Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 19–27

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Best Practice & Research ClinicalObstetrics and Gynaecology

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2

Anovulation with or without PCO, hyperandrogenaemia andhyperinsulinaemia as promoters of endometrial andbreast cancer

Spyros Papaioannou, MD, MRCOG, Honorary Senior Lecturer,University of Birmingham, Consultant Obstetrician and Gynaecologist a,*,John Tzafettas, MD, PhD, FRCOG, Professor of Obstetrics and Gynaecology b

a Heart of England NHS Foundation Trust, Heartlands Hospital, University of Birmingham, Birmingham B9 5SS, UKb 2nd Department of Obstetrics and Gynecology, Aristoteleion University of Thessaloniki, Hippokration Gerneral Hospital,49 Konstantinoupoleos Street, 54642 Thessaloniki, Greece

Keywords:breast cancerendometrial cancerhyperandrogenaemiahyperinsulinaemiaobesityPCOpolycystic ovariesmetabolic syndrome

* Corresponding author. Fax: þ44 121 4243130.E-mail address: spyros.papaioannou@heartofen

1521-6934/$ – see front matter � 2009 Elsevier Ltdoi:10.1016/j.bpobgyn.2008.11.010

The relationship of infertility, endocrinology and cancer hasbecome clearer in recent years. Polycystic ovaries (PCO) increasethe risk of endometrial cancer. Prolonged amenorrhoea, therefore,should be prevented in such cases with the use of cyclicalprogestogens, in order for regular withdrawal bleeds to be inducedand the endometrium protected from long-term unopposed oes-trogen stimulation. There is no secure evidence base on whicha relationship between PCO and breast cancer can be based. Nospecific breast screening for women with PCO is, therefore, rec-ommended. Hyperandrogenaemia and hyperinsulinaemia areconditions whose significance in terms of increasing both endo-metrial and breast cancer risks is increasingly recognised. Theexact mechanism with which they influence carcinogenesis is stillfar from clear. Whether they act in isolation or as expressions ofthe common background of the metabolic syndrome – in inter-action with other components of this syndrome – is still thesubject of research.

� 2009 Elsevier Ltd. All rights reserved.

Fertility concerns are frequently at the forefront of the interaction between women with polycysticovaries (PCO) and their physicians. Most of them present at a young age to their doctors, whounderstandably do not find it easy to input the word cancer into their thoughts about how to best help

gland.nhs.uk (S. Papaioannou).

d. All rights reserved.

S. Papaioannou, J. Tzafettas / Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 19–2720

these women. High androgen or high insulin levels, which can be part of the PCO presentation,similarly are processed with a focus on the immediate medical presentation and rarely with anyconsideration of the future risk of malignancy and how this can be modified.

However, the risk of cancer in these circumstances is recognised by an expanding part of themedical literature. Some associations are much better established than are others. Crucially, inter-ventions are available, which can lower this risk. We cannot deny that women should be given advicewith regards to the information available, lifestyle changes and medical interventions that mightprevent such risk even if prevention, in this case, aims to avoid complications decades into the future.Therefore, an examination of the subject would be important.

Excess body weight on its own, on the other hand, characterised by chronic hyperinsulinaemia andinsulin resistance – which in turn can result in increased androgen production by the ovaries – isimplicated in both cancer risk and cancer mortality. The list of cancers at increased risk of developmentin an ‘obesogenic’ environment includes not only common adult cancers such as endometrial and post-menopausal breast as well as colon and kidney cancer, but also less common malignancies such asleukaemia, multiple myeloma and non-Hodgkin’s lymphoma.1 The pathophysiological mechanismsunderpinning these associations are only starting to be understood. Insulin resistance is at the heart ofmany, but there are several other candidate systems including insulin-like growth factors (IGFs), sexsteroids, adipokines, obesity-related inflammatory markers, the nuclear factor kappa beta (NF-kappa B)system and oxidative stresses. Excess body weight, a medical condition which has reached epidemicproportions, might be central to the interaction of all the components of this discussion with each other.

Anovulation

There is no disagreement that PCO is the most common endocrine condition affecting womenworldwide. About 20% of women in the reproductive age group show some of the elements applied inthe diagnosis of PCO, with half of them also having clinical or biochemical signs of anovulation orandrogen excess (obesity, hirsutism, infertility, etc.) – a separate condition called polycystic ovariansyndrome (PCOS).2,3 The incidence of this condition is higher among certain ethnic groups.4

Until recently, however, there were different definitions of PCO on the two sides of the Atlantic. Thisdiscrepancy came to an end only in 20045 with the publication of a consensus statement by theEuropean Society of Human Reproduction and Embryology and the American Society for ReproductiveMedicine (Rotterdam Criteria – Table 1). Therefore, it is apparent that the interpretation of researchinto the long-term effects of PCO is hindered by the differences between populations included inprevious reports. Nevertheless, some safe conclusions can be drawn about the relationship of PCO andrisk of endometrial cancer. The picture as regards the relationship of PCO and breast cancer is unclear.

