Insulin resistance and other risk factors of cardiovascular disease in abnormal uterine bleeding

Insulin resistance and other risk factors of cardiovascular disease in abnormal uterine bleeding | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Insulin resistance and other risk factors of cardiovascular disease in abnormal uterine bleeding Hannah Shehata, Abigail Berry, Christopher Riba, Andrea Cristine Salcedo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-604656/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Studies indicate the presence of cardiovascular disease risk factors among patients with uterine fibroids and polycystic ovarian syndrome. Investigators were interested in examining the prevalence of cardiovascular disease risk factors and the independent predictors of insulin resistance (IR) among women with abnormal uterine bleeding (AUB). Methods This observational study examined 77 premenopausal subjects with AUB. Their medical history, body mass index, waist hip ratio, fasting insulin level, hemoglobin A1C, creatinine level, and lipid panel were evaluated. The participants were then subdivided using insulin levels and further compared. IR was defined at two different fasting insulin levels: >10µU/mL and > 15µU/mL. Results Of the 77 data sets analyzed, 91% of participants were current or former smokers, 62% had a waist hip ratio > 0.80, 45% were obese, and the majority of participants had dyslipidemia, with high total cholesterol (68%) and elevated LDL (38%) being the most prevalent. 66% of participants were insulin resistant as defined by the lower fasting insulin and 38% were insulin resistant as defined by the upper fasting insulin level. At the lower cutoff, the insulin resistant group was significantly more likely to have a waist hip ratio > 0.8, be obese, and have low HDL levels. At the upper fasting insulin cutoff, the insulin resistant group was significantly more likely to have low HDL levels, elevated triglyceride levels, a waist hip ratio > 0.8, and be obese. Univariate analysis showed statistically significant associations between IR in women with AUB and body mass index, waist hip ratio, and HDL for both fasting insulin cutoffs. Multivariate analysis using the lower fasting insulin cutoff revealed that body mass index and waist hip ratio were significant independent predictors of IR in a woman with AUB. Conclusions This study reveals the prevalence of IR and other predictors of cardiovascular disease are greater in women with AUB in this population than the general population. Body mass index and waist hip ratio are independent predictors of IR in women with AUB. Low HDL levels, elevated triglyceride levels, and ethnicity are also significantly associated with IR in women with AUB depending on the definition used. Nutrition & Dietetics Endocrinology & Metabolism abnormal uterine bleeding insulin resistance cardiovascular disease risk obesity waist hip ratio fasting insulin Background Abnormal uterine bleeding (AUB) is one of the most common reasons reproductive-aged women seek a gynecologic consult. It affects up to 35 percent of women in their lifetime and comprises up to 70 percent of outpatient gynecology visits each year. 1 – 2 AUB is a broad term that is classified by its causes using the PALM-COEIN system and it is often paired with descriptive terms denoting heavy versus intermenstrual bleeding. 1 Insulin is a key anabolic hormone involved in multiple metabolic pathways in the body, including glucose uptake and lipid storage, cell growth and proliferation in the body, and nitric oxide (NO) synthesis by endothelial cells. 3 – 5 Insulin resistance (IR) occurs when increasingly larger amounts of insulin are required to regulate the body’s metabolic pathways, and, even in the face of these increasing insulin levels, cellular activity is diminished compared to a normal person. 3 – 5 IR is a multifactorial disease that has become an epidemic in the United States (US). Although the number of adults affected by IR is not known, one in three adults in the US have prediabetes and an additional 10.5 percent of adults have diabetes mellitus type 2 (DM2). 3 , 6 These numbers are expected to double in the next 10 years since almost 90 percent of Americans having risk factors for IR. 6 Although angiogenesis is a relatively infrequent event in most adult tissues, it occurs repeatedly in the uterus in order to support the monthly cycle of growth, shedding, and repair of the endometrial lining. 7 Both the process of angiogenesis and endometrial repair are tightly regulated by estrogen and progesterone, which involve NO, platelets, immune cells, and multiple growth factors. 2,7−10 Decreased NO production, due to IR, results in an increase in the shear stress on endothelial cells due to diffuse vasoconstriction. 3 , 5 Moreover, decreased NO, hyperglycemia, and the state of IR itself promote the release of inflammatory cytokines and free radical formation, which leads to further endothelial damage, surrounding tissue hypoxia, and, eventually, cellular apoptosis. 3 – 5 This increases vascular permeability, which is worsened by high levels of circulating glucose also directly damaging the glycocalyx and endothelial cells through non-enzymatic glycation. 3 , 5 , 11 Together, these vascular changes allow substrates to leave the blood and form plaques in the tunica intima layer of the blood vessel. 5 This thickening of the blood vessels leads to increased vascular resistance, chronic low-grade inflammation, and atherosclerosis. 3 , 5 Applying this knowledge to the uterus, chronic low-grade inflammation likely reduces the spiral arteries’ ability to meet the high metabolic demands of the endometrium. This leads to an overexpression of angiogenic cytokines and dysfunctional angiogenesis with excessive uterine vessel formation and dilation in an attempt to increase the amount of uterine blood flow. 7 – 8 , 10 , 12 It also results in functionally impaired proliferative and secretory phases of the menstrual cycle where the endometrial lining is not properly repaired during cyclical shedding. Instead, the same inflammatory cytokines and fibrosis-promoting growth factors seen in atherosclerotic disease encourage smooth muscle metaplasia and scarring in the uterus. 