Hyperandrogenism, Polycystic Ovarian Disease

Background: Polycystic ovary syndrome (PCOS) is a common condition, present in 12-21% of women of reproductive age. Up to 70% of women with PCOS remain undiagnosed. Objective: This article summarises the 2011 national PCOS guideline, Evidence-based guideline for the assessment and management of polycystic ovary syndrome, for the general practice context, with particular reference to the needs of Indigenous Australian women. Discussion: Women with PCOS may present with a wide range of symptoms. The Rotterdam criteria are the most widely accepted for diagnosis and the national guideline references these criteria. Women with PCOS have a higher risk of metabolic syndrome and its cardiovascular sequelae. This is particularly important for Indigenous women who are already at increased baseline risk. Management of PCOS involves attention to current symptoms, fertility and psychosocial issues, as well as prevention of related future health problems including diabetes. Resources are available to help guide management and patients may benefit most from a team approach to care.

Polycystic ovary syndrome - an update.

Three years ago, amid concerns that rosiglitazone (Avandia) increases the risk of myocardial infarction and death due to cardiovascular causes, the US Food and Drug Administration (FDA) severely curtailed use of the blood glucose–lowering drug. But now an FDA advisory committee has recommended easing the severe restrictions on prescribing rosiglitazone, used to treat type 2 diabetes mellitus, even though cardiovascular safety concerns remain. AtthejointmeetingoftheEndocrinologic andMetabolicDrugsAdvisoryCommitteeand the Drug Safety and Risk Management Advisory Committee, held June 5 and 6 at FDA headquarters in Silver Spring, Maryland, 13 membersvotedtomodifythehighlyrestrictive riskevaluationandmitigationstrategy(REMS) applying to use of rosiglitazone, 7 voted to removetheREMSaltogether,5votedtokeepthe REMSasis,and1votedforremovalofrosiglitazone from the market. The REMS restricts access to rosiglitazone so that only prescribers who acknowledge the potential increased risk of myocardial infarction are prescribing the drug. The REMS also restricts rosiglitazone to patients who are already taking the drug or who are unable to achieve glycemic control with other medications and, in consultation with their physician, have decided not to take pioglitazone(Actos,theonlyotherthiazolidinedione marketed in the United States) for medical reasons. Thevotewassomewhatofareversalfrom a 2010 FDA meeting of the same advisory committees (although with somewhat different personnel) in which 10 members voted to restrictavailabilityofrosiglitazoneand12voted toremoveitentirelyfromthemarket,whileanother3votedtoleavethelabelunchangedand 7 voted to add warnings. The 2010 vote, and subsequent action by the FDA, followed a decade of increasing concerns about the drug’s cardiovascular safety. Rosiglitazone was given FDA approval in 1999 and quickly became a blockbuster drug for its manufacturer, GlaxoSmithKline (then SmithKline Beecham), ultimately generating morethan$2billioninannualsales,withabout 120 000 US patients taking the medication. But researchers began to sound a safety alarm just a year later. Then, in 2007, a metaanalysisfoundthatrosiglitazoneincreasedthe risk of myocardial infarction by more than 40% compared with a control (placebo or comparator drug) (Nissen SE and Wolski K. N Engl J Med. 2007;356[24]:2457-2471). And just before the 2010 advisory meeting, another study, observational and retrospective, found that compared with pioglitazone, rosiglitazoneincreasedtheriskofstroke,heart failure, and death (Graham DJ et al. JAMA. 2010;304[4]:411-418). Evenasstudieswereattackingthecardiovascular safety of rosiglitazone, a randomized controlled trial, RECORD, published results showingthatcomparedwithatreatmentcombination of metformin and sulfonylurea, rosiglitazonedidnotincreasetheriskofoverallcardiovascular morbidity or mortality, although it did increase the risk of heart failure and some fractures (the latter mainly in women) (Home PD et al. Lancet. 2009;373[9681]:2125-2135). But at the 2010 advisory committee meeting,

Panel Recommends Easing Restrictions on Rosiglitazone Despite Concerns About Cardiovascular Safety

The metabolic aberrations in patients with polycystic ovary syndrome (PCOS) demand a shift in clinical care from symptom driven to the prevention of chronic disease The onset of carbohydrate intolerance or diabetes may be accelerated The lipoprotein lipid profiles are compatible with the effects of insulin resistance Disturbed cholesterol and triglyceride metabolism may eventuate in premature cardiovascular disease

Metabolic aspects of polycystic ovary syndrome.

