{"paper_id":"9d39ca1d-4fb2-4c1e-88e6-dd6f106efc23","body_text":"Cardiometabolic risk factors (CMRFs), including obesity, hypertension,\ndiabetes mellitus, and hyperlipidemia, stand as major contributors to\natherosclerosis, ischemic heart disease, strokes, and certain cancers. Their high\nprevalence renders them a tremendous cause of morbidity and mortality among people\nof different races and backgrounds. The metabolic syndrome (MetS) is a constellation\nof cardiometabolic risk factors and signifies individuals at a high risk of\ndeveloping cardiovascular events.\nWhile it has long been known that polycystic ovarian syndrome (PCOS) is\nassociated with CMRFs, there is emerging evidence that other benign gynecologic\ndisorders (BGDs), such as uterine leiomyomas, endometriosis, and hysterectomy\nwithout oophorectomy, may be associated with cardiometabolic risk. While it is\nthought that CMRFs may contribute to leiomyoma pathogenesis, there is evidence that\nendometriosis may lead to increased cardiovascular risk ( figure 1 ). However, it remains unclear if these\nassociations are causal. Therefore, further experimental research is necessary to\ndelineating the nature of this relationship. This article will discuss the evidence\nof association between cardiometabolic risk and benign gynecologic disorders, the\nunderlying mechanisms, and the implications on healthcare. An overview of the\nbiological mechanisms that underlie the association between CMRFs and BGDs is\npresented in  figure 2 .\n\nObesity is one of the well-recognized risk factors for cardiovascular\ndisease. Recent evidence proposes that it is not merely the presence of\nexcessive fatty tissue per se, but also the type of fat that determines such\nrisk.( 1 ) Obesity is categorized into\nmetabolically healthy obesity (MHO) and metabolically unhealthy obesity\n(MUO).( 1 ) This classification arises\nfrom the difference of type and distribution of body fat. For example, visceral\nadipose tissue (VAT) and intramuscular fat are the major contributors to\nobesity-induced systemic inflammation, insulin resistance, and increased\ncardiovascular risk.( 1 ) From another\nperspective, fat can be classified as white adipose tissue (WAT) and brown\nadipose tissue (BAT).( 2 ) While WAT\nincreases cardiovascular and metabolic complications of obesity, BAT, on the\nother hand, specializes in thermogenesis, and in fact, is associated with\nimproved cardiovascular health.( 3 )\nFemale steroid hormones have been classically implicated in the\npathogenesis of multiple gynecologic disorders and were introduced as one\nmechanism that connects CMRFs and BGDs.( 1 )\nOn one hand, obesity contributes to this association by increasing the hormonal\nburden in the obese female.( 4 ) Peripheral\nadipose tissue can convert androgenic substrates to estrogens, a process\nmediated by the aromatase enzyme and hence, termed aromatization( 1 ) ( Figure 3 ).\nThis conversion rate is higher in the female adipose tissue, where fibroblasts\nplay a vital role in promoting aromatase expression.( 4 ) Interestingly, obesity-induced inflammation, which\nwill be separately discussed in this review, enhances the expression of\naromatase by tumor necrosis factor alpha (TNF-α).( 5 ) It is worth noting, however, that aromatase is\nexpressed at higher levels in the adipose tissue of postmenopausal compared to\npremenopausal women, who in contrast, rely mostly on their ovarian follicles for\naromatization and estrogen production.( 4 )\nTherefore, the obesity-mediated role in increasing the bodily hormonal load\nmight be more pronounced in the postmenopausal female.( 4 )\nUterine leiomyomas have been well-known to be hormone-responsive tumors,\nwhere estrogen and progesterone receptors exist in abundance. This is evidenced\nby their growth during reproductive years and pregnancy and tendency to regress\nafter menopause.( 6 ) Estrogen binds to its\nreceptors, both nuclear and membrane-bound, and initiates a series of cellular\nevents that culminate in enhanced smooth muscle proliferation in the\nleiomyoma.( 7 ) In the most part,\nnuclear estrogen receptors (ERs), both ERα and ERβ, mediate\ntranscriptional activity, while membrane-bound receptors participate in rapid\nsignaling.( 8 ) As opposed to normal\nmyometrium, leiomyomas overexpress ERα and ERβ mRNA,( 9 ) and ERα can be epigenetically\nmodified in these tumors,( 10 ) suggesting\nan enhanced but aberrant effect of estrogen on leiomyomas that may be further\naugmented in the obese female.\nSimilarly, endometriosis is another estrogen-dependent gynecologic\ndisorder, i.e., estrogen facilitates the maintenance and progression of the\nectopic endometrial tissue.( 11 )\nIntriguingly, estrogen and progesterone can additionally recruit stem cells that\nare derived from the bone marrow to the ectopic endometrium enhancing\nvasculogenesis, and eventually, thriving of the endometrial implants.