By Molly Brewer, DVM, MD, MS

Professor and Chair, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Connecticut Health Center, Farmington

Dr. Brewer reports no financial relationships relevant to this field of study.

SYNOPSIS: Obesity has risen significantly worldwide and is associated with an increased risk of morbidity and mortality in women throughout their lives. Risks include infertility, gestational diabetes, type 2 diabetes, heart disease, and cancer.

We are inundated with information about the opioid epidemic. As such, there are increasing constraints on the prescribing of opioids as well as significant funding to address the shocking new death rate from opioid overdose. It has been estimated that of the 20.5 million Americans age 12 years or older who had substance use disorder in 2015, 2 million involved substance use disorders with prescription pain relievers and 591,000 with heroin. Approximately 23% of individuals who use heroin also develop opioid addiction. Drug overdose is the leading cause of accidental death in the United States, with 52,404 lethal drug overdoses in 2015. Opioid addiction is driving this epidemic, with 20,101 overdose deaths related to prescription pain relievers, nearly 50% more than heroin overdose. Between 1999 and 2010, 48,000 women died of prescription pain reliever overdoses.1,2,3 Opioid addiction is a serious health problem particularly in the United States. The attention given to opioid addiction is far more widespread than the attention being given to obesity; however, obesity has a greater effect on morbidity and mortality.

Worldwide, the prevalence of obesity more than doubled between 1980 and 2014. In 2014, more than 1.9 billion adults aged 18 years and older were overweight (body mass index [BMI], 25-30 kg/m2). Of these, more than 600 million adults were obese (BMI > 30 kg/m2). About 13% of the world’s adult population (11% of men and 15% of women) were obese in 2014, and 39% of adults 18 years of age (38% of men and 40% of women) were overweight.4 Obesity accounts for 18% of deaths among Americans between 40 and 85 years of age, according to research from the American Journal of Public Health.5 This translates to 472,755 deaths in 2014. Exposure to risk factors for obesity begins in childhood or adolescence, and now is being recognized as present in utero if the mother is obese. These children have an even higher risk of becoming overweight or obese because of their obese mothers. Consequently, these populations are experiencing all the health dilemmas, including type 2 diabetes and hypertension, associated with their obesity at younger ages.

Women appear to be more susceptible than men to dying from obesity. Black women have the highest probability of dying from obesity or being overweight (27%) followed by white women (21%).5 Women who become obese at a young age have an increased risk of death. For every five BMI points above 25 kg/m2, the increased relative risk of death is 52% for people 35 to 49 years of age (hazard ratio [HR], 1.52; 95% confidence interval [CI], 1.47-1.56), but 21% for people 70 to 89 years of age (HR, 1.21; 95% CI, 1.17-1.25). Deaths from heart disease, stroke, and respiratory disease also increased for people with a BMI > 25 kg/m2, and death from cancer was moderately increased with a hazard ratio that increased linearly with BMI. The number of excess deaths attributed to being overweight or obese varies by region, from 19% in North America to 5% in Eastern Asia.6

Obese women desiring pregnancy have an increased risk of diabetes, anovulation, development of endometrial pathology (endometrial hyperplasia or endometrial cancer), polycystic ovarian syndrome, and infertility. For women who are able to achieve pregnancy, the major risks from obesity are poor neonatal outcome, increased risk of gestational diabetes, increased risk of type 2 diabetes, higher rates of labor dysfunction, cesarean delivery, and intraoperative complications at the time of delivery. Women older than 40 years of age have an increased risk of diabetic complications, endometrial cancer, colon cancer, breast cancer, and death from heart disease. Obesity is affecting women at all ages and is often starting in childhood.

Endometrial Cancer

Obesity is responsible for up to 81% of the endometrial cancer diagnosed worldwide.7 In 2012, 527,600 women were diagnosed with endometrial cancer.8 The mortality rate was 1.7 to 2.4 per 100,000 women. In 2017, an estimated 61,380 cases of endometrial cancer will be diagnosed in the United States, and more than 10,920 deaths.9 This is a 10% increase in both incidence and mortality in just five years. Historically, the age of onset typically was in postmenopausal women and there was a strong association with obesity. Endometrial cancer is now the fourth most common cancer for women in the United States, with the median age of onset in women in their 50s instead of their mid-60s. It is well defined that obesity causes the overwhelming majority of endometrial cancer. Compared to just three years ago, this equates to almost 10,000 more cases and more than 2,000 additional deaths due to endometrial cancer in the United States. Alarmingly, in the past 10 years, the incidence of endometrial cancer in young premenopausal women has increased dramatically because of earlier onset of obesity.

