Gynecologic Oncology 132 (2014) 248–253
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Review
Preventing endometrial cancer risk in polycystic ovarian syndrome (PCOS) women: Could metformin help? Mohamad Nasir Shafiee a,b,⁎, Gulafshana Khan a, Rina Ariffin b, Jafaru Abu c, Caroline Chapman d, Suha Deen e, David Nunns c, David A. Barrett f, Claire Seedhouse g, William Atiomo a a The Division of Obstetrics and Gynaecology and Child Health, School of Medicine, D Floor, East Block, Queen's Medical Centre, Nottingham University Hospital NHS Trust, Derby Road, NG7 2UH, United Kingdom b The Department of Obstetrics and Gynaecology, Faculty of Medicine, UKM Medical Centre, Kuala Lumpur, 56000, Malaysia c The Department of Obstetrics and Gynaecology, City Hospital, Hucknall Road, NG5 1PB, United Kingdom d Centre of Excellence for Autoimmunity in Cancer, School of Graduate Entry Medicine and Health, University of Nottingham, NG5 1PB, United Kingdom e Department of Histopathology, A Floor, East Block, Queen's Medical Centre, Nottingham University Hospital NHS Trust, United Kingdom f Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, United Kingdom g The School of Molecular Biology, Clinical Sciences Building, University of Nottingham, Hucknall Road, NG5 1PB, United Kingdom
H I G H L I G H T S • Endometrial cancer (EC) risk in polycystic ovarian syndrome (PCOS) could be reduced by improving insulin resistance. • Insulin sensitizers like metformin could help to reduce the risk of EC in PCOS. • Understanding the molecular link between EC and PCOS in relation to hyperinsulinaemia is crucial.
a r t i c l e
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Article history: Received 23 August 2013 Accepted 22 October 2013 Available online 30 October 2013 Keywords: Endometrial cancer Endometrial hyperplasia Metformin PCOS
a b s t r a c t Current data indicate that there is a significant risk of endometrial cancer (EC) in women with polycystic ovarian syndrome (PCOS), although further research needed to clarify the exact molecular mechanisms. Endometrial hyperplasia is a premalignant condition that usually heralds EC and it shares identical risk factors with EC. Metabolic syndrome with a triad of obesity, hyperinsulinaemia and diabetes, which is commonly observed in PCOS appears to be a key mechanism in EC pathogenesis. Measures to improve insulin resistance could therefore play a role in reducing the risk of EC in women with PCOS. Metformin is an insulin sensitising agent which is safe, widely available and currently licensed for type-2 diabetes. It has been clearly shown in both animal and human studies that metformin is of value in reversing endometrial hyperplasia. Metformin may therefore prevent EC in PCOS. This article reviews the use of metformin in reducing EC risk in PCOS and makes a case for future research on this topic. © 2013 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial hyperplasia and endometrial cancer: the case for an alternative to progesterone treatment in PCOS . . . . . . . . . . . . Endometrial cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular links between PCOS and EC or EH, and the arguments in favour of a role for metformin in EC prevention in women with PCOS Metformin (insulin sensitizer) in reducing EC risk in women with PCOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . Research published so far on reducing endometrial hyperplasia and endometrial cancer risk in PCOS using metformin (Table 1) . . . . . Conclusion and recommendations for future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Authors' roles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author at: Department of Obstetrics and Gynaecology and Human Development, D Floor East Block, Queen's Medical Centre, University of Nottingham, NG7 2UH, United Kingdom. E-mail address: [email protected] (M.N. Shafiee). 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.10.028
M.N. Shafiee et al. / Gynecologic Oncology 132 (2014) 248–253
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Polycystic ovarian syndrome (PCOS) is a common, complex metabolic disorder affecting approximately 10% of women of reproductive age [1]. The widely accepted criterion for diagnosing PCOS is the Rotterdam, 2004 [2] criteria which requires that women with PCOS have two or more of the following in the absence of any other causes of chronic anovulation; clinical or biochemical evidence of hyperandrogenism, chronic oligo/anovulation and polycystic ovaries on ultrasound. PCOS is one of the commonest reasons women present with gynaecological problems, such as subfertility and abnormal menstrual cycles (oligomenorrhoea/amenorrhoea). Besides these, there are other health concerns related to PCOS which include obesity, cardiovascular disease, sleep apnoea, endometrial hyperplasia and endometrial cancer (EC). The prevalence of EC in women with PCOS varies depending on the criteria used to diagnose PCOS and the different subtypes of EC. It is estimated to be around 20–37% [3–5]. However, a recent systematic review revealed that the risk of EC was three times higher in women with PCOS compared to women without the disease [6]. The risk is even higher, up to three folds in obese women [7], and obesity is a predominant feature in PCOS. Management strategies to reduce the risk of EC in women with PCOS are therefore vital. Current strategies to reduce EC risk in PCOS are aimed at ameliorating risk factors for EC in women with PCOS such as obesity, anovulation and endometrial hyperplasia (EH). Weight loss, the induction of regular menstrual withdrawal bleeding with progestogens in obese amenorrhoeic women with PCOS and the treatment of EH with oral progestogens, the levonorgestrel releasing intrauterine systems or a hysterectomy in PCOS women with atypical hyperplasia have therefore been the main stay of management. Progesterone hormones currently used to treat EH in women with PCOS are however associated with many side effects which make compliance a problem and they do not always work with a relapse rate of 14–30% [8]. An alternative treatment is therefore required. Metformin, a drug used in treating diabetes, which improves insulin resistance, has been shown in animal and some human studies to reverse EH. Metformin may therefore potentially prevent EC in PCOS through improved compliance and better cure rates of EH. Metformin may also help with weight loss as well as improve menstrual cyclicity further ameliorating the risk of EC in PCOS. This article examines the case for the use of metformin in reducing EC risk in PCOS. It begins by briefly outlining the epidemiology of EC and EH and the current challenges with managing EH in general. It then goes on to examine the molecular links between PCOS, EC and EH and the arguments in favour of a role for metformin in EC prevention in women with PCOS. Research published so far on EC risk reduction in PCOS using metformin is next presented and the review ends with some recommendations for future research. Endometrial hyperplasia and endometrial cancer: the case for an alternative to progesterone treatment in PCOS Endometrial cancer A safe and effective way to prevent EC in women with PCOS is important because of the disease burden of EC and its economic costs. Globally, the incidence of endometrial cancer (EC) appears to be on a rising trend, especially with increasing obesity (a key issue in PCOS) rates [9]. It is projected to increase by 50% to 100% in the next 20 years [10,11]. Worldwide, EC comprises 4% of all cancers in
