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  <front>
    <journal-meta>
      <journal-id journal-id-type="publisher-id">IJN</journal-id>
      <journal-title-group>
        <journal-title>International Journal of Nutrition</journal-title>
      </journal-title-group>
      <issn pub-type="epub">2379-7835</issn>
      <publisher>
        <publisher-name>Open Access Pub</publisher-name>
        <publisher-loc>United States</publisher-loc>
      </publisher>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id">IJN-19-2579</article-id>
      <article-id pub-id-type="doi">10.14302/issn.2379-7835.ijn-19-2579</article-id>
      <article-categories>
        <subj-group>
          <subject>research-article</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Cardiovascular Disease and Depression/Anxiety, Two Complication of Menopause Status</article-title>
        <alt-title alt-title-type="running-head">menopause and risk of chronic disease</alt-title>
      </title-group>
      <contrib-group>
        <contrib contrib-type="author">
          <name>
            <surname>Susan</surname>
            <given-names>Darroudi</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842865948">1</xref>
          <xref ref-type="aff" rid="idm1842865372">2</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Maryam</surname>
            <given-names>Saberi-Karimian</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842865948">1</xref>
          <xref ref-type="aff" rid="idm1842865372">2</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Fatemeh</surname>
            <given-names>Sadabadi</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842865948">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Maryam</surname>
            <given-names>Tayefi</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842864940">3</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Batool</surname>
            <given-names>Tayefi</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842865156">4</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Zahra</surname>
            <given-names>Asadi</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842864868">5</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Toktam</surname>
            <given-names>Sahranavard</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842865948">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Sajjad</surname>
            <given-names>Sabour</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842865948">1</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Farnoush</surname>
            <given-names>Kermanshahi</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842864868">5</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Effat</surname>
            <given-names>Bahadory</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842864868">5</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Gordon</surname>
            <given-names>A. Ferns</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842864796">6</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Habibollah</surname>
            <given-names>Esmaily</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842864292">7</xref>
        </contrib>
        <contrib contrib-type="author">
          <name>
            <surname>Majid</surname>
            <given-names>Ghayour-Mobarhan</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842863788">8</xref>
          <xref ref-type="aff" rid="idm1842863068">*</xref>
        </contrib>
      </contrib-group>
      <aff id="idm1842865948">
        <label>1</label>
        <addr-line>Student Research Committee, Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran</addr-line>
      </aff>
      <aff id="idm1842865372">
        <label>2</label>
        <addr-line>Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.</addr-line>
      </aff>
      <aff id="idm1842864940">
        <label>3</label>
        <addr-line>Head, University international Accreditation, International Office, Assistant Professor, Clinical Research Unit, Mashhad University of Medical Sciences, Mashhad, Iran</addr-line>
      </aff>
      <aff id="idm1842865156">
        <label>4</label>
        <addr-line>Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran.</addr-line>
      </aff>
      <aff id="idm1842864868">
        <label>5</label>
        <addr-line>Department of Nutrition, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.</addr-line>
      </aff>
      <aff id="idm1842864796">
        <label>6</label>
        <addr-line>Brighton &amp; Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex BN1 9PH, UK. </addr-line>
