Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2014 Dec 12.
Published in final edited form as: Am J Obstet Gynecol. 2011 Jun 7;205(6):518–525. doi: 10.1016/j.ajog.2011.05.042

Understanding Obesity and Endometrial Cancer Risk: Opportunities for Prevention

Rosemarie E SCHMANDT 1, David A IGLESIAS 1, Ngai Na CO 1, Karen H LU 1,*
PMCID: PMC4264838  NIHMSID: NIHMS645742  PMID: 21802066

Abstract

Worldwide, obesity has become a major public health crisis. Overweight and obesity not only increase the risk of cardiovascular disease and type-2 diabetes, but also are now known risk factors for a variety of cancer types. Among all cancers, increasing body mass index is most strongly associated with endometrial cancer incidence and mortality. The molecular mechanisms underlying how adipose tissue and obesity contribute to the pathogenesis of endometrial cancer are becoming better understood and have revealed a number of rational strategies, both behavioral and pharmaceutical, for the prevention of both primary and recurrent disease.

Keywords: endometrial cancer, estrogen, insulin, obesity, prevention

Obesity and Endometrial Cancer Risk: Mechanisms and Rational Strategies for Cancer Prevention

Obesity is a well-established risk factor for the development of multiple types of cancer, cancer-related mortality, and all-cause mortality1, 2. Among all cancers, increasing body mass index (BMI) and obesity is most strongly associated with endometrial cancer incidence and mortality1. In a recent meta-analysis of 19 reviews and prospective studies, Renehan et al. found that each increase in BMI of 5 kg/m2 significantly increased a woman's risk of developing endometrial cancer (RR 1.59, 95% CI 1.50-1.68)3. In the Million Women Study conducted in the U.K the investigators found that increasing BMI was associated with increased incidence of endometrial cancer (trend in relative risk per 10-units = 2.89, 95% CI 2.62-3.18)1. Endometrial cancer mortality is also adversely impacted by obesity. Calle et al., in a prospective study of over 495,000 women followed for 16 years, showed a significantly increased risk of death in obese women with endometrial cancer. Even more striking was the trend associated with increasing BMI; the relative risk of uterine cancer-related death for women considered obese (BMI 30-34.9 kg/m2) was 2.53 while for morbidly obese women (BMI > 40 kg/m2) it was 6.254. Not only does obesity impact cancer-related death, but through its association with other medical co-morbidities, such as diabetes mellitus and hypertension, it adversely impacts all-cause mortality. In a retrospective review of 380 patients with early endometrial cancer, the Gynecologic Oncology Group (GOG) found that morbid obesity was associated with a higher mortality (HR 2.77, 95% CI 1.21-6.36) from causes other than endometrial cancer or disease recurrence5. Further complicating matters, there is limited public knowledge of the relationship between obesity and cancer risk. A recent survey indicated that up to 58% of women were not aware that obesity increased endometrial cancer risk6.

While it has been presumed that excess estrogen due to the peripheral conversion of androstenedione to estrone accounts for the increased risk of endometrial cancer in obese women, new studies implicate other mechanisms by which obesity promotes endometrial cancer. This review will discuss the current understanding of what factors underlie the association of obesity and endometrial cancer, and what strategies are available for both prevention and treatment.

Obesity and Hormone Imbalance

Estrogen is a known endometrial growth factor. While the ovaries are the primary source of estrogen in pre-menopausal women, peripheral tissues including adipose tissue become the primary sources of circulating estrogen in post-menopausal women7-9. Androgens are converted to estrone and estradiol by the enzyme aromatase in adipose tissue. Aromatase is produced by mesenchymal stromal cells, including adipocyte stem cells, and to a lesser degree by mature adipocytes themselves. Aromatase levels increase as a function of age and obesity and are reflected by an increase in circulating estrogen levels with increasing BMI in postmenopausal women10, 11. Cauley et al, demonstrated greater than 40% increases in both circulating estrone and estradiol in obese (BMI >30) versus normal (BMI < 27) post-menopausal women10. Furthermore, concentrations of estrogens in adipose tissue have been measured at levels several fold above that observed in plasma12, 13. Therefore visceral adipose tissue represents not only a source of estrogen, but also provides an ideal milieu for the growth of metastatic, estrogen sensitive endometrial cancer. Furthermore, serum hormone binding globulin (SHBG) levels decrease with increasing adiposity14. This glycoprotein binds both estrogen and testosterone, and inhibits their activity. Therefore, irrespective of de novo synthesis, obesity can influence biologically active levels of these hormones.

Estrogen promotes the growth of endometrial cancer cells by both direct and indirect regulation of gene transcription. The binding to cytoplasmic estrogen receptors alpha and beta (ERα and ERβ) leads to recruitment of transcriptional co-factors and the direct activation of a wide variety of estrogen responsive genes. Estrogen receptors can also bind in an estrogen-dependent and independent manner to other transcription factors and enhance gene transcription through alternative response elements15, 16. It is also apparent that estrogen itself exerts rapid, non-genomic effects, associated with a variety of cytoplasmic kinase signaling cascades16, 17. 17β-estradiol (E2) treatment activates both the PI3-kinase and MAPK pathways, which are associated with cellular proliferation, and are frequently hyperactivated in cancers. The direct association between estrogen receptors and cell surface receptors, including IGF-1R and EGFR, represents a mechanism that directly links estrogen to the downstream kinase cascades that promote cell growth and tumor progression.

