Reproductive & Maternal Health Resource Center

Reproductive & Maternal Health Resource Center

Issue: January 2021
Source: Healio interviews
Disclosures: Copperman, Dunaif, Eisenberg and Yildiz report no relevant financial disclosures.
January 22, 2021
12 min read
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Better evidence needed to define, treat PCOS

Issue: January 2021
Source: Healio interviews
Disclosures: Copperman, Dunaif, Eisenberg and Yildiz report no relevant financial disclosures.
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Polycystic ovary syndrome is a lifelong endocrine, metabolic and reproductive disorder estimated to affect 5% to 15% of women in the United States, depending on how the condition is characterized.

Beyond reproductive and dermatologic features, PCOS is also associated with a substantial increase in risks for various cardiometabolic abnormalities, lower quality of life, mood disorders, psychosexual dysfunction, body image problems and disordered eating. Yet, awareness of PCOS remains low, in part because of its misleading name — polycystic ovaries are not necessary for a diagnosis — and the still-unknown etiology of a complex condition that affects multiple organ systems in different ways, depending on phenotype.

More population studies of the epidemiology, phenotype and genetics of PCOS in different ethnic and racial groups worldwide are needed, according to Bulent Yildiz, MD.

Photo by Murat Topaloglu. Printed with permission.

“When I give talks on this, the first thing I emphasize is the difficulty to define PCOS,” Bulent Yildiz, MD, professor of endocrinology and metabolism at Hacettepe University School of Medicine in Ankara, Turkey, told Endocrine Today. “This is not a disease. This is a syndrome. With diabetes, even though it has several different phenotypes, you define it by a number. Obesity is also defined by a number. When it comes to PCOS, defining phenotype is extremely difficult. ... This is an underappreciated, underrecognized disorder.”

Accurate and early diagnosis is essential for women with PCOS to prevent long-term health consequences; however, confusion persists over diagnostic criteria and the optimal management of metabolic symptoms. Guidelines from professional societies for the management of PCOS lack rigorous evidence-based recommendations, and large studies with diverse populations of women with PCOS are unavailable.

“The field has been chronically underfunded,” Andrea Dunaif, MD, professor and chief of the Hilda and J. Lester Gabrilove division of endocrinology, diabetes and bone disease at the Mount Sinai Health System and Endocrine Today Editorial Board Member, said in an interview. “PCOS, in part because of the name, is not considered a medical disorder, and it is not embraced by mainstream primary care and internal medicine. That is the audience that needs to be engaged to treat the nonfertility-related issues. You can count on one hand the number of centers that even have reproductive medicine training in endocrine fellowships.”

Evidence lacking

Guidelines, best practices and consensus statements for the management of PCOS have been published by the Endocrine Society, the European Society of Endocrinology and the PCOS Australian Alliance, as well as jointly by the European Society of Human Reproduction and Embryology and the American Society for Reproductive Medicine, and by the American Association of Clinical Endocrinology and the Androgen Excess and PCOS Society. Yet, aside from robust guidelines for infertility management, most PCOS recommendations are labeled as expert opinion.

“The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is to be commended for having the reproductive medicine network that has done major trials on best treatments for infertility — adequately powered, beautiful studies,” Dunaif said. “That just has not been done for any of the other features of this syndrome. What we do, by extrapolation, is there may be randomized controlled trials, but almost all of them, outside of infertility, are very small. One has concerns about how robust the findings are.”

The dearth of studies has resulted in PCOS guidance labeled as “evidence-based,” when only a minority of recommendations are, Yildiz said.

“The most recent international guideline was published in 2018. It includes 166 recommendations for the assessment and management of PCOS,” Yildiz said. “Among those, only 31 are evidence-based, whereas 59 were developed by clinical consensus and 76 were clinical practice points.”

Developing evidence-based recommendations for the metabolic manifestations of PCOS can be a challenge, in part because there are so many different phenotypes and expressions of the syndrome, Esther Eisenberg, MD, MPH, director of the program for reproductive medicine and infertility at the NICHD at the NIH, told Endocrine Today.