( 12 ) Theoretically, obesity should amplify\nthe role of estrogen in endometriosis; however, studies detected an inverse\nrelationship between BMI and stage of endometriosis, possibly suggesting the\npresence of other pathogenic mechanisms that could counteract the role of\novarian steroids.( 13 ) Indeed, Goetz et al\nshowed that endometriosis causes metabolic changes and weight loss in an animal\nmodel.( 14 )\nBesides the effect of obesity on sex hormones, adiposity is also\nassociated with insulin resistance. In fact, BMI and serum insulin levels share\na positive correlation, consequently promoting a hyperinsulinemic state in the\nobese population.( 1 ) Not only does insulin\nresistance predispose to diabetes mellitus, but the ensuing hyperinsulinemia\nadditionally exerts growth-promoting properties( 15 ) both directly and indirectly.( 16 ) The indirect effects of insulin on cellular growth are termed\nthe insulin-IGF hypothesis, which states that chronically elevated insulin\nlevels can downregulate the production of insulin-like growth factor binding\nproteins 1 and 2 (IGFBP-1 and IGFBP-2).( 1 )\nNormally, IGFBP-1 and IGFBP-2 bind to insulin-like growth factor 1 (IGF-1) and\ndecrease its bioavailability.( 1 ) In the\nabsence of this action, bioactive IGF-1 levels rise with a resultant increase in\nits effects on cellular mitogenesis( 1 )\n( Figure 3 ). Despite having no clear\nevidence of an association between uterine fibroids and insulin levels, and some\nstudies, in fact, reporting an inverse association between the two,( 17 ) IGF-1 remains as an important\ncontributor to the pathobiology of uterine fibroids( 18 ), which may propose an indirect role of insulin in\nthese tumors mediated by IGF-1. Nevertheless, more experimental research needs\nto validate this postulated association and its biologic aspects.\nCMRFs promote an inflammatory milieu both locally and systemically( 19 ), which heightens an individual’s\nrisk of developing disorders, including cancers.( 1 ) Inflammatory states were also demonstrated to have a role in the\ndevelopment of some BGDs such as uterine leiomyomas.( 20 ) Obesity is one famous example of an\ninflammation-inducing CMRF( 1 ) ( Figure 3 ). In overweight and obese\nindividuals, adipose tissue exerts paracrine and endocrine actions by secreting\na variety of signaling molecules, including pro-inflammatory cytokines and\nadipokines,( 4 ) with different\nmediators having different effects on promoting and suppressing\ninflammation.( 1 ) On the long term,\nobesity is a major contributor to chronic systemic inflammation, supported by\nelevated levels of pro-inflammatory cytokines, TNF-α and interleukin 6\n(IL-6) in particular, detected in the sera of obese patients.( 21 )\nIn vitro studies have shown that TNF-α has a role in regulating\nleiomyoma cell differentiation. Nair et al ( 20 ) showed increased proliferation of human leiomyoma cells cultured\nin adipocyte-conditioned media or co-cultured with human adipocytes. They also\nfound increased expression of the pro-proliferative protein marker PCNA,\nanti-apoptosis protein BCL-2, and cell cycle division protein cyclin D1.\nAdditionally, they demonstrated increased proliferation of human leiomyoma cells\nexposed to higher concentrations of TNF-α and reversal of these effects\non adding anti-TNF-α-neutralizing antibodies.( 20 )\nSimilarly, endometriosis is associated with systemic inflammation. Iwabe\net al have shown that women with endometriosis had a significantly higher\nconcentration of TNF-α and IL-6 in their peritoneal fluid compared to\nwomen without endometriosis.( 22 )\nMoreover, they concluded in another experiment that TNF-α stimulated the\nproliferation of stromal endometriotic cells by inducing IL-8 expression, an\neffect that was reversed by adding anti-TNF-α and anti-IL-8\nantibodies.( 23 ) In line with these\nfindings, Pizzo et al detected significantly higher levels of TNF-α in\nthe sera of women with endometriosis, particularly in the initial stages,\nsupporting the role of inflammatory mediators early on in the disease\nprocess.( 24 ) Endometriosis is thought\nto create a state of systemic inflammation that can promote the development of\natherosclerotic lesions ( Figure 1 ).\nTherefore, endometriosis can be considered a cardiovascular risk factor.( 25 ) Systemic inflammation may contribute to\natherosclerosis directly by injuring the endothelium and indirectly by inducing\ninsulin resistance and lipid derangements( 26 ) ( Figure 4 ). However,\nwhether the association between endometriosis and cardiovascular risk is causal\nneeds to be further investigated.\nAdipocytes specialize in secreting many polypeptide hormones termed\nadipokines, of which leptin and adiponectin are of importance when addressing\nobesity-related inflammation.( 1 ) Leptin,\nin addition to being involved in appetite suppression, has marked\npro-inflammatory properties and is found at higher serum concentrations in obese\npeople.