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Sex/gender differences in metabolic syndrome among cancer survivors in the US: an NHANES analysis

Sex/gender differences in metabolic syndrome among cancer survivors in the US: an NHANES analysis Background The purpose of this study was to assess the association of metabolic syndrome (MetS) and its individual com- ponents in cancer survivors (CS) by gender, in comparison to participants without a history of cancer who have at least one chronic disease (CD) and those without a chronic disease diagnosis (NCD). Methods Data from participants 40 years and older (n = 12,734) were collected from the 2011 to 2018 National Health and Nutrition Examination Survey dataset. MetS was defined based on the National Cholesterol Education Program’s Adult Treatment Panel III. Chi-square test and multivariate-adjusted logistic regression was used to assess group comparisons and associations respectively. Results Compared to NCD, CS and CD men had increased odds of meeting MetS, OR 2.60 (CI 1.75–3.87) and OR 2.18 (CI 1.59–2.98) respectively. For women, CS and CD participants also had higher odds of meeting MetS criteria compared to their healthy counterparts, OR 2.05 (CI 1.44–2.93) and OR 2.14 (CI 1.63–2.81) respectively. In subgroup analysis by cancer site, CS men with a history of hematologic malignancies (OR 4.88, CI 1.30–18.37) and CS women with cervical cancer (OR 4.25, CI 1.70–10.59) had highest odds of developing MetS, compared to NCD. CS men also showed a strong association with elevated waist circumference, low high density lipoprotein-c, and elevated triglycerides, even by cancer site, but there were no consistent findings among women. Conclusion This study indicates that CS men have a strong association with MetS, especially among those with blood- related cancers. Keywords Metabolic syndrome · Cancer survivorship · Cancer epidemiology · Sex differences · Gender differences The metabolic syndrome (MetS), a collection of metabolic in men than women, but with women experiencing a steeper abnormalities and a proxy of insulin resistance, is linked to increase in prevalence [7]. Many components of MetS type 2 diabetes, cardiovascular disease and cancer [1, 2]. have been linked to sex- or gender-related factors includ- MetS has become a growing public health concern in the ing hormonal status, socio-economic status, and adoption United States. Indeed, with the increase in sedentary life- of unhealthy behaviors [8]. Particularly, there is strong evi- style and obesity in the general population [3, 4], the prev- dence that insulin-resistance and increased abdominal fat alence of MetS is rising, with 25–40% of US population have differential effects in men and women [ 8]. meeting the criteria for diagnosis, depending on the defini - MetS has been shown to influence cancer development tion and cut-off values used for each factor [ 5–7]. Epidemi- and progression, and thus cancer-related mortality [2, 9]. ological studies have noted that incidence of MetS differs by Recent meta-analyses have showed that MetS is associ- sex or gender, for example, being reportedly more prevalent ated with several cancers, including colorectal, and bladder cancers in men, and endometrial, post-menopausal breast, and colorectal cancers in women [2, 10]. Given the grow- ing cancer survival rates, due to improved early detection Adaora Ezeani and treatment [11], MetS can also represent a common long- adaora.ezeani@nih.gov term complication after treatment that affects quality of life. National Cancer Institute, Rockville, MD 20850, USA Cancer survivors with MetS are faced with adverse effects, Johns Hopkins School of Medicine, Baltimore, MD such as atherosclerotic disease or cancer recurrence, which 02115, USA 1 3 Journal of Cancer Survivorship demands proactive assessment and management by health- Metabolic syndrome definition care professionals. The purpose of this study is to assess the association between cancer survivors and MetS and its In accordance with the National Cholesterol Education Pro- individual components to help determine the risk for cardio- gram (NCEP) Adult Treatment Panel III (ATP III) guidelines vascular disease, secondary cancers, and other sequalae due [18], we defined MetS as the presence of at least three of the to MetS. In addition, to compare differences between cancer following: (1) elevated waist circumference (≥ 102 cm for survivors and non-cancer survivors, this study aims to ana- men, ≥ 88 cm for women), (2) low high density lipoprotein lyze the association between MetS and its components to (< 40 mg/dL for men and < 50 mg/dL for women) or current participants without a cancer diagnosis, categorized into a treatment for reduced HDL-C, (3) elevated triglycerides healthy group and group with comorbidities. (≥ 150 mg/dL) or current treatment for elevated triglycer- ides, (4) elevated fasting plasma glucose (≥ 100 mg/dL) or current use of diabetes medication, and (5) elevated blood Methods pressure (systolic blood pressure ≥ 130 or diastolic blood pressure ≥ 85) or current use of blood pressure medication. Study population Covariates The data used in this study were acquired from the US National Health and Nutrition Examination Survey Sociodemographics (NHANES), conducted from 2011 to 2018 by the Centers for Disease Control and Prevention [12]. NHANES is a nation- Questionnaires were used to obtain information on demo- wide, population-based cross-sectional study, representing graphics (age, race, gender, and/or ethnicity), education, non-institutionalized, civilian US population. It is designed and annual family income. Age was categorized into three to assess the health and nutritional status of adults and chil- groups: 40 to 59 years, 60 to 79, and 80 years or older. Gen- dren in the United States. A multistage sampling procedure der was categorized as man or woman. It is important to was used. The current analysis was restricted to adults aged note that NHANES dataset adopts a cisnormative approach 40 years or older. We excluded participants with a history where gender and sex are not differentiated, and therefore, of childhood cancer (n = 13), defined as cancer diagnosis at both measures are considered concordant in this study. Race/ 16 years old or younger, because of the growing evidence ethnicity was categorized as Non-Hispanic White, Non-His- supporting increased risk of metabolic syndrome in pediat- panic Black, Hispanic or Mexican American, and Non-His- ric cancer survivors [13–15]. Pregnant women (n = 14) were panic Asian. Education was self-reported and categorized as excluded due to pregnancy-related metabolic changes and “high school graduate or less” or “some college education or increased waist circumference. Our final analytical sample above”. Marital status was self-reported and categorized as included 12,734 individuals. The study sample was catego- “married or living with a partner”, “widowed, divorced, or rized into three groups or statuses: (1) participants with no separated”, and “never married”. Poverty-to-Income ratio, history of self-reported medical conditions (NCD), (2) par- or the self-reported annual family income divided by the ticipants with a self-reported history of at least one chronic poverty threshold, was categorized into less than or equal to disease and no history of cancer (CD), and (3) participants 1.29, 1.30 to 3.49, and 3.50 or above. with a history of cancer (CS). Participants assigned to the CD group reported a history of medical conditions used Body mass index to calculate the Charlson Comorbidity Index, a tool used to quantify the burden of comorbidity and evaluate risk of Height and weight were measured by trained personnel mortality [16, 17]. NHANES interviewers asked partici- using standardized procedures and calibrated equipment. pants if they had a professional diagnosis of the following: BMI (kg/m ) was calculated as weight in kilograms divided arthritis, gout, congestive heart failure, heart attack, stroke, by the square of height in meters and was categorized as 2 2 a liver condition including hepatitis B and C, kidney dis- healthy weight (BMI 18.5 kg/m to < 25 kg/m ), overweight 2 2 2 ease such as kidney stones and kidney failure, diabetes, and (BMI 25 kg/m to < 30 kg/m ), and obese (BMI ≥ 30 kg/m ). emphysema and/or chronic bronchitis or chronic obstruc- tive pulmonary disease. Participants were assigned to the Smoking status CD group if they replied “yes” to the question “Has a doc- tor or other health professional ever told you that you have Smoking status was assessed from two self-reported items [condition]?”