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women and predominantly involves postmenopausal women [12]. In the United Kingdom, EC is the fourth most common cancer in women with 7,703 cases reported in 2008 and 10,000 women dying every year in Europe with this cancer [13]. The lifetime risk of developing EC is approximately 1 in 46 women in the United Kingdom. With regards to the economic burden of the treatment in early stage EC, the estimated cost was USD 13,199 to USD 14,040 per case, when the standard treatment protocol was practiced [10]. Moreover, in a report that used a simulation model, it is predicted that there would be about 13 million more obese people in the UK by the year 2030 and consequently more cases of cancers amongst other diseases. The cost estimation to treat obesity related diseases is also going to increase by approximately 1.9–2.0 billion pounds sterling per year in the UK [14]. The risk factors consistently linked to EC include family history, obesity, diabetes mellitus, nulliparity, tamoxifen use, estrogen therapy and polycystic ovarian syndrome (PCOS) [15]. A recent systematic review revealed that the risk of EC was three times higher in women with PCOS compared to women without the disease [6]. Endometrial hyperplasia Endometrial hyperplasia (EH) which is a precancerous lesion of the endometrium has identical risk factors to EC and in one study, 30% of women with atypical EH who were treated hormonally progressed to cancer [16]. In addition, previous data has revealed that 40% and 59% of women who were diagnosed as EH and carcinoma-in-situ respectively, developed EC within 2 years when managed expectantly [17]. Concurrent EC was likely to occur in 20–43% [18]. These facts therefore strengthen the case for effective prevention of EC in women at high risk such as PCOS by treating EH in PCOS. In general the incidence of EH varies depending on the pathologic diagnosis with an incidence of 24–44% for simple hyperplasia and 25–38% for atypical hyperplasia [19,20]. The prevalence of EH in women with PCOS however varies from 1 to 48.8% [21–24]. In a study by Tingthanatikul et al., 2006 [21], the prevalence and clinical predictors of EH in amenorrheic women with anovulation were evaluated. Fifty-seven women were enrolled in the study of whom, 43 had PCOS and 14 had idiopathic anovulation. An endometrial biopsy was taken using a pipelle instrument. The results showed that the prevalence of EH was 48.8% and 35.7% in PCOS and idiopathic anovulatory women respectively. In another study [22], 56 women with PCOS presenting with infertility due to anovulation underwent both vaginal ultrasound assessments and endometrial biopsies. Thirty-six PCOS patients (64.3%) had proliferative endometrium and 20 (35.7%) had endometrial hyperplasia. Five of the latter (25%) had cytologic atypia. These studies showing a high prevalence of PCOS however contrast with the results of two studies which suggest a lower prevalence of EH in PCOS [23,24]. In the first study, endometrial biopsies were obtained from 93 women with PCOS compared with 40 healthy women [23]. In women with PCOS, simple endometrial hyperplasia without atypia was found in one patient (1.08%). In the second study [24], a prevalence of EH of 1% was found in women with PCOS. In this study [24], 963 premenopausal women consecutively referred with the diagnoses PCOS and/or hirsutism during 1997–2008 to the Departments of Endocrinology and Gynaecology, Odense University Hospital, Denmark were recruited. In 2011, The Danish data bank of pathology was used to identify women with
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endometrial histology diagnoses. EH was diagnosed in 10 (1.0%) women and EC in one (0.1%) woman suggesting a low prevalence of EH and EC in PCOS. A review of the data in the article however would suggest that of the 963 women recruited into the study, endometrial biopsies were only available for 128 women, suggesting a higher prevalence of EH (8%) and EC (0.8%) in PCOS, than presented in the abstract of the paper. This wide range (1–48.8%) in the reported prevalence of EH in PCOS in the literature may however be a reflection of the heterogeneous nature of the PCOS phenotype and varying diagnostic criteria. The 3 fold increased risk of EC in PCOS, and the link between EH and EC does however suggest that an association between EH and PCOS [6]. There is no standardised guideline for the management of EH [25] and the treatment options depend on the age, fertility concerns and histopathological severity of EH. In one study, total hysterectomy was the treatment in 80% for cases of atypical endometrial hyperplasia [25] where the risk of concurrent EC is substantially high. Progesterone based hormonal therapy (oral and intrauterine device), and/or repeat endometrial assessment are reserved for younger women and those intending childbearing [26–28]. Treatment of EH with progestogens is however not always completely effective. One study for example revealed that 26.9% women with atypical EH who received progestin for at least 3 months had persistent or progression of EH compared to 66.7% in those who did not receive progestin (RR 0.39, 95% CI 0.21– 0.70) [27]. A relapse rate of 14–30% [8] following progesterone therapy in women with EH has also been reported and down regulation of the progesterone receptors has been identified [29]. As fertility is of concern particularly in women with PCOS, long term progestin use may not be ideal in all women. An alternative to progesterone treatment of EH in PCOS is therefore required.
Molecular links between PCOS and EC or EH, and the arguments in favour of a role for metformin in EC prevention in women with PCOS PCOS is thought to be primarily due to dysregulation in endocrine homeostasis of the pituitary–ovarian axis and peripheral cells (liver, adipose tissue and adrenal glands) which, ultimately results in unopposed or inadequately opposed estrogen, hyperandrogenism and insulin resistance [30]. Hyperandrogenism and hypersecretion of luteinizing hormone (LH) are common features in PCOS which result in overexpression of endometrial androgen receptors [31] and endometrial cancer growth in-vitro [32]. However, with regards to the EC risk in PCOS, hyperinsulinaemia appears to play the principal role in its pathogenesis [33–35]. Hyperinsulinaemia and insulin resistance also appear to be linked to the pathogenesis of EC in PCOS regardless of body mass index (BMI) [34]. The molecular mechanism is thought to involve activation of key signalling pathways including PI3K/Akt and Ras/MAPK− although these signalling pathways are shared among insulin, IGF-1 and estrogen pathways. This activation of the PI3K/Akt and Ras/MAPK pathways results in exaggeration of IGF-1 and IGFBP expression which promotes mitogenesis of cancer cells in the endometrium [35] and one study has shown that IGF-1 was significantly abundant in the endometrium in women with EC [36]. Hyperinsulinaemia also contributes to over expression of the LH/hCG and progesterone dysfunction which causes chronic anovulation in the ovarian cycle. This indirect mechanism results in low blood sex hormone binding globulin (SHBG) levels and high blood estrogen and androgen levels, which in turn promote the development of EC. Furthermore animal model experiments on rats found that phosphorylation of Akt, mTOR, and S6K1 was increased in cells which were exposed to insulin and testosterone, exaggerating insulin resistance and cell proliferation [37]. Hence, the reduction of testosterone and the decrease of aromatase activity mediated by metformin may be important for the prevention of endometrial pathology [38]. In addition, the anti-proliferative effect of metformin could inhibit the mTOR mediated S6K1 activation in the endometrium [39].