Endometrial cancer

The risk factors of endometrial cancer are well established and are shown in Table 2. An initialinspection of this table reveals the potential for an association between PCO and endometrial cancer.High or prolonged (i.e., early menarche and late menopause) exposure to oestrogen can be linked to thehigh oestrogen levels that have been documented in women with PCO. Obesity, infertility and fewerbirths are common characteristics of women with PCO, and hypertension and diabetes are morecommon in women with PCO than in controls.

Table 1The Rotterdam criteria.5

Two of the three criteria should be present

� Anovulation� Clinical or biochemical signs of hyperandrogenaemia� Polycystic ovaries on ultrasound examination

In the absence of other endocrinological conditions, congenital adrenal hyperplasia, androgen-secretingtumours and Cushing’s syndrome.

Table 2Risk factors for endometrial cancer.

� Early menarche45

� Late menopause45

� Infertility46,47

� Fewer births45,47

� Hypertension47

� Diabetes48

� Obesity48,49

� Unopposed oestrogen supplementation50

� Tamoxifen51

� Family history52

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The first reference to a possible association between PCO and endometrial cancer was published in19496, 14 years after the classical first description of PCOS by Stein and Leventhal.7 Later, Jafari et al.reported a series of six cases of adenocarcinoma of the endometrium in women with the Stein–Leventhal syndrome (SLS; PCOS)8, where they noted that such women can be young: the average age ofthe patients was 27.8 years. All of them were treated surgically. In another study, 25% of a group ofwomen diagnosed with adenomatous or atypical adenomatous endometrial hyperplasia wereconfirmed on ovarian biopsy to have PCO. The mean age of these women was also a young 25.7 yearsand all of them were nulliparous.9 Furthermore, a study that looked into a group of 2573 infertilewomen who underwent endometrial biopsies confirmed four cases of endometrial cancer – all of themin women diagnosed with PCO.10

Although the association between PCO and endometrial cancer is established, the exact size of theextra risk is difficult to calculate accurately. The risk of developing endometrial cancer was assessed ina group of 1270 women who were diagnosed with ‘chronic anovulation syndrome’. The diagnosis wasbased on macroscopic or pathological evidence of the SLS or a clinical diagnosis of chronic anov-ulation.11 The additional risk of endometrial cancer was identified in this study to be 3.1 (95% confi-dence interval (CI): 1.1–7.3). It suggested that this additional risk might be due to unopposed oestrogen.In a retrospective study of 399 women diagnosed with endometrial cancer matched with a controlgroup of women without the disease of comparable demographic characteristics, an adjusted oddsratio for endometrial cancer of 4.2 (95% CI: 1.7–10.4), for women who reported infertility resulting fromovarian factors, was identified.12

In view of the above findings, the previously accepted principle that prolonged amenorrhoea forPCO women does not matter has shifted towards a proactive approach. Prophylactic cyclical proges-terone administration is recommended for the prevention of endometrial pathology.13 This can be ona monthly basis, although some experts suggest that a withdrawal bleed every 3 months is sufficient.14

It would be important to stress the necessity of ensuring that such women are not pregnant beforestarting them on any medication.

In this treatment, as in other areas of cancer treatment, the literature is characterised bya journey from the radical to a more conservative approach. This is especially important in womenwith PCO diagnosed with endometrial cancer as many of them are young and would much ratherretain their fertility. Histological typing is crucial, as well-differentiated tumours allow more scopefor conservative management.15 Some fertility success stories exist. Muechler et al. inducedovulation with gonadotrophins in a woman with well-differentiated endometrial adenocarcinomatreated with medroxyprogesterone acetate for 6 months, following which she had persistentadenomatous hyperplasia of the endometrium, but not cancer.16 She conceived twice: her firstpregnancy – a twin gestation – ended in a miscarriage; however, she then had a successfulsingleton pregnancy, after which a hysterectomy was performed that showed adenomatoushyperplasia but no malignancy. In Kurabayashi’s series from Japan, high-dose medroxyprogesteroneacetate therapy combined with assisted reproductive technology resulted in a pregnancy in one ofthe two patients with endometrial carcinoma.10 Similarly, Yarali et al. reported a successful preg-nancy in a woman with PCO and endometrial cancer following high-dose progesterone and intra-cytoplasmic sperm injection (ICSI) treatment.17