12 – 19 Atherosclerosis is a widely accepted cause of numerous microvascular and macrovascular diseases that are significantly associated with IR. 3–5,20−23 Multiple studies have demonstrated that women with fibroids and polycystic ovarian syndrome (PCOS) are more likely to have risk factors for cardiovascular disease, but AUB is not currently thought of as an atherosclerotic-related end organ disease. Furthermore, few studies have examined these risk factors in women with AUB as a whole (referred to in this paper as overall AUB). 16–18,24−31 The aim of the present study is to describe the prevalence of insulin resistance and other predictors of cardiovascular disease among women with overall AUB. Methods Study Population This was a cross-sectional observational study conducted at Loma Linda University Medical Center’s outpatient obstetrics and gynecology clinics. Potential study candidates were all premenopausal females between the ages of 18 and 54 years old who presented with a complaint of AUB between September 2018 and October 2019. A candidate was confirmed eligible for enrollment once the diagnosis of AUB was made in the outpatient clinic setting. Women with a history of gynecologic cancer, prior hysterectomy, prior endometrial ablation, prior tamoxifen use, diabetes mellitus type 1, chronic steroid use, or pregnancy were excluded. There were 117 subjects enrolled with a total of 77 data sets analyzed for this study. Ethics Statement The participants gave voluntary, informed, written consent prior to participating in the study. This research study was approved by the Loma Linda University Institutional Review Board and it complied with all relevant national regulations, institutional policies, and the principles of the Declaration of Helsinki as they relate to human participants. All participant identifiers were replaced with identification codes and the data was handled only by the researchers participating in this study. Measured Variables At the time of enrollment, a thorough history was performed. Each participant had her height, weight, and waist to hip ratio (WHR) measured. Overnight fasting blood samples were then obtained to assess each participant’s fasting insulin level (FI), hemoglobin A1C (A1C), creatinine (Cr), and lipid profile. A BMI ≥ 30kg/m 2 was used as the cutoff for obesity and a WHR > 0.80 was considered abnormal. 32 – 33 IR was assessed using two different FI cutoffs: >10µU/mL and > 15µU/mL, which represented both the lower and higher end of the FI cutoffs of prior research. 4,22,34−35 Abnormal A1C values were defined by the prediabetic cut off of ≥ 5.7%, while abnormal lipid levels were defined by the American Heart Association values of HDL 150mg/dL, LDL > 100mg/dL, and triglycerides levels > 150mg/dL. 6,36 Statistical Analysis Statistical analysis was performed using the online statistical software R version 3.5.1. 37 Assuming 33 percent of the general population is IR, the minimum sample size for the present study to have adequate power was calculated to be 36 subjects in each group. 6 Independent t-test, Mann Whitney U test, and chi-square test were calculated with the statistical significance set as P > 0.05. Univariate and multivariate regression analysis were performed using linear regression. Observed associations were expressed as odds ratios with 95 percent confidence intervals. Results Of the 117 participants enrolled, 77 participants completed the measured variables and were included in the analysis. As shown in Table 1, most participants were Hispanic or White females, averaging 37 years of age, with an average of two prior births. Most participants did not have relevant medical or surgical history, except for over 90% being either current or former smokers. Approximately two-thirds of participants had a WHR > 0.80 with the average WHR being 0.86. Almost half of participants were obese with the average BMI being 31.82kg/m². Two-thirds of participants had a FI > 10µiU/mL with 38% having a FI > 15µiU/mL, but only 22% of participants had an A1C ≥ 5.7%. The majority of participants also had dyslipidemia with 68% having high total cholesterol levels and an additional 38% of participants having high LDL levels. Table 2 shows the difference in characteristics between the two groups when IR was defined as FI > 10µiU/mL. Ethnicity was significantly related to IR with all African Americans and Middle Easterners being classified as IR, while none of the Asian participants were classified as IR (p = 0.027). The IR group was significantly more likely to be obese (60.8% versus 15.4%; p < 0.001) and have low HDL levels (41.2% versus 19.2%; p = 0.03) than the non-IR group. There were no statistical differences between the two groups with regards to the other variables analyzed, but it is worth noting that no participants in the non-IR group had a history of DM2 or elevated triglycerides levels, and more than 62% of participants in both groups had high total cholesterol levels. Table 3 depicts the difference in characteristics between the two groups when IR was defined as FI > 15µiU/mL. The IR group was significantly more likely to be obese (75.9% versus 27.1%; p < 0.001), have low HDL levels (48.3% versus 25%; p = 0.016), and have high triglycerides levels (13.8% versus 2.1%; p = 0.032) compared to the non-IR group. Although there were no statistical differences between the two groups regarding the other variables analyzed, again, no Asian participants were classified as IR, and more than 62% of participants in both groups had elevated total cholesterol levels. By univariate regression analysis, factors significantly associated with IR in women with AUB were BMI, WHR, and HDL levels. These associations persisted regardless of the FI level used to define IR (see Table 4). Ethnicity, Cr, triglycerides levels, total cholesterol levels, LDL, history of DM2, history of hypertension, history of migraines, and smoking were not significantly associated with IR in women with AUB in either of the univariate regression analyses. When multivariate regression analysis was performed using FI > 10µiU/mL to define IR, BMI (standardized coefficient β: 1.07, P = 0.015) and WHR (standardized coefficient β: 1.94, P = 0.045) were independent predictors of IR in women with AUB. Regression analysis was not performed using FI > 15µiU/mL. Discussion This study shows the prevalence of IR and other predictors of cardiovascular disease are higher among women from this diverse suburban community with overall AUB (66%) than among the general population. BMI and WHR were shown to be independent predictors of IR in women with AUB. The odds of a woman with AUB having IR was 7 times higher for every 1 unit increase in BMI over 30 kg/m 2 when confounding for other variables. By the same convention, the odds of a woman with AUB having IR was nearly 4 times higher for every 0.1 unit increase in WHR after 0.8. Low HDL levels, elevated triglycerides levels, and ethnicity were also significantly associated with IR in women with AUB, depending on how IR was defined. Similar to prior studies on AUB, the present study’s participants had a high prevalence of risk factors for cardiovascular disease, including smoking (90%), obesity (45%), an elevated WHR (62%), and dyslipidemia. 