Endocrinology of Patients with Endometrial Cancer

Authors

Tarah Pua, MD
Associate Professor, Gynecologic Oncology, New York Presbyterian Queens Hospital Flushing, New York, USA

Linus Chuang, MD
Professor, Gynecologic Oncology, Icahn School of Medicine at Mount Sinai, New York, USA

INTRODUCTION

The unopposed estrogen hypothesis states that increased levels of estrogen and decreased levels of progesterone cooperate to increase mitotic activity in endometrial cells. Sustained proliferation and greater rates of DNA mutation ultimately result in malignant transformation.¹^,² Lending support to this hypothesis, during the follicular phase of the menstrual cycle, progesterone levels are low, estradiol levels are at normal premenopausal levels, and increased endometrial proliferation is observed.² Similarly, women who undergo estrogen replacement without progesterone have an increased risk of endometrial cancer.³^,⁴^,⁵ Unopposed estrogen partially explains the risk factors for endometrial adenocarcinoma such as obesity, diabetes, polycystic ovarian syndrome, nulliparity, hormone replacement and tamoxifen use.

OBESITY

The World Health Organization estimated that 1.9 billion people worldwide were overweight and of these 600 million were obese in 2014.⁶ Obesity has been associated with a 2–5 fold increased risk in endometrial cancer.⁷^,⁸^,⁹^,¹⁰ A meta-analysis of body mass index (BMI) and endometrial cancer risk exhibits a dose response where the risk of cancer increases with increasing BMI.¹¹ The mechanism involves conversion of androstenedione to estrone by the enzyme aromatase.¹²^,¹³ This enzyme is found in adipocytes and fibrovascular stroma in human adipose tissue.¹⁴ Aromatase activity is enhanced by increased adrenal production of cortisol and androgens in obese women.⁷ Estrone can also be reduced by the enzyme 17-β-hydroxysteroid dehydrogenase to form the more potent estrogen, estradiol. In obese women, plasma estradiol levels are also elevated due to a decrease in sex hormone binding globulin (SHBG). Several studies indicate elevated estradiol levels and low SHBG in postmenopausal women with endometrial cancer as compared to controls.¹⁵^,¹⁶^,¹⁷

Elevated levels of estrogen in obese women are not the only risk factor for endometrial cancer. Adipose tissue secretes other hormones like adiponectin and leptin that are linked to endometrial cancer.¹⁸^,¹⁹ Serum adiponectin levels decrease as weight increases and decrease with weight loss.²⁰ Adiponectin binds to two main receptors AdipoR1 and AdipoR2 and one receptor similar to the cadherin family.²¹ Both AdipoR1 and AdipoR2 have been found in endometrial glands during the proliferative and secretory phases of the menstrual cycle. Only AdipoR1 expression was found inversely correlated to higher grade of endometrial adenocarcinoma, metastatic spread and shorter survival.¹⁸ Another in vitro study revealed adiponectin suppresses endometrial cancer proliferation by increasing the expression of an adaptor molecule LKB1 which is involved in the AMP-activated protein kinase (AMPK)/S6 axis. This modulates cell proliferation, cell adhesion, and invasion in endometrial cancer cell lines.²² One study found at least a 6-fold increase in endometrial cancer risk in women with a combination of high BMI and low adiponectin.²³ Similarly a case–control study nested within the European Prospective Investigation into Cancer and Nutrition revealed a reduced endometrial cancer risk with high levels of adiponectin independent of obesity related factors.²⁴ Other studies focused on an increased risk of endometrial cancer with higher leptin-adiponectin ratio.²⁵^,²⁶

Leptin is a protein encoded by the obese gene (Ob). Its receptor ObR belongs to the cytokine family. Leptin induces cell proliferation of endometrial cancer cells by activation of cyclooxygenase-2 through the JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathway.²⁷ Angiogenesis is also induced in malignant endometrial cells and hyperplastic endometrial cells through activation of vascular endothelial growth factor (VEGF) and VEGF receptors.²⁸ Overexpression of leptin and ObR in endometrial cancer was associated with invasion and metastasis of malignant cells.²⁹ In an analysis of six studies, women with high leptin levels had a relative risk of 2.55 of endometrial cancer.³⁰ Mechanistically, leptin enhances aromatase expression and increases estradiol synthesis in endometrial cancer cells.³¹

