PCOS has serious clinical sequelae, including psychological problems (poor self-esteem, anxiety), reproductive manifestations (hirsutism, infertility and pregnancy complications) and metabolic implications (insulin resistance, metabolic syndrome, prediabetes, type 2 diabetes and potentially cardiovascular disease) (figure 1, table 3).
Given the heterogeneous nature of PCOS (table 1) and the spectrum of clinical features, presentation can vary across the life cycle. Essentially PCOS is a chronic condition with manifestations that begin most commonly in adolescence with oligomenorrhoea/amenorrhoea and transition into problems including infertility and metabolic complications over time.
However, when combined with obesity, metabolic features present earlier in life, with diabetes not uncommonly diagnosed on screening in adolescents and women in their 20s and 30s.
Ovarian dysfunction/menstrual cyclicity
Ovarian dysfunction usually manifests as oligomenorrhoea/amenorrhoea resulting from chronic oligoovulation/anovulation. However, prolonged anovulation can lead to dysfunctional uterine bleeding, which may mimic more regular menstrual cycles.
Most patients with PCOS have ovarian dysfunction, although women with regular menstrual cycles can also be diagnosed with PCOS, based on other diagnostic criteria (table 1). Among women with PCOS, 70-80% have oligomenorrhoea or amenorrhoea. Among women with oligomenorrhoea, 80-90% will be diagnosed with PCOS, while only 40% of women with amenorrhoea will be diagnosed with PCOS, as hypothalamic dysfunction is a more common cause.
On history, oligomenorrhoea usually occurs in adolescence, or, if onset is later in life, it often follows weight gain or physical inactivity. Menstrual irregularity is often subsequently camouflaged by use of the oral contraceptive pill (OCP). When the OCP is stopped, underlying irregular cyclicity recurs.
Menorrhagia can occur in the setting of unopposed oestrogen, with endometrial hyperplasia, often exacerbated by elevated oestrogen levels in obesity. While inadequate research exists, it is generally recommended that at least four cycles a year are important to protect against endometrial hyperplasia.
Infertility
PCOS is the most common cause of anovulatory infertility. It accounts for 90-95% of women attending infertility clinics with anovulation. However, 60% of women with PCOS are fertile (defined as the ability to conceive within 12 months), although time to conceive is often increased.
In those with PCOS and infertility, 90% are overweight. Obesity also independently exacerbates infertility, reducing efficacy of infertility treatment and inducing a greater risk of miscarriage.
There is currently an active debate about the suitable BMI range for IVF therapy. Policies range from a BMI limit of 32 to 40, while some countries have no specified BMI limit. Regardless, the risks of pregnancy in overweight women are considerable for both mother and baby. Age-related infertility also exacerbates infertility in these women, and timely planning of families may warrant discussion.
Hyperandrogenism
The clinical and/or biochemical signs of androgen excess in PCOS result primarily from increased synthesis and release of ovarian androgens. Elevated LH and insulin levels synergistically increase stimulation of theca cells to synthesise androgens (table 2). Insulin resistance leads to hyperinsulinaemia, reduces SHBG and raises free circulating testosterone levels. Hyperandrogenism and hyperinsulinaemia impair follicle development in the ovary.
Clinical hyperandrogenism primarily includes hirsutism, acne and male-pattern alopecia. The clinical signs of androgen excess result from the increased exposure to dihydrotestosterone, synthesised in the skin from circulating androgens and affecting hair follicles.
Hirsutism is defined in females as male-type terminal hair growth and distribution. PCOS is a common cause of hirsutism; about 60-80% of women with PCOS have hirsutism, although this varies with race and degree of obesity. Hirsutism should be assessed with a standardised scoring system (Ferriman-Gallwey score [in Caucasian women a score of 8 or higher indicates androgen excess]4). Acne affects one-third of patients.
Male-pattern hair loss (androgenic alopecia) is not frequently seen in PCOS cases, as it usually requires a familial predisposition. Other features of hyperandrogenism include virilisation, which, especially if present as clitoromegaly and rapid in onset, requires exclusion of other causes, including adrenal or ovarian androgen-secreting tumours.