In normal premenstrual endometrium, progesterone counters estrogen-driven proliferation and induces glandular differentiation and decidualization of the endometrial stroma. Conditions that are accompanied by prolonged progesterone deficiencies therefore promote endometrial proliferation and increase the risk of endometrial hyperplasia and its progression to endometrial cancer18,19. For example, nulliparity, irregular menses, and extended, post-menopausal hormone replacement therapy with unopposed estrogen, are associated with increased endometrial cancer risk18-20. In pre-menopausal obese women, lack of progesterone due to anovulation, such as that observed in polycystic ovarian syndrome (PCOS), is also likely to contribute to endometrial cancer risk.

PCOS is a heterogeneous disorder affecting 6-8% of women characterized by androgen excess, menstrual abnormalities due to ovulatory dysfunction, and is often associated with polycystic ovarian morphology21. Obesity is found in approximately 30 to 70% of women with PCOS22. A principle element of this disorder is the presence of insulin resistance, which is worsened by obesity. A recent Australian case-control study of women under the age of 50 years, has shown that women with PCOS had a four-fold greater risk of endometrial cancer as compared to women without PCOS23. When adjusted for BMI, PCOS remained an independent risk factor and was associated with a greater than two-fold increased risk for endometrial cancer.

Type 2 Diabetes and Hyperinsulinemia

Hyperinsulinemia and the insulin resistant state are closely associated with obesity. Epidemiologically, a number of studies have shown a modest association of diabetes with endometrial cancer risk.24-28 Interestingly, in three studies the most significant risks were seen in women who were both obese and diabetic24, 27, 29. A study by Troisi et al examined insulin levels in women with endometrial cancer compared to controls in order to determine if elevated insulin levels could explain the association of obesity and endometrial cancer30. While elevated serum insulin levels, as measured by C-peptide were associated with increased risk of endometrial cancer, elevation of serum insulin levels alone could not account for the association of obesity and endometrial cancer.

Several recent studies, including one by our group, demonstrate an association of insulin resistance with endometrial cancer risk using adiponectin as surrogate marker for insulin resistance31-34. This adipokine can be measured in serum or plasma, and demonstrates levels that are inversely proportional to insulin resistance. Using a case-control study design, our group found that low adiponectin levels were highly associated with endometrial cancer risk, independent of BMI. Subsequently, a large prospective, nested case-control study sponsored by the World Health Organization, performed a study on adiponectin and endometrial cancer risk34. All samples were collected prospectively, and those used for analysis were from a time point prior to the onset of endometrial cancer. This study confirmed that low adiponectin levels were associated with endometrial cancer risk, again independent of BMI, strongly suggesting that insulin resistance is an independent risk factor for endometrial cancer.

The specific effects of hyperinsulinemia on the pathogenesis of obesity-associated cancers are not well defined. Our group has demonstrated that the proliferative effect of estrogen on the endometrium is enhanced in obese versus lean animals35. Using the Zucker rat model of hyperinsulinemia, estrogen induced significantly higher expression of the proproliferative genes, cyclin A and c-myc and in endometrium of obese rats, as compared that observed in lean control animals. Conversely, the estrogen-induced suppression of the cell cycle inhibitor, p27Kip1, and the anti-proliferative genes sFRP4 and RALDH2 are more pronounced in the obese endometrium. Obesity, therefore, alters the balance between pro- and anti-proliferative signals to favor endometrial growth.

Insulin-like Growth Factors

Systemic levels of IGFs are also altered by obesity. Six IGFBPs bind to and modulate IGF bioactivity by interfering with receptor binding. While increased estrogen production directly increases IGF-1 synthesis36,37 sustained hyperinsulinemia results in the decreased synthesis of IGFBP1 and 27. IGFBP1 is most highly expressed by human endometrium38, 39. Therefore, obesity contributes to the simultaneous increase in circulating IGF and decrease in IGFBP1, resulting in the net increase of bioavailable IGF-17, 40, 41.

Insulin and IGF Signaling Pathways

Insulin and IGFs utilize common signaling mechanisms42. As illustrated in figure 3, upon ligand binding, receptor mediated phosphorylation of the Insulin Receptor Substrate 1 (IRS-1) scaffold protein results in the activation of both the PI3K/AKT/mTOR and MAPK signaling pathways, which promote cell survival and proliferation42.

Figure 3. Insulin and IGF-1 signaling drive endometrial cancer progression.

Figure 3

Open in a new tab

The binding of IGF-1 to its receptor leads to IGF-1R autophosphorylation and the subsequent activation of multiple downstream signaling pathways. Cellular proliferation is driven through the PI3K and the MAPK pathways. Behavioral and pharmaceutical interventions, which decrease adiposity and IGF-1 levels, and that activate AMPK, and therefore represent rational therapeutic strategies for the prevention of endometrial cancer.

Hyperactivity of the PI3K/AKT/mTOR pathway is frequently observed in endometrial cancer. The ubiquitously expressed phosphatase and tensin homolog (PTEN) lipid/protein phosphatase dephosphorylates PI3K substrates and acts as a PI3K antagonist and tumor suppressor gene. PTEN inactivation or loss is observed in greater than 40% of type I endometrial cancers. Therefore, coupled with elevated circulating IGF-1, the loss of PTEN promotes the hyperactivity of the PI3K/AKT/mTOR pathway and facilitates endometrial cancer growth in obese individuals. Furthermore, the insulin and IGF receptors simultaneously activate the MAPK signaling pathway, another mechanism that promotes mTOR signaling 42.