( 1 ) Interestingly, leptin\npromotes cellular proliferation and angiogenesis and suppresses apoptosis and\nimmune function, features that are collectively found in neoplastic\nprocesses.( 1 ) On the contrary, obesity\nis accompanied by lower serum adiponectin with levels negatively correlating\nwith BMI.( 27 ) As opposed to leptin,\nadiponectin manifests anti-inflammatory properties and sensitizes cells to\ninsulin, actions that can indirectly suppress neoplastic phenomena.( 1 ) Besides, adiponectin can directly mediate\nthis suppression by sequestering growth factors or binding to adiponectin\nreceptors 1 and 2.( 1 ) This culminates in\ndecreased fatty acid synthesis, cellular proliferation, and DNA mutagenesis as\nwell as increased apoptosis.( 1 )\nMarkowska et al ( 28 ) have shown\nthat leptin genes and leptin proteins were expressed in uterine leiomyomas and\nsurrounding myometrium but were absent in the myometrium of women without\nleiomyomas. Chen et al ( 29 ) found that\nwhile serum adiponectin levels inversely correlated with BMI in women with and\nwithout leiomyomas, serum adiponectin was significantly lower among women with\nleiomyomas.\nRecent studies in certain racial groups identified single nucleotide\npolymorphisms (SNPs) across variable chromosomal regions that are associated\nwith uterine leiomyomas. Of importance, some of these SNPs take place in genes\nthat are also associated with cardiovascular disease states.( 30 ) For example, the gene\noligonucleotide/oligosaccharide-binding fold containing 1 (OBCFC1) is implicated\nin cardiovascular disease, while the gene sirtuin 3 (SIRT3) is involved in MetS,\nobesity, and exercise response.( 30 )\nAdditionally, the gene blocked early in transport 1 homolog (BET1L) plays a role\nin glucose regulation and type 2 diabetes mellitus.( 30 )\nSurgically-induced endometriosis in female mice was shown to dysregulate\nsix hepatic genes involved in metabolism.( 14 ) This dysregulation of gene expression could possibly explain the\nassociation between endometriosis and low BMI of affected females.( 14 ) Four anorexigenic genes, Cyp2r1, Favp4,\nMrc1, and Rock2, were upregulated in mice with endometriosis, while two\nobesogenic genes, Igfbp1 and Mmd2, were downregulated.( 14 ) The mechanism by which endometriosis mediates its\naberrant effect on hepatic genes remains unclear. However, it has been\npostulated that endometrial implants could possibly migrate to the liver by\nmeans of lymphatic, vascular, or transcoelomic peritoneal spread( 31 ), directly affecting hepatic gene\nexpression.( 14 ) In contrast,\nendometriosis induces a state of peritoneal inflammation that can alter the\nregulation of hepatic genes ( 14 ),\npossibly by means of differentially-expressed circulating microRNAs found in\nwomen with endometriosis.( 32 )\nResearch has shown that there may be epigenetic associations between\nCMRFs and BGDs. An example that was extensively discussed is the\nSp/Krüppel-like factor (KLF) family of transcription factors, which is\ninvolved in regulating genes of CYP metabolic enzymes.( 33 ) These enzymes function to metabolize estrogen and\nprogesterone in the endometrium, producing biologically active metabolites that\nplay important roles in endometrial physiology.( 34 ) Once targeted by KLF transcription factors, CYP enzymes genes\ncan be silenced, an action that is mediated by deacetylating promoter histones,\nrendering transcription nonpermissible.( 33 )\nInterestingly, Yin and colleagues( 35 ) have found that knockdown of KLF11 was associated with increased\nproliferation of human leiomyoma smooth muscles, suggesting a possible\nprotective role of this transcription factor against neoplastic growths of the\nmyometrium. Another study done by Daftary et al ( 36 ) has concluded that KLF11 expression was drastically decreased in\nendometrial implants of mice with surgically-induced endometriosis, with KLF11\nknockout animal models manifesting larger and densely-adhesive lesions\nresembling advanced human endometriosis.\nOf great importance to this review, mutations in KLF11 were additionally\ninvolved in the development of human diabetes by dysregulation of insulin and\nglucose transport.( 37 ) KLF11 is normally\nexpressed in human pancreatic islets and beta cells, and in response to high\nserum glucose, KLF mRNA expression increases in pancreatic beta cells.( 38 ) Functioning as a transcription factor,\nglucose-inducible KLF11 binds to the insulin promoter, up-regulating its levels\nand maintaining glucose homeostasis. In addition, a frequent polymorphic Q62R\nvariant was identified in the KLF11 gene and was significantly associated with\nlate-onset type 2 diabetes mellitus in people of northern-European\nancestry.( 38 )\nSome studies have suggested an association of diet with certain BGDs.