From the conceptual point of view, there are several reasons to expect that improvement of insulin sensitivity may produce several benefits in the treatment of a complex disorder like polycystic ovary syndrome (PCOS), including a decrease in insulin and androgen levels, improvement of metabolic comorbidities, and, finally, improved ovulation and fertility. This can be achieved with the help of specific agents, particularly metformin and thiazolidinediones. They may ease the suffering of women with PCOS because insulin resistance and hyperinsulinemia appear to be major contributors to the pathophysiology of the syndrome.

Insulin sensitizers in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disease affecting women, with a prevalence of 6–10% reported when applying the National Institute of Health criteria, but may be increased to 20% using the Rotterdam criteria. Hypertension, dyslipidaemia and insulin resistance are more common in PCOS, even after adjustment for obesity, and there are a plethora of studies reporting surrogate measures of atherosclerosis including increased carotid intima media thickness, more angiographic coronary artery disease, increased endothelial dysfunction and a multitude of serum risk marker changes. However, contradictory results from observational population studies make it difficult to assess the potential for PCOS to enhance cardiovascular morbidity and mortality. Initial studies in patients with PCOS undergoing wedge resection suggested that there was no increase in cardiovascular mortality. Conversely, the Nurses’ Health Study has shown that women with a history of menstrual irregularity have an increased risk of both nonfatal and fatal coronary heart disease, although PCOS was not diagnosed specifically in that study. As testosterone levels tend to fall post menopause, the elevated levels of testosterone during the postmenopausal period may identify a more at risk population. However, recent data have not helped to clarify the situation. A relationship between menstrual irregularity and an increase in the age-adjusted risk for cardiovascular mortality was recently reported, although this was not significant after adjustment for the cohort’s body mass index. Studies in postmenopausal, middle-aged and elderly women have shown that there was a significantly increased age-adjusted risk for incident coronary heart disease and cardiovascular events in the highest quintiles of total, bioavailable and free testosterone relative to the median and bottom quintiles. Although these studies did not distinguish between women with a history of irregular menses or PCOS, the above data have implications for the cardiometabolic role of hyperandrogenaemia that persist after menopause in PCOS women. It is clear that women with PCOS have an increased risk of both impaired glucose tolerance and type 2 diabetes with a reported threeto sevenfold greater risk overall and a twofold higher risk compared with ageand BMI-comparable women with normal cycles. Does this impact on coronary heart disease? Although baseline diabetes is a strong predictor of coronary heart disease mortality, when it was excluded from a multivariate analysis, menstrual irregularity continued to be a strong predictor of coronary heart disease mortality. This controversy on whether PCOS increases cardiovascular risk and events has been brought into sharp focus by Mani et al. in this month’s Clinical Endocrinology. They report on a retrospective study on a PCOS database of 2301 patients over an 11-year period with a total follow-up time of over 12 000 person years. They report that there was an increased prevalence rates for both myocardial infarction and angina from the age of 45–54 years of 1 9% and 2 6%, respectively; 55–64 years of 6 0% and 6 0%, respectively; and a marked increased prevalence rate over the age of 65 years of 27 3% and 27 3%, although the number of subjects in the over 64-year age range was only 11. When age matched with the local population, the odds ratios were significantly increased for both angina and myocardial infarction, with the strongest associations being with age, hypertension and smoking history. However, whilst the age-specific prevalence increased, the overall rates for these conditions did not differ from the reference population as expected from a population where over 80% of the subjects were under 45 years in whom the event rate would be expected to be very low. Hyperandrogenism was unintuitively associated with a lower risk of T2DM and appeared not to correlate with cardiovascular risk indices, the converse suggested by others. In addition, anovulation was not associated with an increase in cardiovascular events, the converse to that suggested in the Nurses Health study. At the end of the observation period, 6% had developed type 2 diabetes at a mean age of 34 5 years in accord with that found in other studies and appeared not to correlate with cardiovascular risk though that appears counter intuitive. Recently, a much larger UK general practice data set of women with PCOS (over 21 000 subjects) reported that there was no evidence of an increase in cardiovascular disease; however, the two studies are difficult to compare in ethnicity, the apparent younger age in the general practice study and length of time of follow up, rigour of the diagnosis of PCOS. Nonetheless, this is reassuring that women with PCOS are not at a significantly increased risk of cardiovascular disease. In addition, this large general practice data set showed a twofold increase in *Please see related paper on pages 926–934 of this issue.

Hyperandrogenism, Polycystic Ovarian Disease

References

Polycystic ovary syndrome - an update.

Panel Recommends Easing Restrictions on Rosiglitazone Despite Concerns About Cardiovascular Safety

Metabolic aspects of polycystic ovary syndrome.

Insulin sensitizers in polycystic ovary syndrome.

Cardiovascular disease in polycystic ovary syndrome

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