AMPK (5’ adenosine monophosphate-activated protein kinase) inhibits signaling through the PI3K/AKT/mTOR pathway by serving as a counterbalance to AKT and ERK activity. AMPK inactivation is commonly associated with obesity (energy/caloric excess) and insulin resistance. When phosphorylated by AMPK, the tuberous sclerosis complex (TSC1/2) prevents mTOR-mediated endometrial proliferation. Inactivation of AMPK therefore represents an additional mechanism contributing to the hyperactivity of mTOR and tumorigenesis in the endometrium.

Adipokines

Adipose tissue is a complex endocrine organ that secretes a variety of both anti- and pro-inflammatory factors classified as “adipokines”. The state of chronic systemic inflammation associated with obesity is increasingly linked to the development of insulin resistance and chronic hyperinsulinemia43-43. For example, secretion of the adipokine, TNFα disrupts insulin receptor signaling by inducing the inhibitory phosphorylation of IRS proteins, thereby uncoupling insulin from downstream signaling cascades44, is associated with In addition to TNFα45, additional pro-inflammatory adipokines associated with endometrial cancer include include leptin46, interleukin-6 (IL-6)47 and resistin48.

In opposition to the pro-inflammatory adipokines, circulating levels of adiponectin are inversely proportional to BMI and insulin resistance, and play a role in increasing insulin sensitivity and as an anti-inflammatory. Adiponectin signals through its receptors (AdipoR1/2) to activate AMPK and inhibit PI3K/AKT/mTOR signaling49, and should therefore inhibit tumor progression driven by the PI3K pathway. In support of this hypothesis, studies performed by our group and others confirm that adiponectin levels are independently and inversely associated with endometrial cancer risk31-34.

Adipokines and other inflammatory proteins associated with obesity, such as C-reactive protein, show promise as biomarkers of endometrial cancer risk 50-52, however, additional studies will be necessary to determine the complex roles of adipokines in the development of insulin resistance and obesity-associated endometrial cancer.

Rational Interventions

These known biochemical mechanisms by which overweight and obesity contribute to endometrial cancer risk suggest several rational strategies for cancer prevention. These include behavioral, pharmaceutical and surgical interventions that prevent or reverse the hormonal and metabolic imbalances associated with obesity and insulin resistance.

Oral Contraceptives

Multiple epidemiologic studies demonstrate that women who use combination estrogen and progesterone oral contraceptives (OCP) decrease their risk of endometrial cancer by 50% 53, 54, 55. While there is no data to support a decreased efficacy in endometrial cancer protection in obese women, there are studies that suggest that obese women have a slightly decreased contraceptive efficacy compared to thin women56. A study by Maxwell et al found that OCP with higher potency progestins may be more effective for women with a higher BMI57. More data will be necessary to refine the optimal OCP for endometrial cancer chemoprevention in an obese population.

The levonorgestrel containing IUD (LNG-IUD) is also an attractive candidate for endometrial cancer prevention. The use of IUDs alone is associated with a lower risk of endometrial cancer58, and the progestin may further protect the endometrium. A few studies have reported the use of the LNG-IUD for reversal of endometrial hyperplasia and cancer, but additional data will be necessary before it can be recommended for cancer prevention.

Synthetic progestogens are commonly used in oral contraceptives and intrauterine devices, and for the treatment of menorrhagia, infertility, and the symptoms of menopause. Progestin therapy is also standard for the treatment of women who have endometrial hyperplasia without atypia, a likely precursor lesion for endometrial cancer59. The response of complex hyperplasia with atypia and well-differentiated endometrial carcinoma to progestin has also been investigated. In studies performed by Wheeler et al, complete remission was observed in 67% of women with complex atypical hyperplasia, while 11% regressed to complex hyperplasia without atypia, and 22% had persistent disease with a median follow-up of 11-months59. In women with well-differentiated endometrial carcinoma, 42% of women demonstrated a complete remission, while 58% had persistent disease over a 12-month follow up period.

Behavioral: Diet and Exercise

Body mass and physical activity are modifiable risk factors, which can be manipulated to favorably impact cancer patient outcome. A recent study of 42,672 post-menopausal women enrolled in the American Cancer Society Cancer Prevention Study II Nutrition Cohort, evaluated the incidence of endometrial cancer in relation to physical activity and BMI60. During the period between 1992 and 2003, a total of 466 new cases of endometrial cancer were diagnosed. Recreational and moderate physical activity was associated with a 33% lower endometrial cancer risk, and the effect was pronounced among women who were overweight or obese.

Circulating estrogen levels correlate with increasing BMI in post-menopausal women, while weight loss either by dietary changes or exercise or a combination thereof reduce estrogen synthesis. Both caloric restriction, as well as the source of calories appears to influence serum hormone concentration. High-fiber, low-fat diet interventions have been shown to lower bioavailable concentration of estradiol in breast cancer survivors even in the absence of concurrent weight loss 61,62, 63.

Physical activity consistently demonstrates a pronounced effect on hormone levels in both lean and obese individuals64-65 and is associated with a decreased risk of post-menopausal breast cancer, as well as breast cancer recurrence. However, diet and exercise are also known to prevent recurrence of tumors types typically unresponsive to hormones, including estrogen-receptor negative breast cancer, suggesting that additional pathways activated by physical activity and diet influence tumor growth66, 67.