Obesity has multiple effects on metabolism. The presence of insulin resistance and hyperinsulinemia is thought to promote both tumorigenesis and tumor progression because of an increase in the production of estrogen and androgens, as well as a decrease in sex hormone binding globulin (SHBG), which increases the availability of free estrogen and androgen. Local inflammation also is believed to play a significant role.10 Insulin resistance and hyperinsulinemia are associated with an increased risk of endometrial cancer, particularly in overweight/obese women.11 Women with type 2 diabetes (non-insulin-dependent) have increased insulin levels for long periods of time, both before and after the disease onset, and it is associated with an increased risk of atypical endometrial hyperplasia and endometrial cancer, independent from obesity.12 Insulin reduces the liver production of SHBG. Chronically high insulin due to insulin resistance increases the production of testosterone. Insulin stimulates the ovarian and adrenal cortex production of androgens (especially androstenedione and testosterone), which is metabolized into estrogen from the aromatase system in adipose tissue and then stimulates proliferation of the estrogen-dependent endometrial tissue. Insulin also has direct proliferative effects on the endometrium, working as a growth factor. Thus, there are several mechanisms in obesity tied to the development of abnormal endometrial tissue. Epidemiological data on postmenopausal women suggest an increased risk of endometrial cancer in populations that have insulin dysfunction, including nondiabetic women with hyperinsulinemia, diabetic women with insulin resistance, and women with metabolic syndrome.13

Breast Cancer

Obese postmenopausal women have significant increases in all estrogens, including estrone, estradiol, and free estradiol, which lead to elevated local estrogen levels in breast tumors that are as much as 10-fold higher compared with the level of serum estrogen. A recent publication showed that BMI and weight gain in women between 20 and 50 years of age was nearly as predictive of breast cancer risk as the Gail model.14 In a study in Alberta, Canada, researchers estimated that 12% of obesity-related cancers in women were attributed to excess body mass, and the largest burden in women was an increase in breast cancer cases.15

Cardiovascular Disease

In addition to cancer, obesity and hyperinsulinemia are associated with other causes of morbidity and mortality in women, in particular cardiovascular disease. Research from a 2012 study using the SEER (Surveillance, Epidemiology, and End Results) registries showed that women with endometrial cancer were more likely to die of cardiovascular disease (35.9%), followed by other causes including other malignancies, than they were to die of their endometrial cancer.16 A similar study showed that women with endometrial cancer who survived their endometrial cancer at 10 years post-diagnosis were most likely to die of cardiovascular disease, suggesting that their obesity is not only associated with an increased risk of death from endometrial cancer, but also death from cardiovascular disease.17 These studies support the hypothesis that obesity, although a strong risk factor for endometrial cancer, also is a strong risk factor for cardiovascular disease.

Childhood Obesity

A meta-analysis showed a strong parent-child obesity association (pooled odds ratio, 2.22; 95% CI, 2.09-2.36), which varied by type of parent-child pair (i.e., parents-child, father-child, and mother-child), the child’s age, the parents’ and child’s weight status, and the country’s economic level. Stronger associations were shown in older children than in younger children, in both parents than in father-only or mother-only, in parental obesity and child obesity than in parental and child overweight, and in high- than in middle-income countries.18 Obese parents have a higher probability of having children who are obese, and this obesity occurs at a much younger age than previously recognized.

Maternal and Neonatal Outcomes Associated with Obesity

In a Swedish study, the risk of childhood cerebral palsy was compared in normal-weight mothers and obese mothers. Overweight mothers had an adjusted HR of cerebral palsy of 1.22 (95% CI, 1.11-1.33); mothers with Class 1 obesity (BMI 30-34.9 kg/m2) had an HR of 1.28 (95% CI, 1.11-1.47); mothers with Class 2 obesity (BMI 35-39.9 kg/m2) had an HR of 1.54 (95% CI, 1.24, 1.93); and women with Class 3 obesity (BMI > 40 kg/m2) had an HR of 2.02 (95% CI, 1.46-2.79) for their children developing cerebral palsy. Results were statistically significant for full-term infants (71% of all children with cerebral palsy), suggesting that obese women have a greater risk of having a child with cerebral palsy, and the greater the obesity the greater the risk.19 Another study showed that high pre-pregnancy BMI resulted in a higher risk of cesarean delivery, with an adjusted OR ratio of 1.95 for the overweight group and 3.26 (CI, 1.57-6.76) for the obese group compared with women of normal weight. Obese women have a greater anesthetic risk, an increased risk of venous thromboembolism, and a five-fold increased risk of neonatal injury at the time of delivery.20 Children born to obese women are more likely to have congenital defects, develop childhood obesity, and develop adult cardiovascular disease.21