In obesity, excess production of free plasma fatty acids from adipose tissue results in insulin resistance. Adiponectin receptors are downregulated in obesity and diabetes,³²^,³³ whereas physical activity increases circulating adiponectin restoring insulin sensitivity.³⁴ The expression of adiponectin receptors is inversely correlated with plasma insulin levels.³³^,³⁵ The interaction of adiponection with adipoR1 and adipoR2 activates AMPK and PPAR-α, respectively, to increase fatty acid oxidation and glucose uptake.³²^,³⁶^,³⁷ Similarly, adiponection stimulates glucose uptake through its interaction with APPL1 and a Ras associated protein 5 (Rab5) to increase membrane translocation of glucose transporter 4 (GLUT4).³⁸

DIABETES

Type 2 diabetes is typically characterized by hyperglycemia, hyperinsulinemia and insulin resistance. A case–control study on the postmenopausal women in the Women’s Health Initiative Observational Study showed that hyperinsulinemia was a risk factor of endometrial cancer independent of estradiol levels or hormonal therapy.³⁹In vitro, insulin induces proliferation and inhibits apoptosis in endometrial cancer cell lines.⁴⁰ Elevated insulin levels cause a decrease in hepatic production of insulin like growth factor binding protein 1 (IGFBP1) and IGFBP2 which results in a rise in plasma levels of IGF1.⁴¹^,⁴² Variations can be detected in insulin, IGF, and its receptor expression in the endometrium during the phases of the menstrual cycle.⁴³ Women with endometrial hyperplasia and endometrial cancer had increased expression of IGFR1 as compared to healthy controls.⁴⁴ Endometrial carcinogenesis results from the activation of the PI3K/AKT and Ras/MAPK pathway triggered by insulin and IGF receptors.⁴⁵ Furthermore Kashima et al. demonstrated estrogen stimulation of IGF which resulted in activation of MAPK signalling in endometrial cancer cells.⁴⁶

Hyperinsulinemia plays another role in the development of endometrial cancer by increasing plasma sex steroid levels. Some studies revealed insulin suppresses SHBG production in hepatic cells.⁴⁷^,⁴⁸ Another proposed mechanism is the lack of SHBG transcription in response to levels of glucose and fructose. Elevated monosaccharides results in downregulation of hepatocyte nuclear factor-4alpha (HNF-4alpha) that controls the SHBG promoter.⁴⁹ Reduction in SHBG results in increase of total and bioavailable plasma sex steroids. Insulin and IGF can also enhance the production of androgens from the ovaries and adrenals.⁴² Evidence suggests that elevated androgens are associated with endometrial hyperplasia which usually precedes endometrial cancer.⁵⁰^,⁵¹ In addition peripheral conversation of androgen to estrogen by aromatase results in a higher risk of endometrial cancer.¹²^,⁴²

POLYCYSTIC OVARIAN SYNDROME (PCOS)

A meta-analysis of five studies totalling 4605 women reported the odds of developing endometrial cancer were three times higher in women with PCOS.⁵² This translates to a 9% lifetime risk of endometrial cancer for women with PCOS compared to a baseline of 3%. A key feature of PCOS is hyperandrogenism which is also seen in postmenopausal women with endometrial cancer.⁵³^,⁵⁴ It is likely that the conversion of androgens to estrogens is the cause for this increased risk of endometrial cancer since androgens do not stimulate endometrial cell proliferation in vitro.⁵⁵^,⁵⁶ In premenopausal women, elevation of testosterone and androstenedione results in the cessation of follicle maturation leading to chronic anovulation.⁵⁷ Elevated estrogen and low progesterone levels are noted in an anovulatory state. Luteinizing hormone (LH) receptors are also overexpressed in the endometrium of young women with anovulatory states in PCOS.⁵⁸ Hypersecretion of LH is another characteristic of PCOS. LH can promote the growth and invasion of human endometrial cancer cells.⁵⁹ The invasiveness of the cancer cells was highly dependent on the expression of LH receptors. In a study by Konishi, LH receptors are overexpressed in atypical endometrial hyperplasia and endometrial cancer but not in normal and simple hyperplasia.⁵⁸