. in the data: “Have you smoked at least 100 cigarettes in your lifetime?” and “Do you smoke cigarettes now?” Smoking 1 3 Journal of Cancer Survivorship status was categorized into three groups: (1) never smok- those who did not meet any goals received 0 points. The ers who reported they have not smoked 100 cigarettes in total score ranges from 0 to 9 points. Individuals meeting their lifetime and do not smoke now; former smokers who approximately half of the DASH targets (DASH score ≥ 4.5) reported they have smoked at least 100 cigarettes in their were considered DASH accordant [23]. lifetime, but do not smoke now; and (3) current smokers who reported they smoked at least 100 cigarettes in their Statistical analysis lifetime and currently smoke either every day or some days. All analyses were performed using NHANES-generated Alcohol use sampling strata, clusters, and weights to generate nationally representative estimates in US civilian population. Categori- Participants were asked if they had at least 12 drinks of alco- cal variables were presented as percentages, and continuous hol in the past year and in their lifetime. Similar to Muntner variables were presented as means with standard deviation. et al., alcohol status was categorized into three categories: We examined group differences in sample characteristics by (1) never drinkers who reported no alcohol drinking or con- status using Chi-square or t-test. We used weighted logis- sumed less than 12 alcoholic drinks in their lifetime and in tic regression to estimate the presence of MetS and each the past year; (2) former drinkers who reported drinking at of its components to CD and CS status, compared to NCD least 12 alcoholic drinks in their lifetime but none in the and stratified by gender. In addition, we repeated the logis - last year; and (3) current drinkers who reported drinking at tic regression analysis to estimate the association between least 12 alcoholic drinks in their lifetime and had at least 12 CS cancer site and presence of MetS and each compo- alcoholic drinks in the last year [19]. nent, compared to NCD. All multivariable logistic regres- sion models were adjusted for demographic characteristics Physical activity such as age, race/ethnicity, education, PIR, BMI, physical activity, DASH score, smoking status, and alcohol use [24, Participants reported the number of days and amount of 25]. Adjusted estimates of association were expressed as time spent participating in moderate or vigorous activity odds ratios with 95% confidence intervals. A two-sided P at work or as recreation. Physical activity was calculated value < 0.05 was considered statistically significant. Stata into metabolic equivalent of task (MET), the ratio between version 17.0 SE was used for all analyses. caloric consumption during physical activity and resting basal metabolic rate. MET were calculated by using the MET value of the activity and multiplying by the dura- Results tion of the activity in minutes. The validity of self-reported physical activity measure, indexed using MET-minutes, Characteristics of the study sample has been demonstrated previously [20]. Participants were categorized into four groups, according to the US Physical Table 1 describes the characteristics of participants included Activity Guidelines for Americans [21]. Participants who in this study. Our study sample included 12,734 participants reported no physical activity were categorized as seden- (52.8% women, 72.3% non-Hispanic White, and mean tary. Those who reported physical activity equal to less than age 58.5 [10.2 SD] years), among whom 4,494 were NCD 500 MET-minutes per week were categorized as “Low”. (36.5%), 6493 CD (47.5%), and 1747 CS (16.0%). In the Participants who reported ≥ 500 and < 1000 MET-minutes total sample, most participants (72.5%) met the criteria for per week were categorized as “Moderate”. Physical activity MetS. Across study groups, there were statistically signifi - levels ≥ 1000 MET-minutes per week were categorized as cant differences in all demographic factors including gender, “High” [21]. average age, race and ethnicity, marital status, education, and poverty-to-income ratio. Compared to CD and CS, most Diet NCD were women, younger, married or living with a part- ner, and belonged to the highest PIR group (Table 1). Dietary intake was assessed by two 24-hr dietary recalls. Based on Mellen et al., a dietary index or DASH score was Cancer survivor status and MetS generated based on the average target values for 9 nutrients: total fat, saturated fat, protein, fiber, cholesterol, calcium, In multivariable adjusted logistic regression analysis magnesium, sodium, and potassium [22, 23]. Individuals (Table 2), compared to NCD men, CS men had 2.6-fold who met the goal for each nutrient received 1 point, those higher odds (OR 2.60; CI 1.75–3.87) and CD men had 2.2- who met an intermediate goal received half of a point, and fold higher odds (OR 2.18; CI 1.59–2.98) of meeting MetS. 1 3 Journal of Cancer Survivorship Table 1 Characteristics of study NCD CD CS Total participants by NCD, CD, and (n = 4,494) (n = 6,493) (n = 1,747) (n = 12,734) CS status *** Gender, % Women 51.1 53.8 54.0 52.8 Men 48.9 46.2 46.0 47.2 *** Mean age (sd) 53.1 (8.4) 60.1 (10.0) 65.7 (9.5) 58.5 (10.2) *** Race/Ethnicity, % Non-Hispanic White 66.9 71.5 87.3 72.3 Non-Hispanic Black 11.5 12.0 5.6 10.8 Hispanic 14.4 12.4 5.1 12.0 Non-Hispanic Asian 7.2 4.1 2.0 4.9 *** Marital status, % Married/living with partner 72.0 64.6 66.4 67.6 Widowed/divorced/separated 19.6 27.7 29.9 25.1 Never married 8.4 7.8 3.7 7.3 *** Education, % High school graduate or less 34.1 41.3 28.1 36.5 Some college or above 65.9 58.7 71.9 63.5 *** Poverty-Income-Ratio, % 13.9 22.6 13.5 18.0 < 1.29 1.30–3.49 32.3 35.8 36.5 34.6 ≥ 3.50 53.8 41.6 50.0 47.4 2 *** BMI category (kg/m ), % Healthy (18.5–24.9) 29.9 18.9 25.9 24.0 Overweight (25.0–29.9) 38.8 30.8 34.4 34.3 31.3 50.3 39.7 41.7 Obese (≥ 30.0) *** Total Physical Activity (METs), % Sedentary 18.7 29.5 28.7 25.4 Low (≤ 499) 13.1 14.4 14.1 13.9 Moderate (500–999) 11.5 9.8 11.3 10.6 56.8 46.3 45.9 50.1 High (≥ 1000) *** Abbreviations: NCD, no self- Smoking, % reported medical condition; CD, Never smoker 62.4 48.6 46.6 53.3 1 or more self-reported medical Former smoker 23.5 32.2 39.4 30.1 conditions; CS, cancer survivor; Current smoker 14.1 19.3 14.1 16.6 BMI, body mass index; MET, *** Alcohol use, % metabolic equivalent of task. Never drinker 10.5 10.8 8.6 10.4 DASH accordant: DASH Former drinker 10.7 16.2 16.2 14.2 score ≥ 4.5. Current drinker 78.8 73.0 75.0 75.4 * p < 0.05, ** p < 0.01, *** DASH accordant, % 11.4 9.2 8.9 10.0 p < 0.001 Both groups also demonstrated higher odds of meeting 4 1.37–4.88) were associated with MetS. In analysis of MetS to 5 MetS component compared to NCD men, particularly components, prostate cancer, melanoma, non-melanoma elevated WC (OR 3.81; CI 2.41–6.04) and low HDL-c (OR skin cancer, and bladder cancer demonstrated statistically 2.52; CI 1.81–3.52) in CS men. CS and CD women also significant association with at least three of the five MetS had higher odds of meeting MetS criteria compared to their components, elevated WC, low HDL-c, and elevated TG. healthy counterparts, OR 2.05 (CI 1.44–2.93) and OR 2.14 In CS women (Table 4), those with cervical (OR 4.25; (CI 1.63–2.81) respectively. CI 1.70–10.59), melanoma (OR 3.51; CI 1.28–9.59), and breast cancer (OR 1.76; CI 1.08–2.89) showed statisti- Cancer site and MetS cally significant association with MetS compared to NCD women. In contrast to CS men, few cancer sites among CS Among CS men (Table 3), those with a history of blood- women exhibited a statistically significant association with related cancer (OR 4.88, CI 1.30–18.37), colorectal can- individual MetS components, compared to their healthy cer (OR 2.87, CI 1.02–8.11), prostate cancer (OR 2.85; CI counterparts. 