Presentation at the 2013 meeting of the Philippine Society for Reproductive Endocrin

1. Metabolic Consequences of PCOS
Iris Thiele Isip Tan MD, MSc, FPCP, FPSEM
Chief, UP Medical Informatics Unit
Associate Professor, UP College of Medicine
“Eggs” by John Loo
http://www.flickr.com/photos/johnloo/5483256997/
27 May 2013
Monday, May 27, 13

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

3. In 25 minutes?!
Me and my boys 2 days ago ...
Monday, May 27, 13

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

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

6. A Baranova et al. Aliment Pharmacol Ther 2011; 33:801-804
Insulin resistance,
obesity and diabetes
Implications
for practice
Metabolic
Syn!ome
& PCOS
Monday, May 27, 13

7. Diamanti-Kandarakis E & Dunaif A.
Endocrine Reviews 2012; 33:981-1030
Monday, May 27, 13

8. 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 Baker
http://www.flickr.com/photos/atbaker/5125230312/
Monday, May 27, 13

9. 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 Lean
PCOS
HA
control
Monday, May 27, 13

10. Hyperinsulinemia is a unique feature
of PCOS and not hyperandrogenic
states in general
Adapted from A Dunaif et al. Aliment J Clin Endocrinol Metab 1987 (34)
PCOS
HA
control
PCOS
HA
control
Obese Lean
Monday, May 27, 13

11. Diamanti-Kandarakis E & Dunaif A. Endocrine Reviews 2012; 33:981-1030
Monday, May 27, 13

12. NICHD PCOS
NICHD PCOS
Obese Lean
HA
control
HA
control
HA & PCO
(ovulatory PCOS)
leaner with milder
metabolic abn/normal
Anov & PCO
normal insulin sensitivity
Monday, May 27, 13

13. 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
Monday, May 27, 13

14. 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
“Malaga - July 2012” by Evo Flash
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Monday, May 27, 13

15. 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

16. Insulin-mediated glucose disposal
was significantly decreased (~35-40%) in PCOS women
Decrease in IMGD in PCOS similar to that seen in T2D
Decreased 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

17. “Push” by Adam Baker
http://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.
Monday, May 27, 13

18. Hyperbolic relationship: Compensatory increase in
insulin secretion when insulin sensitivity declines
β-cell dysfunction in PCOS
Adapted from A. Dunaif & D.T. Finegood J Clin Endocrinol Metab 1996; (81):942-947
Obese PCOS ●
Lean PCOS ▲
AIRg = acute insulin response to glucose
Monday, May 27, 13

19. 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 secretion
highly heritable, associated with specific genetic loci
most powerful predictor of diabetes risk
Monday, May 27, 13

20. 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
Monday, May 27, 13

21. PCOS & (+) FH of DM ●
PCOS & (-) FH of DM ○
75-g OGTT
Ehrmann DA et al. J Clin Endocrinol Metab 2005; (90):66-71
Monday, May 27, 13

22. 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 Fernando
http://www.flickr.com/photos/13923263@N07/1471151698/
Monday, May 27, 13

23. Insulin receptor signaling pathway
Diamanti-Kandarakis E & Dunaif A. Endocrine Reviews 2012; 33:981-1030
Monday, May 27, 13

24. Insulin signaling defects in PCOS
Serine 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

25. Fasting and post-challenge
dysglycemia in PCOS
Adapted from RS Legro et al. J Clin Endocrinol Metab 1999; (84):165-169
Monday, May 27, 13

26. Fasting hyperglycemia
IFG: FBS 100-125 mg/dL OR T2D: FBS > 126 mg/dL
Adapted from RS Legro et al. J Clin Endocrinol Metab 1999; (84):165-169
Monday, May 27, 13

27. Post-challenge hyperglycemia
IGT: 2h >140 mg/dL OR T2D: 2h > 200 mg/dL
Adapted from RS Legro et al. J Clin Endocrinol Metab 1999; (84):165-169
Monday, May 27, 13

28. Postprandial
dysglycemia
peripheral (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

29. Diamanti-Kandarakis E & Dunaif A. Endocrine Reviews 2012; 33:981-1030
Prevalence of glucose intolerance
and T2D in PCOS (US data)
Monday, May 27, 13

30. Prevalence of IGT
& T2D in US PCOS
women
IGT: 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

31. A Baranova et al. Aliment Pharmacol Ther 2011; 33:801-804
Insulin resistance,
obesity and diabetes
Implications
for practice
Metabolic
Syn!ome
& PCOS
Monday, May 27, 13

32. Screening for glucose intolerance
A 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 y
Personal history of gestational diabetes
Family history of type 2 diabetes
Monday, May 27, 13

33. Screening for glucose intolerance
A 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.
Monday, May 27, 13

34. Screening for glucose intolerance
A 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

35. Screening for glucose intolerance
A 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

36. Lifestyle Modification in PCOS
A 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

37. Metformin for PCOS
A 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
Monday, May 27, 13

38. Anti-obesity drugs for PCOS
A 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.
Monday, May 27, 13

39. Bariatric surgery for PCOS
A 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

40. Insulin resistance,
obesity and diabetes
Implications
for practice
Metabolic
Syn!ome
& PCOS
Thank You
www.slideshare.net/isiptan
Monday, May 27, 13