Other commonalities seen in PCOS and endometrial cancer include obesity and insulin resistance. Hyperinsulinemia and insulin resistance is seen in obese and normal women with PCOS.⁶⁰^,⁶¹ Insulin resistance and elevation of androgens worsen with increasing weight.³⁸^,⁶² Thus, reduced levels of SHBG and IGFBP are also noted in PCOS. A treatment utilized in both PCOS and endometrial cancer is the diabetes medication metformin. Metformin is a biguanide that increases insulin sensitivity through inhibition of respiratory complex I in the mitochondria leading to reduced oxidative phosphorylation and reduced ATP production. This deficit in ATP causes activation of AMPK which downregulates gluconeogenesis in the liver.⁶³^,⁶⁴ Inhibition of gluconeogenesis lowers blood glucose thereby attenuating hyperinsulinemia. Endometrial cancer cells grown in serum obtained from women with PCOS that were treated with metformin exhibited reduced invasiveness in vitro.⁶⁵ Treatment of endometrial cancer cells with metformin resulted in apoptosis and decreased cell proliferation through activation of AMPK and inhibition of the mammalian target of rapamycin (mTOR) pathway.⁶⁶ Metformin also reversed progestin resistance in endometrial cancer cell lines.⁶⁷ Thus metformin is currently being evaluated as a treatment adjunct for endometrial cancer.

PARITY

Nulliparity, early menarche, and late menopause increase the risk of endometrial cancer.⁶⁸^,⁶⁹^,⁷⁰^,⁷¹^,⁷²^,⁷³ These factors are interrelated and can be explained by fluctuations in estrogen and progesterone. Nulliparous women do not have the protection of a prolonged progesterone state as seen in pregnancy.⁶⁸^,⁷¹^,⁷³ There is a 2–3 fold increased risk in endometrial cancer in nulliparous women.⁶⁸^,⁶⁹ Women who had five or greater full term births have a 43% endometrial cancer risk reduction compared to baseline population.⁷¹ Another hypothesis to explain the protective effects of pregnancy is the mechanical sloughing of the endometrium during parturition that conceivably sheds any abnormal endometrium.⁶⁸

Women who have early menarche and late menopause are exposed to a longer duration of estrogen exposure. Those experiencing an older age of menarche (>15 years of age) had one third the risk of endometrial cancer as compared to those who had menarche at age 10 or less.⁷³ Women experiencing menopause at age 55 and older had about twice the risk of endometrial cancer as compared to women who had menopause before 45.⁷³ Furthermore there is a positive correlation with increased ovulation frequency and risk of endometrial cancer. Thus the use of oral contraception can decrease the risk of endometrial cancer.⁷⁰^,⁷⁴

Oral contraceptives suppress ovulation by suppressing the secretion of FSH and LH by the anterior pituitary through a negative feedback loop with estrogen and progesterone.⁷⁵ Suppression of FSH disrupts follicle stimulation preventing an increase in estradiol and the mid-cycle LH surge. The effects of oral contraceptives on the endometrium are decidualization and suppression of mitotic activity. A recent meta-analysis revealed a reduction in endometrial cancer risk with a longer duration of oral contraceptive use; every 5 years of use was associated with a risk ratio of 0.76 (95% CI 0.73–0.78; p <0.0001).⁷⁴ The protective effects persist after the cessation of contraceptive use. Furthermore the risk reduction associated with oral contraceptives is observed more in endometrial carcinomas than sarcomas.⁷⁰^,⁷⁴

HORMONE REPLACEMENT

Prolonged estrogenic stimulation of endometrial cells results in endometrial hyperplasia which can predispose to endometrial cancer.⁷⁶ Progesterone counteracts estrogen by down regulating the concentration of estrogen receptors and promoting cell differentiation.²^,⁷⁷ Menopausal estrogen only replacement increases risk of endometrial cancer by as much as 10 fold with 10 years of use.³ Multiple studies reveal that adding a progestin decreases the risk of endometrial cancer. A Danish study followed hormone therapy use in women without cancer or hysterectomy, aged 50–79, from 1995 to 2009. Compared to controls, conjugated estrogen users alone had a relative risk of 4.27 (95% CI 1.92–9.84), while continuous combined estrogen and progesterone therapy users had a RR 1.02 (95% CI 0.87–1.20).⁷⁸ Similarly in the Million Women Study, estrogen only use had a RR of 1.45 (95% CI 1.02–2.06), while combined continuous preparations had a lower relative risk of 0.71 (95% CI 0.56–0.9).⁷⁹ Even with the discontinuation of estrogen only use, the risk of endometrial cancer remains.⁸⁰