Moreover, it has been shown that in women with hyperinsulinaemia and obesity, the risk of developing EC is more significant with an OR of 8.4 compared to 1.67 in those with metabolic syndrome [40]. Friedenreich et al., 2011 [41], also found that a triad of obesity, insulin resistance and diabetes in metabolic syndrome carried significant risks of EC. Even in women without estrogen exposure, hyperinsulinaemia and diabetes, put them at increased risk of EC [42]. Insulin has also been found to accelerate the proliferation of cancer cell in the endometrium in an in-vitro study [43], and the concentration of IGF-1 was correlated well to the malignant cells differentiation [44]. On the other hand, the exact molecular mechanisms and pathways linking PCOS to EC are however not completely understood as the relationship between circulating IGF-1 levels and EC is controversial, with some studies showing an inverse association, no association or even a positive association [45–49]. Further investigation is needed to clarify this relationship and facilitate clinical studies investigating the role of metformin in PCOS. Similar mechanisms have also been implicated in the link between PCOS and EH. In a study of 52 patients with PCOS who underwent dilatation and curettage compared with 32 controls, the expression of p-Akt was significantly higher in the PCOS group compared with the control group with the expression of p-Akt significantly higher in the group with EH and EC compared with those in normal endometria group [50]. A gene expression profile consistent with progesterone resistance and corresponding with EH and EC, has also been identified in women with PCOS [51]. Over activation of the MAPK/ERK signalling pathway in the endometrium of women with PCOS has been linked EH and EC in PCOS [52], with activation of MAPK/ERK signalling pathway affected by insulin resistance and hyperinsulinaemia. Although other factors not directly related to the insulin pathway have been linked to EH and PCOS, including CDK2 and p27 [53], lower levels of steroid sulfatase mRNA and estrogen sulfotransferase [54], Cyr61 overexpression [55], reduced apoptosis [56], and elevated gene and protein expression of androgen receptor, and estrogen receptor β [57], most of the pathways identified in the literature seem to be linked to insulin resistance, making a case for exploring the role of metformin treatment in EH and PCOS. Improvement of insulin resistance also reduces androgen levels. Metformin (insulin sensitizer) in reducing EC risk in women with PCOS Metformin is a biguanide, which lowers the rate of gluconeogenesis in the presence of insulin and is therefore called as insulin sensitizer. Based on the concept that insulin resistance plays a major role in the pathogenesis of PCOS, it has led to an increase in the use of metformin (or other insulin sensitizers) in PCOS in the context of infertility, obesity and hirsutism but not in EC prevention. Metformin has however been shown to exert a chemo protective and anti proliferative effect on numerous cancers [11,58]. It does this by a reduction in cell growth, which is modulated partly via insulin and non-insulin relevant pathways. Metformin also decreases cell growth by activating the growth inhibitory AMPK which interrupts the signalling through P13K/AKT and MAPK pathways in the insulin and IGF1 receptors [45]. In an in-vitro study, metformin was found to increase progesterone receptor expression in EC Ishikawa cell lines whereas IGF-1 and IGF-2 inhibited progesterone receptor mRNA, suggesting metformin had an antitumor effect [14]. This experiment also recognised that metformin had a complimentary antitumor effect with medroxyprogesterone acetate (MPA) in EC. Given the fact that progesterone receptor expression is important in the prevention of EC, the combination of metformin and MPA may be an effective way to control it, especially in progesterone receptor poor cancers. The risk of EC in women with PCOS has traditionally been reduced by inducing a withdrawal bleed every 3 to 4 months with progestogens [22]. However, in the context of the molecular links between EC and
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insulin resistance outlined above, it has been proposed that agents which improve insulin resistance such as metformin may be used to reduce EC risk in this group of women [59]. Studies to evaluate the efficacy or investigate the molecular changes in the endometrium following metformin use in PCOS are however limited.
EH were being estimated. There is therefore a need for more studies investigating the role of metformin in reducing EC risk in PCOS.
Research published so far on reducing endometrial hyperplasia and endometrial cancer risk in PCOS using metformin (Table 1)
This article has examined the case for the use of metformin in reducing EC risk in women with PCOS and the evidence would suggest that given the link between insulin resistance and EC, insulin sensitizers such as metformin could reduce EC risk in PCOS. To date however, there has been scarce research data to support metformin use in PCOS women for EC prevention. There is therefore a need for further research to evaluate this link. This is particularly important as although the pathogenesis of PCOS has been linked with insulin insensitivity and hyperinsulinaemia and a three-fold increase in EC risk in PCOS has been found, the exact molecular mechanisms and pathways linking PCOS to EC are not completely understood. Given the fact that the relationship between circulating IGF-1 levels and EC remains controversial, with some studies showing an inverse association, no association or even a positive association [45–49], further investigation is needed to clarify this relationship. There is therefore a need for more basic science studies and large clinical trials evaluating the role of metformin in reducing EC risk in PCOS.
A search of the Cochrane website of systematic reviews carried out in April 2013 using the search terms “metformin and endometrial hyperplasia” and “metformin and endometrial cancer” did not identify any published or ongoing reviews. Two animal studies addressing this issue were identified in our literature review. In one study, metformin reversed features of EH in mice where EH had been previously caused by estrogen treatment [39]. In the second study metformin significantly reduced all features indicating EH with respect to the control group in rats treated with metformin and estrogen compared with rats treated with estrogen alone [60]. There were two studies on the endometrial cell lines found. A study on the Ishikawa and HEC-1B EC cell demonstrated a synergistic antiproliferative effect of metformin and medroxyprogesterone acetate on endometrial cancer cells [14]. Another study revealed a reduction in in-vitro endometrial cells invasion (inflammation and cell migration) between sera from PCOS women and control after 6 months of metformin treatment [48]. Three human studies were identified. In a case report published in 2003, a 37 year old woman with atypical EH that had failed to respond to treatment with progestogens was successfully treated with metformin [61]. In the second study, simple EH found on biopsy in two women with PCOS was absent after 3 months treatment with metformin and rosiglitazone [49]. In the third study, two women with atypical EH complicating PCOS and who had failed to respond to high-dose progestin therapy had EH reversed after 3 months treatment with metformin [62]. The findings of these studies were summarised in Table 1. No published clinical trials were identified; however, one ongoing study [63] was identified following a search of the relevant databases in which in a pilot study at the University of North Carolina in the USA, the response rate and safety of metformin for the treatment of
Conclusion and recommendations for future research
Authors' roles M.N.S., G.K. and R.A. prepared the article, supervised and edited by W.U.A. J.A., C.C., C.S., D.B., S.D., and D.N. reviewed and commented on the scientific contents. All authors proof read the article before submission.