Maternal obesity is associated with an increased incidence of infertility. Obese women have an increase in metabolic dysfunction with hypercholesterolemia, hyperglycemia, and insulin resistance.22 This metabolic dysfunction creates a high androgen state, anovulation, and an increase in circulating estradiol. This endocrine dysfunction also affects the age of menarche and the development of polycystic ovarian syndrome and subfertility. In addition, hyperinsulinemia creates a chronic low-grade metabolic inflammatory state.23 Among subfertile women, the chance of conception is decreased by 5% for each unit increase in BMI > 29 kg/m2.24

Lifestyle Modifications

A large U.S. study showed that a low carbohydrate diet was inversely related to weight gain (OR, 0.71), whereas a low-fat diet (OR, 1.43) and USDA Dietary Guidelines for Americans diet (OR, 1.24) were associated with increased risk of weight gain. A low carbohydrate diet was inversely related to weight gain among women who were normal weight (OR, 0.72), overweight (OR, 0.67), or obese (OR, 0.63). A low-fat diet was associated with an increased risk of weight gain in women who were normal weight (OR, 1.28), overweight (OR, 1.60), Class 1 obesity (OR, 1.73), or Class 2 obesity (OR, 1.44) at baseline.25 These findings suggest that a low-fat diet may promote weight gain, whereas a reduced-carbohydrate diet may decrease the risk of postmenopausal weight gain. Limiting energy-dense foods, such as carbohydrates, also is an important aspect of improving the underlying metabolic abnormalities that promote endometrial pathology as well as a host of other diseases.

Aerobic exercise is the most important lifestyle change that will help correct the underlying hyperinsulin state and obesity. Physical activity improves glucose uptake by skeletal muscles, which reduces insulin-resistance and insulin level independent of its influence on BMI.26 Physical activity also reduces estrogen and androgen levels, which improves the endocrine dysfunction associated with obesity. In addition to the decrease in metabolic dysfunction with exercise, metformin can reduce the insulin level and the androgen level and, thus, reduce the risk of cancer in women with diabetes or non-diabetic hyperinsulinemia. In patients with polycystic ovarian syndrome, exercise reduces the insulin level and the androgen level and improves ovulation.27

Conclusion

The Milken Institute calculated the direct health care costs of obesity for 2014 in the United States at $427 billion. Together with indirect costs, such as lost productivity, the annual cost to the U.S. economy was $1.4 trillion — more than twice what the United States spends on defense and 8.2% of the entire U.S. gross domestic product.28 Obesity often starts in early childhood, and for many women continues into their early fertile years. Women’s health practitioners have a unique opportunity to influence their obese patients through encouragement and referral.29 The opportunities to reduce morbidity and mortality and improve their quality of life by encouraging lifestyle changes are enormous. We are in a unique position to reduce healthcare costs and improve the quality of life of obese patients and their families, as well as start to affect this staggering epidemic. We have not seen the same focus for obesity that we are seeing with the opioid epidemic. Obesity affects millions of people with significantly higher morbidity and mortality compared to non-obese populations and is an enormous cost to society. Dr. David Meldrum, a reproductive endocrinologist from UC San Diego stated in his commentary on Obesity and Reproduction in Fertility and Sterility in 2017, “If some mysterious phenomenon in the United States was causing three jumbo jets to crash daily with loss of all souls on board and also had caused those individuals 10-20 years of serious health issues and disability, every possible effort would be expended to elucidate the causes and to provide solutions. However, … public health efforts to tackle this crisis (of obesity) have been frustrated by many factors.’”29 Obesity is responsible for a 10-fold increased mortality when compared to the mortality for opioid overdose. When are we going to take this staggering epidemic at least as seriously we are taking the opioid epidemic?

