Two Distinct Subtypes of PCOS Identified in Adolescents

Miriam E. Tucker

June 17, 2022

Polycystic ovary syndrome (PCOS) in adolescents appears to present as two distinct subtypes based on the presence or absence of obesity, new data show.

The findings support the "metabolic" and "reproductive" subtypes previously identified in adult women, say the researchers.

Overall, PCOS affects 7% to 10% of adult women and is associated with significant metabolic and reproductive comorbidities, including type 2 diabetes, metabolic syndrome, subfertility, and endometrial carcinoma.

"Although it's so prevalent, there is still uncertainty regarding its mechanisms, which has really limited development of more effective treatment or prevention approaches," said Angie Chen, who presented the results at ENDO 2022: The Endocrine Society Annual Meeting.

Diagnostic criteria vary, but in general the diagnosis is made by the presence of combinations of hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. In adolescents, only the first two are criteria used for diagnosis of PCOS, and the definition of oligo- and/or anovulation differs from that of adult women.

But there is heterogeneity in PCOS among both adolescents and adult women. "Different combinations result in different clinical presentations," said Chen, a third-year medical student at Northwestern University Feinberg School of Medicine, Chicago, Illinois.

"There are significant differences between different subphenotypes...The heterogeneity is part of the reason for the different diagnostic criteria, and this could make it difficult for providers to make the diagnosis easily," she explained.

"PCOS Is a Diagnosis of Exclusion"

In the retrospective chart review study of 352 adolescent girls diagnosed with PCOS, those without obesity had higher levels of luteal hormone (LH), total testosterone, and androstenedione levels. In contrast, the girls with obesity were more likely to have insulin resistance-driven hyperandrogenemia with lower sex hormone–binding globulin (SHBG) and higher free testosterone levels.

These results support those from a study of adult women published in June 2020 in PLOS Medicine demonstrating "reproducible reproductive and metabolic subtypes of PCOS" that were each associated with novel genetic susceptibility loci.

Asked to comment, session moderator Genevieve Neal-Perry, MD, PhD, told Medscape Medical News: "With PCOS there's a lot of heterogeneity. It's kind of like a diagnosis of exclusion. We know it's not a thyroid problem or a prolactin problem, we know it's not congenital adrenal hyperplasia, so we know it's not these diseases that fit in a bucket. It's a heterogeneous disorder that is reflective of different genetic variants that lead to different phenotypes."

The new study, Neal-Perry said, "is telling us that there are different treatment paradigms that we need to consider." Specifically, women with the metabolic PCOS subtype "are at increased risk for morbidity such as heart disease, fatty liver disease, and things that not just have an impact on their quality of life but also the length of their life."

"Understanding [which form] of PCOS [it is] may have an impact on how we intervene," said Neal-Perry, of the department of obstetrics and gynecology at the University of North Carolina School of Medicine, Chapel Hill.

And although the focus in the reproductive subtype is typically on fertility, patients "seem to be at increased risk for some metabolic dysfunction even if they're thin. They should really be evaluated," she added.

Asked about the possibility of new guidelines, study lead investigator Laura C. Torchen, MD, a pediatric endocrinologist at Lurie Children's Hospital of Chicago, Illinois, told Medscape Medical News: "I don't think we are ready to provide guidelines with different diagnostic criteria and management guidelines by subtype yet. I think more work is needed to delineate mechanisms in these subgroups."

However, Torchen added, "from a research perspective, I feel failure to subgroup girls/women with PCOS has been a barrier to understanding these mechanisms."

"I will say that in my clinical practice I do differentiate in my management decisions — a girl with obesity and normal total testosterone but elevated free testosterone is more likely to have improvement in ovulatory dysfunction with metformin alone, without oral contraceptives, than a girl with elevated total testosterone."

Among Teens With PCOS, Differences Depend on Obesity

Chen and colleagues examined chart data from the PCOS multisite registry, which includes seven academic medical centers, from 2013-2021. The study population included 352 girls aged 13-18 with a diagnosis of PCOS, including 68 who were lean (BMI < 85th percentile) and 284 who had obesity (> 95th percentile). Average BMI was 22.6 kg/m2 for the lean group and 36.1 kg/m2 for those with obesity.

Age at PCOS diagnosis was 15.8 years for the lean group versus 15.3 years for those with obesity, which was a significant difference (P = .03). Age at menarche (first menstrual period) was 12.1 years for the lean group versus 11.6 years for those with obesity, which was also significantly different (P = .02).   

The two groups didn't differ significantly by race or ethnicity. The lean group was 63% White, 13% Black, and 10% Asian; those proportions in the group with obesity were 58%, 18%, and 4%, respectively.  

The metabolic phenotypes differed significantly. The girls with obesity had higher A1c (P < .0001), higher levels of the liver enzyme alanine aminotransferase (ALT) (P = .0006), and higher triglycerides (P = .0016) and lower HDL cholesterol (P < .0001) compared to those without obesity.

Those with obesity also had more severe acanthosis nigricans — dry, dark patches of skin that usually appear in the armpits, neck, or groin (P < .0001). The majority of girls with obesity had mild acanthosis nigricans, but in some it was moderate or severe, while in the lean group, very few girls had any sign of the skin condition and none had a severe case.

In contrast, the girls without obesity had significantly higher total testosterone levels (P = .003) and androstenedione levels (P = .0015) and lower free testosterone (P = .0026) compared to those with obesity.

"We believe that the reason for this discrepancy is because the girls with obesity had lower SHBG as a result of their insulin resistance," Chen said.   

In addition, the lean girls also had higher levels of LH (P = .0001). "This is consistent with the reproductive subphenotype seen in adult women with PCOS and it suggests that the narrow endocrine mechanism is especially important in this population of lean girls," she observed.  

Chen concluded, "In the future we hope that additional studies can elucidate the distinct biological mechanisms underpinning these subphenotypes. This is just the first step of applying 'precision medicine' in PCOS. Ultimately, we'd love to see distinct management guidelines for treatment and prevention of PCOS in the various subphenotypes."

Chen, Torchen, and Neal-Perry have reported no relevant financial relationships.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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