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Breast cancer

An inspection of the risk factors for breast cancer (Table 3) gives us an instant overview of thepossible relationship of PCO with the disease. Many of these risk factors (i.e., early menarche, latemenopause, obesity, nulliparity, fewer births, etc.) are similar or identical with risk factors for endo-metrial cancer, and again relevant to women with PCO. However, in contrast to endometrial cancer, therelationship between PCO and breast cancer remains unclear.

Prospectively collected data for 34 835 women aged between 55 and 69 years enrolled in the IowaWomen’s Health Study recorded 883 cases of breast carcinoma; of these, 14 were among women whoreported a history of the SLS. Following adjustment for age at menarche, age at menopause, parity, oralcontraceptive use, body mass index (BMI), waist-to-hip ratio and family history of breast carcinoma,the relative risk (RR) for breast cancer for women with SLS was 1 (95% CI: 0.6–1.9). The authorsconcluded that despite the high-risk profiles of women with SLS, these results do not suggest that thesyndrome per se is associated with an increased risk of post-menopausal breast carcinoma.18 The risk ofbreast cancer was assessed in a cohort of 786 women diagnosed with PCO who were age matched with1060 control women. There was no significant difference in the incidence of breast cancer between thetwo groups, with the odds ratio for the disease being 1.5 (95% CI: 0.7–2.9).19

Other authors, however, described a significant association of PCO with breast cancer. Coulam et al.followed up a cohort of 1270 women with chronic anovulation. Although the initial data analysis didnot identify a significantly increased risk of breast cancer in this population, when ‘post-menopausal’women were examined separately, there was an RR of 3.6 (95% CI: 1.2–8.3) for the disease. On thecontrary, Gammon and Thompson reported a decreased risk of breast cancer in women with PCO. Ata multicentre, population-based study of 4730 women with breast cancer and 4688 control women,the age-adjusted odds ratio for breast cancer among women with a self-reported history of physician-diagnosed PCO was 0.52 (95% CI: 0.32–0.87).20

Hyperandrogenaemia

The differential diagnosis of hyperandrogenaemia includes PCOS, ovarian and adrenal androgen-secreting tumours, ovarian and adrenal steroidogenic enzyme deficiencies as well as other endo-crine disorders such as hyperprolactinaemia, Cushing’s syndrome and acromegaly. However, itshould be remembered that about 95% of hyperandrogenic women will have PCOS.21 By far, mostresearch has concentrated on PCOS, with little clinical evidence being available about the interactionof hyperandrogenaemia in isolation on endometrial or breast carcinogenesis. It is certain, however,that androgens are involved in many regulatory processes in the mammary and endometrialepithelia.22

Endometrial cancer

The androgen receptor as well as 5a-reductase – the enzyme that catalyses the conversion oftestosterone to the bioactive and potent androgen 5a-dihydrotestosterone (DHT) – have been identified

Table 3Risk factors for breast cancer.

� Early menarche53

� Late menopause54

� Nulliparity55

� Fewer births56

� Increased age at first birth56

� High endogenous oestrogena,57

� Obesitya,58

� Hormone replacement therapy59

� Age56

� Family history/BRCA genes60

a Risks factors specifically associated with post-menopausal breast cancer.

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both in normal endometrial cells as well as in endometrial hyperplasia and endometrial adenocarci-noma cells. We also know that DHT plays a more important role than testosterone itself in the regulationof androgen action in endometrial cancer and the normal human endometrium. This is especially thecase during the secretory phase, in which both androgen receptors and 5a-reductase are increased.23

Furthermore, it is well established that post-menopausal oestrogens originate mainly fromperipheral conversion (aromatisation) of androgens, which are produced by the ovaries and theadrenal glands. Prolonged exposure to unopposed oestrogens, as discussed above, contributes towardsneoplastic endometrial development.

