Metabolic Consequences of Polycystic Ovary Syndrome

Metabolic Consequences of PCOSIris Thiele Isip Tan MD, MSc, FPCP, FPSEM

Chief, UP Medical Informatics UnitAssociate Professor, UP College of Medicine

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27 May 2013Monday, May 27, 13

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A Baranova et al. Aliment Pharmacol Ther 2011; 33:801-804

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In 25 minutes?!Me and my boys 2 days ago ...

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A Baranova et al. Aliment Pharmacol Ther 2011; 33:801-804Monday, May 27, 13

A Baranova et al. Aliment Pharmacol Ther 2011; 33:801-804Monday, May 27, 13


Insulin resistance, obesity and diabetes

Implications for practice

MetabolicSyn!ome

& PCOS

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Diamanti-Kandarakis E & Dunaif A.Endocrine Reviews 2012; 33:981-1030

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Insulin resistance

decreased ability of insulin to mediate metabolic actions requirement for increased amounts of insulin to achieve a given metabolic action

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Insulin responses basally and after a 40 g/m2 oral glucose load

obese & lean PCOS women ● ovulatory hyperandrogenic women ●

age- & weight-comparable ovulatory control women ○Adapted from A Dunaif et al. Aliment J Clin Endocrinol Metab 1987 (34)

PCOS

HA

control

Obese LeanPCOS

HA

control

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Hyperinsulinemia is a unique feature of PCOS and not hyperandrogenic

states in generalAdapted from A Dunaif et al. Aliment J Clin Endocrinol Metab 1987 (34)

PCOS

HA

control

PCOS

HA

control

Obese Lean

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Diamanti-Kandarakis E & Dunaif A. Endocrine Reviews 2012; 33:981-1030

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NICHD PCOSNICHD PCOS

Obese Lean

HA

control HAcontrol

HA & PCO (ovulatory PCOS) leaner with milder

metabolic abn/normal

Anov & PCO normal insulin sensitivity

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Do non-NIH PCOS phenotypes present with similar metabolic risk as the NIH PCOS phenotype?

NIH PCOS greater obesity, abdominal obesity, insulin resistance

& risk factors for T2D

non-NIH PCOS greater metabolic abn than

controls but primarily linked to abdominal

obesity

Moran L & Teede H. Human Reprod Update 2009; 4:477-88

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Increased prevalence of obesity in PCOS

Increased frequency of hyperandrogenism in women with upper (vs lower body) obesity

Androgens can increase visceral fat in women

Androgens can increase muscle mass

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Insulin-mediated glucose disposal (IMGD) in PCOS by euglycemic clamp

Obese Lean


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Insulin-mediated glucose disposalwas significantly decreased (~35-40%) in PCOS women

Decrease in IMGD in PCOS similar to that seen in T2DDecreased IMGD in lean women with normal glucose tolerance

Obese Lean


PCOS

PCOS

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Dysglycemia develops when the β-cell is no longer able to secrete sufficient amounts of

insulin to meet the increased requirements.

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Hyperbolic relationship: Compensatory increase in insulin secretion when insulin sensitivity declines

β-cell dysfunction in PCOSAdapted from A. Dunaif & D.T. Finegood J Clin Endocrinol Metab 1996; (81):942-947

Obese PCOS ●Lean PCOS ▲

AIRg = acute insulin response to glucose

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Adapted from A. Dunaif & D.T. Finegood J Clin Endocrinol Metab 1996; (81):942-947

DI significantly decreased

in both lean & obese PCOS women

Disposition index (DI)product of insulin sensitivity and insulin secretionhighly heritable, associated with specific genetic locimost powerful predictor of diabetes risk

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Defect in glucose-stimulated insulin secretion in PCOS independent of obesity

Abnormality is found as early as adolescence in girls with PCOS & IGT


Adapted from A. Dunaif & D.T. Finegood J Clin Endocrinol Metab 1996; (81):942-947

Defect more pronounced

in women with first-degree relative

with T2D

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PCOS & (+) FH of DM ● PCOS & (-) FH of DM ○

75-g OGTT

Ehrmann DA et al. J Clin Endocrinol Metab 2005; (90):66-71

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Other genes evidently participating in PCOS pathogenesis

Steroid biosynthesis pathway CYP11A, CYP17, SRD5A

Androgen signaling pathway SHBG, SGTA

Obesity-associated gene FTO

Leukotriene metabolism related genes ALOX15, FEM1A, FEM1B

Adipokines & cytokines IL-6, IL-18, hs-CRP, TNFα, TNFR2


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Insulin receptor signaling pathway


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Insulin signaling defects in PCOSSerine phosphorylation of the insulin receptor and IRS-1

secondary to intracellular serine kinases resulting in resistance to metabolic actions of insulin


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Fasting and post-challenge dysglycemia in PCOS

Adapted from RS Legro et al. J Clin Endocrinol Metab 1999; (84):165-169Monday, May 27, 13

Fasting hyperglycemiaIFG: FBS 100-125 mg/dL OR T2D: FBS > 126 mg/dL


Post-challenge hyperglycemiaIGT: 2h >140 mg/dL OR T2D: 2h > 200 mg/dL


Postprandial dysglycemiaperipheral (primarily skeletal muscle) insulin resistance

Most women with PCOS have post-challenge

rather than fasting dysglycemia

Fasting dysglycemia

increased endogenous (liver and kidney) glucose production

Adapted from RS Legro et al. J Clin Endocrinol Metab 1999; (84):165-169

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Prevalence of glucose intolerance and T2D in PCOS (US data)

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Prevalence of IGT & T2D in US PCOS womenIGT: 25-35%3-fold higher than in women of similar age in NHANES II

T2D: 4-10%7.5- to 10-fold higher than in women of similar age in NHANES II

Prevalence of T2D likely underestimated because diagnosed T1D or T2D excluded in cohorts


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MetabolicSyn!ome

& PCOS

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Screening for glucose intoleranceA Consensus Statement by the AE-PCOS Society

Wild et al. J Clin Endocrinol Metab 2010;95:2038-49

75-g OGTT for PCOS women with BMI>30 kg/m2

Lean PCOS women >40 yPersonal history of gestational diabetes

Family history of type 2 diabetes

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Those with IGT should be screened ANNUALLY for developing T2DM, acknowledging efficacy of treating

IGT, but not necessarily IFG, to prevent T2DM.

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Suggest re-screening if normal glucose tolerance every TWO years or sooner

if additional risks are identified

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HbA1c above 6.5% has been proposed as the defining criterion for diabetes. We endorse this criterion for risk

assessment, but further studies are needed.

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Lifestyle Modification in PCOSA Consensus Statement by the AE-PCOS Society


Overweight/obese PCOS women should initially attempt 5-10% weight loss.

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Metformin for PCOSA Consensus Statement by the AE-PCOS Society


Women on lifestyle modification with no improvement in IGT

Women with IGT of normal weight

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Anti-obesity drugs for PCOSA Consensus Statement by the AE-PCOS Society


The use of weight loss medications is not recommended.

Orlistat induces small weight reduction without changing glucose-insulin homeostasis or lipid patterns.

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Bariatric surgery for PCOSA Consensus Statement by the AE-PCOS Society


Option for severely obese women with PCOS, in whom long-term diet-based strategies are seldom successful

BMI >40 kg/m2 or >35 kg/m2 with a high-risk obesity-related condition

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MetabolicSyn!ome

& PCOS

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Health & Medicine

Metabolic Consequences of Polycystic Ovary Syndrome