REFERENCES

  1. Center for Behavioral Health Statistics and Quality. Key substance use and mental health indicators in the United States: Results from the 2015 National Survey on Drug Use and Health (HHS Publication No. SMA 16-4984, NSDUH Series H-51). 2016. Available at: https://www.samhsa.gov/data/sites/default/files/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015/NSDUH-DetTabs-2015.pdf. Accessed June 1, 2017.
  2. National Institute on Drug Abuse. Drug Facts: Heroin. Available at http://www.drugabuse.gov/publications/drugfacts/heroin. Accessed June 1, 2017.
  3. Rudd RA, Seth P, David F, Scholl L. Increases in drug and opioid-involved overdose deaths — United States, 2010-2015. MMWR Morb Mortal Wkly Rep 2016;65:1445–1452.
  4. World Health Organization. Obesity and overweight. Available at: http://www.who.int/mediacentre/factsheets/fs311/en/. Updated 2016. Accessed Feb. 8, 2017.
  5. Masters RK, Reither En, Powers DA, et al. The impact of obesity on US mortality levels: The importance of age and cohort factors in population estimates. Am J Public Health 2013;103:1895-1901.
  6. The Global BMI Mortality Collaboration. Body-mass index and all-cause mortality: Individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet 2016;388:776-786.
  7. Nevadunsky NS, Van Arsdale A, Strickler HD, et al. Obesity and age at diagnosis of endometrial cancer. Obstet Gynecol 2014;124(2 Pt 1):300-306.
  8. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108.
  9. American Cancer Society. Cancer Facts and Figures 2017. Available at: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html. Accessed June 1, 2017.
  10. Calle EE, Kaaks R. Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004;4:579-591.
  11. Gunter MJ, Hoover DR, Yu H, et al. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev 2008;17:921-929.
  12. Barone BB, Yeh HC, Snyder CF, et al. Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: A systematic review and meta-analysis. JAMA 2008;300:2754-2764.
  13. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: A synthetic review. Cancer Epidemiol Biomarkers Prev 2002;11:1531-1543.
  14. Abdelaal M, le Roux CW, Docherty NG. Morbidity and mortality associated with obesity. Ann Transl Med 2017;5:161.
  15. Brenner DR, Poirier AE, Grundy A, et al. Cancer incidence attributable to excess body weight in Alberta in 2012. CMAJ Open 2017;5:E330-E336.
  16. Papatla K, Huang M, Slomovitz B. The obese endometrial cancer patient: How do we effectively improve morbidity and mortality in this patient population? Ann Oncol 2016;27:1988-1994.
  17. Ward KK, Shah NR, Saenz CC, et al. Cardiovascular disease is the leading cause of death among endometrial cancer patients. Gynecol Oncol 2012;126:176–179
  18. Wang Y, Min J, Khuri J, Li M. A systematic examination of the association between parental and child obesity across countries. Adv Nutr 2017;8:436-448.
  19. Villamor E, Tedroff K, Peterson M, et al. Association between maternal body mass index in early pregnancy and incidence of cerebral palsy. JAMA 2017;317:925-936.
  20. Miao M, Dai M, Zhang Y, et al. Influence of maternal overweight, obesity and gestational weight gain on the perinatal outcomes in women with gestational diabetes mellitus. Sci Rep 2017;7:305.
  21. Chandrasekarana S, Neal-Perry G. Long-term consequences of obesity on female fertility and the health of the offspring. Curr Opin Obstet Gynecol 2017;29:180-187.
  22. Lebovitz HE. Insulin resistance: A common link between type 2 diabetes and cardiovascular disease. Diabetes Obes Metab 2006;8:237-249.
  23. Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: Role of free fatty acids and tumor necrosis factor alpha. Arterioscler Thromb Vasc Biol 2005;25:2062-2068.
  24. van der Steeg JW, Steures P, Eijkemans MJ, et al. Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women. Hum Reprod 2008;23:324-328.
  25. Ford C, Chang S, Vitolins MZ, et al. Evaluation of diet pattern and weight gain in postmenopausal women enrolled in the Women’s Health Initiative Observational Study. Br J Nutr 2017;117:1189-1197.
  26. Hawley JA, Lessard SJ. Exercise training-induced improvements in insulin action. Acta Physiol (Oxf) 2008;192:127-135.
  27. Palomba S, Falbo A, Zullo F, Orio F Jr. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: A comprehensive review. Endocr Rev 2009;30:1-50.
  28. Waters H, DeVol R. Weighing Down America: The Health and Economic Impact of Obesity. Available at: http://www.milkeninstitute.org/weighingdownamerica. Accessed March 7, 2016.
  29. Meldrum D. Introduction: Obesity and reproduction. Fertil Steril 2017;107:831-832.