New Evidence Casts Doubt on Some PCOS Diagnoses

By Joy Lee

New research may challenge the current diagnosis and treatment of a complex endocrine disorder that has long perplexed the medical community: Polycystic Ovary Syndrome (PCOS). In a study published in the Archives of Gynecology and Obstetrics in March 2024, researchers suggests that one of the syndrome’s phenotypes, or physical variations, Phenotype D, might not fit the traditional PCOS criteria, raising questions about its classification and treatment. 

PCOS is categorized into four different subtypes, each marked by a unique combination of the following symptoms as established with the “Rotterdam Criteria”: elevated male hormones, ovarian cysts, a slower metabolism, and irregular menstrual cycles. Phenotype D stands apart from its counterparts – Phenotypes A, B, and C – as the only subtype that does not exhibit the main characteristic of the syndrome: elevated male hormone levels.  

“The more we study PCOS, the more it seems like a chimera, it always eludes you,” said Dr. Gianpiero Forte, a researcher in the Research and Development Department of the Experts Group on Inositol in Basic and Clinical Research on PCOS (EGOI-PCOS) based in Rome, Italy. “Within a single phenotype, it’s really hard to code the diagnostic criteria in a very strict way. You have to try and identify which are the causes of the two different expressions of the syndrome.”

“You’re going to see high levels of male hormones in patients with phenotypes A, B, and C. This causes issues such as facial hair growth and acne,” added Dr. Samuel Myers, a colleague of Dr. Forte at ECOI-PCOS . “In Phenotype D patients, you don’t see this hormone imbalance, especially in terms of testosterone.” 

High levels of male hormones, testosterone specifically, is a defining characteristic of the syndrome.  

“It’s easily quantifiable; you can do a blood test and see you’ve got higher testosterone levels,” Dr. Myers said. “It’s a reliable diagnostic test.”  

Because phenotype D challenges traditional diagnostic criteria, researchers in the paper have proposed a question – should phenotype D even be considered a form of PCOS?  

Dr. Vittorio Unfer, the founder of EGOI-PCOS, and his team advocate separating this phenotype from its counterparts in both name and treatment, recognizing the Rotterdam Criteria is an outdated diagnostic mechanism.  

“We have the problem where even if we do split people up into phenotypes, more often than not, you’ll see in papers that they [patients] were diagnosed according to the Rotterdam criteria, and then they’re all treated the same.”  

Dr. Myers explains how including Phenotype D patients into the same treatment as the other phenotypes is controversial. This grouping limits therapy options for phenotype D patients.  

“And we’re not the only people trying to update this; many other groups, even the original writers of the Rotterdam criteria have posted updates, and they continue to evolve,” he said. “But even with the new updated guidelines, the metabolic component isn’t accounted for sufficiently.”  

Other researchers have debated the use of the outdated Rotterdam diagnosis criteria. In the Department of Gynecology at the University of Texas Health San Antonio, researchers assess an international redefined diagnosis criteria for PCOS (3).  In this criterion, the focus is on redefining cyst count and the metabolic factor of the syndrome. The investigators of the new diagnosis guideline concluded that the cutoff of ovarian cysts in a single ovary using an ultrasound should be greater than or equal to 20 individual follicles.  This study concluded that increasing the minimal cyst count not only decreased the number of women with the diagnosis of PCOS, but the women who reach this criterion have greater health risks for metabolic syndrome than those who meet the Rotterdam criteria (3).  

Patients with the three other phenotypes of PCOS experience metabolic issues. In the context of Phenotype D, researchers at EGOI-PCOS concluded there is a connection between metabolic issues and high levels of male hormones, but these symptoms are not the root cause of Phenotype D.  

“Phenotype D is complicated,” said Dr. Forte. “It seems that these patients don’t have any metabolic alterations, they don’t have higher androgens, and they don’t have higher testosterone. So where do these arrested follicles come from? There must be some different trigger to it,” he adds. “Today, we don’t know what that is. That’s probably the first questions that scientists need to answer.” 

In research moving forward, EGOI-PCOS researchers hope to see more holistic studies from different parts of the world along with studies that try to separate Phenotype D from its counterparts, observing not just changes in the hormonal profile but also other metabolic profile changes between two sets of patients. 

This debate in the medical community raises questions of how PCOS diagnosis, mitigation, and treatment should be redefined and distributed. There may be advancements in this field, not because of new treatments or cures, but due to correct diagnoses and classifications. 

“Patients aren’t all the same,” said Dr. Myers. “Patients require different therapies; they have individual needs. These two groups of patients really do require separate and unique therapy choices.”