      </aff>
      <aff id="idm1842864292">
        <label>7</label>
        <addr-line>Department of Biostatistics &amp; Epidemiology, School of Health, Management &amp; Social Determinants of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.</addr-line>
      </aff>
      <aff id="idm1842863788">
        <label>8</label>
        <addr-line>Metabolic Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.</addr-line>
      </aff>
      <aff id="idm1842863068">
        <label>*</label>
        <addr-line>Corresponding Author</addr-line>
      </aff>
      <contrib-group>
        <contrib contrib-type="editor">
          <name>
            <surname>Kavitha</surname>
            <given-names>Menon</given-names>
          </name>
          <xref ref-type="aff" rid="idm1842843444">1</xref>
        </contrib>
      </contrib-group>
      <aff id="idm1842843444">
        <label>1</label>
        <addr-line>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.</addr-line>
      </aff>
      <author-notes>
        <corresp>
  Majid Ghayour-Mobarhan, <addr-line>Ph.D. Biochemistry of Nutrition Research </addr-line><addr-line>Center</addr-line><addr-line>, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, postal code: 99199-91766</addr-line>.                                  Tel: +<phone>985138002288</phone>, Fax: +<phone>985138002287</phone>; Email: <email>ghayourm@mums.ac.ir</email></corresp>
        <fn fn-type="conflict" id="idm1850602364">
          <p>The authors have declared that no competing interest exists. </p>
        </fn>
      </author-notes>
      <pub-date pub-type="epub" iso-8601-date="2019-04-22">
        <day>22</day>
        <month>04</month>
        <year>2019</year>
      </pub-date>
      <volume>4</volume>
      <issue>1</issue>
      <fpage>9</fpage>
      <lpage>18</lpage>
      <history>
        <date date-type="received">
          <day>02</day>
          <month>01</month>
          <year>2019</year>
        </date>
        <date date-type="accepted">
          <day>06</day>
          <month>02</month>
          <year>2019</year>
        </date>
        <date date-type="online">
          <day>22</day>
          <month>04</month>
          <year>2019</year>
        </date>
      </history>
      <permissions>
        <copyright-statement>© </copyright-statement>
        <copyright-year>2019</copyright-year>
        <copyright-holder>Susan Darroudi, et al.</copyright-holder>
        <license xlink:href="http://creativecommons.org/licenses/by/4.0/" xlink:type="simple">
          <license-p>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.</license-p>
        </license>
      </permissions>
      <self-uri xlink:href="http://openaccesspub.org/ijn/article/1061">This article is available from http://openaccesspub.org/ijn/article/1061</self-uri>
      <abstract>
        <sec id="idm1842838340">
          <title>Objective</title>
          <p>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. </p>
        </sec>
        <sec id="idm1842838772">
          <title>Study Design</title>
          <p>A total number of 1763 postmenopausal women (defined by amenorrhea for more than a year, or FSH &gt; 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 </p>
        </sec>
        <sec id="idm1842837836">
          <title>Results</title>
          <p>There was a significant difference in the presence of cardiovascular disease in the natural menopause group compared with other reasons for menopause group (p&lt;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&lt;0.05).   </p>
        </sec>
        <sec id="idm1842837332">
          <title>Discussion</title>
          <p>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.</p>
        </sec>
      </abstract>
      <kwd-group>
        <kwd>Postmenopausal</kwd>
        <kwd>Depression</kwd>
        <kwd>Anxiety</kwd>
        <kwd>Cardiovascular Disease.</kwd>
      </kwd-group>
      <counts>
        <fig-count count="0"/>
        <table-count count="5"/>
        <page-count count="10"/>
      </counts>
    </article-meta>
  </front>
  <body>
    <sec id="idm1842835028" sec-type="intro">
      <title>Introduction</title>
      <sec id="idm1842835244">
        <title>Background</title>
        <p>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<xref ref-type="bibr" rid="ridm1842446428">1</xref>. </p>
        <p>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<xref ref-type="bibr" rid="ridm1842440596">2</xref>. 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<xref ref-type="bibr" rid="ridm1842451012">3</xref>.</p>
