Best Practice & Research Clinical Obstetrics & Gynaecology
Volume 24, Issue 1 , Pages 19-27, February 2010

Anovulation with or without PCO, hyperandrogenaemia and hyperinsulinaemia as promoters of endometrial and breast cancer

  • Spyros Papaioannou, MD, MRCOG (Honorary Senior Lecturer, University of Birmingham, Consultant Obstetrician and Gynaecologist)

      Affiliations

    • Heart of England NHS Foundation Trust, Heartlands Hospital, University of Birmingham, Birmingham B9 5SS, UK
    • Corresponding Author InformationCorresponding author. Fax: +44 121 4243130.
    • ,
  • John Tzafettas, MD, PhD, FRCOG (Professor of Obstetrics and Gynaecology)

      Affiliations

    • 2nd Department of Obstetrics and Gynecology, Aristoteleion University of Thessaloniki, Hippokration Gerneral Hospital, 49 Konstantinoupoleos Street, 54642 Thessaloniki, Greece

published online 23 February 2009.

Article Outline

The relationship of infertility, endocrinology and cancer has become clearer in recent years. Polycystic ovaries (PCO) increase the risk of endometrial cancer. Prolonged amenorrhoea, therefore, should be prevented in such cases with the use of cyclical progestogens, in order for regular withdrawal bleeds to be induced and the endometrium protected from long-term unopposed oestrogen stimulation. There is no secure evidence base on which a relationship between PCO and breast cancer can be based. No specific breast screening for women with PCO is, therefore, recommended. Hyperandrogenaemia and hyperinsulinaemia are conditions whose significance in terms of increasing both endometrial and breast cancer risks is increasingly recognised. The exact mechanism with which they influence carcinogenesis is still far from clear. Whether they act in isolation or as expressions of the common background of the metabolic syndrome – in interaction with other components of this syndrome – is still the subject of research.

Keywords: breast cancer, endometrial cancer, hyperandrogenaemia, hyperinsulinaemia, obesity, PCO, polycystic ovaries, metabolic syndrome

 

Fertility concerns are frequently at the forefront of the interaction between women with polycystic ovaries (PCO) and their physicians. Most of them present at a young age to their doctors, who understandably do not find it easy to input the word cancer into their thoughts about how to best help 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 any consideration 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 the medical literature. Some associations are much better established than are others. Crucially, interventions are available, which can lower this risk. We cannot deny that women should be given advice with regards to the information available, lifestyle changes and medical interventions that might prevent 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 and insulin resistance – which in turn can result in increased androgen production by the ovaries – is implicated in both cancer risk and cancer mortality. The list of cancers at increased risk of development in 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 as leukaemia, multiple myeloma and non-Hodgkin's lymphoma.1 The pathophysiological mechanisms underpinning these associations are only starting to be understood. Insulin resistance is at the heart of many, but there are several other candidate systems including insulin-like growth factors (IGFs), sex steroids, 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 epidemic proportions, might be central to the interaction of all the components of this discussion with each other.

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Anovulation 

There is no disagreement that PCO is the most common endocrine condition affecting women worldwide. About 20% of women in the reproductive age group show some of the elements applied in the diagnosis of PCO, with half of them also having clinical or biochemical signs of anovulation or androgen excess (obesity, hirsutism, infertility, etc.) – a separate condition called polycystic ovarian syndrome (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. This discrepancy came to an end only in 20045 with the publication of a consensus statement by the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine (Rotterdam Criteria – Table 1). Therefore, it is apparent that the interpretation of research into the long-term effects of PCO is hindered by the differences between populations included in previous reports. Nevertheless, some safe conclusions can be drawn about the relationship of PCO and risk of endometrial cancer. The picture as regards the relationship of PCO and breast cancer is unclear.

Table 1. The 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-secreting tumours and Cushing's syndrome.

Endometrial cancer 

The risk factors of endometrial cancer are well established and are shown in Table 2. An initial inspection 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 the high oestrogen levels that have been documented in women with PCO. Obesity, infertility and fewer births are common characteristics of women with PCO, and hypertension and diabetes are more common in women with PCO than in controls.

Table 2. Risk factors for endometrial cancer.