\nSome dietary components, namely fatty acids, can potentiate the levels of\ninflammatory mediators,( 39 ) which happen\nto be elevated in patients with endometriosis( 40 ) as this review previously addressed. Concomitantly, these\ndietary factors are found in close relation to certain CMRFs, including\nhyperlipidemia.( 41 ) Prazzini et al\n( 42 ) have inferred that endometriosis\nis positively associated with red meat consumption but negatively so with green\nvegetable and fruit consumption. In another study, women classified in the fifth\nquintile of animal fat intake demonstrated a 20% greater risk of having\nendometriosis when compared to those in the first quintile.( 43 ) The same study additionally provided evidence of\nincreased risk of endometriosis with trans-unsaturated fats and palmitic acid, a\ntype of saturated fat found in animal products, but not with saturated and\nmonosaturated fat, the major components of animal fat. In contrast, other\ndietary constituents were of possible protective effects against endometriosis.\nWomen consuming each additional 1% of energy from long-chain omega-3 fatty acids\nrather than from trans fats demonstrated a 50% lower risk of\nendometriosis.( 43 )\nAt a cellular level, trans fatty acids can mediate downregulation of\nperoxisome-proliferator activated receptor- γ \n(PPAR- γ ) expression.( 44 ) Lebovic et al ( 44 )\nconcluded that this inhibitory action can promote regression of\nsurgically-induced endometriosis in female rats. Furthermore, trans fatty acids\nelevate the serum levels of inflammatory mediators, such as IL-6 and markers of\nTNF- α activation, which are considered possible contributors to the\npathogenesis of endometriosis.( 39 )\nRelating to cardiovascular risk, a meta-analysis that included six\nobservational studies concluded that adding 50 g serving/day of processed red\nmeats correlated with a 42% higher risk (RR 1.42) of cardiovascular\nevents.( 45 ) Moreover, Skeaff and\nMiller( 46 ) showed in their\nmeta-analysis that trans fatty acid intake significantly correlated with a\nhigher risk of cardiovascular morbidity and mortality.\nBesides the numerous physiological functions of vitamin D, experimental\nstudies demonstrated anti-tumor properties of vitamin D and its\nmetabolites.( 47 ) In the light of this\nreview, vitamin D deficiency correlates with a higher risk of uterine\nleiomyomas.( 48 ) This association is\nreinforced by the observation that uterine leiomyomas are more prevalent among\nAfrican American females, who concomitantly, are known to have lower serum\nlevels of vitamin D.( 49 ) Furthermore, a\nstudy by Halder and colleagues ( 50 )\nshowed that vitamin D receptors were less expressed in 60% of fibroids compared\nto the normal myometrium, implying an increased risk of uterine leiomyomas with\ndecreased vitamin D-mediated cellular signaling. Similarly, women with\nendometriosis were found to have lower serum vitamin D levels compared to\nhealthy women, which can be possibly explained by the loss of the\nanti-proliferative actions of vitamin D, promoting the progression of\nendometriosis.( 51 )\nVitamin D is additionally implicated in cardiovascular disease.( 52 ) Kar and Datta have demonstrated that\npatients with systolic-diastolic hypertension have lower serum levels of vitamin\nD compared to non-hypertensive individuals.( 53 ) In line with this observation, higher serum vitamin D levels\ncorrelated with lower plasma renin activity, indicating a role for vitamin D in\nregulating the renin-angiotensin-aldosterone system.( 54 ) In addition, among type 2 diabetics, a positive\ncorrelation was detected between vitamin D deficiency and Framingham score,\nwhich is used to assess cardiovascular risk, suggesting a protective role for\nvitamin D against cardiovascular disease.( 55 )\nFrom a physiological perspective, vitamin D suppresses inflammatory\nresponses and downregulates the production of pro-inflammatory cytokines,\nincluding TNF- α and IL-6, which are known to participate greatly in\ndeveloping atherosclerosis and increasing cardiovascular risk on one hand,( 56 ) and promoting cellular growth and\ndifferentiation on another.( 4 )\nSeveral growth factors have been implicated in the pathobiology of BGDs,\nincluding uterine leiomyomas. A well-recognized example is insulin-like growth\nfactors (IGFs), which have mitogenic properties that contribute significantly to\nmyomatous proliferation( 57 ) ( Figure 3 ). Both IGF-1 and IGF-2 share this\nassociation with uterine fibroids, with the former having more prominent effects\nas evidenced by studies.( 58 ) In a study\ndone by Burroughs et al,( 59 ) IGF-1 was\nshown to be 7.5 times more expressed in uterine leiomyomas compared to normal\ntissues of Eker rats. In addition, Peng and colleagues( 58 ) concluded a correlation between overexpression of\nIGF-1 and size of the leiomyoma, indicating dysregulated signaling of IGF-1 in\nthese tumors.\nEpidermal growth factor (EGF), another presumed contributor to the\npathobiology of uterine fibroids, was shown to upregulate protein synthesis in\nboth myomatous and normal myometrial cells.