TAMOXIFEN

Tamoxifen is a nonsteroidal triphenylethylene compound that was originally discovered in 1971 as an ovulation inducing agent.⁸¹ It was subsequently used as an estrogen receptor antagonist in women with breast cancer to reduce the risk of relapse.⁸² Though it acts as an antagonist in breast cancer cells, tamoxifen is an estrogen receptor agonist in endometrial cells.⁸³^,⁸⁴In vitro, tamoxifen increases cell proliferation through activation of MAPK, c-MYC, and IGF-1 pathways in endometrial cancer cells.⁸⁵ The effect of tamoxifen on the endometrium appears to affect women with low estrogen. In a chemoprevention trial with tamoxifen, women with elevated estradiol levels did not have an increase in endometrial thickness as opposed to premenopausal amenorrheic women with low estrogen.⁸⁶ Tamoxifen use increases the risk of endometrial cancer 2–3 fold.⁸³ The longer the duration of tamoxifen use, the larger the relative risk of endometrial cancer as compared to controls (RR 2.0 for 2–5 years, RR 6.9 for >5 years, p <0.0001).⁸⁷ In the same study, the 3-year survival of women with endometrial cancer was lower for tamoxifen users of >5 years versus non users, 76% versus 94%, respectively. Some studies did not find a correlation between a more aggressive histological subtype of malignancy with tamoxifen use, while others showed an increase risk in uterine sarcomas.⁸⁷^,⁸⁸^,⁸⁹^,⁹⁰

ESTROGEN AND PROGESTERONE

Estrogen and progesterone are steroid hormones that activate receptors in target tissue to influence endometrial growth. Estrogen binds two types of estrogen receptors: ERα and ERβ, inducing conformational changes in the receptors to form homo- or heterodimers. Receptor dimerization results in nuclear translocation and transcriptional activation.⁹¹^,⁹² Estrogen also interacts with receptor tyrosine kinases like IGF1R that signal through PI3K/AKT and glycogen synthase kinase 3 (GSK3β) pathways to induce endometrial proliferation.⁹³ ERα and ERβ expression levels change during the menstrual cycle. ERα is expressed in both glands and stroma during the proliferative phase and is reduced in the secretory phase following ovulation.⁹⁴ ERβ1 is expressed in the proliferative phase and continues after ovulation, while ERβ2 is downregulated in the glandular epithelium.⁹⁵ Progesterone receptors (PR) are expressed in the proliferative phase and continue through the secretory phase. After ovulation when progesterone levels are high, activation of PR attenuates endometrial proliferation and stimulates differentiation into the secretory epithelium.⁹⁶^,⁹⁷ Moreover, progesterone decreases ER expression in endometrial cells and activates enzymatic pathways that convert estradiol to less bioactive estrone.⁹⁸ When progesterone levels are low as in anovulation or PCOS, endometrial growth continues and becomes hyperplastic.

The specific roles of ER and PR in endometrial cancer remain unclear, though studies have looked at the role of expression in cancer prognosis. A prospective multicenter trial revealed a worse prognosis with loss of ER and PR expression in endometrial cancer.⁹⁹ Earlier stage and well differentiated endometrial adenocarcinomas retain both receptors.¹⁰⁰^,¹⁰¹ This understanding of receptor status prompted the use of tamoxifen and progestin as endometrial cancer treatments. Hormonal treatment options are discussed in detail in another chapter.

Endometrial cancer incidence has been increasing.¹⁰² Standard treatment is surgery, but those who seek fertility sparing measures can be treated with hormones. Similarly, those who are not candidates for surgery are often treated with progestins. Further research into the precise targets of estrogen and progesterone receptors is needed to create novel treatments for endometrial cancer.