•Early menarche45

•Late menopause45

•Infertility46, 47

•Fewer births45, 47

•Hypertension47

•Diabetes48

•Obesity*48, 49

•Unopposed oestrogen supplementation50

•Tamoxifen51

•Family history52

The first reference to a possible association between PCO and endometrial cancer was published in 19496, 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 of the patients was 27.8 years. All of them were treated surgically. In another study, 25% of a group of women diagnosed with adenomatous or atypical adenomatous endometrial hyperplasia were confirmed on ovarian biopsy to have PCO. The mean age of these women was also a young 25.7 years and all of them were nulliparous.9 Furthermore, a study that looked into a group of 2573 infertile women who underwent endometrial biopsies confirmed four cases of endometrial cancer – all of them in women diagnosed with PCO.10

Although the association between PCO and endometrial cancer is established, the exact size of the extra risk is difficult to calculate accurately. The risk of developing endometrial cancer was assessed in a group of 1270 women who were diagnosed with ‘chronic anovulation syndrome’. The diagnosis was based on macroscopic or pathological evidence of the SLS or a clinical diagnosis of chronic anovulation.11 The additional risk of endometrial cancer was identified in this study to be 3.1 (95% confidence 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 control group of women without the disease of comparable demographic characteristics, an adjusted odds ratio for endometrial cancer of 4.2 (95% CI: 1.7–10.4), for women who reported infertility resulting from ovarian factors, was identified.12

In view of the above findings, the previously accepted principle that prolonged amenorrhoea for PCO women does not matter has shifted towards a proactive approach. Prophylactic cyclical progesterone administration is recommended for the prevention of endometrial pathology.13 This can be on a 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 before starting them on any medication.

In this treatment, as in other areas of cancer treatment, the literature is characterised by a journey from the radical to a more conservative approach. This is especially important in women with PCO diagnosed with endometrial cancer as many of them are young and would much rather retain their fertility. Histological typing is crucial, as well-differentiated tumours allow more scope for conservative management.15 Some fertility success stories exist. Muechler et al. induced ovulation with gonadotrophins in a woman with well-differentiated endometrial adenocarcinoma treated with medroxyprogesterone acetate for 6 months, following which she had persistent adenomatous hyperplasia of the endometrium, but not cancer.16 She conceived twice: her first pregnancy – a twin gestation – ended in a miscarriage; however, she then had a successful singleton pregnancy, after which a hysterectomy was performed that showed adenomatous hyperplasia but no malignancy. In Kurabayashi's series from Japan, high-dose medroxyprogesterone acetate therapy combined with assisted reproductive technology resulted in a pregnancy in one of the two patients with endometrial carcinoma.10 Similarly, Yarali et al. reported a successful pregnancy in a woman with PCO and endometrial cancer following high-dose progesterone and intracytoplasmic sperm injection (ICSI) treatment.17

Breast cancer 

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

Table 3. Risk factors for breast cancer.

•Early menarche53

•Late menopause54

•Nulliparity55

•Fewer births56

•Increased age at first birth56

•High endogenous oestrogena57

•Obesitya58

•Hormone replacement therapy59

•Age56

•Family history/BRCA genes60

aRisks factors specifically associated with post-menopausal breast cancer.

Prospectively collected data for 34 835 women aged between 55 and 69 years enrolled in the Iowa Women's Health Study recorded 883 cases of breast carcinoma; of these, 14 were among women who reported a history of the SLS. Following adjustment for age at menarche, age at menopause, parity, oral contraceptive 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 authors concluded that despite the high-risk profiles of women with SLS, these results do not suggest that the syndrome per se is associated with an increased risk of post-menopausal breast carcinoma.18 The risk of breast cancer was assessed in a cohort of 786 women diagnosed with PCO who were age matched with 1060 control women. There was no significant difference in the incidence of breast cancer between the two 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 did not 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 the contrary, Gammon and Thompson reported a decreased risk of breast cancer in women with PCO. At a 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

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Hyperandrogenaemia 

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

Endometrial cancer 

The androgen receptor as well as 5α-reductase – the enzyme that catalyses the conversion of testosterone to the bioactive and potent androgen 5α-dihydrotestosterone (DHT) – have been identified both in normal endometrial cells as well as in endometrial hyperplasia and endometrial adenocarcinoma cells. We also know that DHT plays a more important role than testosterone itself in the regulation of androgen action in endometrial cancer and the normal human endometrium. This is especially the case during the secretory phase, in which both androgen receptors and 5α-reductase are increased.23

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

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

On the other hand, in a study of transplanted human, well-differentiated endometrial cancer in a 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 Human data are unfortunately lacking in a subject that may have value in cancer prevention, and therefore this area should be seen as a research target.

Breast cancer 

Increased ovarian testosterone production has been shown to be associated with an increased risk of both pre- and post-menopausal breast cancer.26, 27, 28 The way androgens work in this case may as well be because of their transformation into excess oestrogen.