Funding This study received no funding.
Conflict of interest All authors declare no conflict of interest.
Table 1 Summary of literature review on “Metformin and Endometrial Hyperplasia” and “Metformin and Endometrial Cancer.” Author, year Tas et al, 2013 [60]
Erdemoglu et al, 2009 [39]
Wang et al, 2011 [14] Tan et al, 2011 [48]
Type of study Animal studies Experimental
Experimental
Cell lines studies Experimental Experimental Human studies
Legro et al, 2007 [49] Session et al, 2003 [61]
Randomised open-label Case report
Shen et al, 2008 [62]
Case report
Description
Findings
Forty oopherectomized Wistar-Albino rats were assigned to receive saline, 17 β estradiol hemihydrate, 17 β estradiol hemihydrate and metformin, 17 β estradiol hemihydrate and MPA for 14 days Forty-eight oophorectomized Balb/c mice were assigned to receive saline, tamoxifen citrate, 17 β estradiol hemihydrate, metformin, tamoxifen citrate with metformin or estradiol with metformin for 3 days
Metformin reduced estrogen-induced endometrial hyperplasia in oophorectomized rats
Interaction of metformin, PR and IGF-II expression in cell lines and assessed the antitumour effect of metformin Sera taken from two groups — PCOS and controls. In vitro invasion assessed in human endometrial cells by woundhealing motility and migration assays Sixteen PCOS recruited. Assessment done at 6-week (baseline), 3-month treatment period of single-agent therapy (rosiglitazone or metformin), and 3-month period of combined therapy One month treatment with metformin in a 37 year old woman with atypical hyperplasia Two PCOS women with atypical hyperplasia and failed progestin therapy. Received 3 months metformin and oral contraception
Metformin increased progesterone receptors expression and inhibited by overexpressed IGF-II in endometrial cancer In vitro invasion in endometrial cells was reduced by sera from PCOS women after 6 months of metformin treatment compared to matched controls One case of adenocarcinoma — excluded. Two simple hyperplasia — resolved with treatment Atypical endometrial hyperplasia regressed after metformin
Metformin with tamoxifen or estradiol reduced the density of endometrial glands and epithelial cell. Metformin with tamoxifen reduced the H-score of S6K1 and immunohistochemical expression of PCNA in endometrial glandular and stromal cells Metformin with estradiol reduced the H-score of S6K1 and immunohistochemical expression of PCNA in endometrial glandular and stromal cells.
Regression of atypical endometrial hyperplasia
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Acknowledgment The Faculty of Medicine, National University of Malaysia (UKM) and the Ministry of Higher Education Malaysia (MoHE) supported the PhD candidate (MNS) for his study leave.
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Am J Obstet Gynecol 2011;20(4):355e1–7. [35] Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Manson JE, Le J, et al. A prospective evaluation of insulin and insulin like growth factor-I as risk factors of endometrial cancer. Cancer Epidemiol Biomarkers Prev 2008;17(4):921–9. [36] Pillay OC, Leonard A, Catalano R, Sharkey A, Hardiman P. Endometrial gene expression in women with polycystic ovarian syndrome. Hum Reprod 2005;20(Suppl. 1):i96. [37] Allemand MC, Irving BA, Asmann YW, Klaus KA, Tatpati L, Coddington CC, et al. Effect of testosterone on insulin stimulated IRS1 Ser phosphorylation in primary rat myotubes–a potential model for PCOS-related insulin resistance. PLoS One 2009;4(1):e4274. 10.1371/journal.pone.0004274 [Epub 2009 Jan 26]. [38] Patel SM, Iqbal N, Kaul S, Ratcliffe SJ, Rickels MR, Reilly MP, et al. Effects of metformin and leuprolide acetate on insulin resistance and testosterone levels in nondiabetic postmenopausal women: a randomized, placebo-controlled trial. Fertil Steril 2010 Nov;94(6):2161–6. [39] Erdemoglu E, Güney M, Giray SG, Take G, Mungan T. Effects of metformin on mammalian target of rapamycin in a mouse model of endometrial hyperplasia. Eur J Obstet Gynecol Reprod Biol 2009;145(2):195–9. [40] Rosato V, Zucchetto A, Bosetti C, Dal ML, Montella M, Pelucchi C, et al. Metabolic syndrome and endometrial cancer risk. Ann Oncol 2011;22(4):884–9. [41] Friedenreich CM, Biel RK, Lau DC, Csizmadi I, Courneya KS, Magliocco AM, et al. Casecontrol study of the metabolic syndrome and metabolic risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev 2011;20(11):2384–95. [42] Rubin G, Petersen HB, Lee NC, Maes EF, Wingo PA, Becker S. Estrogen replacement therapy and the risk of endometrial cancer: remaining controversies. Am J Obstet Gynaecol 1990;162(1):148–54. [43] Lathi RB, Hess AP, Tulac S. Dose-dependent insulin regulation of insulin-like growth factor binding protein-1 in human endometrial stromal cells is mediated by distinct signaling pathways. J Clin Endocrinol Metab 2005;90(3):1599–606. [44] Nagamani M, Hannigan EV, Dinh TV, Stuart CA. Hyperinsulinemia and stromal luteinization of the ovaries in postmenopausal women with endometrial cancer. J Clin Endocrinol Metab 1988;67(1):144–8. [45] Zhang Q, Celestino J, Schmandt R, McCampbell A, Urbauer DL, Meyer LA, et al. Chemopreventive effects of metformin on obesity-associated endometrial proliferation. Am J Obstet Gynecol 2013. 