( 60 ) In their study, Ren and colleagues( 61 ) documented an increased EGF-mediated stimulation\nof DNA synthesis in leiomyomas compared to normal myometrial cells. Binding of\nEGF to its receptor (EGFR) results in distinctive signaling cascades between\nleiomyomas and the normal myometrium despite equal expression of EGFR.( 61 ) This differential signal transmission\nmight point to aberrancy of EGF signaling in leiomyomatous growths.( 61 ) In an experimental study by Park et al\n( 62 ), hyperglycemic milieus were\nshown to create epigenetic alterations in some oncogenic pathways, including the\nEGFR pathway, thereby promoting neoplastic activity. However, this finding has\nbeen documented in mice with breast cancer, and more research is warranted to\nfurther investigate the effect of diabetes-associated hyperglycemia in benign\ntumors such as uterine leiomyomas.\nIGF-1 was shown to share a significant positive association with\nseverity of coronary artery disease, as assessed by Gensini score, which is\ndetermined by the degree of coronary luminal narrowing and location.( 63 ) These observations could be explained\nby the actions of IGF-1 on the vascular smooth muscles, which as a result, show\nenhanced proliferation and migration into the intima, predisposing to higher\nrisk of atherosclerotic vessel disease.( 64 ) Association of EGF with cardiovascular disease was similarly\naddressed in the literature.( 65 ) EGFR and\nits ligands, which are found in vascular smooth muscles and endothelial cells,\nmodulate several functions that can predispose to atherosclerosis, including\ncellular proliferation, differentiation, and inflammation.( 65 ) In fact, they are highly expressed in vascular\nsmooth muscles of intimal atherosclerotic lesions( 66 ) and are implicated in vascular dysfunction\nassociated with diabetes mellitus.( 67 )\nA body of evidence suggests that atherosclerosis and uterine leiomyomas\nmay possibly share common pathogenic features along their development.( 68 ) Atherosclerotic plaques are primarily\ncomposed of smooth muscles that have proliferated and migrated from the vascular\nmedia following intimal injury.( 68 ) When\ncompared to atherosclerotic plaques, uterine leiomyomas similarly represent a\nproliferating population of smooth muscles that originally resides in the\nuterine myometrium, creating a plausible analogy between the two.( 68 ) Furthermore, experiments that analyzed\nthe components of coronary plaques concluded a high possibility of their\nmonoclonality, an inherent feature of benign smooth muscle tumors such as\nuterine leiomyomas.( 69 ) Intriguingly,\ncells from both atheromatous plaques and uterine leiomyomas showed identical\nbehavior when cultured in vitro.( 69 )\nAdditionally, both atheromatous plaques and uterine leiomyomas can undergo\nfibrosis and calcification on the long run.( 68 ) Aksoy and colleagues( 70 )\nhave, in fact, concluded that carotid intima-media thickness, a reliable\nindicator for atherosclerosis, significantly differed among patients with and\nwithout uterine leiomyomas.\nThe immune system is thought to contribute, in part, to the pathogenesis\nof some BGDs. Initial lesions of endometriosis are associated with activation of\nthe innate immune system following retrograde menstruation.( 71 ) This is supported by documenting an increased\nnumber of innate immune cells, including macrophages and natural killer cells,\nin the peritoneal fluid of patients with endometriosis as well as in the lesions\nthemselves.( 72 ) These immune cells\nare rather dysfunctional and in fact, considered contributors to the progression\nof endometriosis by secreting inflammatory cytokines and angiogenic\nfactors.( 73 ) This initial aberrant\nresponse is believed to determine which females are at higher risk of developing\nendometriosis when retrograde menstruation takes place.( 74 ) Interestingly, gut microbiota was demonstrated to\nbe a key factor in initiating such inflammatory responses. Studies depicted its\nrole in priming neutrophils that mount immune reactions in the peritoneal\ncavities of female mice with endometriosis.( 75 )\nGut microbiota seems to undergo structural and functional changes in\npatients with obesity.( 76 ) This may\nmodulate, in part, obesity-induced inflammation, which, in turn, predisposes to\natherosclerotic cardiovascular disease.( 77 ) Whether this modulatory effect of gut microbiota on systemic\ninflammation is contributory to the pathobiology of uterine leiomyomas needs to\nbe further evaluated. In a study done by Le Chatelier et al,( 78 ) individuals with low gene counts, which indicate\ndecreased richness of the gut microbiome, were at higher risk of having abnormal\nlipid profiles, insulin insensitivity, and pro-inflammatory markers compared to\nthose with higher gene counts. This points to a role for the changes in gut\nmicrobiota in promoting metabolic and inflammatory derangements.