1.51–5.38), or non-melanoma skin cancer (OR 2.58; CI 1 3 Journal of Cancer Survivorship Table 2 Odds ratiosa (95% CI) for MetS and its components among CD and CS participants, stratified by sex/gender MetS Elevated WC Low HDL-c Elevated TG Elevated FG Elevated BP Men NCD Ref Ref Ref Ref Ref Ref *** *** *** ** * *** CD 2.18 2.11 2.48 1.78 1.55 1.90 [1.59,2.98] [1.48,3.02] [1.85,3.31] [1.27,2.51] [1.07,2.23] [1.43,2.52] *** *** *** *** *** CS 2.60 3.81 2.52 2.40 1.60 1.95 [1.75,3.87] [2.41,6.04] [1.81,3.52] [1.61,3.60] [0.96,2.69] [1.49,2.56] Women NCD Ref Ref Ref Ref Ref Ref *** *** *** * *** CD 2.14 1.80 1.97 1.34 1.08 1.79 [1.63,2.81] [1.33,2.44] [1.57,2.46] [1.04,1.71] [0.81,1.45] [1.38,2.33] *** *** *** * * ** CS 2.05 1.93 1.79 1.47 1.65 1.68 [1.44,2.93] [1.35,2.76] [1.31,2.44] [1.05,2.04] [1.08,2.50] [1.23,2.28] Abbreviations: MetS, Metabolic syndrome; CS, cancer survivor; CD, 1 or more self-reported medical conditions; WC, waist circumference; HDL-c, high-density lipoprotein cholesterol; TG, triglycerides; FG, fasting plasma glucose; BP, blood pressure. Elevated WC, ≥ 102 cm for men, ≥ 88 cm for women Low HDL-c, < 40 mg/dL for men and < 50 mg/dL for women, or current treatment for reduced HDL-c Elevated TG, ≥ 150 mg/dL or current treatment for elevated triglycerides. Elevated FG (≥ 100 mg/dL) or current use of diabetes medication. Elevated BP, systolic blood pressure ≥ 130, or diastolic blood pressure ≥ 85, or current use of blood pressure medication. Adjusted by age, race/ethnicity, education, PIR, BMI, physical activity, DASH score, smoking status, and alcohol use. * ** *** p < 0.05, p < 0.01, p < 0.001 Table 3 Odds ratiosa (95% CI) for MetS and its components in CS and CD men by cancer site compared to healthy men MetS Elevated WC Low HDL-c Elevated TG Elevated FG Elevated BP NCD Ref Ref Ref Ref Ref Ref *** *** *** ** * *** CD 2.18 2.13 2.48 1.79 1.56 1.90 [1.59,2.98] [1.48,3.05] [1.86,3.31] [1.27,2.52] [1.09,2.24] [1.42,2.52] ** *** ** * ** Prostate 2.85 3.58 2.14 1.97 1.60 2.44 [1.51,5.38] [1.87,6.85] [1.22,3.77] [1.02,3.79] [0.82,3.14] [1.42,4.18] * *** *** Colorectal 2.87 12.30 4.83 1.25 4.91 1.86 [1.02,8.11] [4.12,36.70] [1.99,11.74] [0.37,4.24] [0.64,37.38] [0.61,5.64] ** ** * Melanoma 2.71 4.52 5.42 3.77 3.56 1.98 [0.73,10.09] [1.54,13.26] [1.97,14.93] [1.24,11.40] [0.95,13.43] [0.75,5.23] ** *** * ** Non-melanoma 2.58 5.17 1.96 2.52 1.49 1.72 [1.37,4.88] [2.44,10.95] [1.16,3.31] [1.27,5.01] [0.69,3.21] [0.98,3.02] Blood-related 4.88 1.67 3.60 1.73 1.44 2.05 [1.30,18.37] [0.41,6.85] [0.94,13.79] [0.50,5.95] [0.30,6.83] [0.45,9.29] ** * * Bladder 3.17 6.40 2.78 4.45 2.08 0.76 [0.95,10.62] [1.73,23.69] [1.07,7.18] [1.39,14.25] [0.40,10.79] [0.27,2.15] Other GU 1.51 2.63 2.42 8.45 0.94 1.10 [0.43,5.21] [0.70,9.83] [0.81,7.26] [1.51,47.26] [0.17,5.22] [0.45,2.67] ** ** Other 2.31 3.38 2.73 1.92 2.97 1.45 [0.99,5.39] [1.43,7.98] [1.33,5.60] [0.85,4.31] [0.96,9.15] [0.61,3.46] Abbreviations: MetS, Metabolic syndrome; CS, cancer survivor; GU, genitourinary cancer; WC, waist circumference; HDL-c, high-density lipoprotein cholesterol; TG, triglycerides; FG, fasting plasma glucose; BP, blood pressure. Elevated WC, ≥ 102 cm for men, ≥ 88 cm for women Low HDL-c, < 40 mg/dL for men and < 50 mg/dL for women, or current treatment for reduced HDL-c Elevated TG, ≥ 150 mg/dL or current treatment for elevated triglycerides. Elevated FG (≥ 100 mg/dL) or current use of diabetes medication. Elevated BP, systolic blood pressure ≥ 130, or diastolic blood pressure ≥ 85, or current use of blood pressure medication. Adjusted by age, race/ethnicity, education, PIR, BMI, physical activity, DASH score, smoking status, and alcohol use. * ** *** p < 0.05, p < 0.01, p < 0.001 1 3 Journal of Cancer Survivorship Table 4 Odds ratiosa (95% CI) for MetS and its components in CS and CD women by cancer site compared to healthy women MetS Elevated WC Low HDL-c Elevated TG Elevated FG Elevated BP NCD Ref Ref Ref Ref Ref Ref *** *** *** * *** CD 2.15 1.81 1.98 1.34 1.08 1.79 [1.64,2.82] [1.34,2.44] [1.58,2.48] [1.05,1.72] [0.80,1.45] [1.38,2.33] * * * Breast 1.76 2.22 1.49 1.33 1.51 1.59 [1.08,2.89] [1.15,4.30] [0.96,2.31] [0.78,2.25] [0.95,2.40] [1.03,2.43] Colorectal 1.89 2.30 1.33 1.54 1.11 2.37 [0.79,4.51] [0.47,11.22] [0.74,2.42] [0.60,3.99] [0.46,2.72] [0.49,11.46] * * ** Melanoma 3.51 3.48 1.32 1.07 7.94 1.49 [1.28,9.59] [1.33,9.08] [0.62,2.84] [0.36,3.13] [2.02,31.23] [0.59,3.77] Non-melanoma 1.68 1.87 1.88 1.62 1.24 2.32 [0.81,3.49] [0.79,4.40] [0.97,3.66] [0.82,3.21] [0.54,2.83] [1.20,4.48] Blood-related 2.30 4.22 1.84 2.19 3.54 1.10 [0.49,10.74] [1.05,16.92] [0.57,5.97] [0.48,9.93] [0.42,30.03] [0.27,4.51] ** Cervical 4.25 1.26 2.05 1.30 1.74 1.50 [1.70,10.59] [0.54,2.91] [0.98,4.27] [0.48,3.53] [0.68,4.48] [0.65,3.43] Uterine 2.58 2.76 2.05 2.66 2.10 1.15 [0.66,10.00] [0.91,8.39] [0.70,5.98] [0.52,13.61] [0.77,5.73] [0.34,3.85] ** Other 1.78 1.86 2.23 1.17 1.38 1.28 [0.89,3.53] [0.87,3.94] [1.26,3.95] [0.59,2.34] [0.58,3.26] [0.73,2.24] Abbreviations: MetS, Metabolic syndrome; CS, cancer survivor; WC, waist circumference; HDL-c, high-density lipoprotein cholesterol; TG, triglycerides; FG, fasting plasma glucose; BP, blood pressure. Elevated WC, ≥ 102 cm for men, ≥ 88 cm for women Low HDL-c, < 40 mg/dL for men and < 50 mg/dL for women, or current treatment for reduced HDL-c Elevated TG, ≥ 150 mg/dL or current treatment for elevated triglycerides. Elevated FG (≥ 100 mg/dL) or current use of diabetes medication. Elevated BP, systolic blood pressure ≥ 130, or diastolic blood pressure ≥ 85, or current use of blood pressure medication. Adjusted by age, race/ethnicity, education, PIR, BMI, physical activity, DASH score, smoking status, and alcohol use. * ** *** p < 0.05, p < 0.01, p < 0.001 Discussion Comparison with prior studies and pathogenesis of MetS among cancer survivors Summary of main findings In CS men, the pathogenesis of MetS can be related to the Compared to their NCD counterparts, CS men and women changes in endocrine and metabolic functions due to treat- demonstrated higher odds of meeting MetS criteria and at ment. Similar to this study, CS men with a history of hema- least three of the five individual MetS components than tologic malignancies have been shown to have a high risk CD. In particular, men showed a stronger association with of developing MetS, which has been attributed to exten- MetS than women. Furthermore, certain cancer sites in CS sive treatments such as stem cell transplantation, high dose men and women had statistically significant higher odds of chemotherapy, and irradiation [26, 27]. These treatments MetS and its components, compared to their healthy coun- cause damage to the hypothalamic-pituitary-axis, leading terparts. In CS men, participants with a history of hemato- to deficiencies in growth hormones, thyroid hormones, and logic malignancies had the highest odds of developing MetS androgens related to individual components of MetS [28]. compared to NCD men. For CS women, participants with For prostate cancer survivors, androgen deprivation therapy cervical cancer history exhibited the highest odds of MetS (ADT), a common treatment modality, has also been pro- than their healthy counterparts. In subgroup analyses of the posed as a risk factor for MetS development, due to male individual components of MetS, CS men with cancer sites hypogonadism or low