison, we showed significant differences in risk of anxiety between natural menopause individuals and subjects with the other reasons of the menopause (p<0.05).
Table 4. Prevalence of CVD, Metabolic syndrome, Diabetes, Smoking, Depression and Anxiety in Menopause| Natural menopause | other reasons for menopause | p-value | ||
| Metabolic syndrome | Yes | 520 (56.5%) | 400(43.5%) | < 0.001 |
| no | 378 (44.9%) | 465(55.1%) | ||
| Diabetes Mellitus | Yes | 212(60.2%) | 143 (39.8%) | < 0.001 |
| No | 698 (49.5%) | 710 (50.5%) | ||
| CVD | Yes | 79 (44.1%) | 100 (55.9%) | 0.031 |
| No | 821 (51.8%) | 763 (48.2%) | ||
| Depression | No | 461 (55.0%) | 410 (48.3%) | 0.043 |
| Mild | 176 (19.2%) | 187 (21.9%) | ||
| Moderate | 141 (16.5%) | 166 (19.7%) | ||
| High | 110 (9.4%) | 112 (10.1%) | ||
| Anxiety | No | 412 (47.3%) | 337 (39.9%) | 0.01 |
| Mild | 231 (23.8%) | 222 (25.6%) | ||
| Moderate | 173 (20.6) | 217 (26%) | ||
| High | 87 (8.3%) | 99(8.5%) |
In logistic regression, we made two groups for anxiety (no <9 or yes >10) and depression (no <13 or yes >14). According to logistic regression our results suggested that there is a strong association of anxiety and depression with menopause in univariate and multivariate analysis that adjusted by age (Table 5).
Table 5. Unadjusted and Multivariate-Adjusted Odds Ratios of disease among menopause| Odds Ratio (95% CI) | ||
| Unadjusted | Multivariate adjusted a | |
| Metabolic syndrome (reference: no) | 0.626(0.519-0.756)*** | 0.932(0.752-1.14) |
| Diabetes (reference: no) | 0.648(0.5-0.83)*** | 0.945(0.727-1.23) |
| CVD(reference: no) | 1.36(0.99-1.316)** | 1.85(1.31-2.6)*** |
| Depression (reference: no) | 1.53(1.272-1.86)*** | 1.52(1.23-1.87)*** |
| Anxiety (reference: no) | 1.51(1.255-1.822)*** | 1.56(1.27-1.92)*** |
Discussion
Results interestingly shown prevalence of depression and anxiety in women with other reasons of menopause is higher than participants with a natural menopause. Many observational studies have shown that the transition to menopause is a period of increased risk of depression23,24. Unpredictable hormone fluctuations plus stress, body image, sexuality, infertility, or aging; anyone or a combination of these, causes emotional distress that may result in mood swings or in more severe cases, depression. Determining the cause and extent of your “menopause blues” is very important19. Some study suggested concerns about the physical and social consequences of aging, or her self-esteem may be affected by a culture that values youth and reproductive capacity20.
Results of present study showed that the prevalence of cardiovascular disease was higher in participants with other reasons of menopause compared with natural menopause women. It may be explained by other reasons of menopause which it occurs earlier than normal menopause. It has been reported that cardiovascular disease, osteoporosis, urinary incontinence and depression are just a few of many common and major complaints among midlife women, which in result affects their quality of life22. Recent studies showed that there is not any association between CVD risk and hysterectomy, with ovarian conservation21. Atsma et al., have reported that there was no significant relationship between postmenopausal status and CVD. However, it has been reported that other reasons for menopause had a modest impact on CVD22. Some other studies confirm our observations which indicated that premenopausal women are protected against cardiovascular morbidity and mortality and the lack of ovarian function increased the risk of CVD23.
We also evaluated the anthropometric, biochemical and hematological indices. The BMI and uric acid were higher in the other reasons of menopause compared with natural menopause group.
The results of current study showed in spite of increased CVD in participants with the other reasons for menopause than normal menopause, they have a lower risk of diabetes and as a result, metabolic syndrome. Dørum et al. published conflict results and reported that women who had undergone bilateral oophorectomy had higher BMI and a trend towards higher blood pressure, lower HDL cholesterol, and elevated triglycerides, that all of them make the metabolic syndrome prevalence higher24. It seems that having an abnormal menopause can disarrange insulin hemostasis. Rosano et al., have reported that insulin resistance is significantly higher in postmenopausal women than in premenopausal women25. Although, we cannot identify this irregularity in current research because of no measuring the insulin resistance indices, which should be included in future studies.
It is worthy to mention that this research has some limitation. Our study was cross sectional and this was the most significant limitation of our study. However, it can help us to design a cohort study.
Conclusion
The prevalence of CVD, depression and anxiety was higher in women with other reasons of menopause than subjects with natural menopause in Iranian women. This study evaluated a wide range of disturbances and CVD risk factors in subjects with normal and other reasons for menopause for the first time. But further work is required to establish the accuracy of mentioned findings.
Funding
This study was support by grant from Mashhad University of Medical Science
Acknowledgements
We thank Prof. Gordon A. Ferns for his critical review of this manuscript.
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