16,18,24–25,28−31 The majority of participants did not have an elevated A1C or a history of hypertension or DM2, but this lack of association has been noted in prior studies on overall AUB as well. 28 – 29 Prior studies have found a relationship between AUB and elevated triglycerides levels, but this relationship was only significant in the present study when participants were IR using the higher FI cutoff of > 15µiU/mL. 28–29 Interestingly, the significant inverse relationship between IR and HDL levels in women with AUB in the present study was not seen in prior studies on overall AUB. 28 – 29 Participants with normal HDL levels, which are considered cardioprotective, were almost 70 percent less likely to be IR. 36 Additionally, although a significant relationship between BMI and/or WHR and AUB has been reported in multiple prior studies, the relationship between BMI and/or WHR, IR, and AUB has previously only been shown to be significant in prior studies on AUB due to PCOS. 16,18,24–25,28−31 Some of the strengths of this study were the diverse patient population studied and the broad definition of AUB intentionally used to evaluate the overall relationship between AUB and risk factors for cardiovascular disease. However, this also made it difficult to compare the present study’s results to the results of prior studies, which often only evaluated one specific cause of AUB and included less diverse study populations. Using a diverse study population limits how generalizable the present study’s results are to more homogenous regions. Furthermore, as the pathophysiology causing AUB in women with irregular cycles compared to those with AUB and regular cycles may be different, the prevalence of the different risk factors for cardiovascular disease may not be the same in these different subsets of women. Additionally, as this was a cross-sectional study, it can only identify associations between IR and other cardiovascular disease risk factors among women with AUB. Another weakness of this study was the high attrition rate present with 41 (35%) of the participants being excluded from the analysis due to not completing any laboratory data despite regular reminders by the study’s investigators. Although still included in the analysis, an additional four (3%) of the participants did not complete the required lipid panel and an additional 16 (13.6%) of the participants did not undergo evaluation of their WHR. This selection bias likely affects how generalizable the results from the present study are to women with AUB even. Finally, attempts to limit investigator bias were made by using retrospective self-reports to diagnose AUB, but prior studies have shown these may not be accurate. 38 Implications for Research Further research is needed on the relationship between ethnicity and IR as ethnicity has been shown to be an important predictor of cardiovascular disease in the general population. 39 Although ethnicity was shown to be significantly related to IR in women with AUB when IR was defined as FI > 10 µiU/mL, it may not have been significantly related to IR using the higher FI cutoff due to a small sample size. A follow-up study is currently underway to compare the prevalence of IR and other cardiovascular disease risk factors in women with AUB to normally menstruating women within this same diverse suburban community. Conclusions and Implications The high prevalence of risk factors for cardiovascular disease seen in these women suggests that AUB may be a sentinel finding for DM2 and cardiovascular disease in women later in life. It is vital for clinicians to screen women from diverse suburban communities with AUB for metabolic syndrome and these other cardiovascular disease risk factors. These patients also need to be educated on lifestyle changes they can make to reduce their risk for cardiovascular disease. Abbreviations AUB Abnormal uterine bleeding PALM-COEIN Polyp, Adenomyosis, Leiomyoma, Metaplasia- Coagulopathy, Ovulatory, Endometrial, Iatrogenic, Not otherwise specified IR Insulin resistance NO Nitric oxide DM2 Diabetes mellitus type 2 PCOS polycystic ovarian syndrome FI Fasting insulin BMI Body mass index WHR Waist hip ratio Declarations Ethics approval to participate: The participants gave voluntary, informed, written consent prior to participating in the study. This research study was approved by the Loma Linda University Institutional Review Board and it complied with all relevant national regulations, institutional policies, and the principles of the Declaration of Helsinki as they relate to human participants. All participant identifiers were replaced with identification codes and the data was handled only by the researchers participating in this study. Consent for publication Not applicable Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare they have no competing interests. Funding This study was supported by Loma Linda University Health, Department of Gynecology and Obstetrics. Authors’ contributions AS made substantial contributions to the conception, design of the work, acquisition and interpretation of data, and substantively revised the work. HS made substantial contributions to the acquisition and interpretation of data, drafted and substantively revised the work. AB and CR made substantial contributions to the acquisition of data. All authors have approved the submitted version and agree to be personally accountable for the author’s own contributions to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. Acknowledgements The authors would like to thank Jiahao Peng, MD, PhD, and Wendy Shih, DrPH of the Research Consulting Group of Loma Linda University Health, for their contributions to the analysis of the data. References American College of Obstetricians and Gynecologists. Diagnosis of abnormal uterine bleeding in reproductive-aged women. ACOG Practice Bulletin No. 128. Washington DC; 2012. Davis E, Sparzak PB. Abnormal uterine bleeding (dysfunctional uterine bleeding). StatPearls. Treasure Island FL: StatPearls Publishing; 2020. https://www.ncbi.nlm.nih.gov/books/NBK532913/ . Accessed February 26, 2020. 