“Some [PCOS] guidelines are fairly evidence-based, for example, fertility treatments,” Eisenberg said. “We have good randomized controlled trials and evidence that an aromatase inhibitor, for example, is the optimal treatment for ovulation induction in women with PCOS. If you look at the narrow categories, we do have evidence for at least some of the issues of PCOS. But there is a disconnect because people do not agree on whether the metabolic manifestations are characteristic of PCOS or a consequence.”

Alan B. Copperman

Securing funding for large studies to answer such questions also is difficult.

“The funding for [metabolic outcomes] is not necessarily a straight line,” Eisenberg said. “Here at the NIH, NICHD funds the reproductive issues and some of the other issues related to PCOS, whereas [National Institute of Diabetes and Digestive and Kidney Diseases] might fund studies on metabolic issues, and NHLBI might fund research on cardiac-associated consequences. There is less clarity because of how the money flows. That is an opinion, but that may be why.”

To help drive more research, NICHD in September issued a Notice of Special Interest to announce the opportunity for investigators to apply for funding to optimize treatments of comorbid conditions in adolescents and reproductive-age women with PCOS. The goals of this initiative are to stimulate interdisciplinary scientific collaboration between gynecologists, reproductive endocrinologists, obstetricians and subspecialists in diverse medical fields, including cardiologists, endocrinologists, gastroenterologists and psychiatrists; to advance individualized treatments; to promote translational and clinical research; and to discover and develop novel safe and more effective therapies for adolescents and women with PCOS.

“We know we need to treat the insulin resistance and the underlying issues, but how does that treatment affect the outcomes that are of interest to us?” Eisenberg said. “If you treat the depression with an antidepressant, will that affect gynecologic outcomes? We are looking at a more precise treatment. The more metabolic the phenotype is, the more likely there will be a downstream consequence. Same with endometrial cancer risk.”

Improved PCOS research is needed for better understanding the syndrome and generating evidence to inform the guidelines, Dunaif said.

“The only way to address this gap is to do the studies,” Dunaif said. “We don’t know from appropriately powered randomized clinical trials what the optimal therapies are for hyperandrogenic symptoms, for diabetes prevention, for dyslipidemia. We extrapolate from studies on type 2 diabetes, but PCOS has a distinct mechanism of insulin resistance, and we now know that PCOS differs genetically from type 2 diabetes. .... In this era of precision medicine, it is imperative that there are trials specifically investigating the cardiometabolic consequences of PCOS.”

Areas of uncertainty

Andrea Dunaif

The most recent international PCOS guideline, published in 2018, endorses the Rotterdam PCOS diagnostic criteria for adults. According to Rotterdam criteria, a clinical diagnosis of PCOS requires a woman present with two of the following symptoms: clinical or biochemical hyperandrogenism, ovulatory dysfunction or polycystic ovaries on ultrasound; when irregular menses and hyperandrogenism are present, ultrasound is not necessary for diagnosis. Within 8 years of menarche, both hyperandrogenism and ovulatory dysfunction are required, with ultrasound not recommended, for diagnosis.

The Rotterdam criteria, developed in 2003, expanded the NIH 1990 definition of PCOS, creating two new phenotypes: ovulatory women with polycystic ovaries plus hyperandrogenism and oligo-anovulatory women with polycystic ovaries, but without hyperandrogenism.

All criteria for diagnosis for PCOS are based on expert opinion. There is no evidence that assessment of ovarian morphology is needed for the endocrine or metabolic management of women with hyperandrogenism and chronic anovulation, according to Dunaif. Further, it is now known from the largest analysis to date that PCOS cases defined by the different diagnostic criteria are genetically similar.

Diagnosis is particularly challenging during adolescence and menopause, Yildiz said.

“It is an important step that the recent international guideline recommends against use of ultrasound before 8 years post-menarche due to high incidence of multifollicular ovaries at this stage,” Yildiz said. “It is also helpful defining adolescents being ‘at risk’ who have features suggesting PCOS, but who do not meet diagnostic criteria until full reproductive maturity.”