Weight loss, whether by behavioral changes (diet and exercise) or by surgery, is known to reverse insulin resistance, decrease bioactive IGF-1 levels and prevent the onset of type 2 diabetes. Recently, Pendyala et al conducted expression profiling on rectosigmoid mucosal biopsies obtained from obese women pre and post diet-induced weight loss68. Following a 10% weight loss, tissues demonstrated significant decreases in a variety of inflammatory cytokines including TNFα, IL-6, IL-8, and MCP-1, as well downregulation of markers of proinflammatory pathways, prostaglandin metabolism and transcription factors. This was reflected by decreases in circulating TNFα and IL-8 as well as serum glucose, cholesterol and triglycerides, and lower T-cell and macrophage counts in tissues. Taken together, this data suggest that weight loss reduces colorectal inflammation and uncouples cancer promoting signaling pathways, thereby reducing colorectal cancer risk. In addition to their effects on insulin, IGF and inflammatory signaling, caloric restriction and exercise activate AMPK as a consequence of a systemic increase in AMP secondary to ATP depletion. It is probable that weight loss can play a therapeutic role in the prevention of all obesity-associated cancer types.

Metabolic/Bariatric Surgery

Modest weight loss of 5-10% of body weight through diet and exercise reduces the incidence of type 2 diabetes and other co-morbidities associated with obesity, and is currently recommended as a weight loss goal by the American Cancer Society for overweight cancer survivors69. Unfortunately, the significant lifestyle changes associated with weight loss are difficult to adopt and maintain for many obese and morbidly obese individuals, and many are unsuccessful in maintaining a healthy weight.

By producing a sustained weight loss, bariatric surgery has recently been demonstrated to reduce both cancer risk and recurrence70. Sjostrom et al have demonstrated a reduced cancer risk in a 10-year follow up of individuals in Sweden who underwent bariatric surgery71. Interestingly, this effect favored women (RR 0.58, 95% CI 0.44-0.77) over men (RR 0.97,0.62-1.52). A larger study performed by Adams et al, demonstrated a decreased incidence of cancer in 6,596 U.S. subjects who underwent gastric bypass surgery (HR 0.76, 95% CI 0.65-89, p = 0.006) 72. In agreement with the Swedish study, bariatric surgery produced a more pronounced cancer-preventive effect in women (HR 0.73, 95% CI 0.62-0.87, p = 0.0004) over men (HR 1.02, 0.69-1.52, p = 0.91). The hazard ratio of endometrial cancer was dramatically reduced to 0.22 (95% CI 0.13-0.40, p < 0.0001). These data underscore the profound effect of obesity on endometrial cancer risk and suggest that weight loss, whether by behavioral change or surgical intervention, is critical to endometrial cancer prevention.

Antidiabetic Agents: Metformin

Metformin is an oral anti-hyperglycemic drug long used in the management of type-2 diabetes73. Metformin lowers blood glucose levels by inhibiting gluconeogenesis and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Based on its positive effect on increasing insulin sensitivity, metformin represents a rational chemopreventive agent for endometrial and other obesity-associated cancers. Additional studies suggest the chemopreventive and therapeutic benefits of metformin are mediated through activation of the growth inhibitory AMPK pathway74-75, thereby counteracting the PI3K/AKT/mTOR signaling, as illustrated in figure 3.

These mechanisms of action suggest a promising and novel role for this “old drug” in the chemoprevention of primary and recurrent tumors76, 77. Indeed, this has been demonstrated by retrospective epidemiologic studies. Li et al have demonstrated that diabetic patients who had taken metformin had a significantly lower risk of pancreatic cancer compared with those who had not78. Furthermore, diabetic breast cancer patients receiving metformin demonstrate a greater incidence of pathologic complete response to neoadjuvant therapy79. Metformin use is also associated with a decrease in prostate cancer risk80.

Recently, metformin has further been shown to inhibit aromatase expression by primary cultures of human adipose stromal cells81. If this effect hold true in vivo, we expect that metformin would inhibit the localized production of estrogens in tumor stromal tissue and also decrease circulating levels of estrogen observed in obese individuals. Metformin has also been shown to increase progesterone receptor expression in endometrial cancer cell lines82 and in breast cancer patients83. It is possible, therefore, that metformin augments the anti-proliferative effects of progestins by virtue of amplified PR signaling.

While the multiple mechanisms of action of metformin have biological plausibility for its use as a chemopreventive agent for cancer in general, it is an ideal drug choice for the primary and tertiary prevention of endometrial cancer.

Summary

Current evidence suggests that by targeting the hormonal imbalances and hyperactive proliferative pathways associated with obesity, the lifetime risk of endometrial cancer can be significantly reduced. While achieving and maintaining a healthy body weight by diet and exercise represents the ideal solution to endometrial cancer prevention, the reality of the worldwide obesity epidemic necessitates the availability of pharmaceutical and surgical alternatives to reduce the impact of obesity on endometrial cancer risk.

Figure 1. Overview.

Figure 1

Open in a new tab

The contribution of obesity to endometrial cancer progression and preventive strategies.

Figure 2. The systemic effects of obesity on endometrial cancer initiation and progression.