        <p>Menopause can increase the risk of cardiovascular diseases (CVD)<xref ref-type="bibr" rid="ridm1842550748">4</xref>. CVD is the most important cause of mortality and morbidity                      worldwide<xref ref-type="bibr" rid="ridm1842306084">5</xref>. 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<xref ref-type="bibr" rid="ridm1842305004">6</xref>,<xref ref-type="bibr" rid="ridm1842303276">7</xref>.  </p>
        <p>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<sup>.</sup> Metabolic syndrome (MetS) is used to define the risk of cardiovascular diseases including obesity, dyslipidemia, hypertension and insulin resistance<xref ref-type="bibr" rid="ridm1842303276">7</xref>. 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<xref ref-type="bibr" rid="ridm1842290500">8</xref>.</p>
      </sec>
      <sec id="idm1842831284">
        <title>Objectives</title>
        <p>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. </p>
      </sec>
    </sec>
    <sec id="idm1842831932" sec-type="materials">
      <title>Materials and Methods</title>
      <sec id="idm1842830924">
        <title>Population Study</title>
        <p>In current cross-sectional study, 1556 postmenopausal women (with amenorrhea for more than a year by questioner or FSH &gt; 30-40 mIU/ml )<xref ref-type="bibr" rid="ridm1842297484">9</xref>, 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                previously<xref ref-type="bibr" rid="ridm1842293668">10</xref>. 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 Sciences<xref ref-type="bibr" rid="ridm1842293668">10</xref>.</p>
        <sec id="idm1842822828">
          <title>Anthropometric and Biochemical Measurements </title>
          <p>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<xref ref-type="bibr" rid="ridm1842284628">11</xref>,<xref ref-type="bibr" rid="ridm1842282396">12</xref>, while systolic and diastolic blood pressures were measured by sphygmomanometers<xref ref-type="bibr" rid="ridm1842297484">9</xref>,<xref ref-type="bibr" rid="ridm1842293668">10</xref>,<xref ref-type="bibr" rid="ridm1842284628">11</xref>. 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<xref ref-type="bibr" rid="ridm1842270052">13</xref>,<xref ref-type="bibr" rid="ridm1842266596">14</xref>. </p>
        </sec>
        <sec id="idm1842819804">
          <title>Measurements of Hematological Markers</title>
          <p>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 previously<xref ref-type="bibr" rid="ridm1842263500">15</xref></p>
        </sec>
        <sec id="idm1842819660">
          <title>Clinical Evaluation of Depression and Anxiety</title>
          <p>Depression Inventory (BDI) and Beck Anxiety Inventory (BAI)<xref ref-type="bibr" rid="ridm1842277468">16</xref>,<xref ref-type="bibr" rid="ridm1842273580">17</xref>were completed by all participants<xref ref-type="bibr" rid="ridm1842250412">18</xref>. 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<xref ref-type="bibr" rid="ridm1842250412">18</xref>. </p>
        </sec>
      </sec>
      <sec id="idm1842816276">
        <title>Statistical Analysis</title>
        <p>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 <italic>p </italic>value &lt; 0.05 was considered as significant.  </p>
      </sec>
    </sec>
    <sec id="idm1842816348" sec-type="results">
      <title>Results</title>
      <sec id="idm1842818076">
        <title>Anthropometric Characteristics and the Presence of Dyslipidemia According to Menopause status</title>
        <p>Clinical and demographic characteristics of participants are presented in <xref ref-type="table" rid="idm1849493652">Table 1</xref>. 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 (<xref ref-type="table" rid="idm1849493652">Table 1</xref>).</p>
        <p>Our results demonstrated that the mean of BMI was significantly higher in other reasons of menopause than natural menopause status (p&lt; 0.05). But WC was significantly lower in other reasons of menopause than natural menopause (p&lt; 0.05). Also, there were not significant differences between two groups in HC, mid upper circumference, systolic and diastolic blood pressure (p&gt;0.05).</p>
        <p>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&lt; 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 (<xref ref-type="table" rid="idm1849493652">Table 1</xref>). Moreover, depression and anxiety score in other reasons of menopause group were significantly higher than natural menopause groups.</p>
        <table-wrap id="idm1849493652">
          <label>Table 1.</label>
          <caption>
            <title> Anthropometrics and clinical characteristic according to Menopause status</title>