REFERENCES

1	Siiteri, P.K., Steroid hormones and endometrial cancer. Cancer Res, 1978. 38(11 Pt 2): p. 4360-6.
2	Key, T.J. and M.C. Pike, The dose-effect relationship between 'unopposed' oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer, 1988. 57(2): p. 205-12.
3	Grady, D., et al., Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol, 1995. 85(2): p. 304-13.
4	Weiderpass, E., et al., Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst, 1999. 91(13): p. 1131-7.
5	Allen, N.E., et al., Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European Prospective Investigation Into Cancer and Nutrition. Am J Epidemiol, 2010. 172(12): p. 1394-403.
6	www.who.int/mediacentre/factsheets/fs311/en/. Accessed October 13, 2015.
7	Bergstrom, A., et al., Overweight as an avoidable cause of cancer in Europe. Int J Cancer, 2001. 91(3): p. 421-30.
8	Renehan, A.G., I. Soerjomataram, and M.F. Leitzmann, Interpreting the epidemiological evidence linking obesity and cancer: A framework for population-attributable risk estimations in Europe. Eur J Cancer, 2010. 46(14): p. 2581-92.
9	Renehan, A.G., et al., Incident cancer burden attributable to excess body mass index in 30 European countries. Int J Cancer, 2010. 126(3): p. 692-702.
10	Schouten, L.J., R.A. Goldbohm, and P.A. van den Brandt, Anthropometry, physical activity, and endometrial cancer risk: results from the Netherlands Cohort Study. J Natl Cancer Inst, 2004. 96(21): p. 1635-8.
11	Jenabi, E. and J. Poorolajal, The effect of body mass index on endometrial cancer: a meta-analysis. Public Health, 2015. 129(7): p. 872-80.
12	Siiteri, P.K., Adipose tissue as a source of hormones. Am J Clin Nutr, 1987. 45(1 Suppl): p. 277-82.
13	Ito, K., et al., Biological roles of estrogen and progesterone in human endometrial carcinoma--new developments in potential endocrine therapy for endometrial cancer. Endocr J, 2007. 54(5): p. 667-79.
14	Enriori, C.L. and J. Reforzo-Membrives, Peripheral aromatization as a risk factor for breast and endometrial cancer in postmenopausal women: a review. Gynecol Oncol, 1984. 17(1): p. 1-21.
15	Pettersson, B., R. Bergstrom, and E.D. Johansson, Serum estrogens and androgens in women with endometrial carcinoma. Gynecol Oncol, 1986. 25(2): p. 223-33.
16	Nyholm, H.C., et al., Plasma oestrogens in postmenopausal women with endometrial cancer. Br J Obstet Gynaecol, 1993. 100(12): p. 1115-9.
17	Nisker, J.A., et al., Serum sex hormone-binding globulin capacity and the percentage of free estradiol in postmenopausal women with and without endometrial carcinoma. A new biochemical basis for the association between obesity and endometrial carcinoma. Am J Obstet Gynecol, 1980. 138(6): p. 637-42.
18	Yabushita, H., et al., Clinicopathological roles of adiponectin and leptin receptors in endometrial carcinoma. Oncol Lett, 2014. 7(4): p. 1109-1117.
19	Zheng, Q., H. Wu, and J. Cao, Circulating adiponectin and risk of endometrial cancer. PLoS One, 2015. 10(6): p. e0129824.
20	Liu, Y.M., et al., Adiponectin gene expression in subcutaneous adipose tissue of obese women in response to short-term very low calorie diet and refeeding. J Clin Endocrinol Metab, 2003. 88(12): p. 5881-6.
21	Kadowaki, T. and T. Yamauchi, Adiponectin and adiponectin receptors. Endocr Rev, 2005. 26(3): p. 439-51.
22	Moon, H.S., et al., Direct role of adiponectin and adiponectin receptors in endometrial cancer: in vitro and ex vivo studies in humans. Mol Cancer Ther, 2011. 10(12): p. 2234-43.
23	Dal Maso, L., et al., Circulating adiponectin and endometrial cancer risk. J Clin Endocrinol Metab, 2004. 89(3): p. 1160
24	Cust, A.E., et al., Plasma adiponectin levels and endometrial cancer risk in pre- and postmenopausal women. J Clin Endocrinol Metab, 2007. 92(1): p. 255-63.
25	Ashizawa, N., et al., Serum leptin-adiponectin ratio and endometrial cancer risk in postmenopausal female subjects. Gynecol Oncol, 2010. 119(1): p. 65-9.
