Endocrine Abstracts

Lifestyle interventions and insulin sensitizers play a fundamental role in the treatment of PCOS, particularly in the presence of obesity. The rationale is represented by the reasoning that the decrease in insulin concentration, as a result of improved insulin resistance, may lead to metabolic alterations and have important effects on hyperandrogenism, and, in particular, on fertility. Insulin sensitizers can be added to lifestyle intervention, when obesity is present, although there is preliminary evidence that some behavioural modification in dietary habits may have a positive effect even in normal-weight insulin resistant PCOS women. Hopefully, weight reduction in the management of PCOS should be encouraged before any pharmacological treatment such as insulin sensitizers or antiobesity agents, although this does not represent a common rule worldwide.

Sustained weight loss can completely reverse the phenotype in a subset of obese women with PCOS, supporting the concept that a PCOS ‘secondary’ to obesity may exist. Interestingly, this is associated with a marked improvement of insulin resistance and a normalization of fasting and glucose-stimulated insulin levels. This adds new perspectives on the pathophysiological impact of obesity on PCOS. Future research should however investigate factors determining individual susceptibility to develop this disorder in the presence of obesity.

An important issue is represented by the individual responsiveness to insulin sensitizers, given alone or in combination. The effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action suggests that OCT1 genotype may be a determinant of metformin pharmacokinetics in PCOS. Preliminary clinical studies further support that clustering PCOS women by this genotype may partly explain individual responsiveness to metformin.

In addition, emerging data support the concept that metformin dose has an important impact in ameliorating insulin sensitivity and in decreasing circulation insulin levels.

Finally, insulin resistant PCOS women present an increasing list of monogenic disorders that represent a potential target for specific insulin sensitizers, such as tiazolidinediones.