Figure 2

Open in a new tab

Increased adiposity and inflammation coupled with the decrease in adiponectin synthesis, contribute to insulin resistance. This leads to hyperglycemia and a further compensatory increase in insulin synthesis. Hyperinsulinemia is associated with the decreased synthesis of IGF binding proteins, and increased IGF bioavailability. The simultaneous increase in estrogen production promotes additional IGF-1 synthesis. Signaling through the IGF-1R promotes endometrial proliferation with an increased risk of endometrial cancer.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

The authors report no conflict of interest.

REFERENCES

  • 1.Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ. 2007;335:1134. doi: 10.1136/bmj.39367.495995.AE. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Bessonova L, Marshall SF, Ziogas A, et al. The association of body mass index with mortality in the california Teachers Study. Int J Cancer. doi: 10.1002/ijc.25905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371:569–78. doi: 10.1016/S0140-6736(08)60269-X. [DOI] [PubMed] [Google Scholar]
  • 4.Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–38. doi: 10.1056/NEJMoa021423. [DOI] [PubMed] [Google Scholar]
  • 5.Von Gruenigen VE, Tian C, Frasure H, Waggoner S, Keys H, Barakat RR. Treatment effects, disease recurrence, and survival in obese women with early endometrial carcinoma : a Gynecologic Oncology Group study. Cancer. 2006;107:2786–91. doi: 10.1002/cncr.22351. [DOI] [PubMed] [Google Scholar]
  • 6.Soliman PT, Bassett RL, Jr., Wilson EB, et al. Limited public knowledge of obesity and endometrial cancer risk: what women know. Obstet Gynecol. 2008;112:835–42. doi: 10.1097/AOG.0b013e318187d022. [DOI] [PubMed] [Google Scholar]
  • 7.Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579–91. doi: 10.1038/nrc1408. [DOI] [PubMed] [Google Scholar]
  • 8.Boon WC, Chow JD, Simpson ER. The multiple roles of estrogens and the enzyme aromatase. Prog Brain Res. 2010;181:209–32. doi: 10.1016/S0079-6123(08)81012-6. [DOI] [PubMed] [Google Scholar]
  • 9.Van Kruijsdijk RC, Van Der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev. 2009;18:2569–78. doi: 10.1158/1055-9965.EPI-09-0372. [DOI] [PubMed] [Google Scholar]
  • 10.Cauley JA, Gutai JP, Kuller LH, Ledonne D, Powell JG. The epidemiology of serum sex hormones in postmenopausal women. Am J Epidemiol. 1989;129:1120–31. doi: 10.1093/oxfordjournals.aje.a115234. [DOI] [PubMed] [Google Scholar]
  • 11.Simpson ER, Mendelson CR. Effect of aging and obesity on aromatase activity of human adipose cells. Am J Clin Nutr. 1987;45:290–5. doi: 10.1093/ajcn/45.1.290. [DOI] [PubMed] [Google Scholar]
  • 12.Szymczak J, Milewicz A, Thijssen JH, Blankenstein MA, Daroszewski J. Concentration of sex steroids in adipose tissue after menopause. Steroids. 1998;63:319–21. doi: 10.1016/s0039-128x(98)00019-1. [DOI] [PubMed] [Google Scholar]
  • 13.Geisler J. Breast cancer tissue estrogens and their manipulation with aromatase inhibitors and inactivators. J Steroid Biochem Mol Biol. 2003;86:245–53. doi: 10.1016/s0960-0760(03)00364-9. [DOI] [PubMed] [Google Scholar]
  • 14.Morisset AS, Blouin K, Tchernof A. Impact of diet and adiposity on circulating levels of sex hormone-binding globulin and androgens. Nutr Rev. 2008;66:506–16. doi: 10.1111/j.1753-4887.2008.00083.x. [DOI] [PubMed] [Google Scholar]
  • 15.O'lone R, Frith MC, Karlsson EK, Hansen U. Genomic targets of nuclear estrogen receptors. Mol Endocrinol. 2004;18:1859–75. doi: 10.1210/me.2003-0044. [DOI] [PubMed] [Google Scholar]
  • 16.Marino M, Galluzzo P, Ascenzi P. Estrogen signaling multiple pathways to impact gene transcription. Curr Genomics. 2006;7:497–508. doi: 10.2174/138920206779315737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Marino M, Ascenzi P, Acconcia F. S-palmitoylation modulates estrogen receptor alpha localization and functions. Steroids. 2006;71:298–303. doi: 10.1016/j.steroids.2005.09.011. [DOI] [PubMed] [Google Scholar]
  • 18.Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev. 2002;11:1531–43. [PubMed] [Google Scholar]
  • 19.Schindler AE. Progestogen deficiency and endometrial cancer risk. Maturitas. 2009;62:334–7. doi: 10.1016/j.maturitas.2008.12.018. [DOI] [PubMed] [Google Scholar]
  • 20.Papaioannou S, Tzafettas J. Anovulation with or without PCO, hyperandrogenaemia and hyperinsulinaemia as promoters of endometrial and breast cancer. Best Pract Res Clin Obstet Gynaecol. 2010;24:19–27. doi: 10.1016/j.bpobgyn.2008.11.010. [DOI] [PubMed] [Google Scholar]
