Metabolic Consequences of Polycystic Ovary Syndrome
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Metabolic Consequences of PCOSIris Thiele Isip Tan MD, MSc, FPCP, FPSEM
Chief, UP Medical Informatics UnitAssociate Professor, UP College of Medicine
“Eggs” by John Loo http://www.flickr.com/photos/johnloo/5483256997/
27 May 2013Monday, May 27, 13
A Baranova et al. Aliment Pharmacol Ther 2011; 33:801-804
Monday, May 27, 13
In 25 minutes?!Me and my boys 2 days ago ...
Monday, May 27, 13
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
A Baranova et al. Aliment Pharmacol Ther 2011; 33:801-804
Insulin resistance, obesity and diabetes
Implications for practice
MetabolicSyn!ome
& PCOS
Monday, May 27, 13
Diamanti-Kandarakis E & Dunaif A.Endocrine Reviews 2012; 33:981-1030
Monday, May 27, 13
Insulin resistance
decreased ability of insulin to mediate metabolic actions requirement for increased amounts of insulin to achieve a given metabolic action
“Push” by Adam Bakerhttp://www.flickr.com/photos/atbaker/5125230312/
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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
Monday, May 27, 13
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
Monday, May 27, 13
Diamanti-Kandarakis E & Dunaif A. Endocrine Reviews 2012; 33:981-1030
Monday, May 27, 13
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
Diamanti-Kandarakis E & Dunaif A. Endocrine Reviews 2012; 33:981-1030
Monday, May 27, 13
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
Diamanti-Kandarakis E & Dunaif A. Endocrine Reviews 2012; 33:981-1030
PCOS
PCOS
Monday, May 27, 13
“Push” by Adam Bakerhttp://www.flickr.com/photos/atbaker/5125230312/
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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Obese PCOS ●Lean PCOS ▲
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
Obese PCOS ●Lean PCOS ▲
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
A Baranova et al. Aliment Pharmacol Ther 2011; 33:801-804
“A Sister’s Love” by Carmella Fernandohttp://www.flickr.com/photos/13923263@N07/1471151698/
Monday, May 27, 13
Insulin receptor signaling pathway
Diamanti-Kandarakis E & Dunaif A. Endocrine Reviews 2012; 33:981-1030
Monday, May 27, 13
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
Diamanti-Kandarakis E & Dunaif A. Endocrine Reviews 2012; 33:981-1030
Monday, May 27, 13
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
Adapted from RS Legro et al. J Clin Endocrinol Metab 1999; (84):165-169Monday, May 27, 13
Post-challenge hyperglycemiaIGT: 2h >140 mg/dL OR T2D: 2h > 200 mg/dL
Adapted from RS Legro et al. J Clin Endocrinol Metab 1999; (84):165-169Monday, May 27, 13
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
Monday, May 27, 13
Diamanti-Kandarakis E & Dunaif A. Endocrine Reviews 2012; 33:981-1030
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
Diamanti-Kandarakis E & Dunaif A. Endocrine Reviews 2012; 33:981-1030
Monday, May 27, 13
A Baranova et al. Aliment Pharmacol Ther 2011; 33:801-804
Insulin resistance, obesity and diabetes
Implications for practice
MetabolicSyn!ome
& PCOS
Monday, May 27, 13
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
Monday, May 27, 13
Screening for glucose intoleranceA Consensus Statement by the AE-PCOS Society
Wild et al. J Clin Endocrinol Metab 2010;95:2038-49
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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Screening for glucose intoleranceA Consensus Statement by the AE-PCOS Society
Wild et al. J Clin Endocrinol Metab 2010;95:2038-49
Suggest re-screening if normal glucose tolerance every TWO years or sooner
if additional risks are identified
Monday, May 27, 13
Screening for glucose intoleranceA Consensus Statement by the AE-PCOS Society
Wild et al. J Clin Endocrinol Metab 2010;95:2038-49
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.
Monday, May 27, 13
Lifestyle Modification in PCOSA Consensus Statement by the AE-PCOS Society
Wild et al. J Clin Endocrinol Metab 2010;95:2038-49
Overweight/obese PCOS women should initially attempt 5-10% weight loss.
Monday, May 27, 13
Metformin for PCOSA Consensus Statement by the AE-PCOS Society
Wild et al. J Clin Endocrinol Metab 2010;95:2038-49
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
Wild et al. J Clin Endocrinol Metab 2010;95:2038-49
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
Wild et al. J Clin Endocrinol Metab 2010;95:2038-49
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
Monday, May 27, 13
Insulin resistance, obesity and diabetes
Implications for practice
MetabolicSyn!ome
& PCOS
Thank Youwww.slideshare.net/isiptan
Monday, May 27, 13
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