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. 2020 Jun:12:41-48.
doi: 10.1016/j.coemr.2020.02.013. Epub 2020 Mar 9.

Endocrine-Metabolic Dysfunction in Polycystic Ovary Syndrome: an Evolutionary Perspective

Daniel A Dumesic  1 , David H Abbott  2 , Smriti Sanchita  1 , Gregorio D Chazenbalk  1
Affiliations

Endocrine-Metabolic Dysfunction in Polycystic Ovary Syndrome: an Evolutionary Perspective

Daniel A Dumesic et al. Curr Opin Endocr Metab Res. 2020 Jun.

Abstract

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-anovulation and polycystic ovarian morphology, with metabolic dysfunction from insulin resistance and abdominal fat accumulation worsened by obesity. As ancestral traits, these features could have favored abdominal fat deposition for energy use during starvation, but have evolved into different PCOS phenotypes with variable metabolic dysfunction. Adipose dysfunction in PCOS from hyperandrogenemia and hyperinsulinemia likely constrains subcutaneous (SC) fat storage, promoting lipotoxicity through ectopic lipid accumulation and oxidative stress, insulin resistance and inflammation in non-adipose tissue. Recent findings of inherently exaggerated SC abdominal stem cell development to adipocytes in women with PCOS, and PCOS-like traits in adult female monkeys with natural hyperandrogenemia, imply common ancestral origins of PCOS in both human and nonhuman primates.

Keywords: adipocyte; adipose stem cells; developmental programming; hyperandrogenism; insulin resistance; polycystic ovary syndrome.

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Figures

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1.
A) Differences in adipose insulin resistance (adipose-IR) between normal-weight women with PCOS (N=10) and controls (N=18) (P<0.01). B) Significant negative and positive correlations of adipose-IR with and insulin sensitivity (Si) and serum total testosterone (T), respectively, in the same normal-weight women with PCOS and controls combined. Adipose-IR is the product of fasting circulating insulin (pmol/L) and total fatty acid (mmol/L) levels. Filled circles and columns, women with PCOS; Open circles and columns, controls. *, P < 0.01 by Student’s t-test [Modified from reference 6]. SI units: T ng/dL × 0.0347.
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2.
Temporal changes of A) ZFP423 protein expression and B) lipid content in subcutaneous (SC) abdominal ASCs cultured in adipogenic medium for up to 12 days. Values are expressed as median ± 95% confidence intervals of 8 age and BMI pair-matched normal-weight women with PCOS and controls. Significant correlations of C) log ZFP423 protein expression (day 0.5) with fasting plasma glucose levels, and of D) log lipid content (day 12) with serum free T levels in the same pair-matched normal-weight women with PCOS and controls. ZFP423 protein expression and lipid content values are expressed as Texas Red and Oil-Red-O fluorescence, respectively, divided by DAPI [Modified from reference 31]. Filled circles, women with PCOS; Open circles, controls. SI units: glucose mg/dL × 0.056; free T pg/mL × 3.47.
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Metabolic thrift in PCOS. Inherently enhanced subcutaneous (SC) abdominal adipogenesis in the presence of hyperandrogenism constrains SC fat storage and promotes preferential intra-abdominal fat accumulation. In SC abdominal adipose, the combination of androgen-induced catecholamine lipolytic resistance with insulin-mediated lipogenic/anti-lipolytic activities favors fat storage and can be counterbalanced by insulin resistance that favors increased circulating glucose and free fatty acid levels for energy use. An increased amount of highly-lipolytic intra-abdominal adipose also enhances free fatty acid delivery to the liver and muscle for energy storage or use. When energy intake exceeds energy utilization, increased free fatty acid availability overwhelms the capacity of target tissues to oxidize fat or convert diacylglycerol to triacylglycerol, worsening insulin resistance and increasing the risks of developing metabolic syndrome and lipotoxicity [, , –20, 36, 37, 40].
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References

    1. Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific Statement on the Diagnostic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr Rev 2015;36(5):487–525. - PMC - PubMed
    1. Abbott DH, Dumesic DA, Levine JE Hyperandrogenic Origins of Polycystic Ovary Syndrome – Implications for Pathophysiology and Therapy. Expert Rev Endocrinol Metab 2019;14(2):131–143. - PMC - PubMed

    2. ** This paper investigates the pathogenic origins of PCOS through animal models derived from experimentally-induced hyperandrogenism during gestation, or from naturally-occurring PCOS-like traits that demonstrate similar reproductive, neuroendocrine and metabolic abnormalities.

    1. Brennan KM, Kroener LL, Chazenbalk GD, Dumesic DA. Polycystic Ovary Syndrome: Impact of Lipotoxicity on Metabolic and Reproductive Health. Obstet Gynecol Surv 2019;74(4):223–231. - PMC - PubMed
    1. Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ on behalf of the International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod 2018;33:1602–1618. - PMC - PubMed

    2. * These international evidence-based guidelines include several recommendations that address the assessment and management of polycystic ovary syndrome (PCOS) with the goal of improving health outcomes of women with PCOS.

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