testosterone. In one study, patients associated with MetS had higher odds of having elevated who received ADT had higher prevalence of MetS (55%) WC, low HDL-c, and elevated TG compared to NCD men. than patients treated with radiotherapy and/or prostatectomy (22%), or healthy controls (20%) [5, 29]. Furthermore, observational studies have shown a positive association between level of hypogonadism and degree of obesity in men, as well as an inverse relationship between testosterone 1 3 Journal of Cancer Survivorship levels and visceral fat mass [30]. Low testosterone has also elevated TG have also been demonstrated to be risk factors been linked to adverse lipid profile [ 31] and hypertension for multiple cancers, including colon cancer, melanoma, [32, 33], two components of MetS. and prostate cancer [41]. For example, low HDL-c was For CS women, previous epidemiological studies have reported to be related to an increase in lung cancer inci- also supported correlation between MetS and a history of dence and associated with a 15-fold increase in hematologic cervical cancer [34, 35]. Penaranda et al., showed that CS malignancy development [42]. In addition, hypertriglyceri- women with cervical cancer history had higher odds of MetS demia has been reported to be associated with prostate can- in both unadjusted and adjusted analyses (which accounted cer [43]. The probable mechanism through which elevated for multiple sexual partners, multiparity, hormonal con- triglycerides increase cancer risk is through the generation traceptive use, and history of smoking) compared to those of reactive oxygen species and oxidative stress, which cause without MetS [35]. A limited number studies have investi- DNA damage [10]. Mechanisms that may link low HDL-c gated the relationship between a history of cervical cancer with cancer are not well understood. One possible mecha- and MetS, but it is hypothesized that MetS can be related to nism may involve chronic inflammation, resulting from low estrogen (e.g. caused by direct damage to the ovaries decreased HDL-c levels, which has been implicated in can- from abdomino-pelvic radiotherapy), abdominal adiposity, cer development [10, 44]. and increased inflammatory markers, such as adipokines MetS is a common long-term complication of cancer that and other cytokines, from persistent human papillomavirus affects health outcomes and quality of life. The develop - infection [5, 36]. Moreover, in our study, none of the spe- ment of the MetS in cancer survivors has been associated cific MetS components were significantly associated with with signs of early atherosclerosis and cancer recurrence. cervical cancer in CS women. Moreover, there were very Considering the direct cardiovascular toxicity of most can- few statistically significant associations between individual cer treatments, this group faces an increased risk of cardio- MetS components and other cancer sites in CS women. Syn- vascular disease, and the presence of MetS provides the ergism, or clustering of MetS components, may be neces- environment for development of secondary cancers. Our sary for the development of MetS, and long-term risk may study also highlights the gender differences in risk of MetS be underestimated at any point in time in CS women. and, consequently, cardiovascular disease, which may be of Individual components of MetS have been reported to potential relevance for prevention. With prolonged cancer be carcinogenic, which may lead to increased risk in recur- survival rates, prevalence of MetS is expected to increase, rence in CS. In subgroup analysis of MetS components, and therefore, it is important for healthcare professionals to most CS men had higher odds of having elevated WC, low acknowledge the risk of MetS and establish suitable screen- HDL-c, and elevated TG compared to NCD men. Studies ing, follow-up and appropriate interventions. have repeatedly reported that components of MetS related to hyperglycemia, obesity, and dyslipidemia promote can- Strengths and limitations cer development as well as growth [2, 5]. Epidemiological studies have revealed that an elevated WC, BMI, or waist- The strengths of this study include a large sample size provid- hip-ratio, indicators of obesity, are linked with several can- ing enough statistical power to conduct stratified analyses, cer types and cancer-related mortality [10, 37, 38]. Elevated and the use of a representative sample of the US popula- WC has been shown to be a major determinant of higher tion, providing results can be extrapolated to the population prevalence of MetS in prostate cancer survivors [5, 29]. using US census data. Our multivariable analysis included Conversely, MetS has been theorized to be a major risk fac- a robust adjustment using wide variety of covariates includ- tor for prostate cancer development. In a prospective cohort ing dietary intake and physical activity. All anthropometric of 16,209 men aged 40–49 years, men in the upper quartile or biochemical components of MetS were objectively mea- for two components of MetS were 23% more likely to be sured with validated tools. diagnosed with prostate cancer, and those who met three cri- This study also has a few limitations. As a cross-sectional teria for MetS were 56% more likely to be diagnosed with study, it is difficult to draw causal inference between cancer prostate cancer compared to the rest of the cohort [39]. In the status and MetS or each of its components, as well as to pathophysiology of obesity and cancer, hyperinsulinemia establish the temporal sequence between cancer status and related to insulin resistance increases the bioavailability of MetS. These results should be considered hypothesis-gen- insulin-like growth factor (IGF)-1 [10, 40]. Receptors for erating, which requires prospective studies to further char- insulin and IGF-1 are expressed in most cancer cells, and acterized the risk of MetS among cancer survivors. Other receptor activation results in signaling pathways capable of limitations in this study are inherent to the use of NHANES stimulating cancer cell proliferation, protection from apop- dataset, which includes nonresponse bias, recall bias, and totic stimuli, invasion and metastasis [40]. Low HDL-c and inability to differentiate between sex and gender. Although 1 3 Journal of Cancer Survivorship 5. de Haas EC, et al. The metabolic syndrome in cancer survivors. NHANES collects data on a wide variety of variables, there Lancet Oncol. 2010;11(2):193–203. are unmeasured confounders such as type of cancer treat- 6. Aguilar M, et al. Prevalence of the metabolic syndrome in the United States, 2003–2012. JAMA. 2015;313(19):1973–4. ment, a factor implicated in development of MetS, and 7. Hirode G, Wong RJ. Trends in the prevalence of meta- years since treatment completion. It is also difficult to draw bolic syndrome in the United States, 2011–2016. JAMA. definitive conclusions given that several definitions of MetS 2020;323(24):2526–8. exist, and we used only one of these. A gold standard for 8. Pucci G, et al. Sex- and gender-related prevalence, cardiovascular risk and therapeutic approach in metabolic syndrome: a review of MetS diagnosis has not been established and each definition the literature. Pharmacol Res. 2017;120:34–42. emphasizes different aspects of MetS, which may explain 9. Gathirua-Mwangi WG, et al. Metabolic syndrome and total can- the differences in results in various studies. cer mortality in the Third National Health and Nutrition Examina- tion Survey. Cancer Causes Control. 2017;28(2):127–36. 10. Cowey S, Hardy RW. The metabolic syndrome: a high-risk state for cancer? Am J Pathol. 2006;169(5):1505–22. Conclusion 11. Miller KD et al. Cancer treatment and survivorship statis- tics, 2019 CA: A Cancer Journal for Clinicians, 2019. 69(5): With an aging US population and concurrent increases in p. 363–385. 