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Physicians must make closing practice gaps a priority in PCOS

Issue: October 2014

ByRicardo Azziz, MD

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The modern era of polycystic ovary syndrome research began with its initial description in 1935 by Irving Stein and Michael Leventhal.

Despite much subsequent study, practice gaps in the evaluation and treatment of PCOS remain, stemming from a poor understanding of current literature, the varying needs and presentations of patients, variable resources and clinical presentations around the globe, and deficits in the available science.

Practice gaps are in three main areas: evaluating patients with possible PCOS, counseling patients with PCOS and treating patients with PCOS.

Evaluating patients

Data suggest, but don’t yet confirm, that two clinical complaints may be sufficient to identify most women with PCOS: those consistent with signs of hyperandrogenism and those of ovulatory dysfunction. This strategy must be fully evaluated in prospective studies in larger populations of unselected women.

Since most populations studied are self-selected (ie, women who sought medical care), the symptoms that we most often recognize as being part of PCOS are likely distorted by those that are of most concern to patients or by the clinical focus of the provider. Larger studies that screen unselected populations will give a fuller, less biased picture of the disorder.

There are three sets in use today: the NIH 1990 criteria, in which women with PCOS must evidence both hyperandrogenism and oligo-ovulation; the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) or “Rotterdam” criteria of 2003, which requires two of three features: hyperandrogenism, ovulatory dysfunction or polycystic ovarian morphology (PCOM); and the Androgen Excess and PCOS Society (AE-PCOS) 2006 criteria, in which PCOS is defined by the presence of hyperandrogenism and ovarian dysfunction.

Ricardo Azziz

Note that the Rotterdam 2003 and AE-PCOS 2006 criteria are simply expansions of the original NIH 1990 criteria. In addition, all three criteria view PCOS as a diagnosis of exclusion, meaning disorders that cause similar features to PCOS must first be ruled out.

In practice, criteria are being selected according to the clinical focus the practitioner or the availability (or lack of) of diagnostic tools. For example, if the intended focus is hyperandrogenism, the criteria used would likely be that of the AE-PCOS 2006; if ultrasonography is not readily available, the criteria used would be NIH 1990, and so on.

A recent NIH consensus meeting recommended the Rotterdam 2003 criteria, which captures the broadest set of women with PCOS, but only when it is clear which phenotypes the patient demonstrates. In truth, only studies that use a phenomics process to determine alignment of the disorder’s clinical features with either molecular or genetic defects will allow us to determine which criteria — or which collection of phenotypes — depicts a specific disorder. Remember, there may be more than one PCOS.

Should all patients undergo ovarian ultrasonography, androgen levels or measures to exclude disorders that cause features similar to PCOS?

Again, we need epidemiologic trials that identify PCOS in unselected populations and use effective logic trees to detect the disorder. For example, if Rotterdam 2003 were used, then patients with possible PCOS could be separated into three groups: those with clinically evident hyperandrogenism and ovulatory dysfunction; those with clinically evident ovulatory dysfunction but without signs of hyperandrogenism; and those with hyperandrogenism and no signs of ovulatory dysfunction.

For the first group, it would remain only to exclude related/mimicking disorders. The second group would require first measuring circulating androgens to determine the presence of subclinical hyperandrogenemia or transvaginal ultrasonography to detect PCOM and then, if either is positive, excluding related/mimicking disorders. The third group should be first evaluated for subclinical ovulatory dysfunction and, if confirmed, exclude related/mimicking disorders. Again, more research is needed.

Defining ‘normal’

Understanding and accurately diagnosing “abnormal” depends on how we define “normal.” This is especially critical for a disorder like PCOS that varies greatly in presentation and is highly prevalent in the population. How much menstrual irregularity is too much? How much excess hair growth constitutes hirsutism? How is hyperandrogenemia defined?

Questions like these must be addressed, taking into account the traits of the population being assessed, the techniques and tools used for measurement, and the statistical methods used to define normal.

Long-term follow-up

Few studies exist that follow the development into adulthood of young girls with menstrual irregularity or who are daughters or sisters of women with PCOS. Likewise, few studies exist on women with PCOS in or approaching menopause, or for their postmenopausal risks for CVD, diabetes, etc.

Little is known about cardiovascular risks, particularly among women followed over time into older age. The effects of other cofounders, such as obesity, ethnicity, and PCOS subphenotypes, is surmised but unconfirmed; and the effect of common therapies on the long-term risk of these and other morbidities is unknown. Again, prospective longitudinal studies are critically needed.

The complex genetic character of PCOS makes it highly likely that genetic variants will be present in male relatives of women with the disorder. The genetic traits that determine metabolic and vascular dysfunction associated with PCOS may be of significance in affected men. The lack of studies on the subject means risks to males are as yet unknown.

Focusing on comorbidities, practice gaps

The risk for obesity in PCOS appears to be exaggerated because of the bias inherent in studying self-selected or clinically referred populations. Nonetheless, it is clear that excess weight is a concern for many women with the disorder. Attempts to determine the mechanisms underlying the excess weight gain and the optimum diet for weight loss in PCOS women have yet to provide clear answers.

What is the optimum therapy for the dermatologic symptoms of the syndrome?

This question remains to be answered, especially for PCOS women not presenting with infertility. Should the initial therapy for hirsutism be single agent vs. multi-agent? What metrics should be monitored throughout therapy and beyond? Thus far, most studies have been short-term, open-label, retrospective, non-randomized or uncontrolled observations.

When and how often should metabolic dysfunction be assessed?

Many women with PCOS are at increased risk for metabolic dysfunction. But who should be tested, and what tests should be performed for the initial assessment? And which tests should be repeated over time and how often?

Addressing such practice gaps will require significant resources and the dedication of a coalition of patients and patient advocacy groups, governmental agencies, researchers and clinicians and their associated professional organizations, and corporate and industry partners. It should be a priority, since PCOS is the most common endocrine/metabolic disorder of women, affecting millions worldwide, and associated with infertility, diabetes and other morbidities.