10.1016/j.ajog.2013.03.008 [pii: S0002–9378(13) 00262–7 [Epub ahead of print]]. [46] Saltzman BS, Doherty JA, Hill DA. Diabetes and endometrial cancer: an evaluation of the modifying effects of other known risk factors. Am J Epidemiol 2008;167(5):607–14. [47] Navarro M, Baserga R. Limited redundancy of survival signals from the type 1 insulin-like growth factor receptor. Endocrinology 2001;142(3):1073–81. [48] Tan BK, Adya R, Chen J, Lehnert H, Sant Cassia LJ, Randeva HS. Metformin treatment exerts anti-invasive and antimetastatic effects in human endometrial carcinoma cells. J Clin Endocrinol Metab 2011;96(3):808–16. [49] Legro RS, Zaino RJ, Demers LM, Kunselman AR, Gnatuk CL, Williams NI, et al. The effects of metformin and rosiglitazone, alone and in combination, on the ovary and endometrium in polycystic ovary syndrome. Am J Obstet Gynecol 2007;196:402.e1–402.e10. [50] Zhang HY, Zhang YF, Han YK, Xue FX, Zhao XH, Zhang XL. Activation and significance of the PI3K/Akt pathway in endometrium with polycystic ovary syndrome patients. Zhonghua Fu Chan Ke Za Zhi 2012;47(1):19–23. [51] Savaris RF, Groll JM, Young SL, DeMayo FJ, Jeong JW, Hamilton AE, et al. Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles. J Clin Endocrinol Metab 2011;96(6):1737–46. [52] Song XR, Zhang HY, Zhang YF, Han YK, Li KJ. Extracellular signal-regulated protein kinase activation in endometrium with polycystic ovary syndrome and its significance. Zhonghua Fu Chan Ke Za Zhi 2010;45(10):767–71. [53] Villavicencio A, Goyeneche A, Telleria C, Bacallao K, Gabler F, Fuentes A, et al. Involvement of Akt, Ras and cell cycle regulators in the potential development of endometrial hyperplasia in women with polycystic ovarian syndrome. Gynecol Oncol 2009;115(1):102–7. [54] Bacallao K, Leon L, Gabler F, Soto E, Romero C, Valladares L, et al. In situ estrogen metabolism in proliferative endometria from untreated women with polycystic ovarian syndrome with and without endometrial hyperplasia. J Steroid Biochem Mol Biol 2008;110(1–2):163–9. [55] MacLaughlan SD, Palomino WA, Mo B, Lewis TD, Lininger RA, Lessey BA. Endometrial expression of Cyr61: a marker of estrogenic activity in normal and abnormal endometrium. Obstet Gynecol 2007;110(1):146–54. [56] Villavicencio A, Bacallao K, Gabler F, Fuentes A, Albornoz J, Casals A, et al. Deregulation of tissue homeostasis in endometria from patients with polycystic
M.N. Shafiee et al. / Gynecologic Oncology 132 (2014) 248–253 ovarian syndrome with and without endometrial hyperplasia. Gynecol Oncol 2007;104(2):290–5. [57] Villavicencio A, Bacallao K, Avellaira C, Gabler F, Fuentes A, Vega M. Androgen and estrogen receptors and co-regulators levels in endometria from patients with polycystic ovarian syndrome with and without endometrial hyperplasia. Gynecol Oncol 2006;103(1):307–14. [58] Engelman JA, Cantley LC. Chemoprevention meets glucose control. Cancer Prev Res (Phila) 2010;3(9):1049–52. [59] Kacalska O, Krzyczkowska-Sendrakowska M, Milewicz T, Zabińska-Popiela M, Bereza T, Krzysiek-Maczka G, et al. Molecular action of insulin-sensitizing agents. Endokrynol Pol 2005;56(3):308–13.
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Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Review
Preventing endometrial cancer risk in polycystic ovarian syndrome (PCOS) women: Could metformin help? Mohamad Nasir Shafiee a,b,⁎, Gulafshana Khan a, Rina Ariffin b, Jafaru Abu c, Caroline Chapman d, Suha Deen e, David Nunns c, David A. Barrett f, Claire Seedhouse g, William Atiomo a a The Division of Obstetrics and Gynaecology and Child Health, School of Medicine, D Floor, East Block, Queen's Medical Centre, Nottingham University Hospital NHS Trust, Derby Road, NG7 2UH, United Kingdom b The Department of Obstetrics and Gynaecology, Faculty of Medicine, UKM Medical Centre, Kuala Lumpur, 56000, Malaysia c The Department of Obstetrics and Gynaecology, City Hospital, Hucknall Road, NG5 1PB, United Kingdom d Centre of Excellence for Autoimmunity in Cancer, School of Graduate Entry Medicine and Health, University of Nottingham, NG5 1PB, United Kingdom e Department of Histopathology, A Floor, East Block, Queen's Medical Centre, Nottingham University Hospital NHS Trust, United Kingdom f Centre for Analytical Bioscience, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, United Kingdom g The School of Molecular Biology, Clinical Sciences Building, University of Nottingham, Hucknall Road, NG5 1PB, United Kingdom
H I G H L I G H T S • Endometrial cancer (EC) risk in polycystic ovarian syndrome (PCOS) could be reduced by improving insulin resistance. • Insulin sensitizers like metformin could help to reduce the risk of EC in PCOS. • Understanding the molecular link between EC and PCOS in relation to hyperinsulinaemia is crucial.