Biochemical hyperandrogenism is present in most patients with PCOS. Measurement of biochemical androgens in PCOS is limited by poor accuracy and reproducibility of assays, which are designed for significantly higher levels of androgens in males. In general it is recommended that free testosterone or free androgen index, which is derived by the lab from SHBG and total testosterone measurements, are performed. Tests for dehydroepiandrosterone-sulphate (DHEAS) and androstenedione are not routinely recommended in PCOS.
Metabolic features: PCOS, impaired glucose tolerance and type 2 diabetes mellitus
Insulin resistance and diabetes
While a full discussion of the mechanisms involved in hyperinsulinaemia and cardiovascular disease is beyond the scope of this review, mechanisms are likely to be complex. Insulin resistance appears to affect 60-80% of women with PCOS.
The cause of insulin resistance is complex and multifactorial, with genetic and environmental contributors. While these include obesity, lean women with PCOS also have abnormalities of insulin secretion and action compared with weight-matched controls.
Specific abnormalities of insulin metabolism identified in women with PCOS include reduced secretion, reduced hepatic extraction, impaired suppression of hepatic gluconeogenesis, and abnormalities in insulin-receptor signalling.
Insulin resistance appears to contribute to the reproductive manifestations of PCOS. Interestingly, there is a paradoxical expression of insulin resistance in PCOS whereby insulin-stimulated androgen production persists, while its role in glucose metabolism is impaired. Therefore, insulin resistance in PCOS results in hyperinsulinaemia with its associated diverse and complex effects on regulating lipid metabolism, protein synthesis and modulation of androgen production.
A subgroup of women with PCOS and insulin resistance also develops insufficient pancreatic insulin output or beta-cell failure. In this setting, insulin output cannot overcome insulin resistance, and hyperglycaemia develops. In this setting women with PCOS are at increased risk of developing impaired glucose tolerance (IGT) and type 2 diabetes (with prevalence rates of 31.3% and 7.5%, respectively, compared with 14% for IGT and zero for type 2 diabetes in age- and weightmatched non-PCOS control women).5
There is also emerging evidence that women with PCOS have a greater chance of developing gestational diabetes, with a recent meta-analysis reporting an odds ratio of 2.94.6 These elevated risks occur both independently of obesity, and as a result of obesity. Furthermore, the International Diabetes Federation has identified PCOS as a significant non-modifiable risk factor for type 2 diabetes.
Women with PCOS also appear more likely to develop abnormal glucose metabolism at a younger age and may demonstrate a more rapid conversion from IGT to type 2 diabetes. The rate of conversion from IGT to type 2 diabetes in the general population was estimated in the AusDiab (Australian Diabetes, Obesity and Lifestyle) study as 2.9% per year for females. An Australian study in PCOS has reported a substantially higher conversion rate (8.7% per year over 6.2 years),7 but this has not been uniformly reported.
There are few adequately powered studies assessing the natural history of IGT, type 2 diabetes and cardiovascular disease in PCOS. Because of this, there is a need for a definitive, large, long-term prospective study assessing these risks in women with PCOS.
It is increasingly clear that IGT is also a clinically relevant state, the identification of which can lead to interventions that improve long-term outcomes. IGT has been found to increase the risk of cardiovascular disease, mortality and progression to diabetes in general populations. Recent AusDiab data found a mortality rate of 5.5% over five years for people with IGT vs 1.9% for those with normal glucose tolerance.
Furthermore, lifestyle intervention together with use of metformin can prevent IGT progression to type 2 diabetes (although use of metformin in this way would be off-label), strengthening the argument for early detection of IGT, especially in this group of women who are at high risk of type 2 diabetes.
In PCOS:
-
Insulin resistance is increased.
-
Metabolic profiles are adverse.
-
IGT is more common.
-
Type 2 diabetes risk is increased 4-7-fold.
-
Cardiovascular risk factors are elevated.