( 77 )\n\nStudies have documented associations of some components of the MetS with\nuterine leiomyomas ( Figure 1 ). For\ninstance, hypertensive females were at higher risk of being diagnosed with\nuterine leiomyomas compared to their non-hypertensive counterparts.( 79 – 81 ) Faerstein and colleagues( 79 ) concluded that this risk is higher among females with a first\ndiagnosis of hypertension before 35 years of age and among hypertensives\nrequiring medications. Additionally, they found that myomatous females had a\nhigher mean duration of hypertension compared to controls, suggesting an\nincreased risk with a longer duration of hypertension.( 79 ) Reverse-causality was the popular explanation for\nthis association, where myomatous growths result in urinary tract\nobstruction.( 79 ) Nevertheless,\nhypertension may be involved in inducing smooth muscle injury and inflammatory\nmilieus that promote myomatous proliferation, possibly by actions of\ntransforming growth factor-β (TGF- β),( 82 ) in a mechanism similar to that of atheromatous\nplaque formation.( 80 )\nUterine leiomyomas were shown to share a positive association with\ndiabetes mellitus by some studies. Tak et al ( 81 ) showed that females with uterine leiomyomas were more likely to\nbe diabetic compared to non-myomatous females, and that women with three or more\nmyomas had a significantly higher fasting plasma glucose than those with one\nmyoma. In contrast, Velez Edwards et al ( 83 ) detected a protective role for type 2 diabetes mellitus against\nuterine leiomyomas, more pronounced among European Americans and those treated\nwith insulin. In line with this finding, a study by Baird et al ( 17 ) showed an inverse relationship between IGF-1 and\ninsulin, which are elevated in diabetes mellitus, and uterine fibroids despite\ntheir hypothesis predicting a positive correlation. This possibly suggests that\nvascular pathologies contributed to by diabetes mellitus might hinder the\ndevelopment of myomatous growths. ( 17 )\nA linkage between uterine leiomyomas and obesity has been reported by\nsome studies. Takeda et al ( 80 ) have\nshown that overweight is significantly associated with uterine leiomyomas among\nJapanese women, a finding that was reiterated by Tak et al, ( 81 ) who found that myomatous South Korean women had\nsignificantly higher waist circumferences and body fat levels than their\ncontrols, and that the number and size of leiomyomas correlated positively with\nBMI. Nevertheless, Sato et al( 84 )\ninferred that women with occult obesity, i.e., body fat over 30% and BMI under\n24, were at highest risk for developing uterine leiomyomas. This implies that\nBMI might not be an inclusive indicator of obesity and associated risks, and\nthat parameters of central adiposity such as waist-to-hip ratio correlate more\nstrongly with visceral fat implicated in systemic inflammation and\ncardiometabolic complications.( 1 )\nThe relationship between uterine fibroids and hyperlipidemia was\ndocumented in the literature. Tak et al ( 81 ) found higher low-density lipoprotein cholesterol (LDL-C) and\nlower high-density lipoprotein cholesterol (HDL-C) levels among women with\nuterine leiomyomas. In addition, they concluded that the number of myomas\ncorrelated positively with triglyceride levels but negatively with HDL-C levels.\nA study done by Uimari et al ( 85 )\ndemonstrated that the risk of uterine leiomyomas increases for each 1 mmol/L\nincrease in LDL-C, triglycerides, and total cholesterol (TC) levels. Estrogen is\na known modulator of lipid metabolism, and aberrant estrogen signaling is\nhypothesized to contribute to derangement of lipids and development of uterine\nfibroids.( 85 ) However, Takeda et al\nfailed to document a significant association between hypertriglyceridemia and\nuterine leiomyomas.( 80 )\nThe risk of uterine leiomyomas correlated with the MetS. Takeda et al\n( 80 ) found that myomatous risk rose\nsignificantly with the number of MetS risk factors, while Tak et al ( 81 ) also demonstrated that MetS was more\nprevalent among women with multiple leiomyomas. Despite the available evidence\nof the relationship between uterine fibroids and CMRFs, more inclusive studies\nand mechanistic research is essential to decide on whether this association is\ncausal or rather observational.\nCMRFs have not only been implicated in the pathogenesis of\nendometriosis, but, in fact, endometriosis was shown to exert systemic effects\nand create dysfunctional inflammatory milieus that could significantly\ncontribute to cardiovascular risk( 25 )\n( Figures 1  and  4 ). In a cross-sectional study conducted by Melo et\nal,( 86 ) women with endometriosis had\nhigher levels of TC, LDL-C, triglycerides, and HDL-C and a lower HDL-C:TC ratio.\nThe documentation of an atherogenic lipid profile in endometriosis patients can\nraise multiple hypotheses. On one hand, endometriosis induces a state of\nsystemic inflammation, which, in turn, can alter lipid metabolism leading to\nderanged lipid parameters.