Cardiovascular Disease and Depression / Anxiety , Two Complication of Menopause Status

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). DOI: 10.14302/issn.2379-7835.ijn-19-2579 Freely Available Online www.openaccesspub.org | IJN CC-license DOI : 10.14302/issn.2379-7835.ijn-19-2579 Vol-4 Issue 1 Pg. no.10 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 appear [1]. 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 oophorectomy[2]. 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 issue [3]. Menopause can increase the risk of cardiovascular diseases (CVD) [4]. CVD is the most important cause of mortality and morbidity worldwide [5]. 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 population [6, 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 both [6]. Metabolic syndrome (MetS) is used to define the risk of cardiovascular diseases including obesity, dyslipidemia, hypertension and insulin resistance [7]. 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 aging [8]. 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. Corresponding author: Majid Ghayour-Mobarhan, Ph.D. Biochemistry of Nutrition Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, postal code: 99199-91766. Tel: +985138002288, Fax: +985138002287; Email: ghayourm@mums.ac.ir Running title: Menopause and risk of chronic disease


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 appear [1].
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 oophorectomy [2].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 issue [3].
Menopause can increase the risk of cardiovascular diseases (CVD) [4].CVD is the most important cause of mortality and morbidity worldwide [5].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 population [6,7].
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 both [6].Metabolic syndrome (MetS) is used to define the risk of cardiovascular diseases including obesity, dyslipidemia, hypertension and insulin resistance [7].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 aging [8].

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.

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],

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 described [11,12], while systolic and diastolic blood pressures were measured by sphygmomanometers [9][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 previously [13,14].

Clinical Evaluation of Depression and Anxiety
Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) [16,17] were completed by all participants [18].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 anxiety [18].

Statistical Analysis
Data were analyzed using SPSS- All the analyses were two-sided and p value < 0.05 was considered as significant.

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

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.
Logistic regression analysis was performed to determine the odds ratio (OR) of the association between demographic, biochemical and hematological ( MCHC and platelets are an independent predictive risk factor for menopause (Table 3).

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).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).

Depression and Anxiety
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).

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 depression [23,24].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 important [19].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 capacity [20].
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 life [22].Recent studies showed that there is not any association between CVD risk and hysterectomy, with ovarian conservation [21].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 CVD [22].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 CVD [23].
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 higher [24].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 women [25].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.

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,

Table 3 .
Association between demographic, biochemical and hematological parameters with menopause # .

Table 4 .
Prevalence of CVD, Metabolic syndrome, Diabetes, Smoking, Depression and Anxiety in Menopause