12. Statistics NCfH. National Health and Nutrition Examination Sur- chronic conditions, prevalence of MetS is increasing and vey; Available from: http://www.cdc.gov/nchs/nhanes.htm. becoming a major concern. Detecting and controlling the 13. Pluimakers VG, et al. Metabolic syndrome as cardiovascular risk components of MetS, especially the preeminent ones, may factor in childhood cancer survivors. Crit Rev Oncol Hematol. improve length and quality of life for cancer survivors. 2019;133:129–41. 14. Chueh HW, Yoo JH. Metabolic syndrome induced by anticancer Furthermore, efforts aimed at improving lifestyle patterns treatment in childhood cancer survivors. Ann Pediatr Endocrinol including physical activity and dietary habits or use of med- Metab. 2017;22(2):82–9. ications, which can reduce metabolic aberrations, can have 15. Scott JX, Latha MS, Aruna R. Approach to metabolic syndrome in profound health benefits for cancer survivors. childhood cancer survivors. 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Relationship between met- Springer Nature or its licensor (e.g. a society or other partner) holds abolic syndrome and history of cervical cancer among a US exclusive rights to this article under a publishing agreement with the national population International Scholarly Research Notices, author(s) or other rightsholder(s); author self-archiving of the accepted 2013. 2013. manuscript version of this article is solely governed by the terms of 36. Baker R, et al. Increased plasma levels of adipokines and inflam - such publishing agreement and applicable law. matory markers in older women with persistent HPV infection. Cytokine. 2011;53(3):282–5. 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Cancer Survivorship: Research and Practice Springer Journals

Sex/gender differences in metabolic syndrome among cancer survivors in the US: an NHANES analysis

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Copyright © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
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Abstract

Background The purpose of this study was to assess the association of metabolic syndrome (MetS) and its individual com- ponents in cancer survivors (CS) by gender, in comparison to participants without a history of cancer who have at least one chronic disease (CD) and those without a chronic disease diagnosis (NCD). Methods Data from participants 40 years and older (n = 12,734) were collected from the 2011 to 2018 National Health and Nutrition Examination Survey dataset. MetS was defined based on the National Cholesterol Education Program’s Adult Treatment Panel III. Chi-square test and multivariate-adjusted logistic regression was used to assess group comparisons and associations respectively. Results Compared to NCD, CS and CD men had increased odds of meeting MetS, OR 2.60 (CI 1.75–3.87) and OR 2.18 (CI 1.59–2.98) respectively. For women, CS and CD participants also had higher odds of meeting MetS criteria compared to their healthy counterparts, OR 2.05 (CI 1.44–2.93) and OR 2.14 (CI 1.63–2.81) respectively. In subgroup analysis by cancer site, CS men with a history of hematologic malignancies (OR 4.88, CI 1.30–18.37) and CS women with cervical cancer (OR 4.25, CI 1.70–10.59) had highest odds of developing MetS, compared to NCD. CS men also showed a strong association with elevated waist circumference, low high density lipoprotein-c, and elevated triglycerides, even by cancer site, but there were no consistent findings among women. Conclusion This study indicates that CS men have a strong association with MetS, especially among those with blood- related cancers. Keywords Metabolic syndrome · Cancer survivorship · Cancer epidemiology · Sex differences · Gender differences The metabolic syndrome (MetS), a collection of metabolic in men than women, but with women experiencing a steeper abnormalities and a proxy of insulin resistance, is linked to increase in prevalence [7]. Many components of MetS type 2 diabetes, cardiovascular disease and cancer [1, 2]. have been linked to sex- or gender-related factors includ- MetS has become a growing public health concern in the ing hormonal status, socio-economic status, and adoption United States. Indeed, with the increase in sedentary life- of unhealthy behaviors [8]. Particularly, there is strong evi- style and obesity in the general population [3, 4], the prev- dence that insulin-resistance and increased abdominal fat alence of MetS is rising, with 25–40% of US population have differential effects in men and women [ 8]. meeting the criteria for diagnosis, depending on the defini - MetS has been shown to influence cancer development tion and cut-off values used for each factor [ 5–7]. Epidemi- and progression, and thus cancer-related mortality [2, 9]. ological studies have noted that incidence of MetS differs by Recent meta-analyses have showed that MetS is associ- sex or gender, for example, being reportedly more prevalent ated with several cancers, including colorectal, and bladder cancers in men, and endometrial, post-menopausal breast, and colorectal cancers in women [2, 10]. Given the grow- ing cancer survival rates, due to improved early detection Adaora Ezeani and treatment [11], MetS can also represent a common long- adaora.ezeani@nih.gov term complication after treatment that affects quality of life. National Cancer Institute, Rockville, MD 20850, USA Cancer survivors with MetS are faced with adverse effects, Johns Hopkins School of Medicine, Baltimore, MD such as atherosclerotic disease or cancer recurrence, which 02115, USA 1 3 Journal of Cancer Survivorship demands proactive assessment and management by health- Metabolic syndrome definition care professionals. The purpose of this study is to assess the association between cancer survivors and MetS and its In accordance with the National Cholesterol Education Pro- individual components to help determine the risk for cardio- gram (NCEP) Adult Treatment Panel III (ATP III) guidelines vascular disease, secondary cancers, and other sequalae due [18], we defined MetS as the presence of at least three of the to MetS. In addition, to compare differences between cancer following: (1) elevated waist circumference (≥ 102 cm for survivors and non-cancer survivors, this study aims to ana- men, ≥ 88 cm for women), (2) low high density lipoprotein lyze the association between MetS and its components to (< 40 mg/dL for men and < 50 mg/dL for women) or current participants without a cancer diagnosis, categorized into a treatment for reduced HDL-C, (3) elevated triglycerides healthy group and group with comorbidities. (≥ 150 mg/dL) or current treatment for elevated triglycer- ides, (4) elevated fasting plasma glucose (≥ 100 mg/dL) or current use of diabetes medication, and (5) elevated blood Methods pressure (systolic blood pressure ≥ 130 or diastolic blood pressure ≥ 85) or current use of blood pressure medication. Study population Covariates The data used in this study were acquired from the US National Health and Nutrition Examination Survey Sociodemographics (NHANES), conducted from 2011 to 2018 by the Centers for Disease Control and Prevention [12]. NHANES is a nation- Questionnaires were used to obtain information on demo- wide, population-based cross-sectional study, representing graphics (age, race, gender, and/or ethnicity), education, non-institutionalized, civilian US population. It is designed and annual family income. Age was categorized into three to assess the health and nutritional status of adults and chil- groups: 40 to 59 years, 60 to 79, and 80 years or older. Gen- dren in the United States. A multistage sampling procedure der was categorized as man or woman. It is important to was used. The current analysis was restricted to adults aged note that NHANES dataset adopts a cisnormative approach 40 years or older. We excluded participants with a history where gender and sex are not differentiated, and therefore, of childhood cancer (n = 13), defined as cancer diagnosis at both measures are considered concordant in this