ENDO 2017 & American Association of Endocrine Surgeons:

In PCOS, What's Metabolic Function Got to Do with It?

Polycystic ovary syndrome (PCOS) is associated with obesity, type 2 diabetes (T2D), infertility, and excessive body hair.

Since the etiology of this condition remains largely unknown, a panel of experts at ENDO 2017, the Endocrine Society's 99th Annual Endocrine Annual Meeting and Expo, proposed genomics research to increase our understanding of the pathogenesis of PCOS, and to develop future targeted therapeutics for this vexing disease.

"Obesity is the most important contributor to metabolic dysfunction in women, especially in those with PCOS," Hector Francisco Escobar-Morreale, PhD, MD, professor of medicine at the University of Alcalá and head of the Department of Endocrinology of Hospital Universitario Ramón y Cajal in Madrid, Spain, told EndocrineWeb .

"This happens because obesity aggravates the negative effects that androgen excess exerts on metabolic function by favoring visceral adiposity and adipose tissue dysfunction," said Dr. Escobar-Morreale.

Omics Explains Female Metabolic Dysfunction

The real advantages of Omics research are that it is unbiased, but it nearly always generates more questions than answers,1 said Dr. Escobar-Morreale.

Dr. Escobar-Morreale’s team used Omics approaches to identify genes, proteins, and pathways unique to PCOS to analyze adipose tissue or plasma ± PCOS tissues.1

“These studies revealed that PCOS altered insulin, body weight, oxidative stress, inflammation, lipid, and immune pathways,” said Dr. Escobar-Morreale. His research team identified 4 altered plasma proteins in patients with PCOS patients, finding that the haptoglobulin beta chain (Hp beta) was the most dramatically decreased, and given its correlation with the Hp2 allele, may be associated with decreased antioxidant and anti-inflammatory activities.1

Pear-shape women are at higher risk for PCOS, metabolic disease

PCOS is Heterogeneous

There are specific metabolic abnormalities associated with PCOS and obesity.1 On a practical level, Dr. Escobar-Morreale stressed that “PCOS has a highly heterogeneous clinical presentation and in particular the source of androgenic excess must be characterized to minimize the known cardiometabolic and side effect risks associated with antiandrogenic therapies.”

"In our latest studies, including proteomics and transcriptomics of visceral and subcutaneous adipose tissue, and nontargeted studies of gut microbiome, the impact of obesity on the profiles found in women with PCOS resembles that found in healthy men, and is opposite to that observed in healthy women," he told EndocrineWeb.

"This suggests that the masculinization of women with PCOS, resulting from androgen excess, is not limited to dermocutaneous symptoms but also extends to adipose tissue distribution and function, as well as to metabolism," said Dr. Escobar-Morreale.

Elisabet Stener-Victorin, PhD, a research leader in reproductive endocrinology and metabolism at the Karolinska Institute in Stockholm, Sweden, discussed how hyperandrogenic (HA) PCOS affects adipocyte dysfunction, methylation epigenetics, and gene transcription. 

Adipocyte size and waist circumference presented as the strongest factors to explain insulin resistance in women with PCOS, according to Dr. Stener-Victorin. Moreover, the prevalence of metabolic syndrome was 2- to 5-fold higher in women with PCOS compared with controls.

Often overlooked has been the fact that adipose tissue is, in fact, heterogeneous, including variation in stem cells, progenitors, and mature adipocytes, said Dr. Stener-Victorin.

Adiponectin May Correct Metabolic Dysfunction

“Despite all that is known regarding adipocyte differentiation in endocrinology, we still do not have basic data on adipocyte differentiation for PCOS patients, but this should be done next,” she said. “It is also important that we examine whether a PCOS mother can exert HA-dependent epigenetic effects on offspring, questions her team is actively examining.” 

On a practical level, Dr. Stener-Victorin stressed thatandrogenic status, abdominal obesity, and age, should be taken into account when evaluating metabolic risks in women with PCOS.” 

Expanding on the beneficial role exercise plays in glucose metabolism, her team used electroacupuncture to examine its effects on glucose uptake and whether transcriptional alterations occur,2 she said. Electroacupuncture was delivered using a needle as an electrode not only to impart sensory stimuli but also to directly stimulate muscle contraction.2

The researchers observed that glucose uptake was increased by just one single bout of electroacupuncture with almost 20% of the gene transcription was altered, she said. Most significantly, following 5 weeks of electroacupuncture treatment, HbA1c decreased and circulating and adipose tissue androgens improved in women with PCOS.2

"Treatment that lowers adiponectin, including weight reduction and exercise, is crucial in the prevention and treatment of metabolic dysfunction in women with PCOS," Dr. Stener-Victorin told EndocrineWeb to explain the clinical relevance of these findings.

Know the Phenotype of PCOS

The heterogeneity of PCOS clinical presentations and our perceptions of PCOS are biased due to an overwhelming preference for referrals coming from patients who are obese with PCOS, said Ricardo Azziz, MD, MPH, MBA, chief officer of academic health and hospital affairs at the State University of New York in Albany.  

"The patients with PCOS that we see in our clinics are more obese, more severely hyperandrogenic (HA)—more the full phenotype—than the average PCOS patients actually are. To get to know the true face of PCOS will require us to examine patients identified through the study of unselected, medically unbiased, populations," said Dr. Azziz.

“Endocrinologists must distinguish between PCOS phenotypes: A-—HA and ovulatory dysfunction (OD), and polycystic ovaries (PO); B— HA and OD; C —HA and PO; D— OD and PO,” Dr. Azziz told EndocrineWeb.

Patients with PCOS were more frequently diagnosed with the A phenotype, and the two most important factors driving referrals appear to be HA and obesity, but obesity does not play a direct role in the prevalence of PCOS.3

Rather, a linear relationship appears to exist between metabolic dysfunction and the severity of the menstrual disorder in PCOS, with the least metabolic disturbance has been seen in PCOS patients without HA, said Dr. Azziz. However, more epidemiological studies are needed to properly assess the distinction of PCOS phenotypes before it will be possible to establish an optimal global health policy for PCOS.

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