  • 21.Goodarzi MO, Dumesic DA, Chazenbalk G, Azziz R. Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. Nat Rev Endocrinol. 2011 doi: 10.1038/nrendo.2010.217. [DOI] [PubMed] [Google Scholar]
  • 22.Vrbikova J, Hainer V. Obesity and polycystic ovary syndrome. Obes Facts. 2009;2:26–35. doi: 10.1159/000194971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Fearnley EJ, Marquart L, Spurdle AB, Weinstein P, Webb PM. Polycystic ovary syndrome increases the risk of endometrial cancer in women aged less than 50 years: an Australian case-control study. Cancer Causes Control. 2010;21:2303–8. doi: 10.1007/s10552-010-9658-7. [DOI] [PubMed] [Google Scholar]
  • 24.Shoff SM, Newcomb PA. Diabetes, body size, and risk of endometrial cancer. Am J Epidemiol. 1998;148:234–40. doi: 10.1093/oxfordjournals.aje.a009630. [DOI] [PubMed] [Google Scholar]
  • 25.Weiderpass E, Persson I, Adami HO, Magnusson C, Lindgren A, Baron JA. Body size in different periods of life, diabetes mellitus, hypertension, and risk of postmenopausal endometrial cancer (Sweden). Cancer Causes Control. 2000;11:185–92. doi: 10.1023/a:1008946825313. [DOI] [PubMed] [Google Scholar]
  • 26.Anderson KE, Anderson E, Mink PJ, et al. Diabetes and endometrial cancer in the Iowa women's health study. Cancer Epidemiol Biomarkers Prev. 2001;10:611–6. [PubMed] [Google Scholar]
  • 27.Salazar-Martinez E, Lazcano-Ponce EC, Lira-Lira GG, et al. Case-control study of diabetes, obesity, physical activity and risk of endometrial cancer among Mexican women. Cancer Causes Control. 2000;11:707–11. doi: 10.1023/a:1008913619107. [DOI] [PubMed] [Google Scholar]
  • 28.Parazzini F, La Vecchia C, Negri E, et al. Diabetes and endometrial cancer: an Italian case-control study. Int J Cancer. 1999;81:539–42. doi: 10.1002/(sici)1097-0215(19990517)81:4<539::aid-ijc6>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  • 29.Friberg E, Mantzoros CS, Wolk A. Diabetes and risk of endometrial cancer: a population-based prospective cohort study. Cancer Epidemiol Biomarkers Prev. 2007;16:276–80. doi: 10.1158/1055-9965.EPI-06-0751. [DOI] [PubMed] [Google Scholar]
  • 30.Troisi R, Potischman N, Hoover RN, Siiteri P, Brinton LA. Insulin and endometrial cancer. Am J Epidemiol. 1997;146:476–82. doi: 10.1093/oxfordjournals.aje.a009301. [DOI] [PubMed] [Google Scholar]
  • 31.Soliman PT, Wu D, Tortolero-Luna G, et al. Association between adiponectin, insulin resistance, and endometrial cancer. Cancer. 2006;106:2376–81. doi: 10.1002/cncr.21866. [DOI] [PubMed] [Google Scholar]
  • 32.Dal Maso L, Augustin LS, Karalis A, et al. Circulating adiponectin and endometrial cancer risk. J Clin Endocrinol Metab. 2004;89:1160–3. doi: 10.1210/jc.2003-031716. [DOI] [PubMed] [Google Scholar]
  • 33.Petridou E, Mantzoros C, Dessypris N, et al. Plasma adiponectin concentrations in relation to endometrial cancer: a case-control study in Greece. J Clin Endocrinol Metab. 2003;88:993–7. doi: 10.1210/jc.2002-021209. [DOI] [PubMed] [Google Scholar]
  • 34.Cust AE, Kaaks R, Friedenreich C, et al. Plasma adiponectin levels and endometrial cancer risk in pre- and postmenopausal women. J Clin Endocrinol Metab. 2007;92:255–63. doi: 10.1210/jc.2006-1371. [DOI] [PubMed] [Google Scholar]
  • 35.Zhang Q, Shen Q, Celestino J, et al. Enhanced estrogen-induced proliferation in obese rat endometrium. Am J Obstet Gynecol. 2009;200:186, e1–8. doi: 10.1016/j.ajog.2008.08.064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Klotz DM, Hewitt SC, Ciana P, et al. Requirement of estrogen receptor-alpha in insulin-like growth factor-1 (IGF-1)-induced uterine responses and in vivo evidence for IGF-1/estrogen receptor cross-talk. J Biol Chem. 2002;277:8531–7. doi: 10.1074/jbc.M109592200. [DOI] [PubMed] [Google Scholar]
  • 37.Hewitt SC, Li Y, Li L, Korach KS. Estrogen-mediated regulation of Igf1 transcription and uterine growth involves direct binding of estrogen receptor alpha to estrogen-responsive elements. J Biol Chem. 2010;285:2676–85. doi: 10.1074/jbc.M109.043471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Rutanen EM. Insulin-like growth factors in endometrial function. Gynecol Endocrinol. 1998;12:399–406. doi: 10.3109/09513599809012842. [DOI] [PubMed] [Google Scholar]
  • 39.Rutanen EM. Insulin-like growth factors and insulin-like growth factor binding proteins in the endometrium. Effect of intrauterine levonorgestrel delivery. Hum Reprod. 2000;15(Suppl 3):173–81. doi: 10.1093/humrep/15.suppl_3.173. [DOI] [PubMed] [Google Scholar]
  • 40.Cust AE, Allen NE, Rinaldi S, et al. Serum levels of C-peptide, IGFBP-1 and IGFBP-2 and endometrial cancer risk; results from the European prospective investigation into cancer and nutrition. Int J Cancer. 2007;120:2656–64. doi: 10.1002/ijc.22578. [DOI] [PubMed] [Google Scholar]