          </caption>
          <table rules="all" frame="box">
            <tbody>
              <tr>
                <td> </td>
                <td>Natural menopause</td>
                <td>Other reasons for menopause</td>
                <td>p-value</td>
              </tr>
              <tr>
                <td>N</td>
                <td>900</td>
                <td>863</td>
                <td> </td>
              </tr>
              <tr>
                <td>Age (years)</td>
                <td>54.32±3.88</td>
                <td>48.12±7.06</td>
                <td>&lt; 0.001</td>
              </tr>
              <tr>
                <td>BMI (Kg/m<sup>2</sup>)</td>
                <td>28.0±4.8</td>
                <td>29.4±4.9</td>
                <td>0.007</td>
              </tr>
              <tr>
                <td>Waist circumference (cm)</td>
                <td>101.4±12.6</td>
                <td>95.7±12.8</td>
                <td>&lt; 0.001</td>
              </tr>
              <tr>
                <td>Hip circumference (cm)</td>
                <td>104.87±9.89</td>
                <td>106.04±10.63</td>
                <td>0.2</td>
              </tr>
              <tr>
                <td>Mid upper circumference (cm)</td>
                <td>30.50±3.71</td>
                <td>31.25±5.51</td>
                <td>0.094</td>
              </tr>
              <tr>
                <td>Systolic  blood pressure (mmHg)</td>
                <td>128.7±22.3</td>
                <td>122.8±19.6</td>
                <td>0.76</td>
              </tr>
              <tr>
                <td>Diastolic  blood pressure (mmHg)</td>
                <td>81.7±11.5</td>
                <td>79.6±11.7</td>
                <td>0.63</td>
              </tr>
              <tr>
                <td>FBG (mg/dl)</td>
                <td>98.91±48.28</td>
                <td>96.13±36.39</td>
                <td>0.27</td>
              </tr>
              <tr>
                <td>Uric acid (mg/dl)</td>
                <td>4.41±1.31</td>
                <td>4.49±1.25</td>
                <td>0.007</td>
              </tr>
              <tr>
                <td>Cholesterol (mg/dl)</td>
                <td>206.99±41.38</td>
                <td>198.05±40.02</td>
                <td>0.9</td>
              </tr>
              <tr>
                <td>Triglyceride (mg/dl)</td>
                <td>127(92-179)</td>
                <td>125(91-173)</td>
                <td>0.9</td>
              </tr>
              <tr>
                <td>HDL (mg/dl)</td>
                <td>46.6±9.9</td>
                <td>47.2±10.5</td>
                <td>0.13</td>
              </tr>
              <tr>
                <td>LDL (mg/dl)</td>
                <td>127.9±37.8</td>
                <td>112.2±39.5</td>
                <td>&lt;0.001</td>
              </tr>
              <tr>
                <td>hs-CRP (mg/l)</td>
                <td>1.98(1.18-4.19)</td>
                <td>2.41(1.25-5.76)</td>
                <td>0.02</td>
              </tr>
              <tr>
                <td>BUN (mg/dl)</td>
                <td>13.65±4.55</td>
                <td>11.95±4.09</td>
                <td>&lt;0.001</td>
              </tr>
              <tr>
                <td>Creatinine (mg/dl)</td>
                <td>0.83±0.27</td>
                <td>0.79±0.20</td>
                <td>0.014</td>
              </tr>
              <tr>
                <td> Total Bilirubin (mg/dl)</td>
                <td>0.43±0.24</td>
                <td>0.41±0.18</td>
                <td>0.26</td>
              </tr>
              <tr>
                <td>Direct Bilirubin (mg/dl)</td>
                <td>0.29±0.14</td>
                <td>0.26±0.12</td>
                <td>0.076</td>
              </tr>
              <tr>
                <td>AST (mg/dl)</td>
                <td>25.18±16.08</td>
                <td>22.39±10.93</td>
                <td>0.003</td>
              </tr>
              <tr>
                <td>ALT (mg/dl)</td>
                <td>16.61±13.37</td>
                <td>16.59±10.53</td>
                <td>0.9</td>
              </tr>
              <tr>
                <td>Depression score</td>
                <td>14.43</td>
                <td>15.53</td>
                <td>0.029</td>
              </tr>
              <tr>
                <td>Anxiety score</td>
                <td>12.46</td>
                <td>13.92</td>
                <td>0.006</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="idm1842722660">
              <label/>