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Waist circumference and waist-hip ratio: Report of a WHO expert consultation. Geneva; 2008. Ghasemi A, Tohidi M, Derakhshan A, et al. Cut-off points of homeostasis model assessment of insulin resistance, beta-cell function, and fasting serum insulin to identify future type 2 diabetes: Tehran lipid and glucose study. Acta Diabetol. 2015;52:905–15. doi: 10.1007/s00592-015-0730-3 . Lee S, Choi S, Kim HJ, et al. Cutoff values of surrogate measures of insulin resistance for metabolic syndrome in Korean non-diabetic adults. J Korean Med Sci. 2006;21(4):695–700. doi: 10.3346/jkms.2006.21.4.695 . Grundy SM, Stone NJ, Bailey AL, et al. AHA/ACC/AACVPR/ AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/ NLA/PCNA guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol, 2018; 139:e1082–143. doi: 10.1161/CIR.0000000000000625 . R Core Team. R: A language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2018. https://www.R-project.org . Small CM, Manatunga AK, Marcus M. Validity of self-reported menstrual cycle length. Ann Epidemiol. 2007;17:163–70. Meadows TA, Bhatt DL, Cannon CP, et al. Ethnic differences in cardiovascular risks and mortality in atherothrombotic disease: Insights from the Reduction of Atherothrombosis for Continued Health (REACH) registry. Mayo Clin Proc. 2011;86(10):960–7. doi: 10.4065/mcp.2011.0010 . Tables Due to technical limitations, table 1, 2, 3, 4 is only available as a download in the Supplemental Files section. Supplementary Files Table1.png Table 1: Description of the study population Table2.png Table 2: Comparison of characteristics between insulin resistant and non-insulin resistant groups with insulin resistance defined as fasting insulin levels >10uIU/mL Table3.png Table 3: Comparison of characteristics between insulin resistant and non-insulin resistant groups with insulin resistance defined as fasting insulin levels >15uIU/m Table4.png Table 4: Univariate analysis of risk factors for insulin resistance in women with abnormal uterine bleeding Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-604656","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research","associatedPublications":[],"authors":[{"id":36269566,"identity":"12b8a6b4-9c49-4996-af9f-e22b9c83a756","order_by":0,"name":"Hannah Shehata","email":"","orcid":"","institution":"Loma Linda University Health: Loma Linda University Adventist Health Sciences Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hannah","middleName":"","lastName":"Shehata","suffix":""},{"id":36269567,"identity":"84653c98-f574-45b6-81ab-3a0e38273ac8","order_by":1,"name":"Abigail 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Salcedo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABB0lEQVRIiWNgGAWjYDCCA0DMA2YxNzAwsDHIgQUfEKeFEazFGCyYQIqWxAYQG58WvtuHnz14u8dGXr79YOOHD2U26fPDDj8E2mInp9uAXYvkuTRzwznP0gw3nElslpxxLi134+00A6CWZGOzA9i1GJxhMJPmOXCYcQNDYhszb9vh3I2zE0BaDiRuw6mF/RtQy3/7+f0P25j/th1ON5yd/oGAFh6QLQcSG24AbWFsO5wgL52D3xbJMzxlknMOJCdvuPGwWbLnHNBT0jkFBxIMcPuF7wz7Nok3B+xs5/cnH/zwowwYdLPTN3/4UGEnh0sLFqeCVRoQqxwE5BtIUT0KRsEoGAUjAQAAnA1ot0gQO7UAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-4803-3587","institution":"Loma Linda University Health: Loma Linda University Adventist Health Sciences Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"Cristine","lastName":"Salcedo","suffix":""}],"badges":[],"createdAt":"2021-06-09 02:32:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-604656/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-604656/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":13702118,"identity":"6ba99710-e758-4090-83f2-d82e784c81c7","added_by":"auto","created_at":"2021-09-17 13:33:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":240821,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-604656/v1/a3940375-6a7f-4f97-bb1f-5766b1d9f06b.pdf"},{"id":11014047,"identity":"25c2f9c6-b02f-4873-b472-b6f39811afc8","added_by":"auto","created_at":"2021-07-01 16:48:38","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":215663,"visible":true,"origin":"","legend":"Table 1: Description of the study population","description":"","filename":"Table1.png","url":"https://assets-eu.researchsquare.com/files/rs-604656/v1/29b1953ee26483f1928f39ce.png"},{"id":11013779,"identity":"5e720461-a5e6-42db-93ab-9d3600af8c60","added_by":"auto","created_at":"2021-07-01 16:45:38","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":234613,"visible":true,"origin":"","legend":"Table 2: Comparison of characteristics between insulin resistant and non-insulin resistant groups with insulin resistance defined as fasting insulin levels \u003e10uIU/mL","description":"","filename":"Table2.png","url":"https://assets-eu.researchsquare.com/files/rs-604656/v1/bf9d97660e977d9034b43870.png"},{"id":11014048,"identity":"7b88ceab-759e-4b21-8adf-4aaa7342309f","added_by":"auto","created_at":"2021-07-01 16:48:38","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":206653,"visible":true,"origin":"","legend":"Table 3: Comparison of characteristics between insulin resistant and non-insulin resistant groups with insulin resistance defined as fasting insulin levels \u003e15uIU/m","description":"","filename":"Table3.png","url":"https://assets-eu.researchsquare.com/files/rs-604656/v1/1c0393dc7e9b695788adb5a6.png"},{"id":11013777,"identity":"f1d75609-93d7-40b7-bb70-7cf73525aedd","added_by":"auto","created_at":"2021-07-01 16:45:38","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":96751,"visible":true,"origin":"","legend":"Table 4: Univariate analysis of risk factors for insulin resistance in women with abnormal uterine bleeding","description":"","filename":"Table4.png","url":"https://assets-eu.researchsquare.com/files/rs-604656/v1/dc42a2bface769e5662a65bf.png"}],"financialInterests":"","formattedTitle":"Insulin resistance and other risk factors of cardiovascular disease in abnormal uterine bleeding","fulltext":[{"header":"Background","content":" \u003cp\u003eAbnormal uterine bleeding (AUB) is one of the most common reasons reproductive-aged women seek a gynecologic consult. It affects up to 35 percent of women in their lifetime and comprises up to 70 percent of outpatient gynecology visits each year.