As discussed above, in post-menopausal women, androgens, chiefly androstenedione, are the main sources 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 free androgen concentration, which is the biological active fraction of androgen, is increased. At the same time, obesity accelerates the peripheral conversion of androgens to oestrogens, and unopposed oestrogens contribute to an increased risk of endometrial cancer and may well contribute to an increased risk of breast cancer as well, as described earlier. A relationship between these factors and familial breast cancer has been also proposed.31

Androgens can also directly increase the risk of cancer by increasing the proliferation of cells after binding to androgen receptors.32 One hypothesis also claims that the hormonal promotion of mammary 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 may result in infertility as well.33

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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 than type II diabetes. In a large population-based, nationwide, case-control study in Sweden, among post-menopausal women aged 50–74 years, there were 709 cases of histologically verified endometrial cancer. These were matched with data from 3368 controls. The odds ratio for endometrial cancer in patients with type II diabetes was 1.5 (95% CI: 1.0–2.1), while for patients with type I diabetes it was nearly 10 times as high at 13.3 (95% CI: 3.1–56.4).34

In addition, obesity in the case of hyperinsulinaemia seems to play a central role in the modulation of this risk. In a prospective cohort study of 36 773 women, including 225 endometrial adenocarcinoma cases, and after adjustments, the RR for endometrial cancer among women with diabetes compared with 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 has been confirmed to result from long-term consumption of a high-glycaemic load diet: high glucose-load diet 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 cancer have higher fasting serum insulin levels and significantly higher insulin responses after glucose administration than normal women.37

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

Breast cancer 

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

The incidences of breast cancer, type II diabetes and the metabolic syndrome have increased over the past decades, with obesity reaching epidemic proportions, especially in industrialised countries. Insulin resistance, hyperinsulinaemia and changes in the signalling of growth hormones and steroid hormones associated with diabetes may affect the risk of breast cancer. A review of the epidemiological evidence supports a modest association between type II diabetes and the risk of 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 well as the risk of recurrence and mortality in breast cancer, regardless of oestrogen receptor status, on the other.41, *42 One of the mechanisms that have been hypothesised to explain this effect is that the presence of hyperinsulinaemia can increase the ovarian production of androgens, and the abnormal hormonal profile may stimulate proliferative activity in the mammary epithelium, which in turn increases the risk of epithelial atypia and carcinogenesis.43 Another possibility is that hyperinsulinaemia and IGFs cause both hyperandrogenaemia during the reproductive years and an increased 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 increased circulating insulin and IGF concentrations, which act as mitogens, results in higher susceptibility to breast cancer. Insulin resistance develops as a metabolic adaptation to increased levels of circulating non-esterified fatty acids released from adipose tissue, especially intra-abdominal adipose tissue. Increasing concentrations of these non-esterified fatty acids force the liver, muscles and other 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 prevent elevated concentrations of glucose in the blood, the pancreas secretes increasing amounts of insulin in both the fed and fasted states.44 Furthermore, adipocytes also make up the bulk of the human breast, with epithelial cells accounting for only approximately 10% of human breast volume. Therefore, it may be that the increased local production of such substances in the breast might be part of the problem.

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

To summarise, the subject of infertility and cancer is best addressed by the assumption that both of these conditions are results of a process which is common in its nature and present with infertility in younger women with the focus progressively shifting towards cancer as age advances. At the centre of this process is excess body weight – more adequately termed the metabolic syndrome. The relatively recent, in the history of mankind, event of food – more specifically processed food – oversupply has resulted in the metabolic syndrome becoming the common background of women who consult their gynaecologist starting with infertility (or menstrual irregularities) and then, later in their lives, move on to the physicians' consulting rooms for treatment of diabetes, hypertension and hypercholesterolaemia, eventually finding themselves in the oncologist's theatre or radiotherapy room for cancer.

The question of PCO or non-PCO is not only of least priority, in many cases there is no clear answer to this. The long history of changing diagnostic criteria for PCO testifies to the practical difficulties that this superficially easy distinction hides. However, in most of these cases, the manifestations of the metabolic syndrome, insulin resistance, high androgen levels and others take the lead towards the unwanted consequences of this condition, regardless of the incidence of PCO. PCO may provide the background for easier and faster transition from a healthy state to the unhealthy state of the metabolic syndrome. In the process of evolution, human life has uncovered that financial progress, with food becoming 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 to human 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 result in increased risk of cancer not only of the endometrium but also of the breast. The external appearance of these women, regardless of the diagnostic classification that we accept, has changed little from that described by Stein and Leventhal all these years ago. The frequency of such women in our consulting rooms, however, has massively increased. The advice we give them is simple, sound and apparently saves lives: losing weight, a healthy diet and exercise can put the destructive forces of the metabolic syndrome back into the Pandora's box. However, human nature (unchanged from the era of Greek mythology to date) might mean that the conditions described in this article will persist with us for a long time to come.

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Conflict of interest 

The authors declare that they have no conflicts of interest.

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.

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PII: S1521-6934(09)00023-6

doi:10.1016/j.bpobgyn.2008.11.010

Best Practice & Research Clinical Obstetrics & Gynaecology
Volume 24, Issue 1 , Pages 19-27, February 2010

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