              <p>Data are presented as mean (SD) or inter quartile range. Using ANCOVA analyses with age included as model covariates</p>
            </fn>
            <fn id="idm1842722588">
              <label/>
              <p>BMI: body mass index, FBG: fasting blood glucose, HDL: high density lipoprotein, LDL: low density                       lipoprotein, hs-CRP: high sensitive C reactive protein, BUN: blood urea nitrogen, AST: aspartate transaminase, ALT: alanine transaminase</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
      </sec>
      <sec id="idm1842721292">
        <title>Comparison of Hematological Parameters Between Groups </title>
        <p>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 <xref ref-type="table" rid="idm1849378196">Table 2</xref> clearly defined that individuals with a natural menopause had a significantly higher level of MCHC and platelets than the other groups (p&lt;0.05). In contrast, the level of WBC was lower in the natural menopause group (p&lt;0.05) (<xref ref-type="table" rid="idm1849378196">Table 2</xref>). But there were no expressive differences between groups with regard to RBC, HCT, Hb, MCV, MCH, RDW, PDW and MPV.</p>
        <table-wrap id="idm1849378196">
          <label>Table 2.</label>
          <caption>
            <title> CBC markers according to Menopause status </title>
          </caption>
          <table rules="all" frame="box">
            <tbody>
              <tr>
                <td> </td>
                <td>Natural menopause</td>
                <td>Natural menopause</td>
                <td>p-value</td>
              </tr>
              <tr>
                <td>WBC</td>
                <td>5.86±1.44</td>
                <td>5.91±1.43</td>
                <td>0.34</td>
              </tr>
              <tr>
                <td>RBC</td>
                <td>4.72±0.4</td>
                <td>4.72±0.41</td>
                <td>0.97</td>
              </tr>
              <tr>
                <td>HGB</td>
                <td>13.39±1.08</td>
                <td>13.13±1.31</td>
                <td>0.07</td>
              </tr>
              <tr>
                <td>HCT</td>
                <td>40.28±3.45</td>
                <td>39.95±3.12</td>
                <td>0.08</td>
              </tr>
              <tr>
                <td>MCV</td>
                <td>84.37±5.36</td>
                <td>84.79±5.73</td>
                <td>0.6</td>
              </tr>
              <tr>
                <td>MCH</td>
                <td>28.32±2.11</td>
                <td>27.92±2.46</td>
                <td>0.42</td>
              </tr>
              <tr>
                <td>MCHC</td>
                <td>33.15±1.25</td>
                <td>32.87±1.4</td>
                <td>0.001</td>
              </tr>
              <tr>
                <td>PLT</td>
                <td>239.78±61.26</td>
                <td>235.30±59.16</td>
                <td>0.004</td>
              </tr>
              <tr>
                <td>RDW</td>
                <td>41.57±2.98</td>
                <td>41.36±2.88</td>
                <td>0.094</td>
              </tr>
              <tr>
                <td>PDW</td>
                <td>12.87±2.03</td>
                <td>12.94±1.93</td>
                <td>0.46</td>
              </tr>
              <tr>
                <td>MPV</td>
                <td>10.09±1.07</td>
                <td>10.14±0.92</td>
                <td>0.27</td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="idm1842679716">
              <label/>
              <p>Data are presented as mean (SD). Using ANCOVA analyses with age included as model covariates. CBC: cell blood count, WBC: Wight blood cell, RBC: red blood cell, HGB: hemoglobin, HCT: hematocrit, MCV: Mean Corpuscular Volume, MCH: Mean Corpuscular Hemoglobin, MCHC: Mean Corpuscular Hemoglobin                             Concentration, PLT: platelets, RDW: Red Cell Distribution Width, PDW: Platelets Distribution Width, MPW: Mean platelet volume.</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <p>Logistic regression analysis was performed to determine the odds ratio (OR) of the association between demographic, biochemical and hematological (<xref ref-type="table" rid="idm1849318220">Table 3</xref>). 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 (<xref ref-type="table" rid="idm1849318220">Table 3</xref>).</p>
        <table-wrap id="idm1849318220">
          <label>Table 3.</label>
          <caption>
            <title> Association between demographic, biochemical and hematological parameters with menopause#.</title>
          </caption>
          <table rules="all" frame="box">