study. Race/ 16 years old or younger, because of the growing evidence ethnicity was categorized as Non-Hispanic White, Non-His- supporting increased risk of metabolic syndrome in pediat- panic Black, Hispanic or Mexican American, and Non-His- ric cancer survivors [13–15]. Pregnant women (n = 14) were panic Asian. Education was self-reported and categorized as excluded due to pregnancy-related metabolic changes and “high school graduate or less” or “some college education or increased waist circumference. Our final analytical sample above”. Marital status was self-reported and categorized as included 12,734 individuals. The study sample was catego- “married or living with a partner”, “widowed, divorced, or rized into three groups or statuses: (1) participants with no separated”, and “never married”. Poverty-to-Income ratio, history of self-reported medical conditions (NCD), (2) par- or the self-reported annual family income divided by the ticipants with a self-reported history of at least one chronic poverty threshold, was categorized into less than or equal to disease and no history of cancer (CD), and (3) participants 1.29, 1.30 to 3.49, and 3.50 or above. with a history of cancer (CS). Participants assigned to the CD group reported a history of medical conditions used Body mass index to calculate the Charlson Comorbidity Index, a tool used to quantify the burden of comorbidity and evaluate risk of Height and weight were measured by trained personnel mortality [16, 17]. NHANES interviewers asked partici- using standardized procedures and calibrated equipment. pants if they had a professional diagnosis of the following: BMI (kg/m ) was calculated as weight in kilograms divided arthritis, gout, congestive heart failure, heart attack, stroke, by the square of height in meters and was categorized as 2 2 a liver condition including hepatitis B and C, kidney dis- healthy weight (BMI 18.5 kg/m to < 25 kg/m ), overweight 2 2 2 ease such as kidney stones and kidney failure, diabetes, and (BMI 25 kg/m to < 30 kg/m ), and obese (BMI ≥ 30 kg/m ). emphysema and/or chronic bronchitis or chronic obstruc- tive pulmonary disease. Participants were assigned to the Smoking status CD group if they replied “yes” to the question “Has a doc- tor or other health professional ever told you that you have Smoking status was assessed from two self-reported items [condition]?”. in the data: “Have you smoked at least 100 cigarettes in your lifetime?” and “Do you smoke cigarettes now?” Smoking 1 3 Journal of Cancer Survivorship status was categorized into three groups: (1) never smok- those who did not meet any goals received 0 points. The ers who reported they have not smoked 100 cigarettes in total score ranges from 0 to 9 points. Individuals meeting their lifetime and do not smoke now; former smokers who approximately half of the DASH targets (DASH score ≥ 4.5) reported they have smoked at least 100 cigarettes in their were considered DASH accordant [23]. lifetime, but do not smoke now; and (3) current smokers who reported they smoked at least 100 cigarettes in their Statistical analysis lifetime and currently smoke either every day or some days. All analyses were performed using NHANES-generated Alcohol use sampling strata, clusters, and weights to generate nationally representative estimates in US civilian population. Categori- Participants were asked if they had at least 12 drinks of alco- cal variables were presented as percentages, and continuous hol in the past year and in their lifetime. Similar to Muntner variables were presented as means with standard deviation. et al., alcohol status was categorized into three categories: We examined group differences in sample characteristics by (1) never drinkers who reported no alcohol drinking or con- status using Chi-square or t-test. We used weighted logis- sumed less than 12 alcoholic drinks in their lifetime and in tic regression to estimate the presence of MetS and each the past year; (2) former drinkers who reported drinking at of its components to CD and CS status, compared to NCD least 12 alcoholic drinks in their lifetime but none in the and stratified by gender. In addition, we repeated the logis - last year; and (3) current drinkers who reported drinking at tic regression analysis to estimate the association between least 12 alcoholic drinks in their lifetime and had at least 12 CS cancer site and presence of MetS and each compo- alcoholic drinks in the last year [19]. nent, compared to NCD. All multivariable logistic regres- sion models were adjusted for demographic characteristics Physical activity such as age, race/ethnicity, education, PIR, BMI, physical activity, DASH score, smoking status, and alcohol use [24, Participants reported the number of days and amount of 25]. Adjusted estimates of association were expressed as time spent participating in moderate or vigorous activity odds ratios with 95% confidence intervals. A two-sided P at work or as recreation. Physical activity was calculated value < 0.05 was considered statistically significant. Stata into metabolic equivalent of task (MET), the ratio between version 17.0 SE was used for all analyses. caloric consumption during physical activity and resting basal metabolic rate. MET were calculated by using the MET value of the activity and multiplying by the dura- Results tion of the activity in minutes. The validity of self-reported physical activity measure, indexed using MET-minutes, Characteristics of the study sample has been demonstrated previously [20]. Participants were categorized into four groups, according to the US Physical Table 1 describes the characteristics of participants included Activity Guidelines for Americans [21]. Participants who in this study. Our study sample included 12,734 participants reported no physical activity were categorized as seden- (52.8% women, 72.3% non-Hispanic White, and mean tary. Those who reported physical activity equal to less than age 58.5 [10.2 SD] years), among whom 4,494 were NCD 500 MET-minutes per week were categorized as “Low”. (36.5%), 6493 CD (47.5%), and 1747 CS (16.0%). In the Participants who reported ≥ 500 and < 1000 MET-minutes total sample, most participants (72.5%) met the criteria for per week were categorized as “Moderate”. Physical activity MetS. Across study groups, there were statistically signifi - levels ≥ 1000 MET-minutes per week were categorized as cant differences in all demographic factors including gender, “High” [21]. average age, race and ethnicity, marital status, education, and poverty-to-income ratio. Compared to CD and CS, most Diet NCD were women, younger, married or living with a part- ner, and belonged to the highest PIR group (Table 1). Dietary intake was assessed by two 24-hr dietary recalls. Based on Mellen et al., a dietary index or DASH score was Cancer survivor status and MetS generated based on the average target values for 9 nutrients: total fat, saturated fat, protein, fiber, cholesterol, calcium, In multivariable adjusted logistic regression analysis magnesium, sodium, and potassium [22, 23]. Individuals (Table 2), compared to NCD men, CS men had 2.6-fold who met the goal for each nutrient received 1 point, those higher odds (OR 2.60; CI 1.75–3.87) and CD men had 2.2- who met an intermediate goal received half of a point, and fold higher odds (OR 2.18; CI 1.59–2.98) of meeting MetS. 1 3 Journal of Cancer Survivorship Table 1 Characteristics of study NCD CD CS Total participants by NCD, CD, and (n = 4,494) (n = 6,493) (n = 1,747) (n = 12,734) CS status *** Gender, % Women 51.1 53.8 54.0 52.8 Men 48.9 46.2 46.0 47.2 *** Mean age (sd) 53.1 (8.4) 60.1 (10.0) 65.7 (9.5) 58.5 (10.2) *** Race/Ethnicity, % Non-Hispanic White 66.9 71.5 87.3 72.3 Non-Hispanic Black 11.5 12.0 5.6 10.8 Hispanic 14.4 12.4 5.1 12.0 Non-Hispanic Asian 7.2 4.1 2.0 4.9 *** Marital status, % Married/living with partner 72.0 64.6 66.4 67.6 Widowed/divorced/separated 19.6 27.7 29.9 25.1 Never married 8.4 7.8 3.7 