Paul Hardiman

Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis

BACKGROUND Polycystic ovary syndrome (PCOS) is a common condition affecting ∼8% of women. The objective of the present study was to quantify separately the risk of endometrial cancer, ovarian cancer and breast cancer in women with PCOS compared with non-PCOS controls, and quantify separately the risk to women of all ages as well as the risk to premenopausal women. METHODS We conducted a systematic review and meta-analysis of observational studies. Studies were eligible for inclusion if they compared women with PCOS to non-PCOS groups for fatal or non-fatal gynaecological cancers. Studies listed in MEDLINE and EMBASE published up to 7 October 2013 in any language were identified, and relevant papers were also searched by hand. Relevant data (for example, study design, source of control data, diagnostic criteria) were extracted and tabulated. RESULTS From 698 references, 11 studies (5 of endometrial cancer and 3 each of ovarian and breast cancer) met the inclusion criteria for the meta-analysis (919 women with PCOS and 72054 non-PCOS controls). Using the Mantel–Haenszel method, with fixed or random effects model as appropriate, women with PCOS were at a significantly increased risk of endometrial cancer (odds ratio (OR), 2.79; 95% confidence interval (CI), 1.31–5.95, P < 0.008), but the risk of ovarian and breast cancers was not significantly increased (OR, 1.41; 95% CI, 0.93–2.15, P < 0.11 and OR, 0.95; 95% CI, 0.64–1.39, P < 0.78, respectively). However when studies which included women aged over 54 years were excluded from the analysis, the risk for women with PCOS increased further for endometrial cancer (OR, 4.05; 95% CI, 2.42–6.76, P < 0.00001), became significantly increased for ovarian cancer (OR, 2.52; 95% CI, 1.08–5.89, P < 0.03), but remained non-significant for breast cancer (OR, 0.78; 95% CI, 0.46–1.32, P < 0.35). CONCLUSIONS This is the first meta-analysis to examine gynaecological cancers in women with PCOS younger than 54 years of age compared with controls of similar age. Current data suggest that women of all ages with PCOS are at an increased risk of endometrial cancer but the risk of ovarian and breast cancer was not significantly increased overall. These results highlight the potential risk of gynaecological cancer morbidities associated with PCOS. However, the available evidence is far from robust and variation in diagnostic criteria for PCOS, associated risk factors (particularly obesity), and selection bias in the studies may have resulted in an exaggeration of the increased risk. Furthermore, women who have PCOS should also be made aware that any increased risk for endometrial cancer must be judged in the context of its relatively low incidence in the general population. A large well-controlled prospective study is required in order to gain a more accurate estimate of the risk of gynaecological cancers in women with PCOS. PROSPERO CRD REGISTRATION NUMBER CRD42012003500.

Impaired Carotid Viscoelastic Properties in Women With Polycystic Ovaries

Background—The purpose of this study was to assess the elastic properties of the carotid arteries in women with polycystic ovarian syndrome, asymptomatic women with polycystic ovaries, and healthy controls. Methods and Results—We recruited the following 60 subjects: 20 symptomatic women with polycystic ovaries attending the reproductive endocrinology clinics, 20 asymptomatic women with polycystic ovaries attending the family planning clinic, and 20 staff volunteers as healthy controls with normal ovaries on transvaginal scan. Compliance and stiffness index were assessed in the common and internal carotid arteries using duplex ultrasound equipped with an echo-locked arterial wall–tracking system. Compliance was significantly lower in the common carotid artery in symptomatic and asymptomatic women with polycystic ovaries than in the controls (10.7, 14.1, and 19.2 %mm Hg−1×10−2, respectively). The arterial stiffness index was correspondingly increased (12.3, 10.2, and 6.7, respectively). Similar results were obtained in the internal carotid artery for compliance (10.1, 11.0, and 16.9 %mm Hg−1×10−2, respectively) and stiffness index (14.8, 16.2, and 8.7, respectively). Conclusions—The results of this study provide additional evidence of vascular dysfunction in women with polycystic ovaries and are compatible with the hypothesis that they are at increased risk from coronary artery disease and stroke.

Umbilical vein testosterone in female infants born to mothers with polycystic ovary syndrome is elevated to male levels

The aetiology of polycystic ovary syndrome (PCOS) is poorly understood, but an intrauterine hyperandrogenic environment has been implicated. This study was designed to assess whether the female offspring of mothers with PCOS are exposed to raised levels of testosterone (T) in utero. In this case–control study, three groups of pregnant women were recruited from the labour ward: PCOS women with a female baby (n = 10, PCOS girls); control women with a female baby (n = 20, control girls) and control women with a male baby (n = 10, control boys). Maternal and umbilical vein (UV) blood was assayed for T levels. UV T in PCOS girls was significantly raised, compared with control girls (p < 0.012). The difference in UV T between PCOS girls and control boys was not significant (p < 0.254). This is the first demonstration of a hyperandrogenic in utero environment in PCOS pregnancies; UV T in female infants is raised to male levels.