            <tbody>
              <tr>
                <td> </td>
                <td colspan="2">Odds Ratio (95% CI)</td>
              </tr>
              <tr>
                <td> </td>
                <td>Univariate</td>
                <td>Multivariate<xref ref-type="table-fn" rid="idm1842643828">a</xref></td>
              </tr>
              <tr>
                <td>BMI</td>
                <td>1.027(1.008-1.047)<xref ref-type="table-fn" rid="idm1842644548">**</xref></td>
                <td>1.14(1.08-1.2)<xref ref-type="table-fn" rid="idm1842643468">***</xref></td>
              </tr>
              <tr>
                <td>Waist circumference</td>
                <td>0.963(0.955-0.97)<xref ref-type="table-fn" rid="idm1842643468">***</xref></td>
                <td>0.928(0.91-0.947)<xref ref-type="table-fn" rid="idm1842643468">***</xref></td>
              </tr>
              <tr>
                <td>Uric acid</td>
                <td>1.047(0.974-1.124)</td>
                <td>1.268(1.096-1.467)<xref ref-type="table-fn" rid="idm1842644548">**</xref></td>
              </tr>
              <tr>
                <td>LDL</td>
                <td>0.991(0.988-0.993)<xref ref-type="table-fn" rid="idm1842643468">***</xref></td>
                <td>0.998(0.994-1.002)</td>
              </tr>
              <tr>
                <td>BUN</td>
                <td>0.888(0.861-0.916)<xref ref-type="table-fn" rid="idm1842643468">***</xref></td>
                <td>0.94(0.897-0.985)<xref ref-type="table-fn" rid="idm1842644548">**</xref></td>
              </tr>
              <tr>
                <td>Creatinine</td>
                <td>0.331(0.193-0.566)<xref ref-type="table-fn" rid="idm1842644548">**</xref></td>
                <td>1.3(0.492-3.45)</td>
              </tr>
              <tr>
                <td>AST</td>
                <td>0.976(0.965-0.988)<xref ref-type="table-fn" rid="idm1842644548">**</xref></td>
                <td>0.984(0.969-0.999)<xref ref-type="table-fn" rid="idm1842643200">*</xref></td>
              </tr>
              <tr>
                <td>MCHC</td>
                <td>0.819(0.76-0.88)<xref ref-type="table-fn" rid="idm1842643468">***</xref></td>
                <td>0.775(0.677-0.888)<xref ref-type="table-fn" rid="idm1842643468">***</xref></td>
              </tr>
              <tr>
                <td>PLT</td>
                <td>0.999(0.997-1.0)</td>
                <td>0.997(0.994-1)<xref ref-type="table-fn" rid="idm1842643200">*</xref></td>
              </tr>
            </tbody>
          </table>
          <table-wrap-foot>
            <fn id="idm1842644764">
              <label/>
              <p>CI, confidence interval</p>
            </fn>
            <fn id="idm1842643828">
              <label>a</label>
              <p>: In multivariate analysis age and all factors in table inter to model</p>
            </fn>
            <fn id="idm1842643200">
              <label>*</label>
              <p>: p&lt; 0.05</p>
            </fn>
            <fn id="idm1842643468">
              <label>***</label>
              <p>: p&lt; 0.001,</p>
            </fn>
            <fn id="idm1842644548">
              <label>**</label>
              <p>: p&lt; 0.01</p>
            </fn>
            <fn id="idm1842645124">
              <label>#</label>
              <p> logistic regression has done; dependent variable was menopause status</p>
            </fn>
          </table-wrap-foot>
        </table-wrap>
        <sec id="idm1842643756">
          <title>Metabolic Syndrome</title>
          <p>In this study, we investigated metabolic syndrome in natural menopause individuals compared to other reasons of menopause groups (<xref ref-type="table" rid="idm1849254868">Table 4</xref>). 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&lt; 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 (<xref ref-type="table" rid="idm1849197380">Table 5</xref>). </p>
        </sec>
        <sec id="idm1842641236">
          <title>Diabetes</title>
          <p>In this study, we investigated diabetes in the natural menopause individuals compared with other reasons of menopause groups (<xref ref-type="table" rid="idm1849254868">Table 4</xref>). 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&lt;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 (<xref ref-type="table" rid="idm1849197380">Table 5</xref>).</p>
        </sec>
        <sec id="idm1842641380">
          <title>CVD</title>
          <p>We have investigated the risk of cardiovascular disease in two groups (<xref ref-type="table" rid="idm1849254868">Table 4</xref>). 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&lt;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 (<xref ref-type="table" rid="idm1849197380">Table 5</xref>). </p>