7.3 *** Education, % High school graduate or less 34.1 41.3 28.1 36.5 Some college or above 65.9 58.7 71.9 63.5 *** Poverty-Income-Ratio, % 13.9 22.6 13.5 18.0 < 1.29 1.30–3.49 32.3 35.8 36.5 34.6 ≥ 3.50 53.8 41.6 50.0 47.4 2 *** BMI category (kg/m ), % Healthy (18.5–24.9) 29.9 18.9 25.9 24.0 Overweight (25.0–29.9) 38.8 30.8 34.4 34.3 31.3 50.3 39.7 41.7 Obese (≥ 30.0) *** Total Physical Activity (METs), % Sedentary 18.7 29.5 28.7 25.4 Low (≤ 499) 13.1 14.4 14.1 13.9 Moderate (500–999) 11.5 9.8 11.3 10.6 56.8 46.3 45.9 50.1 High (≥ 1000) *** Abbreviations: NCD, no self- Smoking, % reported medical condition; CD, Never smoker 62.4 48.6 46.6 53.3 1 or more self-reported medical Former smoker 23.5 32.2 39.4 30.1 conditions; CS, cancer survivor; Current smoker 14.1 19.3 14.1 16.6 BMI, body mass index; MET, *** Alcohol use, % metabolic equivalent of task. Never drinker 10.5 10.8 8.6 10.4 DASH accordant: DASH Former drinker 10.7 16.2 16.2 14.2 score ≥ 4.5. Current drinker 78.8 73.0 75.0 75.4 * p < 0.05, ** p < 0.01, *** DASH accordant, % 11.4 9.2 8.9 10.0 p < 0.001 Both groups also demonstrated higher odds of meeting 4 1.37–4.88) were associated with MetS. In analysis of MetS to 5 MetS component compared to NCD men, particularly components, prostate cancer, melanoma, non-melanoma elevated WC (OR 3.81; CI 2.41–6.04) and low HDL-c (OR skin cancer, and bladder cancer demonstrated statistically 2.52; CI 1.81–3.52) in CS men. CS and CD women also significant association with at least three of the five MetS had higher odds of meeting MetS criteria compared to their components, elevated WC, low HDL-c, and elevated TG. healthy counterparts, OR 2.05 (CI 1.44–2.93) and OR 2.14 In CS women (Table 4), those with cervical (OR 4.25; (CI 1.63–2.81) respectively. CI 1.70–10.59), melanoma (OR 3.51; CI 1.28–9.59), and breast cancer (OR 1.76; CI 1.08–2.89) showed statisti- Cancer site and MetS cally significant association with MetS compared to NCD women. In contrast to CS men, few cancer sites among CS Among CS men (Table 3), those with a history of blood- women exhibited a statistically significant association with related cancer (OR 4.88, CI 1.30–18.37), colorectal can- individual MetS components, compared to their healthy cer (OR 2.87, CI 1.02–8.11), prostate cancer (OR 2.85; CI counterparts. 1.51–5.38), or non-melanoma skin cancer (OR 2.58; CI 1 3 Journal of Cancer Survivorship Table 2 Odds ratiosa (95% CI) for MetS and its components among CD and CS participants, stratified by sex/gender MetS Elevated WC Low HDL-c Elevated TG Elevated FG Elevated BP Men NCD Ref Ref Ref Ref Ref Ref *** *** *** ** * *** CD 2.18 2.11 2.48 1.78 1.55 1.90 [1.59,2.98] [1.48,3.02] [1.85,3.31] [1.27,2.51] [1.07,2.23] [1.43,2.52] *** *** *** *** *** CS 2.60 3.81 2.52 2.40 1.60 1.95 [1.75,3.87] [2.41,6.04] [1.81,3.52] [1.61,3.60] [0.96,2.69] [1.49,2.56] Women NCD Ref Ref Ref Ref Ref Ref *** *** *** * *** CD 2.14 1.80 1.97 1.34 1.08 1.79 [1.63,2.81] [1.33,2.44] [1.57,2.46] [1.04,1.71] [0.81,1.45] [1.38,2.33] *** *** *** * * ** CS 2.05 1.93 1.79 1.47 1.65 1.68 [1.44,2.93] [1.35,2.76] [1.31,2.44] [1.05,2.04] [1.08,2.50] [1.23,2.28] Abbreviations: MetS, Metabolic syndrome; CS, cancer survivor; CD, 1 or more self-reported medical conditions; WC, waist circumference; HDL-c, high-density lipoprotein cholesterol; TG, triglycerides; FG, fasting plasma glucose; BP, blood pressure. Elevated WC, ≥ 102 cm for men, ≥ 88 cm for women Low HDL-c, < 40 mg/dL for men and < 50 mg/dL for women, or current treatment for reduced HDL-c Elevated TG, ≥ 150 mg/dL or current treatment for elevated triglycerides. Elevated FG (≥ 100 mg/dL) or current use of diabetes medication. Elevated BP, systolic blood pressure ≥ 130, or diastolic blood pressure ≥ 85, or current use of blood pressure medication. Adjusted by age, race/ethnicity, education, PIR, BMI, physical activity, DASH score, smoking status, and alcohol use. * ** *** p < 0.05, p < 0.01, p < 0.001 Table 3 Odds ratiosa (95% CI) for MetS and its components in CS and CD men by cancer site compared to healthy men MetS Elevated WC Low HDL-c Elevated TG Elevated FG Elevated BP NCD Ref Ref Ref Ref Ref Ref *** *** *** ** * *** CD 2.18 2.13 2.48 1.79 1.56 1.90 [1.59,2.98] [1.48,3.05] [1.86,3.31] [1.27,2.52] [1.09,2.24] [1.42,2.52] ** *** ** * ** Prostate 2.85 3.58 2.14 1.97 1.60 2.44 [1.51,5.38] [1.87,6.85] [1.22,3.77] [1.02,3.79] [0.82,3.14] [1.42,4.18] * *** *** Colorectal 2.87 12.30 4.83 1.25 4.91 1.86 [1.02,8.11] [4.12,36.70] [1.99,11.74] [0.37,4.24] [0.64,37.38] [0.61,5.64] ** ** * Melanoma 2.71 4.52 5.42 3.77 3.56 1.98 [0.73,10.09] [1.54,13.26] [1.97,14.93] [1.24,11.40] [0.95,13.43] [0.75,5.23] ** *** * ** Non-melanoma 2.58 5.17 1.96 2.52 1.49 1.72 [1.37,4.88] [2.44,10.95] [1.16,3.31] [1.27,5.01] [0.69,3.21] [0.98,3.02] Blood-related 4.88 1.67 3.60 1.73 1.44 2.05 [1.30,18.37] [0.41,6.85] [0.94,13.79] [0.50,5.95] [0.30,6.83] [0.45,9.29] ** * * Bladder 3.17 6.40 2.78 4.45 2.08 0.76 [0.95,10.62] [1.73,23.69] [1.07,7.18] [1.39,14.25] [0.40,10.79] [0.27,2.15] Other GU 1.51 2.63 2.42 8.45 0.94 1.10 [0.43,5.21] [0.70,9.83] [0.81,7.26] [1.51,47.26] [0.17,5.22] [0.45,2.67] ** ** Other 2.31 3.38 2.73 1.92 2.97 1.45 [0.99,5.39] [1.43,7.98] [1.33,5.60] [0.85,4.31] [0.96,9.15] [0.61,3.46] Abbreviations: MetS, Metabolic syndrome; CS, cancer survivor; GU, genitourinary cancer; WC, waist circumference; HDL-c, high-density lipoprotein cholesterol; TG, triglycerides; FG, fasting plasma glucose; BP, blood pressure. Elevated WC, ≥ 102 cm for men, ≥ 88 cm for women Low HDL-c, < 40 mg/dL for men and < 50 mg/dL for women, or current treatment for reduced HDL-c Elevated TG, ≥ 150 mg/dL or current treatment for elevated triglycerides. Elevated FG (≥ 100 mg/dL) or current use of diabetes medication. Elevated BP, systolic blood pressure ≥ 130, or diastolic blood pressure ≥ 85, or current use of blood pressure medication. Adjusted by age, race/ethnicity, education, PIR, BMI, physical activity, DASH score, smoking status, and alcohol use. * ** *** p < 0.05, p < 0.01, p < 0.001 1 3 Journal of Cancer Survivorship Table 4 Odds ratiosa (95% CI) for MetS and its components in CS and CD women by cancer site compared to healthy women MetS Elevated WC Low HDL-c Elevated TG Elevated FG Elevated BP NCD Ref Ref Ref Ref Ref Ref *** *** *** * *** CD 2.15 1.81 1.98 1.34 1.08 1.79 [1.64,2.82] [1.34,2.44] [1.58,2.48] [1.05,1.72] [0.80,1.45] [1.38,2.33] * * * Breast 1.76 2.22 1.49 1.33 1.51 1.59 [1.08,2.89] [1.15,4.30] [0.96,2.31] [0.78,2.25] [0.95,2.40] [1.03,2.43] Colorectal 1.89 2.30 1.33 1.54 1.11 2.37 [0.79,4.51] [0.47,11.22] [0.74,2.42] [0.60,3.99] [0.46,2.72] [0.49,11.46] * * ** Melanoma 3.51 3.48 1.32 1.07 7.94 1.49 [1.28,9.59] [1.33,9.08] [0.62,2.84] [0.36,3.13] [2.02,31.23] [0.59,3.77] Non-melanoma 1.68 1.87 1.88 1.62 1.24 2.32 [0.81,3.49] [0.79,4.40] [0.97,3.66] [0.82,3.21] [0.54,2.83] [1.20,4.48] Blood-related 2.30 4.22 1.84 2.19 3.54 1.10 [0.49,10.74] [1.05,16.92] [0.57,5.97] [0.48,9.93] [0.42,30.03] [0.27,4.51] ** Cervical 4.25 1.26 2.05 1.30 1.74 1.50 [1.70,10.59] [0.54,2.91] [0.98,4.27] [0.48,3.53] [0.68,4.48] [0.65,3.43] Uterine 2.58 2.76 2.05 2.66 2.10 1.15 [0.66,10.00] [0.91,8.39] [0.70,5.98] [0.52,13.61] [0.77,5.73] [0.34,3.85] ** Other 1.78 1.86 2.23 1.17 1.38 1.28 [0.89,3.53] [0.87,3.94] [1.26,3.95] [0.59,2.34] [0.58,3.26] [0.73,2.24] Abbreviations: MetS, Metabolic syndrome; CS, cancer survivor; WC, waist circumference; HDL-c, high-density lipoprotein cholesterol; TG, triglycerides; FG, fasting plasma glucose; BP, blood pressure. Elevated WC, ≥ 102 cm for men, ≥ 88 cm for women Low HDL-c, < 40 mg/dL for men and < 50 mg/dL for women, or current treatment for reduced HDL-c Elevated TG, ≥ 150 mg/dL or current treatment for elevated triglycerides. Elevated FG (≥ 100 mg/dL) or current use of diabetes medication. Elevated BP, systolic blood pressure ≥ 130, or diastolic blood pressure ≥ 85, or current use of blood pressure medication. Adjusted by age, race/ethnicity, education, PIR, BMI, physical activity, DASH