  • 41.Lukanova A, Zeleniuch-Jacquotte A, Lundin E, et al. Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer. Int J Cancer. 2004;108:262–8. doi: 10.1002/ijc.11544. [DOI] [PubMed] [Google Scholar]
  • 42.Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8:915–28. doi: 10.1038/nrc2536. [DOI] [PubMed] [Google Scholar]
  • 43.Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132:2169–80. doi: 10.1053/j.gastro.2007.03.059. [DOI] [PubMed] [Google Scholar]
  • 44.Nieto-Vazquez I, Fernandez-Veledo S, Kramer DK, Vila-Bedmar R, Garcia-Guerra L, Lorenzo M. Insulin resistance associated to obesity: the link TNF-alpha. Arch Physiol Biochem. 2008;114:183–94. doi: 10.1080/13813450802181047. [DOI] [PubMed] [Google Scholar]
  • 45.Shaarawy M, Abdel-Aziz O. Serum tumour necrosis factor alpha levels in benign and malignant lesions of the endometrium in postmenopausal women. A preliminary study. Acta Oncol. 1992;31:417–20. doi: 10.3109/02841869209088282. [DOI] [PubMed] [Google Scholar]
  • 46.Cymbaluk A, Chudecka-Glaz A, Rzepka-Gorska I. Leptin levels in serum depending on Body Mass Index in patients with endometrial hyperplasia and cancer. Eur J Obstet Gynecol Reprod Biol. 2008;136:74–7. doi: 10.1016/j.ejogrb.2006.08.012. [DOI] [PubMed] [Google Scholar]
  • 47.Ferdeghini M, Gadducci A, Prontera C, et al. Serum interleukin-6 levels in uterine malignancies. Preliminary data. Anticancer Res. 1994;14:735–7. [PubMed] [Google Scholar]
  • 48.Hlavna M, Kohut L, Lipkova J, et al. Relationship of resistin levels with endometrial cancer risk. Neoplasma. 2011;58:124–8. doi: 10.4149/neo_2011_02_124. [DOI] [PubMed] [Google Scholar]
  • 49.Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest. 2006;116:1776–83. doi: 10.1172/JCI29044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Dossus L, Rinaldi S, Becker S, et al. Obesity, inflammatory markers, and endometrial cancer risk: a prospective case-control study. Endocr Relat Cancer. 17:1007–19. doi: 10.1677/ERC-10-0053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Wang T, Rohan TE, Gunter MJ, et al. A Prospective Study of Inflammation Markers and Endometrial Cancer Risk in Postmenopausal Hormone Non-Users. Cancer Epidemiol Biomarkers Prev. doi: 10.1158/1055-9965.EPI-10-1222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Wen W, Cai Q, Xiang YB, et al. The modifying effect of C-reactive protein gene polymorphisms on the association between central obesity and endometrial cancer risk. Cancer. 2008;112:2409–16. doi: 10.1002/cncr.23453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Kaufman DW, Shapiro S, Slone D, et al. Decreased risk of endometrial cancer among oral-contraceptive users. N Engl J Med. 1980;303:1045–7. doi: 10.1056/NEJM198010303031807. [DOI] [PubMed] [Google Scholar]
  • 54.Beral V, Hannaford P, Kay C. Oral contraceptive use and malignancies of the genital tract. Results from the Royal College of General Practitioners' Oral Contraception Study. Lancet. 1988;2:1331–5. doi: 10.1016/s0140-6736(88)90869-0. [DOI] [PubMed] [Google Scholar]
  • 55.Combination oral contraceptive use and the risk of endometrial cancer. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. JAMA. 1987;257:796–800. [PubMed] [Google Scholar]
  • 56.Lopez LM, Grimes DA, Chen-Mok M, Westhoff C, Edelman A, Helmerhorst FM. Hormonal contraceptives for contraception in overweight or obese women. Cochrane Database Syst Rev. 2010;7:CD008452. doi: 10.1002/14651858.CD008452.pub2. [DOI] [PubMed] [Google Scholar]
  • 57.MAXWELL GL, SCHILDKRAUT JM, CALINGAERT B, et al. Progestin and estrogen potency of combination oral contraceptives and endometrial cancer risk. Gynecol Oncol. 2006;103:535–40. doi: 10.1016/j.ygyno.2006.03.046. [DOI] [PubMed] [Google Scholar]
  • 58.Beining RM, Dennis LK, Smith EM, Dokras A. Meta-analysis of intrauterine device use and risk of endometrial cancer. Ann Epidemiol. 2008;18:492–9. doi: 10.1016/j.annepidem.2007.11.011. [DOI] [PubMed] [Google Scholar]
  • 59.Wheeler DT, Bristow RE, Kurman RJ. Histologic alterations in endometrial hyperplasia and well-differentiated carcinoma treated with progestins. Am J Surg Pathol. 2007;31:988–98. doi: 10.1097/PAS.0b013e31802d68ce. [DOI] [PubMed] [Google Scholar]
  • 60.Patel AV, Feigelson HS, Talbot JT, et al. The role of body weight in the relationship between physical activity and endometrial cancer: results from a large cohort of US women. Int J Cancer. 2008;123:1877–82. doi: 10.1002/ijc.23716. [DOI] [PubMed] [Google Scholar]