( 26 ) In the\npresence of other CMRFs, oxidized lipids, namely LDL-C, create endothelial\ninjuries and perpetuate a cascade of events that results in atherosclerotic\nplaque formation( 86 ) ( Figure 4 ). From another perspective, oxidization of\nexudated lipids in the peritoneal cavity can enhance the growth of endometrial\nimplants and promote the development of advanced adhesive disease, suggesting a\nmutual etiopathogenic mechanism for both endometriosis and atherosclerosis\nmediated by abnormal lipids and their injurious properties.( 87 )\nIn a prospective cohort study done by Mu et al,( 87 ) women with laparoscopically-confirmed\nendometriosis demonstrated a higher risk of hypercholesterolemia and\nhypertension compared to women without endometriosis. In addition, they\nconcluded that women with either hypercholesterolemia or hypertension had a\nsignificantly higher risk of laparoscopically-confirmed endometriosis than women\nwith neither CMRF.\nMany studies have discussed the association of hysterectomy and\ncardiovascular risk. The Women’s Health Initiative (WHI) Observational\nStudy( 88 ) demonstrated that women\nwith history of hysterectomy were more likely to be obese, diabetic,\nhypertensive, and hypercholesterolemic at baseline compared to women with no\nsuch history. In addition, they were less likely to engage in physical activity\nand had higher intake of saturated fat. Hysterectomized women in the study were\nmore likely to report prior cardiovascular events, including myocardial\ninfarctions, congestive heart failure, and coronary interventions, compared to\ntheir non-hysterectomized counterparts. Upon following them up, women with\nhistory of hysterectomy with or without oophorectomy suffered more\ncardiovascular events, both fatal and non-fatal, compared to those with intact\nuteri. The increased prevalence of self-reported cardiovascular events at\nbaseline and after follow-up among hysterectomized females can be explained by\nthe more prevalent CMRFs these women had, which can possibly be attributed to\ntheir lower socioeconomic status and poorer access to health care.( 88 ) CMRFS may additionally contribute to\nBGDs, such as uterine leiomyomas and endometriosis, as this article previously\ndiscussed, and hence, to a higher chance of undergoing a hysterectomy( 88 ) ( figures\n5 ). On the other hand, hysterectomy is known to compromise the blood\nsupply to the preserved ovaries through anastomotic vessels, and in turn,\npredisposes to an earlier onset of menopause. Surgical menopause may possibly\nthereby deprive a previously premenopausal female of the protective effects of\nestrogen against cardiovascular disease.( 89 )\nIngelsson et al ( 89 ) have\ndocumented an increased cardiovascular risk upon following up hysterectomized\nfemales younger than 50 years of age at the time of operation, but a lower risk\namong women older than 50 years of age when compared to their controls. This\ndifferential risk between the two age groups might be due to selection bias,\nwhere women undergoing hysterectomy for benign indications at an older age are\nof a better baseline health than those who do not. On the other hand, the\nhormonal effects of hysterectomy might be more prominent in premenopausal\nfemales compared to women who have already gone through menopause as well as\ndependent on whether a concomitant bilateral oophorectomy was performed.( 89 )\nOn the contrary, the Study of Women’s Health across the Nation\n(SWAN)( 90 ) inferred that hysterectomy\nwith ovarian conservation is not a predictor of subsequent increased\ncardiovascular risk. In addition, the Coronary Artery Risk Development in Young\nAdults (CARDIA) Study( 91 ) concluded that\npostmenopausal levels of CMRFs were not influenced by hysterectomy status and\nrather reflect the Cardiometabolic profile prior to surgery. Nevertheless, the\npresence of multiple hypotheses underlying the relationship between CMRFs,\nhysterectomy, and cardiovascular events necessitates more comprehensive studies\nto further explore the exact nature of this relationship and its temporal\ncomponent.\nLaughlin-Tommaso et al ( 92 ) have\nfound that obesity shares a significant association with hysterectomy performed\nfor benign indications with ovarian conservation. However, this finding may, in\npart, be attributed to selecting comorbid patients for surgical treatment to\navoid the adverse effects of oral contraceptives on cardiovascular risk. In a\nstudy done by Ding et al,( 93 )\nhysterectomized females were at higher risk of receiving a diagnosis of\nhypertension during the follow-up period. The exact mechanism that connects\nhypertension and hysterectomy remains largely undetermined. It is hypothesized\nthat the development of hypertension is associated with the hormonal changes\nfollowing hysterectomy.