A biological marker that could be measured to diagnose PCOS would be helpful, Eisenberg said.

“There are issues with AMH, but there are lots of data in certain age ranges that show it can be an excellent biomarker of PCOS,” Eisenberg said. “There are caveats, of course. I hope that, ultimately, the field can move to using AMH or something that might be measurable to make diagnosis a little easier.”

Once a diagnosis is made, apart from ovulation induction, there are virtually no adequately powered randomized clinical trials, or even high-quality observational studies, of optimal therapies for PCOS. Given this information vacuum, therapeutic recommendations are based on meta-analyses of small studies in which the outcome of interest was frequently not a primary endpoint of the original trial, or on extrapolation from studies in other disorders, according to Dunaif.

Genetic clues

Dunaif and colleagues have identified two distinct subtypes of PCOS associated with novel gene regions, a discovery that could improve disease diagnosis and potentially provide new pathways for drug targets.

The findings, published in PLOS Medicine in June, are based on a mathematical analysis that used clustering of clinical, metabolic and hormonal data from more than 800 women with PCOS. Using clinical, biochemical and genotype data from their previously published PCOS genome-wide association study (GWAS), the researchers conducted cluster analysis in the GWAS cohort of 893 PCOS cases (median age, 28 years; median BMI, 35.4 kg/m²). The clusters were then replicated in an independent, ungenotyped cohort of 263 PCOS cases (median age, 28 years; median BMI, 35.7 kg/m²).

The clustering revealed two distinct PCOS subtypes: a “reproductive” group (21% to 23%) characterized by higher levels of luteinizing hormone and sex hormone-binding globulin with relatively low BMI and insulin levels; and a “metabolic” group (37% to 39%) characterized by higher BMI and glucose and insulin levels with lower SHBG and luteinizing hormone levels, Dunaif said.

Esther Eisenberg

“This is something that investigators in the field have suspected, but none of us had previously been able to robustly characterize,” Dunaif said. “One could think that perhaps these subtypes represent extremes of a normal distribution, but what the cluster analysis allows you to test using an unbiased approach is whether these traits aggregate with each other.”

The researchers performed a GWAS on the genotyped cohort, limiting cases to reproductive or metabolic phenotypes, and identified alleles in four loci associated with the reproductive subtype at genome-wide significance, as well as one locus associated with the metabolic subtype. They then developed a predictive model to classify a separate, family-based cohort of 73 women with PCOS and found that the subtypes tended to cluster in families.

“The importance of these findings, if they are replicated and proven to be generalizable, is that the subtypes identify genetically discrete groups, suggesting they are biologically relevant in contrast to the groups identified by the current diagnostic criteria, which are genetically similar. This type of ‘omics’ approach is allowing us to move from PCOS classification based on expert opinion, which is subjective, to classification based on demonstrable biologic differences,” Dunaif said.

Such research is key to gain insight into the best diagnostics and therapeutics, according to Alan B. Copperman, MD, director of the division of reproductive endocrinology and infertility and vice chair of the department of obstetrics, gynecology and reproductive science at Mount Sinai Medical Center.

“It is important to create these big networks of data, to build these in silico models of information where we can figure out with diagnostics and therapeutics how to change the health and trajectory of a whole population,” Copperman told Endocrine Today. “Data is not going to cure people with PCOS. What we can do with data is identify at-risk people, modify lifestyles, and put them on a trajectory to not be as symptomatic, to not suffer from the severe obesity, metabolic syndrome and CV complications. We can identify these at-risk patients early and change something that is going to alter their outcome. We need data for this, and we need funding for this.”

Timely diagnosis key

Experts agree that management of PCOS begins with a timely diagnosis; however, confusion over diagnostic criteria and poor understanding of the condition often lead to one of two problems — adolescents erroneously receiving a diagnosis of PCOS, or women who wait years for treatment.