score, smoking status, and alcohol use. * ** *** p < 0.05, p < 0.01, p < 0.001 Discussion Comparison with prior studies and pathogenesis of MetS among cancer survivors Summary of main findings In CS men, the pathogenesis of MetS can be related to the Compared to their NCD counterparts, CS men and women changes in endocrine and metabolic functions due to treat- demonstrated higher odds of meeting MetS criteria and at ment. Similar to this study, CS men with a history of hema- least three of the five individual MetS components than tologic malignancies have been shown to have a high risk CD. In particular, men showed a stronger association with of developing MetS, which has been attributed to exten- MetS than women. Furthermore, certain cancer sites in CS sive treatments such as stem cell transplantation, high dose men and women had statistically significant higher odds of chemotherapy, and irradiation [26, 27]. These treatments MetS and its components, compared to their healthy coun- cause damage to the hypothalamic-pituitary-axis, leading terparts. In CS men, participants with a history of hemato- to deficiencies in growth hormones, thyroid hormones, and logic malignancies had the highest odds of developing MetS androgens related to individual components of MetS [28]. compared to NCD men. For CS women, participants with For prostate cancer survivors, androgen deprivation therapy cervical cancer history exhibited the highest odds of MetS (ADT), a common treatment modality, has also been pro- than their healthy counterparts. In subgroup analyses of the posed as a risk factor for MetS development, due to male individual components of MetS, CS men with cancer sites hypogonadism or low testosterone. In one study, patients associated with MetS had higher odds of having elevated who received ADT had higher prevalence of MetS (55%) WC, low HDL-c, and elevated TG compared to NCD men. than patients treated with radiotherapy and/or prostatectomy (22%), or healthy controls (20%) [5, 29]. Furthermore, observational studies have shown a positive association between level of hypogonadism and degree of obesity in men, as well as an inverse relationship between testosterone 1 3 Journal of Cancer Survivorship levels and visceral fat mass [30]. Low testosterone has also elevated TG have also been demonstrated to be risk factors been linked to adverse lipid profile [ 31] and hypertension for multiple cancers, including colon cancer, melanoma, [32, 33], two components of MetS. and prostate cancer [41]. For example, low HDL-c was For CS women, previous epidemiological studies have reported to be related to an increase in lung cancer inci- also supported correlation between MetS and a history of dence and associated with a 15-fold increase in hematologic cervical cancer [34, 35]. Penaranda et al., showed that CS malignancy development [42]. In addition, hypertriglyceri- women with cervical cancer history had higher odds of MetS demia has been reported to be associated with prostate can- in both unadjusted and adjusted analyses (which accounted cer [43]. The probable mechanism through which elevated for multiple sexual partners, multiparity, hormonal con- triglycerides increase cancer risk is through the generation traceptive use, and history of smoking) compared to those of reactive oxygen species and oxidative stress, which cause without MetS [35]. A limited number studies have investi- DNA damage [10]. Mechanisms that may link low HDL-c gated the relationship between a history of cervical cancer with cancer are not well understood. One possible mecha- and MetS, but it is hypothesized that MetS can be related to nism may involve chronic inflammation, resulting from low estrogen (e.g. caused by direct damage to the ovaries decreased HDL-c levels, which has been implicated in can- from abdomino-pelvic radiotherapy), abdominal adiposity, cer development [10, 44]. and increased inflammatory markers, such as adipokines MetS is a common long-term complication of cancer that and other cytokines, from persistent human papillomavirus affects health outcomes and quality of life. The develop - infection [5, 36]. Moreover, in our study, none of the spe- ment of the MetS in cancer survivors has been associated cific MetS components were significantly associated with with signs of early atherosclerosis and cancer recurrence. cervical cancer in CS women. Moreover, there were very Considering the direct cardiovascular toxicity of most can- few statistically significant associations between individual cer treatments, this group faces an increased risk of cardio- MetS components and other cancer sites in CS women. Syn- vascular disease, and the presence of MetS provides the ergism, or clustering of MetS components, may be neces- environment for development of secondary cancers. Our sary for the development of MetS, and long-term risk may study also highlights the gender differences in risk of MetS be underestimated at any point in time in CS women. and, consequently, cardiovascular disease, which may be of Individual components of MetS have been reported to potential relevance for prevention. With prolonged cancer be carcinogenic, which may lead to increased risk in recur- survival rates, prevalence of MetS is expected to increase, rence in CS. In subgroup analysis of MetS components, and therefore, it is important for healthcare professionals to most CS men had higher odds of having elevated WC, low acknowledge the risk of MetS and establish suitable screen- HDL-c, and elevated TG compared to NCD men. Studies ing, follow-up and appropriate interventions. have repeatedly reported that components of MetS related to hyperglycemia, obesity, and dyslipidemia promote can- Strengths and limitations cer development as well as growth [2, 5]. Epidemiological studies have revealed that an elevated WC, BMI, or waist- The strengths of this study include a large sample size provid- hip-ratio, indicators of obesity, are linked with several can- ing enough statistical power to conduct stratified analyses, cer types and cancer-related mortality [10, 37, 38]. Elevated and the use of a representative sample of the US popula- WC has been shown to be a major determinant of higher tion, providing results can be extrapolated to the population prevalence of MetS in prostate cancer survivors [5, 29]. using US census data. Our multivariable analysis included Conversely, MetS has been theorized to be a major risk fac- a robust adjustment using wide variety of covariates includ- tor for prostate cancer development. In a prospective cohort ing dietary intake and physical activity. All anthropometric of 16,209 men aged 40–49 years, men in the upper quartile or biochemical components of MetS were objectively mea- for two components of MetS were 23% more likely to be sured with validated tools. diagnosed with prostate cancer, and those who met three cri- This study also has a few limitations. As a cross-sectional teria for MetS were 56% more likely to be diagnosed with study, it is difficult to draw causal inference between cancer prostate cancer compared to the rest of the cohort [39]. In the status and MetS or each of its components, as well as to pathophysiology of obesity and cancer, hyperinsulinemia establish the temporal sequence between cancer status and related to insulin resistance increases the bioavailability of MetS. These results should be considered hypothesis-gen- insulin-like growth factor (IGF)-1 [10, 40]. Receptors for erating, which requires prospective studies to further char- insulin and IGF-1 are expressed in most cancer cells, and acterized the risk of MetS among cancer survivors. 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Journal

Journal of Cancer Survivorship: Research and Practice – Springer Journals

Published: Jun 22, 2023

Keywords: Metabolic syndrome; Cancer survivorship; Cancer epidemiology; Sex differences; Gender differences

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