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e AUB is a broad term that is classified by its causes using the PALM-COEIN system and it is often paired with descriptive terms denoting heavy versus intermenstrual bleeding.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eInsulin is a key anabolic hormone involved in multiple metabolic pathways in the body, including glucose uptake and lipid storage, cell growth and proliferation in the body, and nitric oxide (NO) synthesis by endothelial cells.\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Insulin resistance (IR) occurs when increasingly larger amounts of insulin are required to regulate the body\u0026rsquo;s metabolic pathways, and, even in the face of these increasing insulin levels, cellular activity is diminished compared to a normal person.\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e IR is a multifactorial disease that has become an epidemic in the United States (US). Although the number of adults affected by IR is not known, one in three adults in the US have prediabetes and an additional 10.5 percent of adults have diabetes mellitus type 2 (DM2).\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e These numbers are expected to double in the next 10 years since almost 90 percent of Americans having risk factors for IR.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAlthough angiogenesis is a relatively infrequent event in most adult tissues, it occurs repeatedly in the uterus in order to support the monthly cycle of growth, shedding, and repair of the endometrial lining.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Both the process of angiogenesis and endometrial repair are tightly regulated by estrogen and progesterone, which involve NO, platelets, immune cells, and multiple growth factors.\u003csup\u003e2,7\u0026minus;10\u003c/sup\u003e Decreased NO production, due to IR, results in an increase in the shear stress on endothelial cells due to diffuse vasoconstriction.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Moreover, decreased NO, hyperglycemia, and the state of IR itself promote the release of inflammatory cytokines and free radical formation, which leads to further endothelial damage, surrounding tissue hypoxia, and, eventually, cellular apoptosis.\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e This increases vascular permeability, which is worsened by high levels of circulating glucose also directly damaging the glycocalyx and endothelial cells through non-enzymatic glycation.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Together, these vascular changes allow substrates to leave the blood and form plaques in the tunica intima layer of the blood vessel.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e This thickening of the blood vessels leads to increased vascular resistance, chronic low-grade inflammation, and atherosclerosis.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eApplying this knowledge to the uterus, chronic low-grade inflammation likely reduces the spiral arteries\u0026rsquo; ability to meet the high metabolic demands of the endometrium. This leads to an overexpression of angiogenic cytokines and dysfunctional angiogenesis with excessive uterine vessel formation and dilation in an attempt to increase the amount of uterine blood flow.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e It also results in functionally impaired proliferative and secretory phases of the menstrual cycle where the endometrial lining is not properly repaired during cyclical shedding. Instead, the same inflammatory cytokines and fibrosis-promoting growth factors seen in atherosclerotic disease encourage smooth muscle metaplasia and scarring in the uterus.\u003csup\u003e\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAtherosclerosis is a widely accepted cause of numerous microvascular and macrovascular diseases that are significantly associated with IR.\u003csup\u003e3\u0026ndash;5,20\u0026minus;23\u003c/sup\u003e Multiple studies have demonstrated that women with fibroids and polycystic ovarian syndrome (PCOS) are more likely to have risk factors for cardiovascular disease, but AUB is not currently thought of as an atherosclerotic-related end organ disease. Furthermore, few studies have examined these risk factors in women with AUB as a whole (referred to in this paper as overall AUB).\u003csup\u003e16\u0026ndash;18,24\u0026minus;31\u003c/sup\u003e The aim of the present study is to describe the prevalence of insulin resistance and other predictors of cardiovascular disease among women with overall AUB.\u003c/p\u003e "},{"header":"Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population\u003c/h2\u003e \u003cp\u003eThis was a cross-sectional observational study conducted at Loma Linda University Medical Center\u0026rsquo;s outpatient obstetrics and gynecology clinics. Potential study candidates were all premenopausal females between the ages of 18 and 54 years old who presented with a complaint of AUB between September 2018 and October 2019. A candidate was confirmed eligible for enrollment once the diagnosis of AUB was made in the outpatient clinic setting. Women with a history of gynecologic cancer, prior hysterectomy, prior endometrial ablation, prior tamoxifen use, diabetes mellitus type 1, chronic steroid use, or pregnancy were excluded. There were 117 subjects enrolled with a total of 77 data sets analyzed for this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEthics Statement\u003c/h2\u003e \u003cp\u003e The participants gave voluntary, informed, written consent prior to participating in the