Polycystic ovary syndrome (PCOS) is a common condition affecting 10% of women during their re-productive years. Women with this condition may experience a myriad of symptoms such as anxiety, depression, irregular menstrual cycles, infertility, and metabolic problems. Yet about two-thirds of women with PCOS go undiagnosed. An international consortium, including Australia’s Centre for Research Excellence in PCOS, the European Society of Human Reproduction and Embryology, and American Society of Reproductive Medicine, hopes to change that by helping clinicians around the world more consistently diagnose and care for women with the condition with a new international guideline (available at www.monash.edu, search PCOS guideline, accessed July 23, 2018).
“It’s a global initiative with the intention of improving the health and the quality of life of women with PCOS and supporting their health professionals to partner with them to do so,” said lead author of the guideline Helena Teede, MBBS, PhD, a professor of women’s health and director of the Monash Centre for Health Research and Implementation at Monash University in Melbourne.
In addition to providing comprehensive information for clinicians on assessing and diagnosing PCOS, the evidence-based guideline delves into some of the choices laboratorians face in selecting appropriate tests. It takes a middle ground in the debate over whether mass spectrometry is the best tool for diagnosing hyperandrogenism, and it recommends against using anti-Müllerian hormone (AMH) until more data are available.
The guideline included the input of more than 1,800 women and more than 1,000 health professionals, including endocrinologists, fertility specialists, pediatricians, and gynecologists, from around the world. The women surveyed as part of the guideline process provided detailed information about how clinicians can best meet their needs. “Women with PCOS are generally experiencing delays in diagnosis,” Teede explained. In fact, studies have found it may take years and seeing three or more clinicians for a woman to get a diagnosis of PCOS. “Many women complain of dissatisfaction with care,” she said. “They often get to see one specialty group that focuses on one area such as infertility, but doesn’t look after the emotional, psychological, or metabolic features.”
One of the factors behind this fragmented and specialty-centric care for PCOS is that individual specialty groups in various countries have released their own guidelines, explained Richard Legro, MD, professor of obstetrics and gynecology and public health sciences at Penn State University in Hershey, Pennsylvania. This has resulted in a “profusion of guidelines, and a lot of confusion,” said Legro, who served on the new guideline’s advisory panel.
Such guidelines often fail to provide the information needed by primary care physicians, who are usually the first clinicians consulted by women with PCOS, Teede noted. To reduce the confusion, the international guideline is intended to be comprehensive and useful to all clinicians regardless of specialty or country. The guideline recommends simplified application of Rotterdam Criteria to diagnose PCOS (right). Women should have irregular menstrual cycles and hyperandrogenism and only need an ultra-sound if one of these features are present.
However, the guideline recommends against ultrasound for adolescents suspected of having PCOS. “Polycystic ovarian morphology is so prevalent in adolescents as a normal pubertal transition stage that it’s unhelpful in diagnosis,” Teede said.
Legro emphasized that the international guideline reflects the current evidence base and will be updated regularly as new data emerge. Teede noted that the consortium is currently working to es-tablish cluster-based cutoffs for PCOS diagnostic criteria that will help identify women who are likely to have clinical complications of PCOS. “Things will change over the next five years as we hone in on those very specific questions,” she said.
The Right Tests
The international guideline takes on two of the key questions for laboratories supporting clinicians trying to diagnose PCOS—how to best identify hyperandrogenism and whether AMH is ready for primetime. They do a better job than most guidelines by being very specific in which types of assays should be used,” said Joely Straseski, PhD, medical director of endocrinology and co-director of the auto-mated core laboratory at the University of Utah in Salt Lake City. Straseski also chairs the Clinical Laboratory News board of editors.
The guideline recommends liquid chromatography-mass spectrometry and extraction chromatography immunoassays to assess free testosterone levels in women suspected of having PCOS, but not direct immunoassays, Teede explained. “As long as the assay performs comparatively to mass spectrometry, the assay can be used [to as-sess testosterone],” Legro said. Previous recommendations that testosterone only be measured with mass spectrometry have met pushback because of the cost, he noted. Also, mass spectrometry is not accessible in many parts of the world.
“If you want a truly solid, accurate testosterone measurement in women, who typically have lower testosterone concentrations, mass spectrometry is really the way to go,” said Robert Nerenz, PhD, assistant director of clinical chemistry at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire. “Immunoassays just have pretty poor specificity at the low end and so they’ll generate a testosterone value that isn’t entirely testosterone.” Nerenz noted, however, that at least one study evaluating multivariable models for the diagnosis of PCOS, of which Teede was a co-author, failed to show a major advantage to using mass spec-trometry for testosterone measurement compared with immunoassay (Hum Reprod 2017;32:418–22).
Some laboratorians were critical of the new guideline’s recommendation that free androgen index (FAI) was an option to assess hyperandrogenism along with calculated bioavailable testosterone or free testosterone. William Winter, MD, a professor of pathology and pediatrics at the University of Florida in Gainesville and the endocrinology unit director at University of Florida’s health pathology laboratories, said that use of FAI for this purpose was not supported by the literature he reviewed. Straseski was also surprised by the inclusion of FAI. “Some people have found that the FAI performs differently in men than it does in women, and it may not correlate well with direct and calculated testosterone measurements,” Straseski said. “In most cases, free testosterone is a better measurement than FAI.”
The guideline also recommends against using AMH, which has been proposed as a biochemical alternative to using ultrasound to detect ovarian cysts. “AMH is still a moving target in terms of assay development,” Legro explained. He noted there are many different assays, and unanswered questions about what they measure and what AMH levels mean. For example, he noted that AMH levels may fluctuate with both age and whether a woman has gone through menopause.
Straseski said more standardization is needed before AMH can be used. “I’m optimistic that it will be more useful for diagnosis in the future,” she said. “Without standardized reference materials, I do not think it’s there right now.” Winter noted that a recent study found that AMH had only a modest ability to diagnose PCOS (Arch Gynecol Obstet 2018;298:207–15). “Future studies are required to determine the value of AMH in the diagnosis of PCOS,” he said.
If large multicenter trials are able to provide good standardization for use of AMH, the test may give laboratories a bigger role in diagnosing PCOS. Nerenz explained that clinicians may currently diagnose the condition without biochemical testing, using clinical indicators alone. “One of the big appeals of AMH, from my perspective, is that it really allows laboratorians to get involved in a PCOS diagnostic process that we’re sort of playing a peripheral role in otherwise,” he said.
In the meantime, the guidelines provide clinicians and laboratorians a common playbook for diagnosing PCOS, Straseski said: “It helps us to guide clinicians to the laboratory tests that will be most useful for them.”
Bridget M. Kuehn is a science writer in Brookfield, Illinois. +Email: bridgetmkuehn[at]gmail.com.