26	Gong, T.T., et al., Circulating adiponectin, leptin and adiponectin-leptin ratio and endometrial cancer risk: Evidence from a meta-analysis of epidemiologic studies. Int J Cancer, 2015. 137(8): p. 1967-78.
27	Gao, J., et al., Leptin induces functional activation of cyclooxygenase-2 through JAK2/STAT3, MAPK/ERK, and PI3K/AKT pathways in human endometrial cancer cells. Cancer Sci, 2009. 100(3): p. 389-95.
28	Carino, C., et al., Leptin regulation of proangiogenic molecules in benign and cancerous endometrial cells. Int J Cancer, 2008. 123(12): p. 2782-90.
29	Zhang, Y., et al., Correlation analysis between the expressions of leptin and its receptor (ObR) and clinicopathology in endometrial cancer. Cancer Biomark, 2014. 14(5): p. 353-9.
30	Wang, P.P., et al., High leptin level is an independent risk factor of endometrial cancer: a meta-analysis. Cell Physiol Biochem, 2014. 34(5): p. 1477-84.
31	Liu, L., et al., Leptin promotes human endometrial carcinoma cell proliferation by enhancing aromatase (P450arom) expression and estradiol formation. Eur J Obstet Gynecol Reprod Biol, 2013. 170(1): p. 198-201.
32	Yamauchi, T., et al., Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med, 2007. 13(3): p. 332-9.
33	Tsuchida, A., et al., Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J Biol Chem, 2004. 279(29): p. 30817-22.
34	Bluher, M., et al., Circulating adiponectin and expression of adiponectin receptors in human skeletal muscle: associations with metabolic parameters and insulin resistance and regulation by physical training. J Clin Endocrinol Metab, 2006. 91(6): p. 2310-6.
35	Weyer, C., et al., Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab, 2001. 86(5): p. 1930-5.
36	Yamauchi, T., et al., Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature, 2003. 423(6941): p. 762-9.
37	Yoon, M.J., et al., Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes, 2006. 55(9): p. 2562-70.
38	Mao, X., et al., APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol, 2006. 8(5): p. 516-23.
39	Gunter, M.J., 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(4): p. 921-9.
40	Zhao, J., et al., [Effects of insulin on proliferation and apoptosis of endometrial carcinoma cell]. Zhonghua Fu Chan Ke Za Zhi, 2007. 42(10): p. 696-700.
41	Ayabe, T., et al., Increased circulating levels of insulin-like growth factor-I and decreased circulating levels of insulin-like growth factor binding protein-1 in postmenopausal women with endometrial cancer. Endocr J, 1997. 44(3): p. 419-24.
42	Kaaks, R., A. Lukanova, and M.S. Kurzer, Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev, 2002. 11(12): p. 1531-43.
43	Mioni, R., et al., Insulin receptor and glucose transporters mRNA expression throughout the menstrual cycle in human endometrium: a physiological and cyclical condition of tissue insulin resistance. Gynecol Endocrinol, 2012. 28(12): p. 1014-8.
44	McCampbell, A.S., et al., Overexpression of the insulin-like growth factor I receptor and activation of the AKT pathway in hyperplastic endometrium. Clin Cancer Res, 2006. 12(21): p. 6373-8.
45	Ogawa, K., C. Sun, and A. Horii, Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade. Oncol Rep, 2005. 14(6): p. 1481-5.
46	Kashima, H., et al., Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells: involvement of the mitogen-activated protein kinase pathway followed by up-regulation of cyclin D1 and cyclin E. Endocr Relat Cancer, 2009. 16(1): p. 113-22.
47	Nestler, J.E., et al., A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab, 1991. 72(1): p. 83-9.
48	Plymate, S.R., et al., Regulation of sex hormone binding globulin (SHBG) production in Hep G2 cells by insulin. Steroids, 1988. 52(4): p. 339-40.
49	Selva, D.M., et al., Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest, 2007. 117(12): p. 3979-87.
50	Terada, S., et al., Effects of testosterone on the development of endometrial tumors in female rats. Gynecol Obstet Invest, 1993. 36(1): p. 29-33.
51	Vitoratos, N., et al., The role of androgens in the late-premenopausal woman with adenomatous hyperplasia of the endometrium. Int J Gynaecol Obstet, 1991. 34(2): p. 157-61.