        </sec>
        <sec id="idm1842640588">
          <title>Depression and Anxiety</title>
          <p>Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were used for classification individuals to four groups, no (&lt;13), mild (13-19), moderate (20-28) and severe (29-63) for depression and no (&lt;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 (<xref ref-type="table" rid="idm1849254868">Table 4</xref>). 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 (<xref ref-type="table" rid="idm1849254868">Table 4</xref>). 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&lt;0.05).</p>
          <table-wrap id="idm1849254868">
            <label>Table 4.</label>
            <caption>
              <title> Prevalence of CVD, Metabolic syndrome, Diabetes, Smoking, Depression and Anxiety in Menopause</title>
            </caption>
            <table rules="all" frame="box">
              <tbody>
                <tr>
                  <td> </td>
                  <td> </td>
                  <td>Natural menopause</td>
                  <td>other reasons for menopause</td>
                  <td>p-value</td>
                </tr>
                <tr>
                  <td>Metabolic syndrome</td>
                  <td>Yes</td>
                  <td>520 (56.5%)</td>
                  <td>400(43.5%)</td>
                  <td>&lt; 0.001</td>
                </tr>
                <tr>
                  <td/>
                  <td>no</td>
                  <td>378 (44.9%)</td>
                  <td>465(55.1%)</td>
                  <td/>
                </tr>
                <tr>
                  <td>Diabetes Mellitus</td>
                  <td>Yes</td>
                  <td>212(60.2%)</td>
                  <td>143 (39.8%)</td>
                  <td>&lt; 0.001</td>
                </tr>
                <tr>
                  <td/>
                  <td>No</td>
                  <td>698 (49.5%)</td>
                  <td>710 (50.5%)</td>
                  <td/>
                </tr>
                <tr>
                  <td>CVD </td>
                  <td>Yes</td>
                  <td>79 (44.1%)</td>
                  <td>100 (55.9%)</td>
                  <td>0.031</td>
                </tr>
                <tr>
                  <td/>
                  <td>No</td>
                  <td>821 (51.8%)</td>
                  <td>763 (48.2%)</td>
                  <td/>
                </tr>
                <tr>
                  <td>Depression</td>
                  <td>No</td>
                  <td>461 (55.0%)</td>
                  <td>410 (48.3%)</td>
                  <td>0.043</td>
                </tr>
                <tr>
                  <td/>
                  <td>Mild</td>
                  <td>176 (19.2%)</td>
                  <td>187 (21.9%)</td>
                  <td/>
                </tr>
                <tr>
                  <td/>
                  <td>Moderate</td>
                  <td>141 (16.5%)</td>
                  <td>166 (19.7%)</td>
                  <td/>
                </tr>
                <tr>
                  <td/>
                  <td>High</td>
                  <td>110 (9.4%)</td>
                  <td>112 (10.1%)</td>
                  <td/>
                </tr>
                <tr>
                  <td>Anxiety</td>
                  <td>No</td>
                  <td>412 (47.3%)</td>
                  <td>337 (39.9%)</td>
                  <td>0.01</td>
                </tr>
                <tr>
                  <td/>
                  <td>Mild</td>
                  <td>231 (23.8%)</td>
                  <td>222 (25.6%)</td>
                  <td/>
                </tr>
                <tr>
                  <td/>
                  <td>Moderate</td>
                  <td>173 (20.6)</td>
                  <td>217 (26%)</td>
                  <td/>
                </tr>
                <tr>
                  <td/>
                  <td>High</td>
                  <td>87 (8.3%)</td>
                  <td>99(8.5%)</td>
                  <td/>
                </tr>
              </tbody>
            </table>
          </table-wrap>
          <p>In logistic regression, we made two groups for anxiety (no &lt;9 or yes &gt;10) and depression (no &lt;13 or yes &gt;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 (<xref ref-type="table" rid="idm1849197380">Table 5</xref>).</p>
          <table-wrap id="idm1849197380">
            <label>Table 5.</label>
            <caption>
