Heritability of PCOS provides clues for metabolic risk

Issue: December 2015

BOSTON — Polycystic ovary syndrome is the most powerful predictor of type 2 diabetes in young women, but the disorder also offers clues for clinicians about metabolic risk in that patient’s first-degree relatives, according to a presenter at the Cardiometabolic Health Congress.

Andrea E. Dunaif, MD, of the Northwestern University Feinberg School of Medicine, said women with PCOS, characterized by hyperandrogenism and chronic anovulation, are at a substantially increased risk for developing type 2 diabetes with a very young age of onset. By adolescence, about 30% of girls with obesity and PCOS already have impaired glucose tolerance; 10% have developed type 2 diabetes, Dunaif said.

Andrea E. Dunaif

“In terms of insulin resistance with PCOS, it’s much like what we see with type 2 diabetes, where we have decreasing insulin sensitivity,” Dunaif said during a presentation. “And if you have a normal beta cell, you’re able to put out enough insulin to compensate for the decrease in insulin sensitivity. When the beta cell begins to fail, you can’t compensate for the degree of insulin resistance, and you start seeing the values falling.”

Most women with PCOS have normal glucose tolerance and are at an exceptionally high risk for type 2 diabetes, according to Dunaif.

Hyperinsulinemic-euglycemic clamp testing in women with PCOS reveals markedly decreased insulin-mediated glucose disposal, independent of obesity, and a magnitude of decrease similar to much older women with type 2 diabetes, according to Dunaif.

“So this is a major disorder of insulin action,” she said. “At the molecular level … the number of insulin receptors is unchanged, but their ability to signal the cascade of intracellular signaling events is impaired. … We don’t see this phenotype in type 2 diabetes or simple obesity.”

PCOS heritability

Heritability of PCOS has been inferred from studies of the syndrome in various populations and twin studies, Dunaif said. The data suggest that the condition is passed down through either sex and can manifest in multiple ways.

PCOS is a complex genetic disease, like type 2 diabetes or obesity, according to Dunaif. “These conditions have a non-Mendelian inheritance pattern, but they [run] in families. Your risk for the disorder is increased [if in the family],” she said.

A patient with a sibling with PCOS has a 5.7-fold increased risk for developing the syndrome, Dunaif said. Approximately 40% of reproductive-age females with PCOS have a first-degree relative with a form of the syndrome, either the classic form or a form characterized by high circulating androgen levels. Studies also show a 70% concordance for PCOS in monozygotic twins, according to Dunaif.

Diagnosis, screening

Dunaif recommended that clinicians get a detailed family history from patients and screen for the condition among family members of women diagnosed with PCOS.

“Indeed, the first-degree relatives [of women with PCOS] are at risk for metabolic abnormalities,” Dunaif said, including type 2 diabetes. “We can look at the sisters [of women with PCOS] and tell by the testosterone levels if the sisters are affected or unaffected.”

Studies conducted by Dunaif and others in the young daughters of women with PCOS also suggest that there is evidence for disease earlier than the onset of menarche. Even in girls aged 8 to 12 years, Dunaif said, insulin sensitivity measurements were markedly different from controls.

“These are 8- to 12-year-old girls ... normoglycemic and already at strikingly high risk for type 2 diabetes before they even manifest the features of the syndrome,” she said. “This is exciting in that we might be able to intervene early with therapies that preserve beta-cell function in these girls who are at risk.

“People have talked about the paradox of how you can have insulin driving these reproductive abnormalities when there is resistance to insulin’s metabolic actions,” Dunaif said. “There is selective insulin resistance. Only the metabolic pathways are compromised, and growth pathways, the myogenic pathways, are preserved, and in fact, in certain tissues, they’re constitutively turned on.”

New name for PCOS

In 2012, the NIH convened a state-of-the-science meeting on PCOS, and an expert panel noted that the name “polycystic ovary syndrome” was “a distraction and an impediment to progress,” Dunaif said.

“There are no cysts on the ovaries,” she said. “You don’t need to have polycystic ovaries to have the diagnosis, and it keeps the disorder from being recognized as a long-term complicated metabolic disorder.”

Although the panel recommended a name change, no change has been made yet. Most international physician and patient groups agree on a change to “metabolic reproductive syndrome,” or MRS, Dunaif said — but it remains to be seen if that will become the new name.

“With the patient groups, it’s going to be a challenge because they don’t want to be labeled anything,” she said. – by Regina Schaffer

Reference:

Dunaif AE. Insulin resistance and polycystic ovary syndrome: pathogenesis, evaluation and treatment. Presented at: Cardiometabolic Health Congress; Oct. 21-24, 2015; Boston.

Disclosure: Dunaif reports no relevant financial disclosures.