Polycystic ovary syndrome, diabetes and cardiovascular disease: risks and risk factors.

Polycystic ovary syndrome is one of the most common endocrine disorders in the human, affecting approximately 10% of women of reproductive age. Although originally considered a gynaecological disorder, the syndrome is associated with a wide range of endocrine and metabolic abnormalities, including insulin resistance. Affected women are at an increased risk of developing gestational and non-insulin dependent diabetes and there is an association with cardiovascular risk factors including obesity, hypertension, dyslipidaemia, hyperhomocysteinaemia, increased intima media thickness and impaired vascular elasticity. The effect on cardiovascular mortality is currently unclear. However, in view of the proven links with diabetes and the cardiovascular risk markers, this condition should be considered within the province of physicians as well as gynaecologists.

Peripheral blood flow in menopausal women who have hot flushes and in those who do not.

OBJECTIVE--To compare blood pressure, heart rate, and peripheral vascular responsiveness in menopausal women who have hot flushes and in those who do not, and to assess the effect on these variables of treating women who have hot flushes with oestriol, a natural oestrogen, given vaginally. DESIGN--An open, non-randomised cohort study of flushing and non-flushing menopausal women. A before and after investigation of the effects of vaginal oestriol treatment on the circulation. SETTING--Referral based endocrinology clinic. PATIENTS--88 Consecutive menopausal women, 63 complaining of frequent hot flushes and 25 who had not flushed for at least a year. INTERVENTION--Treatment with vaginal oestriol 0.5 mg at night for six weeks in 18 of the women who had hot flushes. MEASUREMENTS AND MAIN RESULTS--Peripheral blood flow was measured by venous occlusion plethysmography at rest and in response to stressful mental arithmetic and anoxic forearm exercises. Blood flow in the forearm and its variability were significantly higher in flushing than in non-flushing women (4.1 (SD 1.7) and 3.1 (0.9) ml/100 ml tissue/min and 17% and 13% respectively). Blood pressure, heart rate, and blood flow in the hand were, however, similar in the two groups. No difference was found in the peripheral incremental response to either stress or anoxic exercise. Vaginal oestriol significantly lowered forearm blood flow from 4.4 (1.5) to 3.3 (1.1) ml/100 ml tissue/min but dilator responsiveness was unaffected. CONCLUSIONS--The peripheral circulation is different in menopausal women who have hot flushes compared with those who do not, with selective vasodilatation in the forearm. The lowered blood flow in the forearm after vaginal oestriol in flushing women may be relevant to the alleviation of vasomotor symptoms induced by oestrogen treatment.

Familial associations in women with polycystic ovary syndrome

OBJECTIVE To confirm whether there was a familial association between polycystic ovary syndrome (PCOS) and thromboembolic disease, ovarian or breast cancer, diabetes, and heart disease. DESIGN Cross-sectional study. SETTING A university hospital in the United Kingdom. PATIENT(S) Two hundred and seventeen women with and without PCOS under the care of the same consultant gynecologist at a teaching hospital. INTERVENTION(S) Questionnaire survey. MAIN OUTCOME MEASURE(S) Prevalence of a personal or positive family history of thromboembolism, ovarian cancer, breast cancer, diabetes, and heart attacks. RESULT(S) In an analysis of the replies from 41 women with PCOS and 66 controls, we found a statistically significant positive family history of breast cancer and heart attacks among women with PCOS. There was no statistically significant difference in the mean age, ethnic origin, or prevalence of a family history of other diseases. CONCLUSION(S) Our results show a positive association between polycystic ovary syndrome and a family history of breast cancer and heart disease. These associations may be genetic in origin, or secondary to a complex interplay of genetic, intrauterine, and environmental factors. More studies are required to confirm these findings and determine the factors that explain these associations.

Internal carotid-artery response to 5% carbon dioxide in women with polycystic ovaries

Although polycystic ovary syndrome is associated with hypertension, hyperlipidaemia, and insulin resistance, mortality from cerebrovascular disease is not increased. We previously reported lower downstream resistance in the internal carotid artery in women with polycystic ovary syndrome. This study was designed to assess vascular reactivity by measuring the response to inhalation of 5% carbon dioxide. We studied 34 young women with polycystic ovary syndrome, 15 with symptomless polycystic ovaries, and 18 controls.