  • 61.Rock CL, Flatt SW, Thomson CA, et al. Effects of a high-fiber, low-fat diet intervention on serum concentrations of reproductive steroid hormones in women with a history of breast cancer. J Clin Oncol. 2004;22:2379–87. doi: 10.1200/JCO.2004.09.025. [DOI] [PubMed] [Google Scholar]
  • 62.Key TJ, Allen NE, Spencer EA, Travis RC. Nutrition and breast cancer. Breast. 2003;12:412–6. doi: 10.1016/s0960-9776(03)00145-0. [DOI] [PubMed] [Google Scholar]
  • 63.Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95:1218–26. doi: 10.1093/jnci/djg022. [DOI] [PubMed] [Google Scholar]
  • 64.McTiernan A, Wu L, Chen C, et al. Relation of BMI and physical activity to sex hormones in postmenopausal women. Obesity (Silver Spring) 2006;14:1662–77. doi: 10.1038/oby.2006.191. [DOI] [PubMed] [Google Scholar]
  • 65.Friedenreich CM, Woolcott CG, McTiernan A, et al. Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women. J Clin Oncol. 2010;28:1458–66. doi: 10.1200/JCO.2009.24.9557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.McTiernan A. Mechanisms linking physical activity with cancer. Nat Rev Cancer. 2008;8:205–11. doi: 10.1038/nrc2325. [DOI] [PubMed] [Google Scholar]
  • 67.McTiernan A, Irwin M, Vongruenigen V. Weight, physical activity, diet, and prognosis in breast and gynecologic cancers. J Clin Oncol. 2010;28:4074–80. doi: 10.1200/JCO.2010.27.9752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Pendyala S, Neff LM, Suarez-Farinas M, Holt PR. Diet-induced weight loss reduces colorectal inflammation: implications for colorectal carcinogenesis. Am J Clin Nutr. 2011;93:234–42. doi: 10.3945/ajcn.110.002683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Doyle C, Kushi LH, Byers T, et al. Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices. CA Cancer J Clin. 2006;56:323–53. doi: 10.3322/canjclin.56.6.323. [DOI] [PubMed] [Google Scholar]
  • 70.Ashrafian H, Ahmed K, Rowland SP, et al. Metabolic surgery and cancer: protective effects of bariatric procedures. Cancer. doi: 10.1002/cncr.25738. [DOI] [PubMed] [Google Scholar]
  • 71.Sjostrom L, Gummesson A, Sjostrom CD, et al. Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial. Lancet Oncol. 2009;10:653–62. doi: 10.1016/S1470-2045(09)70159-7. [DOI] [PubMed] [Google Scholar]
  • 72.Adams TD, Stroup AM, Gress RE, et al. Cancer incidence and mortality after gastric bypass surgery. Obesity (Silver Spring) 2009;17:796–802. doi: 10.1038/oby.2008.610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Ungar G, Freedman L, Shapiro SL. Pharmacological studies of a new oral hypoglycemic drug. Proc Soc Exp Biol Med. 1957;95:190–2. doi: 10.3181/00379727-95-23163. [DOI] [PubMed] [Google Scholar]
  • 74.Zhou G, Myers R, LI Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–74. doi: 10.1172/JCI13505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Jalving M, Gietema JA, Lefrandt JD, et al. Metformin: taking away the candy for cancer? Eur J Cancer. 2010;46:2369–80. doi: 10.1016/j.ejca.2010.06.012. [DOI] [PubMed] [Google Scholar]
  • 76.Engelman JA, Cantley LC. Chemoprevention meets glucose control. Cancer Prev Res (Phila) 2010;3:1049–52. doi: 10.1158/1940-6207.CAPR-10-0178. [DOI] [PubMed] [Google Scholar]
  • 77.Ben Sahra I, Le Marchand-Brustel Y, Tanti JF, Bost F. Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther. 2010;9:1092–9. doi: 10.1158/1535-7163.MCT-09-1186. [DOI] [PubMed] [Google Scholar]
  • 78.Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137:482–8. doi: 10.1053/j.gastro.2009.04.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27:3297–302. doi: 10.1200/JCO.2009.19.6410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Wright JL, Stanford JL. Metformin use and prostate cancer in Caucasian men: results from a population-based case-control study. Cancer Causes Control. 2009;20:1617–22. doi: 10.1007/s10552-009-9407-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Brown KA, Hunger NI, Docanto M, Simpson ER. Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase. Breast Cancer Res Treat. 2010;123:591–6. doi: 10.1007/s10549-010-0834-y. [DOI] [PubMed] [Google Scholar]
  • 82.Xie Y, Wang YL, Yu L, et al. Metformin promotes progesterone receptor expression via inhibition of mammalian target of rapamycin (mTOR) in endometrial cancer cells. J Steroid Biochem Mol Biol. doi: 10.1016/j.jsbmb.2010.12.006. [DOI] [PubMed] [Google Scholar]
  • 83.Berstein LM, Boyarkina MP, Tsyrlina EV, Turkevich EA, Semiglazov VF. More favorable progesterone receptor phenotype of breast cancer in diabetics treated with metformin. Med Oncol. 2010 doi: 10.1007/s12032-010-9572-6. [DOI] [PubMed] [Google Scholar]

RESOURCES