( 94 ) This can be\nsupported by the observation that postmenopausal women have higher blood\npressure than their premenopausal counterparts, suggesting a possible modulatory\nrole for ovarian hormones on blood pressure control.( 95 )\n\nThe body of evidence this review presents of the association between CMRFs\nand BGDs creates novel preventive and therapeutic approaches that gynecologists and\nother healthcare providers can put into practice. These include screening measures,\ncardiovascular risk modification, and medical therapy ( figure 5 ).\nScreening of patients with CMRFs for BGDs and vice versa would have a\nremarkable role in the prevention of either disease state. Not only does early\ndetection of CMRFs halt the occurrence of cardiovascular events, but early\nmodification of these factors can, perhaps, prevent the development of uterine\nleiomyomas and hysterectomy. On the other hand, screening of myomatous and\nhysterectomized women as well as females with endometriosis for CMRFs and\nassociated complications such as ischemic heart disease can substantially aid in\nprimary and secondary prevention of Cardiometabolic phenomena. For instance,\ncarotid intima-media thickness can possibly be more liberally used as a\nscreening measure for subclinical atherosclerosis among women with uterine\nleiomyomas knowing it significantly differs among myomatous and non-myomatous\nfemales.( 70 ) Office screening for\ncardiovascular disease using classic CMRF assessment can be more liberally\napplied as well. The research evidence this review provides should stimulate\ngynecologists and other healthcare providers to engage in preventive strategies\nagainst BGDs and cardiovascular disease.\nGiven the multiple mechanisms by which obesity may mediate its role in\nthe pathogenesis of many BGDs, weight loss stands as a significant measure to\nprevent cardiovascular and gynecologic diseases. Systemic inflammation can, at\nleast in part, be improved with weight loss. Reduction of IL-6 and C-reactive\nprotein (CRP) in the sera of subjects who lost weight( 4 ) through caloric restriction and exercise had been\ndocumented. Estrogen levels were similarly demonstrated to decrease with\nintentional weight loss.( 96 )\nBarry et al found that high-intensity interval training and\nmoderate-intensity continuous training can have immunomodulatory actions on IL-6\nand IL-10, which suggests a potential role for exercise in obesity-induced\nsystemic inflammation.( 97 ) In fact,\nathletic females were shown to have a lower lifetime risk of benign tumors of\nthe reproductive tract, including those of the uterus, compared to their\nnon-athletic counterparts.( 98 )\nDietary modifications are also introduced to counteract CMRFs.( 99 ) As previously mentioned in this review,\ndecreased richness of gut microbiota was shown to influence the development of\nCMRFs, such as obesity, hyperlipidemia, insulin resistance, and systemic\ninflammation.( 78 ) These changes in\nthe gut microbiota were shown to be greatly modulated by dietary factors,\nparticularly fat intake;( 99 ) for example,\nhigh-fat diets can alter the composition of gut microbiota by reducing the\nquantity of beneficial species. Consequently, this increases the serum levels of\nlipopolysaccharides, promoting a systemic inflammatory milieu.( 100 ) As opposed to the unfavorable effects of\nsaturated fatty acids on gut microbiota, ingestion of oleic acid and omega-3\npolyunsaturated fatty acid can, in fact, have remarkably beneficial modulatory\neffects on gut microbiota, thereby decreasing the risk of obesity and its\ncomplications.( 99 )\nIn a large database analysis, statin use was found to be associated\nwith a lower risk of having uterine leiomyomas and leiomyoma-associated\nsymptoms.( 101 ) This can possibly\nbe mediated by the anti-mitogenic and pro-apoptotic actions of statins on\nleiomyoma cells and tumor growth inhibition in leiomyoma animal model.( 102 , 103 ) In addition, simvastatin was demonstrated to inhibit\nproduction of extracellular matrix at clinically relevant levels.( 104 ) These results support the\npotential therapeutic use of statins for uterine leiomyomas and related\nsymptoms.( 105 , 106 ) Similarly, statins have shown promise in the\ntreatment of endometriosis in animal models.( 107 , 108 )\nTo counteract the adverse outcomes associated with high-fat intake\non gut microbiota, probiotics or synbiotics can presumably be\nadministered.( 99 ) Depending on\nthe type, probiotic use has been associated with prevention of weight gain,\nregulation of glucose metabolism, and suppression of inflammatory states\nassociated with obesity.( 99 )\n\nFuture research is needed to further investigate whether the association\nbetween CMRFs and BGDs is more than observational. More mechanistic research will\nenhance our understanding of the underlying cellular and molecular mechanisms\ninvolved.","source_license":"CC0","license_restricted":false}