              <title> Unadjusted and Multivariate-Adjusted Odds Ratios of disease among menopause</title>
            </caption>
            <table rules="all" frame="box">
              <tbody>
                <tr>
                  <td> </td>
                  <td colspan="2">Odds Ratio (95% CI)</td>
                </tr>
                <tr>
                  <td> </td>
                  <td>Unadjusted</td>
                  <td>Multivariate adjusted <xref ref-type="table-fn" rid="idm1842556772">a</xref></td>
                </tr>
                <tr>
                  <td>Metabolic syndrome (reference: no)</td>
                  <td>0.626(0.519-0.756)<xref ref-type="table-fn" rid="idm1842554756">***</xref></td>
                  <td>0.932(0.752-1.14)</td>
                </tr>
                <tr>
                  <td>Diabetes (reference: no)</td>
                  <td>0.648(0.5-0.83)<xref ref-type="table-fn" rid="idm1842554756">***</xref></td>
                  <td>0.945(0.727-1.23)</td>
                </tr>
                <tr>
                  <td>CVD(reference: no)</td>
                  <td>1.36(0.99-1.316)<xref ref-type="table-fn" rid="idm1842556628">**</xref></td>
                  <td>1.85(1.31-2.6)<xref ref-type="table-fn" rid="idm1842554756">***</xref></td>
                </tr>
                <tr>
                  <td>Depression (reference: no)</td>
                  <td>1.53(1.272-1.86)<xref ref-type="table-fn" rid="idm1842554756">***</xref></td>
                  <td>1.52(1.23-1.87)<xref ref-type="table-fn" rid="idm1842554756">***</xref></td>
                </tr>
                <tr>
                  <td>Anxiety (reference: no)</td>
                  <td>1.51(1.255-1.822)<xref ref-type="table-fn" rid="idm1842554756">***</xref></td>
                  <td>1.56(1.27-1.92)<xref ref-type="table-fn" rid="idm1842554756">***</xref></td>
                </tr>
              </tbody>
            </table>
            <table-wrap-foot>
              <fn id="idm1842555116">
                <label/>
                <p>CI, confidence interval</p>
              </fn>
              <fn id="idm1842556772">
                <label>a</label>
                <p>: In multivariate model each disease adjusted for age.</p>
              </fn>
              <fn id="idm1842554756">
                <label>***</label>
                <p>: p&lt; 0.001</p>
              </fn>
              <fn id="idm1842556628">
                <label>**</label>
                <p>: p&lt; 0.01</p>
              </fn>
            </table-wrap-foot>
          </table-wrap>
        </sec>
      </sec>
    </sec>
    <sec id="idm1842554396" sec-type="discussion">
      <title>Discussion</title>
      <p>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<xref ref-type="bibr" rid="ridm1842238748">23</xref>,<xref ref-type="bibr" rid="ridm1842231428">24</xref>. 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<xref ref-type="bibr" rid="ridm1842249476">19</xref>. 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<xref ref-type="bibr" rid="ridm1842247892">20</xref>. </p>
      <p>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<xref ref-type="bibr" rid="ridm1842241844">22</xref>. Recent studies showed that there is not any association between CVD risk and hysterectomy, with ovarian conservation<xref ref-type="bibr" rid="ridm1842244796">21</xref>. 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<xref ref-type="bibr" rid="ridm1842241844">22</xref>. 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<xref ref-type="bibr" rid="ridm1842238748">23</xref>.</p>
      <p>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.</p>
      <p>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<xref ref-type="bibr" rid="ridm1842231428">24</xref>. 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<xref ref-type="bibr" rid="ridm1842229556">25</xref>. Although, we cannot identify this irregularity in current research because of no measuring the insulin resistance indices, which should be included in future studies. </p>
      <p>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.</p>
    </sec>
    <sec id="idm1842547700" sec-type="conclusions">
      <title>Conclusion </title>
      <p>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.</p>
    </sec>
    <sec id="idm1842548420">
      <title>Funding</title>
      <p>This study was support by grant from Mashhad University of Medical Science</p>
    </sec>
  </body>
  <back>
    <ack>
      <p>We thank Prof.  Gordon A. Ferns for his critical review of this manuscript. </p>
    </ack>
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