a r t i c l e
i n f o
Article history: Received 23 August 2013 Accepted 22 October 2013 Available online 30 October 2013 Keywords: Endometrial cancer Endometrial hyperplasia Metformin PCOS
a b s t r a c t Current data indicate that there is a significant risk of endometrial cancer (EC) in women with polycystic ovarian syndrome (PCOS), although further research needed to clarify the exact molecular mechanisms. Endometrial hyperplasia is a premalignant condition that usually heralds EC and it shares identical risk factors with EC. Metabolic syndrome with a triad of obesity, hyperinsulinaemia and diabetes, which is commonly observed in PCOS appears to be a key mechanism in EC pathogenesis. Measures to improve insulin resistance could therefore play a role in reducing the risk of EC in women with PCOS. Metformin is an insulin sensitising agent which is safe, widely available and currently licensed for type-2 diabetes. It has been clearly shown in both animal and human studies that metformin is of value in reversing endometrial hyperplasia. Metformin may therefore prevent EC in PCOS. This article reviews the use of metformin in reducing EC risk in PCOS and makes a case for future research on this topic. © 2013 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial hyperplasia and endometrial cancer: the case for an alternative to progesterone treatment in PCOS . . . . . . . . . . . . Endometrial cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Endometrial hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular links between PCOS and EC or EH, and the arguments in favour of a role for metformin in EC prevention in women with PCOS Metformin (insulin sensitizer) in reducing EC risk in women with PCOS . . . . . . . . . . . . . . . . . . . . . . . . . . . . Research published so far on reducing endometrial hyperplasia and endometrial cancer risk in PCOS using metformin (Table 1) . . . . . Conclusion and recommendations for future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Authors' roles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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⁎ Corresponding author at: Department of Obstetrics and Gynaecology and Human Development, D Floor East Block, Queen's Medical Centre, University of Nottingham, NG7 2UH, United Kingdom. E-mail address: [email protected] (M.N. Shafiee). 0090-8258/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ygyno.2013.10.028
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Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Polycystic ovarian syndrome (PCOS) is a common, complex metabolic disorder affecting approximately 10% of women of reproductive age [1]. The widely accepted criterion for diagnosing PCOS is the Rotterdam, 2004 [2] criteria which requires that women with PCOS have two or more of the following in the absence of any other causes of chronic anovulation; clinical or biochemical evidence of hyperandrogenism, chronic oligo/anovulation and polycystic ovaries on ultrasound. PCOS is one of the commonest reasons women present with gynaecological problems, such as subfertility and abnormal menstrual cycles (oligomenorrhoea/amenorrhoea). Besides these, there are other health concerns related to PCOS which include obesity, cardiovascular disease, sleep apnoea, endometrial hyperplasia and endometrial cancer (EC). The prevalence of EC in women with PCOS varies depending on the criteria used to diagnose PCOS and the different subtypes of EC. It is estimated to be around 20–37% [3–5]. However, a recent systematic review revealed that the risk of EC was three times higher in women with PCOS compared to women without the disease [6]. The risk is even higher, up to three folds in obese women [7], and obesity is a predominant feature in PCOS. Management strategies to reduce the risk of EC in women with PCOS are therefore vital. Current strategies to reduce EC risk in PCOS are aimed at ameliorating risk factors for EC in women with PCOS such as obesity, anovulation and endometrial hyperplasia (EH). Weight loss, the induction of regular menstrual withdrawal bleeding with progestogens in obese amenorrhoeic women with PCOS and the treatment of EH with oral progestogens, the levonorgestrel releasing intrauterine systems or a hysterectomy in PCOS women with atypical hyperplasia have therefore been the main stay of management. Progesterone hormones currently used to treat EH in women with PCOS are however associated with many side effects which make compliance a problem and they do not always work with a relapse rate of 14–30% [8]. An alternative treatment is therefore required. Metformin, a drug used in treating diabetes, which improves insulin resistance, has been shown in animal and some human studies to reverse EH. Metformin may therefore potentially prevent EC in PCOS through improved compliance and better cure rates of EH. Metformin may also help with weight loss as well as improve menstrual cyclicity further ameliorating the risk of EC in PCOS. This article examines the case for the use of metformin in reducing EC risk in PCOS. It begins by briefly outlining the epidemiology of EC and EH and the current challenges with managing EH in general. It then goes on to examine the molecular links between PCOS, EC and EH and the arguments in favour of a role for metformin in EC prevention in women with PCOS. Research published so far on EC risk reduction in PCOS using metformin is next presented and the review ends with some recommendations for future research. Endometrial hyperplasia and endometrial cancer: the case for an alternative to progesterone treatment in PCOS Endometrial cancer A safe and effective way to prevent EC in women with PCOS is important because of the disease burden of EC and its economic costs. Globally, the incidence of endometrial cancer (EC) appears to be on a rising trend, especially with increasing obesity (a key issue in PCOS) rates [9]. It is projected to increase by 50% to 100% in the next 20 years [10,11]. Worldwide, EC comprises 4% of all cancers in
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women and predominantly involves postmenopausal women [12]. In the United Kingdom, EC is the fourth most common cancer in women with 7,703 cases reported in 2008 and 10,000 women dying every year in Europe with this cancer [13]. The lifetime risk of developing EC is approximately 1 in 46 women in the United Kingdom. With regards to the economic burden of the treatment in early stage EC, the estimated cost was USD 13,199 to USD 14,040 per case, when the standard treatment protocol was practiced [10]. Moreover, in a report that used a simulation model, it is predicted that there would be about 13 million more obese people in the UK by the year 2030 and consequently more cases of cancers amongst other diseases. The cost estimation to treat obesity related diseases is also going to increase by approximately 1.9–2.0 billion pounds sterling per year in the UK [14]. The risk factors consistently linked to EC include family history, obesity, diabetes mellitus, nulliparity, tamoxifen use, estrogen therapy and polycystic ovarian syndrome (PCOS) [15]. A recent systematic review revealed that the risk of EC was three times higher in women with PCOS compared to women without the disease [6]. Endometrial hyperplasia Endometrial hyperplasia (EH) which is a precancerous lesion of the endometrium has identical risk factors to EC and in one study, 30% of women with atypical EH who were treated hormonally progressed to cancer [16]. In addition, previous data has revealed that 40% and 59% of women who were diagnosed as EH and carcinoma-in-situ respectively, developed EC within 2 years when managed expectantly [17]. Concurrent EC was likely to occur in 20–43% [18]. These facts therefore strengthen the case for effective prevention of EC in women at high risk such as PCOS by treating EH in PCOS. In general the incidence of EH varies depending on the pathologic diagnosis with an incidence of 24–44% for simple hyperplasia and 25–38% for atypical hyperplasia [19,20]. The prevalence of EH in women with PCOS however varies from 1 to 48.8% [21–24]. In a study by Tingthanatikul et al., 2006 [21], the prevalence and clinical predictors of EH in amenorrheic women with anovulation were evaluated. Fifty-seven women were enrolled in the study of whom, 43 had PCOS and 14 had idiopathic anovulation. An endometrial biopsy was taken using a pipelle instrument. The results showed that the prevalence of EH was 48.8% and 35.7% in PCOS and idiopathic anovulatory women respectively. In another study [22], 56 women with PCOS presenting with infertility due to anovulation underwent both vaginal ultrasound assessments and endometrial biopsies. Thirty-six PCOS patients (64.3%) had proliferative endometrium and 20 (35.7%) had endometrial hyperplasia. Five of the latter (25%) had cytologic atypia. These studies showing a high prevalence of PCOS however contrast with the results of two studies which suggest a lower prevalence of EH in PCOS [23,24]. In the first study, endometrial biopsies were obtained from 93 women with PCOS compared with 40 healthy women [23]. In women with PCOS, simple endometrial hyperplasia without atypia was found in one patient (1.08%). In the second study [24], a prevalence of EH of 1% was found in women with PCOS. In this study [24], 963 premenopausal women consecutively referred with the diagnoses PCOS and/or hirsutism during 1997–2008 to the Departments of Endocrinology and Gynaecology, Odense University Hospital, Denmark were recruited. In 2011, The Danish data bank of pathology was used to identify women with
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endometrial histology diagnoses. EH was diagnosed in 10 (1.0%) women and EC in one (0.1%) woman suggesting a low prevalence of EH and EC in PCOS. A review of the data in the article however would suggest that of the 963 women recruited into the study, endometrial biopsies were only available for 128 women, suggesting a higher prevalence of EH (8%) and EC (0.8%) in PCOS, than presented in the abstract of the paper. This wide range (1–48.8%) in the reported prevalence of EH in PCOS in the literature may however be a reflection of the heterogeneous nature of the PCOS phenotype and varying diagnostic criteria. The 3 fold increased risk of EC in PCOS, and the link between EH and EC does however suggest that an association between EH and PCOS [6]. There is no standardised guideline for the management of EH [25] and the treatment options depend on the age, fertility concerns and histopathological severity of EH. In one study, total hysterectomy was the treatment in 80% for cases of atypical endometrial hyperplasia [25] where the risk of concurrent EC is substantially high. Progesterone based hormonal therapy (oral and intrauterine device), and/or repeat endometrial assessment are reserved for younger women and those intending childbearing [26–28]. Treatment of EH with progestogens is however not always completely effective. One study for example revealed that 26.9% women with atypical EH who received progestin for at least 3 months had persistent or progression of EH compared to 66.7% in those who did not receive progestin (RR 0.39, 95% CI 0.21– 0.70) [27]. A relapse rate of 14–30% [8] following progesterone therapy in women with EH has also been reported and down regulation of the progesterone receptors has been identified [29]. As fertility is of concern particularly in women with PCOS, long term progestin use may not be ideal in all women. An alternative to progesterone treatment of EH in PCOS is therefore required.
