Introduction
It is well known that in young women with PCOS, the cardiovascular (CV) risk is increased . In fact, in these patients, all CV risk factors including atherogenic dyslipidemia, LDL (low-density lipoproteins) levels, C-reactive protein, hypertension, and metabolic syndrome are elevated . In addition, several markers of clinical and subclinical atherosclerosis, including carotid intima-media thickness and coronary artery calcium may be altered .
The concept of CV risk factors was introduced by the original Framingham investigators and risk factors are antecedents of atherosclerosis whose levels predict subsequent cardiovascular events and are targets for therapy . In the general population, there is a good correlation between cardiovascular risk and cardiovascular diseases . On the contrary, in women with PCOS, most data suggest that the increased cardiovascular risk does not translate into a proportionally high number of CV diseases . The exact mechanisms of this discrepancy are unclear but may depend on changes in hormone production that occur in PCOS patients moving from young to late adult reproductive age and menopause . In addition, most original data on CV risk in PCOS were obtained in US patients diagnosed by NIH (National Institutes of Health) criteria and may not reflect the heterogeneity of the syndrome and the low prevalence of obesity in some populations.
CV risk factors in different PCOS phenotypes
PCOS is a very heterogeneous disorder that may present with at least four different phenotypes (A, B, C, D) . CV risk seems to be different depending on the phenotype with a higher prevalence of risk factors in patients diagnosed by NIH criteria (phenotypes A and B) compared to the other PCOS Phenotypes (C and D). In fact, these last phenotypes are generally considered mild forms of PCOS with little or no metabolic disturbances and no need for follow-up for risk of type 2 diabetes or cardiovascular alterations.
However, our recent data in a large population of women with PCOS (1215 patients) have shown that also phenotype C presents important metabolic alterations with considerable risk for developing type 2 diabetes and cardiovascular diseases . In fact, while patients with phenotype C have a lower prevalence of obesity, type 2 diabetes, and metabolic syndrome compared to the phenotypes A and B, their metabolic alterations are significantly more common than in controls.
Moreover, in patients with phenotype C, prediabetes and lipid alterations are as common as in PCOS patients with phenotype A ( Figs. 1–3 ) suggesting that phenotype C cannot be considered a PCOS phenotype with no metabolic alterations. Instead, these patients, while not presenting fertility problems, should be carefully evaluated for metabolic alterations and will need close follow-up because they present important cardiovascular and metabolic risks.
In our study, only normoandrogenic (phenotype D) women with PCOS have a normal metabolic status suggesting that the role of increased androgens in inducing metabolic alterations may be more important than previously thought. However, our experience with this subgroup of PCOS patients is limited and larger groups of patients with phenotype D (with a careful diagnosis of normal androgen levels) should be evaluated.
Influence of obesity on CV and metabolic risk of PCOS
In the general population, there is increasing evidence that obesity is offsetting improvements in CV mortality and blocking possible improvements in longevity in countries like the United States . Consistent with the concept that obesity is an important factor in determining or increasing CV and metabolic risk factors, several studies have shown that differences in prevalence and severity of obesity between studied populations with PCOS are important in determining the prevalence of CV and metabolic risk factors.
In the Scandinavian population, the prevalence of type 2 diabetes is not increased in normal-weight women with PCOS . In our population, where the prevalence of obesity was only 34% in patients with phenotype A and 15% in patients with phenotype C, metabolic syndrome and lipid alterations are less prevalent than in the US population . Similar data have been reported in other Mediterranean populations, where the prevalence of obesity in PCOS is between 10% and 31%, and the prevalence of CV and metabolic risk factors in PCOS is low . Instead, in the United States of America (USA), the mean BMI of PCOS patients is generally around 35 with a prevalence of obesity of about 80% and the prevalence of CV and metabolic risk factors is high . When obesity is prevalent, it is also difficult or impossible to find differences between PCOS phenotypes. In the study of Shroff et al. patients with phenotype C were as obese (BMI 35.4) as women with phenotype A (BMI 35) and had a similarly high prevalence of metabolic syndrome (42.3% versus 36.1%) .
These findings suggest that in PCOS women, CV and metabolic risk factors are highly influenced by obesity and therefore there are different depending on the studied population. Because of it, the calculation of CV future events using CV risk data obtained in a different population may be incorrect and overestimate the real prevalence of the risk.
Changes of hormonal production and CV risk factors in women with PCOS moving from young to late reproductive age
In most patients, during late reproductive age, the severity of PCOS reduces, and in some patients, the syndrome may not be diagnosed anymore . In fact, in PCOS, moving from 20–25 to 40–45 years age, ovarian androgen secretion reduces by 20%–30% and ovulation appears in about 50% of anovulatory patients with a number of these women having spontaneous pregnancies and children ( Table 1 ).
| Moving from 20–25 to 40–45 years age, in PCOS the following changes occur: |
| Androgen secretion reduces by 20%–30% |
| Ovulation appears in at least 50% of PCOS patients |
| A number of these women will have spontaneous pregnancies and children |
These changes influence not only the reproductive life but also the metabolic and CV risk of PCOS patients. In our follow-up study, more than 50% of PCOS patients showed a progressive normalization of CV risk factors ( Fig. 4 ). Similar results have been reported by other studies . This improvement of hormonal and metabolic pattern in PCOS with age means that increased CV risk factors during young adult age will not determine a proportionate increase of CV events after menopause.
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