In post-menopausal women, ovarian stromal hyperplasia is associated with increased androgenproduction by the ovaries, which – through above pathway – can lead to the development of endo-metrial pathology. There is a possibility that in cases of endometrial pathology, an increased productionof aromatisable androgens by post-menopausal ovaries leads to elevated pre-hormone availability forthe formation of oestrogen in utero. Following the conversion of ovarian androgens, a reaction cata-lysed by the cytochrome p450 aromatase enzyme system, oestrogens may function even as a localmitogenic factor, eventually leading to the development of endometrial cancer. The local availability ofandrogens and the local activity of aromatase may be relevant for this process. If this hypothesis provesto be right, it may give rise to the introduction of aromatase inhibitors in treatment strategies ofhormone-dependent endometrial malignancies.24

On the other hand, in a study of transplanted human, well-differentiated endometrial cancer ina nude mouse model, both aromatisable and non-aromatisable androgens have had little growth-promoting effect on endometrial carcinoma. Oestradiol is the most potent growth stimulus.25 Humandata are unfortunately lacking in a subject that may have value in cancer prevention, and therefore thisarea should be seen as a research target.

Breast cancer

Increased ovarian testosterone production has been shown to be associated with an increased riskof both pre- and post-menopausal breast cancer.26–28 The way androgens work in this case may as wellbe because of their transformation into excess oestrogen.

As discussed above, in post-menopausal women, androgens, chiefly androstenedione, are the mainsources of oestrogens.29 Especially in obese patients and even more so in patients with a high waist-to-hip ratio, the concentration of sex-hormone-binding globulin (SHBG) is low30, and as a result the freeandrogen concentration, which is the biological active fraction of androgen, is increased. At the sametime, obesity accelerates the peripheral conversion of androgens to oestrogens, and unopposed oes-trogens contribute to an increased risk of endometrial cancer and may well contribute to an increasedrisk of breast cancer as well, as described earlier. A relationship between these factors and familialbreast cancer has been also proposed.31

Androgens can also directly increase the risk of cancer by increasing the proliferation of cells afterbinding to androgen receptors.32 One hypothesis also claims that the hormonal promotion ofmammary carcinogenesis is likely to be greatest between puberty and the first full-term pregnancy.Hyperandrogenaemia at puberty and during the reproductive years interferes with ovulation and mayresult in infertility as well.33

Hyperinsulinaemia

Endometrial cancer

It is well established that diabetes is a risk factor for endometrial cancer. More specifically, type I(insulin-dependent) diabetes appears to have a much higher association with this condition thantype II diabetes. In a large population-based, nationwide, case-control study in Sweden, amongpost-menopausal women aged 50–74 years, there were 709 cases of histologically verified endometrialcancer. These were matched with data from 3368 controls. The odds ratio for endometrial cancer inpatients with type II diabetes was 1.5 (95% CI: 1.0–2.1), while for patients with type I diabetes it wasnearly 10 times as high at 13.3 (95% CI: 3.1–56.4).34

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In addition, obesity in the case of hyperinsulinaemia seems to play a central role in the modulationof this risk. In a prospective cohort study of 36 773 women, including 225 endometrial adenocarcinomacases, and after adjustments, the RR for endometrial cancer among women with diabetes comparedwith non-diabetic women was 1.94 (95% CI: 1.23–3.08). Among obese diabetics, the RR was 6.39 (95%CI: 3.28–12.06) compared with non-obese, non-diabetic women.35 Chronic hyperinsulinaemia hasbeen confirmed to result from long-term consumption of a high-glycaemic load diet: high glucose-loaddiet consumers have a significantly higher risk of endometrial cancer (RR: 1.20; 95% CI: 1.06–1.37),further elevated for obese women (RR: 1.54; 95% CI: 1.18–2.03).36 Patients with endometrial cancerhave higher fasting serum insulin levels and significantly higher insulin responses after glucoseadministration than normal women.37

Nevertheless, insulin resistance has been found to increase the risk of endometrial cancer inde-pendently from BMI.38

Breast cancer

The metabolic syndrome consists of visceral adiposity, insulin resistance, hyperglycaemia andhyperinsulinaemia with or without clinically manifest diabetes mellitus, low high-density lipoproteincholesterol serum levels and hypertension. All of the above have been related to an increased risk ofbreast cancer.39

The incidences of breast cancer, type II diabetes and the metabolic syndrome have increasedover the past decades, with obesity reaching epidemic proportions, especially in industrialisedcountries. Insulin resistance, hyperinsulinaemia and changes in the signalling of growth hormonesand steroid hormones associated with diabetes may affect the risk of breast cancer. A review ofthe epidemiological evidence supports a modest association between type II diabetes and the riskof breast cancer, which appears to be more consistent among post-menopausal, than among pre-menopausal, women.40

Hyperinsulinaemia has been found to correlate with increasing BMI, on the one hand, as wellas the risk of recurrence and mortality in breast cancer, regardless of oestrogen receptor status, onthe other.41,42 One of the mechanisms that have been hypothesised to explain this effect is thatthe presence of hyperinsulinaemia can increase the ovarian production of androgens, and theabnormal hormonal profile may stimulate proliferative activity in the mammary epithelium, whichin turn increases the risk of epithelial atypia and carcinogenesis.43 Another possibility is thathyperinsulinaemia and IGFs cause both hyperandrogenaemia during the reproductive years and anincreased risk of breast cancer in pre- and post-menopausal women.