Molecular links between PCOS and EC or EH, and the arguments in favour of a role for metformin in EC prevention in women with PCOS PCOS is thought to be primarily due to dysregulation in endocrine homeostasis of the pituitary–ovarian axis and peripheral cells (liver, adipose tissue and adrenal glands) which, ultimately results in unopposed or inadequately opposed estrogen, hyperandrogenism and insulin resistance [30]. Hyperandrogenism and hypersecretion of luteinizing hormone (LH) are common features in PCOS which result in overexpression of endometrial androgen receptors [31] and endometrial cancer growth in-vitro [32]. However, with regards to the EC risk in PCOS, hyperinsulinaemia appears to play the principal role in its pathogenesis [33–35]. Hyperinsulinaemia and insulin resistance also appear to be linked to the pathogenesis of EC in PCOS regardless of body mass index (BMI) [34]. The molecular mechanism is thought to involve activation of key signalling pathways including PI3K/Akt and Ras/MAPK− although these signalling pathways are shared among insulin, IGF-1 and estrogen pathways. This activation of the PI3K/Akt and Ras/MAPK pathways results in exaggeration of IGF-1 and IGFBP expression which promotes mitogenesis of cancer cells in the endometrium [35] and one study has shown that IGF-1 was significantly abundant in the endometrium in women with EC [36]. Hyperinsulinaemia also contributes to over expression of the LH/hCG and progesterone dysfunction which causes chronic anovulation in the ovarian cycle. This indirect mechanism results in low blood sex hormone binding globulin (SHBG) levels and high blood estrogen and androgen levels, which in turn promote the development of EC. Furthermore animal model experiments on rats found that phosphorylation of Akt, mTOR, and S6K1 was increased in cells which were exposed to insulin and testosterone, exaggerating insulin resistance and cell proliferation [37]. Hence, the reduction of testosterone and the decrease of aromatase activity mediated by metformin may be important for the prevention of endometrial pathology [38]. In addition, the anti-proliferative effect of metformin could inhibit the mTOR mediated S6K1 activation in the endometrium [39].
Moreover, it has been shown that in women with hyperinsulinaemia and obesity, the risk of developing EC is more significant with an OR of 8.4 compared to 1.67 in those with metabolic syndrome [40]. Friedenreich et al., 2011 [41], also found that a triad of obesity, insulin resistance and diabetes in metabolic syndrome carried significant risks of EC. Even in women without estrogen exposure, hyperinsulinaemia and diabetes, put them at increased risk of EC [42]. Insulin has also been found to accelerate the proliferation of cancer cell in the endometrium in an in-vitro study [43], and the concentration of IGF-1 was correlated well to the malignant cells differentiation [44]. On the other hand, the exact molecular mechanisms and pathways linking PCOS to EC are however not completely understood as the relationship between circulating IGF-1 levels and EC is controversial, with some studies showing an inverse association, no association or even a positive association [45–49]. Further investigation is needed to clarify this relationship and facilitate clinical studies investigating the role of metformin in PCOS. Similar mechanisms have also been implicated in the link between PCOS and EH. In a study of 52 patients with PCOS who underwent dilatation and curettage compared with 32 controls, the expression of p-Akt was significantly higher in the PCOS group compared with the control group with the expression of p-Akt significantly higher in the group with EH and EC compared with those in normal endometria group [50]. A gene expression profile consistent with progesterone resistance and corresponding with EH and EC, has also been identified in women with PCOS [51]. Over activation of the MAPK/ERK signalling pathway in the endometrium of women with PCOS has been linked EH and EC in PCOS [52], with activation of MAPK/ERK signalling pathway affected by insulin resistance and hyperinsulinaemia. Although other factors not directly related to the insulin pathway have been linked to EH and PCOS, including CDK2 and p27 [53], lower levels of steroid sulfatase mRNA and estrogen sulfotransferase [54], Cyr61 overexpression [55], reduced apoptosis [56], and elevated gene and protein expression of androgen receptor, and estrogen receptor β [57], most of the pathways identified in the literature seem to be linked to insulin resistance, making a case for exploring the role of metformin treatment in EH and PCOS. Improvement of insulin resistance also reduces androgen levels. Metformin (insulin sensitizer) in reducing EC risk in women with PCOS Metformin is a biguanide, which lowers the rate of gluconeogenesis in the presence of insulin and is therefore called as insulin sensitizer. Based on the concept that insulin resistance plays a major role in the pathogenesis of PCOS, it has led to an increase in the use of metformin (or other insulin sensitizers) in PCOS in the context of infertility, obesity and hirsutism but not in EC prevention. Metformin has however been shown to exert a chemo protective and anti proliferative effect on numerous cancers [11,58]. It does this by a reduction in cell growth, which is modulated partly via insulin and non-insulin relevant pathways. Metformin also decreases cell growth by activating the growth inhibitory AMPK which interrupts the signalling through P13K/AKT and MAPK pathways in the insulin and IGF1 receptors [45]. In an in-vitro study, metformin was found to increase progesterone receptor expression in EC Ishikawa cell lines whereas IGF-1 and IGF-2 inhibited progesterone receptor mRNA, suggesting metformin had an antitumor effect [14]. This experiment also recognised that metformin had a complimentary antitumor effect with medroxyprogesterone acetate (MPA) in EC. Given the fact that progesterone receptor expression is important in the prevention of EC, the combination of metformin and MPA may be an effective way to control it, especially in progesterone receptor poor cancers. The risk of EC in women with PCOS has traditionally been reduced by inducing a withdrawal bleed every 3 to 4 months with progestogens [22]. However, in the context of the molecular links between EC and
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insulin resistance outlined above, it has been proposed that agents which improve insulin resistance such as metformin may be used to reduce EC risk in this group of women [59]. Studies to evaluate the efficacy or investigate the molecular changes in the endometrium following metformin use in PCOS are however limited.