“Someone 2 years post-menarche with irregular menses needs aggressive evaluation and management, and a specific diagnosis made,” Dunaif said. “Too often, they go to the gynecologist and are just started on birth control pills without a diagnostic evaluation. Or a health care provider will make a diagnosis of PCOS based solely on an ovarian ultrasound in the absence of any symptoms of PCOS, unaware of the fact that almost all adolescent girls have polycystic ovarian morphology.”

Yildiz, who said up to 1 in 3 women have polycystic ovarian morphology, said too many young girls may receive an incorrect diagnosis.

“In and of itself, polycystic ovarian morphology does not mean anything,” Yildiz said. “In young girls, it resembles the multifollicular ovaries. We should not label everyone.”

Another issue in the U.S. is that clinical radiologists rarely interpret ovarian sonography according to Rotterdam criteria, Dunaif said.

“Unfortunately, there has been an increased focus on ultrasound in the recent international guidelines, and what I see in my practice is more confusion than there ever was,” Dunaif said. “A patient comes in with an ultrasound that has not been read appropriately — there is no ovarian volume and no follicle count provided, the two things you need for assessment of polycystic ovarian morphology according to the Rotterdam criteria. Then the patient is confused. Clinicians are less willing to become engaged in PCOS rather than more willing. The emphasis on ovarian morphology as part of the diagnostic criteria has led to adverse, unanticipated consequences, and guidelines emphasizing ultrasound don’t allow for different practices in different countries.”

For women who receive a diagnosis of PCOS, clinicians must emphasize that it is a lifelong disorder that can be managed, Yildiz said.

“There is no cure. It will always be with you, but you can live with it as long as problems are managed,” Yildiz said. “For androgen excess — the most common complaint of women — oral contraceptives are still the best option. The field is not moving forward because there is not much interest for the development of new drugs. PCOS is not lupus or diabetes or rheumatoid arthritis. The pipeline is very thin. That is why the best option remains oral contraceptives.”

Controlling insulin resistance early is also important, Eisenberg said.

“From my personal experience taking care of women with PCOS, a low glycemic index diet is No. 1,” Eisenberg said. “Whether insulin resistance is foundational to PCOS or consequential, it remains one of the main features of PCOS and affects everything downstream, from weight gain and obesity to cardiovascular disease. That can be controlled, either by diet or medication. A low glycemic index diet is the first-line management and probably needs to be included in any management plan.”

More to learn

Many researchers still do not fully understand the etiopathogenesis of PCOS, and several scientific questions remain to be addressed, Yildiz said.

“The phenotypic presentation of PCOS differs between referral and unselected populations and varies within an individual over time and between individuals of different ethnic and geographic regions,” Yildiz said. “More precise population studies of the epidemiology, phenotype and genetics of PCOS worldwide are crucially needed. Studies in different ethnic and racial groups and in different parts of the world will also help us better understand the role of environmental factors for the development of PCOS.”

Neuroimaging studies could also reveal potential links between insulin resistance in PCOS and the central nervous system, Yildiz said.

“For other disorders, you have good animal models. In PCOS, animal models do not fully reflect the human phenotype,” Yildiz said. “It is so important to do the research in humans to learn more. In that regard, structural and functional brain imaging is an important tool to understand human behavior and hormonal changes. Similar to what is shown in diabetes and obesity, we and others have observed important variations in brain imaging of obese and nonobese PCOS women. I hope we will have more functional and structural imaging studies to understand the role of the central nervous system and how we can link it to insulin resistance, mood disorders and disordered eating in PCOS. This is a very exciting, emerging field.”

Better disease models could also help answer such questions, Copperman said.

“We still have not done a good enough job of disease modeling,” Copperman said. “I don’t know if that means genome-wide association studies of diverse groups — marrying that data to deep phenotypic data and environmental data, app data and biometrics — but it needs to be to create disease models that will help us with diagnostics and therapeutics to truly personalize medicine for these women.

“We need more advocacy for funding, participation in multicenter trials, more studies of diverse populations, so we meet all patient needs and have appropriate representation,” Copperman said. “All that will get us closer to disease management and better health.”