study. This research study was approved by the Loma Linda University Institutional Review Board and it complied with all relevant national regulations, institutional policies, and the principles of the Declaration of Helsinki as they relate to human participants. All participant identifiers were replaced with identification codes and the data was handled only by the researchers participating in this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMeasured Variables\u003c/h2\u003e \u003cp\u003eAt the time of enrollment, a thorough history was performed. Each participant had her height, weight, and waist to hip ratio (WHR) measured. Overnight fasting blood samples were then obtained to assess each participant\u0026rsquo;s fasting insulin level (FI), hemoglobin A1C (A1C), creatinine (Cr), and lipid profile. A BMI\u0026thinsp;\u0026ge;\u0026thinsp;30kg/m\u003csup\u003e2\u003c/sup\u003e was used as the cutoff for obesity and a WHR\u0026thinsp;\u0026gt;\u0026thinsp;0.80 was considered abnormal.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e IR was assessed using two different FI cutoffs: \u0026gt;10\u0026micro;U/mL and \u0026gt;\u0026thinsp;15\u0026micro;U/mL, which represented both the lower and higher end of the FI cutoffs of prior research.\u003csup\u003e4,22,34\u0026minus;35\u003c/sup\u003e Abnormal A1C values were defined by the prediabetic cut off of \u0026ge;\u0026thinsp;5.7%, while abnormal lipid levels were defined by the American Heart Association values of HDL\u0026thinsp;\u0026lt;\u0026thinsp;50mg/dL, total cholesterol levels\u0026thinsp;\u0026gt;\u0026thinsp;150mg/dL, LDL\u0026thinsp;\u0026gt;\u0026thinsp;100mg/dL, and triglycerides levels\u0026thinsp;\u0026gt;\u0026thinsp;150mg/dL.\u003csup\u003e6,36\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using the online statistical software R version 3.5.1.\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e Assuming 33 percent of the general population is IR, the minimum sample size for the present study to have adequate power was calculated to be 36 subjects in each group.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e Independent t-test, Mann Whitney U test, and chi-square test were calculated with the statistical significance set as P\u0026thinsp;\u0026gt;\u0026thinsp;0.05. Univariate and multivariate regression analysis were performed using linear regression. Observed associations were expressed as odds ratios with 95 percent confidence intervals.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cp\u003eOf the 117 participants enrolled, 77 participants completed the measured variables and were included in the analysis. As shown in Table\u0026nbsp;1, most participants were Hispanic or White females, averaging 37 years of age, with an average of two prior births. Most participants did not have relevant medical or surgical history, except for over 90% being either current or former smokers. Approximately two-thirds of participants had a WHR\u0026thinsp;\u0026gt;\u0026thinsp;0.80 with the average WHR being 0.86. Almost half of participants were obese with the average BMI being 31.82kg/m\u0026sup2;. Two-thirds of participants had a FI\u0026thinsp;\u0026gt;\u0026thinsp;10\u0026micro;iU/mL with 38% having a FI\u0026thinsp;\u0026gt;\u0026thinsp;15\u0026micro;iU/mL, but only 22% of participants had an A1C\u0026thinsp;\u0026ge;\u0026thinsp;5.7%. The majority of participants also had dyslipidemia with 68% having high total cholesterol levels and an additional 38% of participants having high LDL levels.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;2 shows the difference in characteristics between the two groups when IR was defined as FI\u0026thinsp;\u0026gt;\u0026thinsp;10\u0026micro;iU/mL. Ethnicity was significantly related to IR with all African Americans and Middle Easterners being classified as IR, while none of the Asian participants were classified as IR (p\u0026thinsp;=\u0026thinsp;0.027). The IR group was significantly more likely to be obese (60.8% versus 15.4%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and have low HDL levels (41.2% versus 19.2%; p\u0026thinsp;=\u0026thinsp;0.03) than the non-IR group. There were no statistical differences between the two groups with regards to the other variables analyzed, but it is worth noting that no participants in the non-IR group had a history of DM2 or elevated triglycerides levels, and more than 62% of participants in both groups had high total cholesterol levels.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;3 depicts the difference in characteristics between the two groups when IR was defined as FI\u0026thinsp;\u0026gt;\u0026thinsp;15\u0026micro;iU/mL. The IR group was significantly more likely to be obese (75.9% versus 27.1%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), have low HDL levels (48.3% versus 25%; p\u0026thinsp;=\u0026thinsp;0.016), and have high triglycerides levels (13.8% versus 2.1%; p\u0026thinsp;=\u0026thinsp;0.032) compared to the non-IR group. Although there were no statistical differences between the two groups regarding the other variables analyzed, again, no Asian participants were classified as IR, and more than 62% of participants in both groups had elevated total cholesterol levels.\u003c/p\u003e \u003cp\u003eBy univariate regression analysis, factors significantly associated with IR in women with AUB were BMI, WHR, and HDL levels. These associations persisted regardless of the FI level used to define IR (see Table\u0026nbsp;4). Ethnicity, Cr, triglycerides levels, total cholesterol levels, LDL, history of DM2, history of hypertension, history of migraines, and smoking were not significantly associated with IR in women with AUB in either of the univariate regression analyses. When multivariate regression analysis was performed using FI\u0026thinsp;\u0026gt;\u0026thinsp;10\u0026micro;iU/mL to define IR, BMI (standardized coefficient β: 1.07, P\u0026thinsp;=\u0026thinsp;0.015) and WHR (standardized coefficient β: 1.94, P\u0026thinsp;=\u0026thinsp;0.045) were independent predictors of IR in women with AUB. Regression analysis was not performed using FI\u0026thinsp;\u0026gt;\u0026thinsp;15\u0026micro;iU/mL.