52	Haoula, Z., M. Salman, and W. Atiomo, Evaluating the association between endometrial cancer and polycystic ovary syndrome. Hum Reprod, 2012. 27(5): p. 1327-31.
53	Lukanova, A., et al., Circulating levels of sex steroid hormones and risk of endometrial cancer in postmenopausal women. Int J Cancer, 2004. 108(3): p. 425-32.
54	Nagamani, M., et al., Ovarian steroid secretion in postmenopausal women with and without endometrial cancer. J Clin Endocrinol Metab, 1986. 62(3): p. 508-12.
55	Legro, R.S., et al., Role of androgens in the growth of endometrial carcinoma: an in vivo animal model. Am J Obstet Gynecol, 2001. 184(3): p. 303-8.
56	Tuckerman, E.M., et al., Do androgens have a direct effect on endometrial function? An in vitro study. Fertil Steril, 2000. 74(4): p. 771-9.
57	Franks, S., H. Mason, and D. Willis, Follicular dynamics in the polycystic ovary syndrome. Mol Cell Endocrinol, 2000. 163(1-2): p. 49-52.
58	Konishi, I., et al., Increased expression of LH/hCG receptors in endometrial hyperplasia and carcinoma in anovulatory women. Gynecol Oncol, 1997. 65(2): p. 273-80.
59	Dabizzi, S., et al., Luteinizing hormone increases human endometrial cancer cells invasiveness through activation of protein kinase A. Cancer Res, 2003. 63(14): p. 4281-6.
60	Morales, A.J., et al., Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. J Clin Endocrinol Metab, 1996. 81(8): p. 2854-64.
61	Rittmaster, R.S., N. Deshwal, and L. Lehman, The role of adrenal hyperandrogenism, insulin resistance, and obesity in the pathogenesis of polycystic ovarian syndrome. J Clin Endocrinol Metab, 1993. 76(5): p. 1295-300.
62	Pasquali, R., et al., Body fat distribution has weight-independent effects on clinical, hormonal, and metabolic features of women with polycystic ovary syndrome. Metabolism, 1994. 43(6): p. 706-13.
63	Foretz, M., et al., Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest, 2010. 120(7): p. 2355-69.
64	Hardie, D.G., AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev, 2011. 25(18): p. 1895-908.
65	Tan, B.K., et al., Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells. J Clin Endocrinol Metab, 2011. 96(3): p. 808-16.
66	Cantrell, L.A., et al., Metformin is a potent inhibitor of endometrial cancer cell proliferation--implications for a novel treatment strategy. Gynecol Oncol, 2010. 116(1): p. 92-8.
67	Zhang, Z., et al., Metformin reverses progestin resistance in endometrial cancer cells by downregulating GloI expression. Int J Gynecol Cancer, 2011. 21(2): p. 213-21.
68	Albrektsen, G., et al., Is the risk of cancer of the corpus uteri reduced by a recent pregnancy? A prospective study of 765,756 Norwegian women. Int J Cancer, 1995. 61(4): p. 485-90.
69	Brinton, L.A., et al., Reproductive, menstrual, and medical risk factors for endometrial cancer: results from a case-control study. Am J Obstet Gynecol, 1992. 167(5): p. 1317-25.
70	Dossus, L., et al., Reproductive risk factors and endometrial cancer: the European Prospective Investigation into Cancer and Nutrition. Int J Cancer, 2010. 127(2): p. 442-51.
71	Hinkula, M., et al., Grand multiparity and incidence of endometrial cancer: a population-based study in Finland. Int J Cancer, 2002. 98(6): p. 912-5.
72	Kvale, G., I. Heuch, and G. Ursin, Reproductive factors and risk of cancer of the uterine corpus: a prospective study. Cancer Res, 1988. 48(21): p. 6217-21.
73	McPherson, C.P., et al., Reproductive factors and risk of endometrial cancer. The Iowa Women's Health Study. Am J Epidemiol, 1996. 143(12): p. 1195-202.
74	Collaborative Group on Epidemiological Studies on Endometrial, C., Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27 276 women with endometrial cancer from 36 epidemiological studies. Lancet Oncol, 2015. 16(9): p. 1061-70.
75	Sondheimer, S.J., Oral contraceptives: mechanism of action, dosing, safety, and efficacy. Cutis, 2008. 81(1 Suppl): p. 19-22.
