Diagnosing the diagnosis: why we must standardize the defining features of polycystic ovary syndrome.

Barth and colleagues have recently reviewed the diagnosis of polycystic ovary. In their insightful examination, they conclude that the current diagnostic criteria are insufficiently robust for clinical research. In fact, I would argue that currently available diagnostic criteria at present are insufficiently robust even for clinical care. We should note that this argument has significant economic and health-care consequences. Polycystic ovary syndrome (PCOS) is one of the most common endocrinopathies of women, affecting between 7 and 10% of all reproductive-aged women, with significant associated morbidities. However, as for many other syndromes, the disorder is diagnosable only by a collection of signs and features, and no single test is available for its diagnosis. There are currently three principal definitions of PCOS in widespread use. The core group of patients diagnosable as having the disorder are those demonstrating: (1) clinical or biochemical evidence of hyperandrogenism; and (2) ovulatory dysfunction; after (3) exclusion of other similarly appearing disorders (e.g. non-classic adrenal hyperplasia, Cushing’s syndrome, androgen-secreting tumours, etc.). This definition was first described in the proceedings of a 1990 National Institutes of Health (NIH)-sponsored expert conference on the subject. A second expert conference was convened by the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) in Rotterdam in May 2003, which defined the disorder as affecting any individual that had two out of the following three features: (1) clinical and/or biochemical hyperandrogenism; (2) ovulatory dysfunction or (3) polycystic ovarian morphology. Like the NIH 1990 criteria, the diagnosis of PCOS was one of exclusion and required ruling out similarly presenting disorders. This definition basically expanded the original NIH 1990 criteria by considering two additional phenotypes of the disorder, namely women who had ovulatory dysfunction and hyperandrogenism, but normal ovulation, and women who had ovulatory dysfunction and polycystic ovarian morphology, but no clinical or biochemical evidence of hyperandrogenism. Finally, the Androgen Excess Society convened an expert taskforce to review published literature and arrived at a somewhat more evidence-based contemporary definition of the disorder. The recommendations of this taskforce represented a compromise between the NIH 1990 and the Rotterdam 2003 criteria in that they suggested that PCOS be defined by the presence of: (1) clinical and/or biochemical hyperandrogenism; (2) ovarian dysfunction, including ovulatory dysfunction and/or polycystic ovarian morphology; and (3) the exclusion of related or similarly appearing disclosures. What criteria to use for defining PCOS has significant implications for patient care, clinical research and public health. For example, the prevalence of PCOS as defined by the NIH 1990 criteria appears to be approximately 6.5% among reproductive-aged women. Alternatively, the prevalence of the disorder as defined by the Rotterdam 2003 criteria could be almost twice as high. Use of a broader definition could make it more difficult to complete meaningful research on PCOS. Most affected would be large populational genetic studies, whose ability to detect the role of candidate genes is predicated on the inclusion of large numbers of relatively homogeneous patients. Comparability between studies is also detrimentally affected by the great variability in potential phenotypes that are included in different studies. Finally, clinical practice, diagnosis and counselling will be affected by the criteria selected, as the incidence of associated morbidities with PCOS, such as insulin resistance and risk of diabetes, are more prevalent with certain phenotypes of PCOS. Notwithstanding the ongoing debate regarding which specific criteria should be used for diagnosing PCOS, it is clear that a much more fundamental problem has been mostly ignored and has been brought to our attention by Dr Barth and his colleagues. They eloquently note that if the features themselves are not well-defined, meaningful use of the proposed diagnostic criteria are severely hampered. For example, biochemical evidence of hyperandrogenism is a criterion that has been present in all three currently used definitions of PCOS. However, what does this exactly mean? We need to clearly define which androgens are being measured. Should we include total testosterone (T)? Or free T? Or DHEAS? Or androstenedione? Or other lesserknown androgen metabolites? Should we define biochemical hyperandrogenism as the collection or combination of