\u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eThis study shows the prevalence of IR and other predictors of cardiovascular disease are higher among women from this diverse suburban community with overall AUB (66%) than among the general population. BMI and WHR were shown to be independent predictors of IR in women with AUB. The odds of a woman with AUB having IR was 7 times higher for every 1 unit increase in BMI over 30 kg/m\u003csup\u003e2\u003c/sup\u003e when confounding for other variables. By the same convention, the odds of a woman with AUB having IR was nearly 4 times higher for every 0.1 unit increase in WHR after 0.8. Low HDL levels, elevated triglycerides levels, and ethnicity were also significantly associated with IR in women with AUB, depending on how IR was defined.\u003c/p\u003e \u003cp\u003eSimilar to prior studies on AUB, the present study\u0026rsquo;s participants had a high prevalence of risk factors for cardiovascular disease, including smoking (90%), obesity (45%), an elevated WHR (62%), and dyslipidemia.\u003csup\u003e16,18,24\u0026ndash;25,28\u0026minus;31\u003c/sup\u003e The majority of participants did not have an elevated A1C or a history of hypertension or DM2, but this lack of association has been noted in prior studies on overall AUB as well.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Prior studies have found a relationship between AUB and elevated triglycerides levels, but this relationship was only significant in the present study when participants were IR using the higher FI cutoff of \u0026gt;\u0026thinsp;15\u0026micro;iU/mL.\u003csup\u003e28\u0026ndash;29\u003c/sup\u003e Interestingly, the significant inverse relationship between IR and HDL levels in women with AUB in the present study was not seen in prior studies on overall AUB.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e Participants with normal HDL levels, which are considered cardioprotective, were almost 70 percent less likely to be IR.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e Additionally, although a significant relationship between BMI and/or WHR and AUB has been reported in multiple prior studies, the relationship between BMI and/or WHR, IR, and AUB has previously only been shown to be significant in prior studies on AUB due to PCOS.\u003csup\u003e16,18,24\u0026ndash;25,28\u0026minus;31\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSome of the strengths of this study were the diverse patient population studied and the broad definition of AUB intentionally used to evaluate the overall relationship between AUB and risk factors for cardiovascular disease. However, this also made it difficult to compare the present study\u0026rsquo;s results to the results of prior studies, which often only evaluated one specific cause of AUB and included less diverse study populations. Using a diverse study population limits how generalizable the present study\u0026rsquo;s results are to more homogenous regions. Furthermore, as the pathophysiology causing AUB in women with irregular cycles compared to those with AUB and regular cycles may be different, the prevalence of the different risk factors for cardiovascular disease may not be the same in these different subsets of women. Additionally, as this was a cross-sectional study, it can only identify associations between IR and other cardiovascular disease risk factors among women with AUB.\u003c/p\u003e \u003cp\u003eAnother weakness of this study was the high attrition rate present with 41 (35%) of the participants being excluded from the analysis due to not completing any laboratory data despite regular reminders by the study\u0026rsquo;s investigators. Although still included in the analysis, an additional four (3%) of the participants did not complete the required lipid panel and an additional 16 (13.6%) of the participants did not undergo evaluation of their WHR. This selection bias likely affects how generalizable the results from the present study are to women with AUB even. Finally, attempts to limit investigator bias were made by using retrospective self-reports to diagnose AUB, but prior studies have shown these may not be accurate.\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eImplications for Research\u003c/h2\u003e \u003cp\u003eFurther research is needed on the relationship between ethnicity and IR as ethnicity has been shown to be an important predictor of cardiovascular disease in the general population.\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e Although ethnicity was shown to be significantly related to IR in women with AUB when IR was defined as FI\u0026thinsp;\u0026gt;\u0026thinsp;10 \u0026micro;iU/mL, it may not have been significantly related to IR using the higher FI cutoff due to a small sample size. A follow-up study is currently underway to compare the prevalence of IR and other cardiovascular disease risk factors in women with AUB to normally menstruating women within this same diverse suburban community.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eConclusions and Implications\u003c/h2\u003e \u003cp\u003eThe high prevalence of risk factors for cardiovascular disease seen in these women suggests that AUB may be a sentinel finding for DM2 and cardiovascular disease in women later in life. It is vital for clinicians to screen women from diverse suburban communities with AUB for metabolic syndrome and these other cardiovascular disease risk factors. These patients also need to be educated on lifestyle changes they can make to reduce their risk for cardiovascular disease.