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.
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. 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.
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). The incidence of this condition is higher among certain ethnic groups.
Until recently, however, there were different definitions of PCO on the two sides of the Atlantic. This discrepancy came to an end only in 2004 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.
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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.
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The first reference to a possible association between PCO and endometrial cancer was published in 1949 , 14 years after the classical first description of PCOS by Stein and Leventhal. Later, Jafari et al. reported a series of six cases of adenocarcinoma of the endometrium in women with the Stein–Leventhal syndrome (SLS; PCOS) , 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. 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.
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. 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.
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. This can be on a monthly basis, although some experts suggest that a withdrawal bleed every 3 months is sufficient. 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. 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. 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. 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.
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.
a Risks 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. 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).
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).
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. 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.
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.
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.
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. 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. 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. 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 low , 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.
Androgens can also directly increase the risk of cancer by increasing the proliferation of cells after binding to androgen receptors. 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.
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