EH were being estimated. There is therefore a need for more studies investigating the role of metformin in reducing EC risk in PCOS.
Research published so far on reducing endometrial hyperplasia and endometrial cancer risk in PCOS using metformin (Table 1)
This article has examined the case for the use of metformin in reducing EC risk in women with PCOS and the evidence would suggest that given the link between insulin resistance and EC, insulin sensitizers such as metformin could reduce EC risk in PCOS. To date however, there has been scarce research data to support metformin use in PCOS women for EC prevention. There is therefore a need for further research to evaluate this link. This is particularly important as although the pathogenesis of PCOS has been linked with insulin insensitivity and hyperinsulinaemia and a three-fold increase in EC risk in PCOS has been found, the exact molecular mechanisms and pathways linking PCOS to EC are not completely understood. Given the fact that the relationship between circulating IGF-1 levels and EC remains controversial, with some studies showing an inverse association, no association or even a positive association [45–49], further investigation is needed to clarify this relationship. There is therefore a need for more basic science studies and large clinical trials evaluating the role of metformin in reducing EC risk in PCOS.
A search of the Cochrane website of systematic reviews carried out in April 2013 using the search terms “metformin and endometrial hyperplasia” and “metformin and endometrial cancer” did not identify any published or ongoing reviews. Two animal studies addressing this issue were identified in our literature review. In one study, metformin reversed features of EH in mice where EH had been previously caused by estrogen treatment [39]. In the second study metformin significantly reduced all features indicating EH with respect to the control group in rats treated with metformin and estrogen compared with rats treated with estrogen alone [60]. There were two studies on the endometrial cell lines found. A study on the Ishikawa and HEC-1B EC cell demonstrated a synergistic antiproliferative effect of metformin and medroxyprogesterone acetate on endometrial cancer cells [14]. Another study revealed a reduction in in-vitro endometrial cells invasion (inflammation and cell migration) between sera from PCOS women and control after 6 months of metformin treatment [48]. Three human studies were identified. In a case report published in 2003, a 37 year old woman with atypical EH that had failed to respond to treatment with progestogens was successfully treated with metformin [61]. In the second study, simple EH found on biopsy in two women with PCOS was absent after 3 months treatment with metformin and rosiglitazone [49]. In the third study, two women with atypical EH complicating PCOS and who had failed to respond to high-dose progestin therapy had EH reversed after 3 months treatment with metformin [62]. The findings of these studies were summarised in Table 1. No published clinical trials were identified; however, one ongoing study [63] was identified following a search of the relevant databases in which in a pilot study at the University of North Carolina in the USA, the response rate and safety of metformin for the treatment of
Conclusion and recommendations for future research
Authors' roles M.N.S., G.K. and R.A. prepared the article, supervised and edited by W.U.A. J.A., C.C., C.S., D.B., S.D., and D.N. reviewed and commented on the scientific contents. All authors proof read the article before submission.
Funding This study received no funding.
Conflict of interest All authors declare no conflict of interest.
Table 1 Summary of literature review on “Metformin and Endometrial Hyperplasia” and “Metformin and Endometrial Cancer.” Author, year Tas et al, 2013 [60]
Erdemoglu et al, 2009 [39]
Wang et al, 2011 [14] Tan et al, 2011 [48]
Type of study Animal studies Experimental
Experimental
Cell lines studies Experimental Experimental Human studies
Legro et al, 2007 [49] Session et al, 2003 [61]
Randomised open-label Case report
Shen et al, 2008 [62]
Case report
Description
Findings
Forty oopherectomized Wistar-Albino rats were assigned to receive saline, 17 β estradiol hemihydrate, 17 β estradiol hemihydrate and metformin, 17 β estradiol hemihydrate and MPA for 14 days Forty-eight oophorectomized Balb/c mice were assigned to receive saline, tamoxifen citrate, 17 β estradiol hemihydrate, metformin, tamoxifen citrate with metformin or estradiol with metformin for 3 days
Metformin reduced estrogen-induced endometrial hyperplasia in oophorectomized rats
Interaction of metformin, PR and IGF-II expression in cell lines and assessed the antitumour effect of metformin Sera taken from two groups — PCOS and controls. In vitro invasion assessed in human endometrial cells by woundhealing motility and migration assays Sixteen PCOS recruited. Assessment done at 6-week (baseline), 3-month treatment period of single-agent therapy (rosiglitazone or metformin), and 3-month period of combined therapy One month treatment with metformin in a 37 year old woman with atypical hyperplasia Two PCOS women with atypical hyperplasia and failed progestin therapy. Received 3 months metformin and oral contraception
Metformin increased progesterone receptors expression and inhibited by overexpressed IGF-II in endometrial cancer In vitro invasion in endometrial cells was reduced by sera from PCOS women after 6 months of metformin treatment compared to matched controls One case of adenocarcinoma — excluded. Two simple hyperplasia — resolved with treatment Atypical endometrial hyperplasia regressed after metformin
Metformin with tamoxifen or estradiol reduced the density of endometrial glands and epithelial cell. Metformin with tamoxifen reduced the H-score of S6K1 and immunohistochemical expression of PCNA in endometrial glandular and stromal cells Metformin with estradiol reduced the H-score of S6K1 and immunohistochemical expression of PCNA in endometrial glandular and stromal cells.
Regression of atypical endometrial hyperplasia
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Acknowledgment The Faculty of Medicine, National University of Malaysia (UKM) and the Ministry of Higher Education Malaysia (MoHE) supported the PhD candidate (MNS) for his study leave.
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