-
Cardiovascular disease risk is likely to be increased.
We therefore postulate that detecting and treating IGT is particularly clinically relevant for women with PCOS, to identify those at high risk for progression to type 2 diabetes and for aggressive cardiovascular risk factor reduction.
Although IGT and type 2 diabetes are clinically relevant and common in PCOS, there are no screening guidelines specifically to detect IGT or diabetes in this population. However, guidelines have been designed to screen for diabetes in the general population. These guidelines frequently use fasting glucose as a screening test and only progress to an oral glucose tolerance test (OGTT) if the fasting level is abnormal, yet impaired fasting glucose is a poor predictor of IGT, especially in PCOS. Furthermore, in general populations impaired fasting glucose and IGT comprise two distinct subgroups with only partial overlap.
Likewise, in PCOS, fasting plasma glucose levels >6.1mmol/L are also a poor predictor of IGT, leading to recommendations by our group and others, including the Rotterdam PCOS Consensus Workshop Group, to perform an OGTT in obese women with PCOS. In our work to date, testing fasting glucose levels misses 80% of IGT in women with PCOS and we strongly endorse screening with an OGTT in overweight/obese women with PCOS every 1-2 years.
As a final point here, emerging data show an increased risk of metabolic syndrome, IGT and diabetes in first-degree family members of women with PCOS and in relatives with other risk factors for diabetes (eg, age, family history, overweight, high-risk ethnic group). Therefore screening for cardiometabolic abnormalities may be warranted in this group.
Cardiovascular disease risk
Alongside insulin resistance, metabolic syndrome, IGT and diabetes, women with PCOS also have an increased prevalence of traditional risk factors (eg, hyperlipidaemia) and novel risk factors (increased homocysteine levels, inflammation, oxidative stress and leucocyte counts and impaired fibrinolysis) for cardiovascular disease.
Our group has demonstrated that early clinical and subclinical markers of atherosclerosis (endothelial dysfunction, impaired pulsewave velocity, increased carotid intima-media wall thickness, presence of carotid plaque and increased coronary artery calcification) are more advanced in PCOS and are associated with insulin resistance and obesity.
There is a lack of longterm studies in PCOS to appropriately address the issue of cardiovascular disease risk. However, the higher rates of metabolic syndrome and increased macrovascular disease in people with type 2 diabetes would be expected to lead to increased cardiovascular disease. The AusDiab study reported that 65% of deaths due to cardiovascular disease occurred in subjects with type 2 diabetes or impaired fasting glucose (IFG) or IGT; a 50-60% greater cardiovascular mortality risk for subjects with IFG or IGT; and a twofold increased risk for subjects with type 2 diabetes.8 Recent epidemiological studies have strongly suggested PCOS women are at increased CVD risk.
As women with PCOS are a population at high risk for developing type 2 diabetes, they are also likely to have increased cardiovascular and metabolic mortality and morbidity.
Psychosocial factors
Most research has focused on the biological and physiological aspects of the syndrome. However, the consequent impact of physical symptoms, infertility and long-term health-related concerns on mood and psychological wellbeing of women with PCOS is also likely to be considerable.
Although research in this area is inadequate, it suggests that challenges to feminine identity and body image due to obesity, acne and excess hair, compromise quality of life in women with PCOS. Limited studies to date have reported that women who have PCOS are more prone to depression, anxiety, low self-esteem, negative body image and psychosexual dysfunction and have reduced quality of life, although further research is needed.
The other critical aspect of psychosocial impact in PCOS is the negative impact of mood disturbance, poor self-esteem and reduced psychological wellbeing on readiness to change and on ability to implement and sustain successful lifestyle changes that are so critical in this condition. Hence these issues need to be explored and addressed as a critical part of PCOS assessment and management.
This article first appeared in Australian Doctor, How to treat on 29 August 2008 and has been reproduced here with permission.
Australian Doctor, How to treat: Polycystic ovary syndrome 437.44 Kb
Content Updated 20 November, 2009