\u003c/p\u003e \u003c/div\u003e "},{"header":"Abbreviations","content":" \u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAUB\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAbnormal uterine bleeding\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePALM-COEIN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePolyp, Adenomyosis, Leiomyoma, Metaplasia- Coagulopathy, Ovulatory, Endometrial, Iatrogenic, Not otherwise specified\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInsulin resistance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNitric oxide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDM2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDiabetes mellitus type 2\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePCOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epolycystic ovarian syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFasting insulin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBMI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBody mass index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWaist hip ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval to participate:\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe participants gave voluntary, informed, written consent prior to participating in the study. This research study was approved by the Loma Linda University Institutional Review Board and it complied with all relevant national regulations, institutional policies, and the principles of the Declaration of Helsinki as they relate to human participants. All participant identifiers were replaced with identification codes and the data was handled only by the researchers participating in this study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Loma Linda University Health, Department of Gynecology and Obstetrics.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026rsquo; contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAS made substantial contributions to the conception, design of the work, acquisition and interpretation of data, and substantively revised the work. HS made substantial contributions to the acquisition and interpretation of data, drafted and substantively revised the work. AB and CR made substantial contributions to the acquisition of data. All authors have approved the submitted version and agree to be personally accountable for the author\u0026rsquo;s own contributions to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Jiahao Peng, MD, PhD, and Wendy Shih, DrPH of the Research Consulting Group of Loma Linda University Health, for their contributions to the analysis of the data.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAmerican College of Obstetricians and Gynecologists. Diagnosis of abnormal uterine bleeding in reproductive-aged women. ACOG Practice Bulletin No. 128. 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Ann Epidemiol. 2007;17:163\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeadows TA, Bhatt DL, Cannon CP, et al. Ethnic differences in cardiovascular risks and mortality in atherothrombotic disease: Insights from the Reduction of Atherothrombosis for Continued Health (REACH) registry. Mayo Clin Proc. 2011;86(10):960\u0026ndash;7. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4065/mcp.2011.0010\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eDue to technical limitations, table 1, 2, 3, 4 is only available as a download in the Supplemental Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"abnormal uterine bleeding, insulin resistance, cardiovascular disease risk, obesity, waist hip ratio, fasting insulin","lastPublishedDoi":"10.21203/rs.3.rs-604656/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-604656/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eStudies indicate the presence of cardiovascular disease risk factors among patients with uterine fibroids and polycystic ovarian syndrome. Investigators were interested in examining the prevalence of cardiovascular disease risk factors and the independent predictors of insulin resistance (IR) among women with abnormal uterine bleeding (AUB).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis observational study examined 77 premenopausal subjects with AUB. Their medical history, body mass index, waist hip ratio, fasting insulin level, hemoglobin A1C, creatinine level, and lipid panel were evaluated. The participants were then subdivided using insulin levels and further compared. IR was defined at two different fasting insulin levels: \u0026gt;10\u0026micro;U/mL and \u0026gt;\u0026thinsp;15\u0026micro;U/mL.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf the 77 data sets analyzed, 91% of participants were current or former smokers, 62% had a waist hip ratio\u0026thinsp;\u0026gt;\u0026thinsp;0.80, 45% were obese, and the majority of participants had dyslipidemia, with high total cholesterol (68%) and elevated LDL (38%) being the most prevalent. 66% of participants were insulin resistant as defined by the lower fasting insulin and 38% were insulin resistant as defined by the upper fasting insulin level. At the lower cutoff, the insulin resistant group was significantly more likely to have a waist hip ratio\u0026thinsp;\u0026gt;\u0026thinsp;0.8, be obese, and have low HDL levels. At the upper fasting insulin cutoff, the insulin resistant group was significantly more likely to have low HDL levels, elevated triglyceride levels, a waist hip ratio\u0026thinsp;\u0026gt;\u0026thinsp;0.8, and be obese. Univariate analysis showed statistically significant associations between IR in women with AUB and body mass index, waist hip ratio, and HDL for both fasting insulin cutoffs. Multivariate analysis using the lower fasting insulin cutoff revealed that body mass index and waist hip ratio were significant independent predictors of IR in a woman with AUB.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis study reveals the prevalence of IR and other predictors of cardiovascular disease are greater in women with AUB in this population than the general population. Body mass index and waist hip ratio are independent predictors of IR in women with AUB. Low HDL levels, elevated triglyceride levels, and ethnicity are also significantly associated with IR in women with AUB depending on the definition used.\u003c/p\u003e","manuscriptTitle":"Insulin resistance and other risk factors of cardiovascular disease in abnormal uterine bleeding","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-07-01 16:45:37","doi":"10.21203/rs.3.rs-604656/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a4905c5-0615-425e-bb42-471904256968","owner":[],"postedDate":"July 1st, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":5399973,"name":"Nutrition \u0026 Dietetics"},{"id":5399974,"name":"Endocrinology \u0026 Metabolism"}],"tags":[],"updatedAt":"2021-07-01T16:45:38+00:00","versionOfRecord":[],"versionCreatedAt":"2021-07-01 16:45:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-604656","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-604656","identity":"rs-604656","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}