76	Kurman, R.J., P.F. Kaminski, and H.J. Norris, The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer, 1985. 56(2): p. 403-12.
77	Henriet, P., H.P. Gaide Chevronnay, and E. Marbaix, The endocrine and paracrine control of menstruation. Mol Cell Endocrinol, 2012. 358(2): p. 197-207.
78	Morch, L.S., et al., The influence of hormone therapies on type I and II endometrial cancer: A nationwide cohort study. Int J Cancer, 2015.
79	Beral, V., et al., Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet, 2005. 365(9470): p. 1543-51.
80	Ali, A.T., Reproductive factors and the risk of endometrial cancer. Int J Gynecol Cancer, 2014. 24(3): p. 384-93.
81	Klopper, A. and M. Hall, New synthetic agent for the induction of ovulation: preliminary trials in women. Br Med J, 1971. 1(5741): p. 152-4.
82	Mourits, M.J., et al., Tamoxifen treatment and gynecologic side effects: a review. Obstet Gynecol, 2001. 97(5 Pt 2): p. 855-66.
83	Cohen, I., Endometrial pathologies associated with postmenopausal tamoxifen treatment. Gynecol Oncol, 2004. 94(2): p. 256-66.
84	Gal, D., et al., Oncogenic potential of tamoxifen on endometria of postmenopausal women with breast cancer--preliminary report. Gynecol Oncol, 1991. 42(2): p. 120-3.
85	Shang, Y. and M. Brown, Molecular determinants for the tissue specificity of SERMs. Science, 2002. 295(5564): p. 2465-8.
86	Chang, J., et al., Variation in endometrial thickening in women with amenorrhea on tamoxifen. Breast Cancer Res Treat, 1998. 48(1): p. 81-5.
87	Bergman, L., et al., Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen. Lancet, 2000. 356(9233): p. 881-7.
88	Barakat, R.R., et al., Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histologic features. Gynecol Oncol, 1994. 55(2): p. 164-8.
89	Fisher, B., et al., Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst, 1998. 90(18): p. 1371-88.
90	Silva, E.G., C.S. Tornos, and M. Follen-Mitchell, Malignant neoplasms of the uterine corpus in patients treated for breast carcinoma: the effects of tamoxifen. Int J Gynecol Pathol, 1994. 13(3): p. 248-58.
91	Heldring, N., et al., Estrogen receptors: how do they signal and what are their targets. Physiol Rev, 2007. 87(3): p. 905-31.
92	Nilsson, S., et al., Mechanisms of estrogen action. Physiol Rev, 2001. 81(4): p. 1535-65.
93	Zhu, L. and J.W. Pollard, Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling. Proc Natl Acad Sci U S A, 2007. 104(40): p. 15847-51.
94	Critchley, H.O., et al., Estrogen receptor beta, but not estrogen receptor alpha, is present in the vascular endothelium of the human and nonhuman primate endometrium. J Clin Endocrinol Metab, 2001. 86(3): p. 1370-8.
95	Critchley, H.O., et al., Wild-type estrogen receptor (ERbeta1) and the splice variant (ERbetacx/beta2) are both expressed within the human endometrium throughout the normal menstrual cycle. J Clin Endocrinol Metab, 2002. 87(11): p. 5265-73.
96	Savouret, J.F., et al., Characterization of the hormone responsive element involved in the regulation of the progesterone receptor gene. EMBO J, 1991. 10(7): p. 1875-83.
97	Patel, B., et al., Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update, 2015. 21(2): p. 155-73.
98	Clark, B.F., Absence of oestradiol-17 beta dehydrogenase from the progesterone-dominated mouse uterus. J Endocrinol, 1980. 85(1): p. 155-9.
99	Trovik, J., et al., Hormone receptor loss in endometrial carcinoma curettage predicts lymph node metastasis and poor outcome in prospective multicentre trial. Eur J Cancer, 2013. 49(16): p. 3431-41.
100	Zhang, Y., et al., Prognostic role of hormone receptors in endometrial cancer: a systematic review and meta-analysis. World J Surg Oncol, 2015. 13: p. 208.
101	Gehrig, P.A., et al., Estrogen receptor status, determined by immunohistochemistry, as a predictor of the recurrence of stage I endometrial carcinoma. Cancer, 1999. 86(10): p. 2083-9.
102	Evans, T., et al., Differential trends in the rising incidence of endometrial cancer by type: data from a UK population-based registry from 1994 to 2006. Br J Cancer, 2011. 104(9): p. 1505-10.