Obesity may be the starting point of the chain of events that, through the effects of increasedcirculating insulin and IGF concentrations, which act as mitogens, results in higher susceptibility tobreast cancer. Insulin resistance develops as a metabolic adaptation to increased levels of circu-lating non-esterified fatty acids released from adipose tissue, especially intra-abdominal adiposetissue. Increasing concentrations of these non-esterified fatty acids force the liver, muscles andother tissues to shift towards storage and oxidation of fats for energy. In the metabolic syndrome,tissues are not able to absorb, store and metabolise glucose efficiently. Therefore, to preventelevated concentrations of glucose in the blood, the pancreas secretes increasing amounts ofinsulin in both the fed and fasted states.44 Furthermore, adipocytes also make up the bulk of thehuman breast, with epithelial cells accounting for only approximately 10% of human breastvolume. Therefore, it may be that the increased local production of such substances in the breastmight be part of the problem.

Despite many proposed potential pathways, the mechanisms underlying an association betweendiabetes and breast cancer risk remain unclear, particularly because the two diseases share several riskfactors, including obesity, a sedentary lifestyle and, possibly, intake of saturated fat and refinedcarbohydrates that may confound this association.

To summarise, the subject of infertility and cancer is best addressed by the assumption that both ofthese conditions are results of a process which is common in its nature and present with infertility inyounger women with the focus progressively shifting towards cancer as age advances. At the centre ofthis process is excess body weight – more adequately termed the metabolic syndrome. The relatively

S. Papaioannou, J. Tzafettas / Best Practice & Research Clinical Obstetrics and Gynaecology 24 (2010) 19–27 25

recent, in the history of mankind, event of food – more specifically processed food – oversupply hasresulted in the metabolic syndrome becoming the common background of women who consult theirgynaecologist starting with infertility (or menstrual irregularities) and then, later in their lives, moveon to the physicians’ consulting rooms for treatment of diabetes, hypertension and hyper-cholesterolaemia, eventually finding themselves in the oncologist’s theatre or radiotherapy room forcancer.

The question of PCO or non-PCO is not only of least priority, in many cases there is no clear answer tothis. The long history of changing diagnostic criteria for PCO testifies to the practical difficulties thatthis superficially easy distinction hides. However, in most of these cases, the manifestations of themetabolic syndrome, insulin resistance, high androgen levels and others take the lead towardsthe unwanted consequences of this condition, regardless of the incidence of PCO. PCO may provide thebackground for easier and faster transition from a healthy state to the unhealthy state of the metabolicsyndrome. In the process of evolution, human life has uncovered that financial progress, with foodbecoming more widely available at least in the West than ever before, has biological consequences.Human physiology has not been constructed to support increasing BMIs – a process that leads tohuman pathophysiology, morbidity and mortality.

It is difficult to study PCO in isolation to hyperandrogenaemia or hyperinsulinaemia and vice versa.The evidence is, however, moving towards the acceptance that all of these factors collaborate to resultin increased risk of cancer not only of the endometrium but also of the breast. The external appearanceof these women, regardless of the diagnostic classification that we accept, has changed little from thatdescribed by Stein and Leventhal all these years ago. The frequency of such women in our consultingrooms, however, has massively increased. The advice we give them is simple, sound and apparentlysaves lives: losing weight, a healthy diet and exercise can put the destructive forces of the metabolicsyndrome back into the Pandora’s box. However, human nature (unchanged from the era of Greekmythology to date) might mean that the conditions described in this article will persist with us fora long time to come.

Practice points

� Women with PCO should have regular withdrawal bleeds induced.� Young women with PCO and abnormal uterine bleeding should have endometrial biopsies

done.� There is no evidence to justify a breast cancer-screening programme for women with PCO.

Research agenda

� The exact relationship of PCO with the risk of breast cancer.� The exact influence of excess androgen in human endometrial carcinoma development and

the potential for medical modification of this process towards risk reduction.� The interaction of insulin, androgens and the metabolic syndrome in general with the process

of carcinogenesis.

Conflict of interest

The authors declare that they have no conflicts of interest.

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