Risk of coronary heart disease and risk of stroke in women with polycystic ovary syndrome: A systematic review and meta-analysis

Women with polycystic ovary syndrome (PCOS), one of the commonest endocrine conditions in the human, are more likely than other women to have increased blood pressure, endothelial dysfunction, reduced arterial compliance, central obesity, dyslipidaemia, low grade chronic inflammation, and increased endothelin-1 and homocysteine [1]. A recent meta-analysis found an increased incidence of cardiovascular events in women with PCOS, but did not distinguish between coronary heart disease and stroke and did not consider fatal and non-fatal events separately [2]. The present metaanalysis aimed to quantify the risk of non-fatal stroke and coronary heart disease as separate disease events in women with PCOS compared to healthy women. The Mantel–Haenszel method was used, with a random effects model in most cases, to generate an odds ratio (OR) for all included studies combined. Results were considered statistically significant where the probability value was below the 0.05 threshold. Review Manager statistical software, version 5.1, was used to analyse data. Heterogeneity was assessed using I and chi square statistics. Nine studies met the inclusion criteria (see list of included studies here [www.ijc.com/references). Women with PCOS were at increased risk of non-fatal stroke and non-fatal CHD but the odds ratios did not reach statistical significance (OR, 1.61; 95% CI, 0.82–3.15; P = 0.17 and OR, 1.63; 95% CI, 0.96–2.78; P = 0.07, respectively). In the five studies where the average age was more than 45 years old, the risk in PCOS was significantly increased for non-fatal stroke (OR, 1.94; 95% confidence interval, 1.19–3.17) and non-significantly increased in the six studies of CHD (OR, 1.70; 95% confidence interval, 0.92–3.11) (Fig. 1). For the three studies where the BMI was similar and the mean age was over 45 in the groups the risk was non-significantly increased for womenwith PCOS for stroke (OR, 1.67; 95% confidence interval, 0.70– 4.02) and for the three studies of CHD (OR, 2.04; 95% confidence interval, 0.60–6.97). The Newcastle–Ottawa scale suggests that the methodological quality of the included studies was moderate. Funnel plots found that although publication bias cannot be ruled out, the asymmetry observed may be due to the relatively young age of the patients in one study. Women with PCOS appear to be at increased risk of non-fatal stroke and possibly CHD. Although this study was not designed to investigate mechanism, the higher blood pressure and atherogenic lipid profile in women with PCOS may be contributory. In any case, clinicians and policymakers might focus on screening women with PCOS as soon as it is diagnosed, and focus on applying preventative measures, such as lifestyle interventions, appropriate to reducing the risk of stroke. Whilst the results of the present meta-analysis did not provide evidence of increased risk of CVD in PCOS entirely independent of BMI, evidence of cardiovascular risk in leanwomenwith PCOS [3] supports the hypothesis of the potential for an independent role of PCOS in CVD, perhaps due to the abdominal obesity in PCOS [5]. Future studies of PCOS should measure waist circumference in order to assess abdominal obesity. Furthermore, many women with PCOS receive treatments (the oral contraceptive pill, antiandrogens, insulin sensitizers or laparoscopic ovarian diathermy) which are likely to modify the risk of later cardiovascular events [4]. Future studies should therefore also assess the impact of these interventions on cardiovascular risk in women with PCOS. These findings have important implications for disease prevention and screening in women. At present, weight management, changes in dietary composition and exercise should be the primary interventions, although pharmacologic treatment of hypertension, dyslipidaemia or insulin resistancemay be requiredwhere lifestyle modification proves ineffective. No funding supported the preparation of this paper. The authors have nothing to disclose. We would like to thank Dr Richard Morris of University College London for his advice on statistical matters.

Testosterone and mood dysfunction in women with polycystic ovarian syndrome compared to subfertile controls

Women with polycystic ovarian syndrome (PCOS) have been found to suffer from fertility problems and mood dysfunction. To control for any effect of fertility problems, the present study compared mood dysfunction in women with PCOS to non-PCOS women with fertility problems. Seventy-six women with PCOS and 49 subfertile controls reported their anxiety, depression and aggression levels, and the relationship between mood and testosterone (T) was assessed. Controlling for age and BMI using MANCOVA, women with PCOS were significantly more neurotic (had difficulty coping with stress) than controls, had more anger symptoms, were significantly more likely to withhold feelings of anger and had more quality of life problems related to the symptoms of their condition (acne, hirsutism, menstrual problems and emotions). In a subgroup of 30 women matched on age, BMI and ethnicity, it was found that women with PCOS were significantly more anxious and depressed than controls. T was not generally correlated with mood states. This is the first study to identify problems with neuroticism and withholding anger in women with PCOS. These mood problems appear to be mainly attributable to PCOS symptoms, though other factors, such as hypoglycaemia, cannot be ruled out.

Ovarian cancer and infertility: a genetic link?

A genetic mechanism may be responsible for the increased incidence of ovarian cancer in some infertile women (ie, those who failed to conceive despite treatment).