Is Lean PCOS different from Obese PCOS?OCP Risks in PCOS No clear data on whether OCs have increased...

Is Lean PCOS different from Obese PCOS?Kathleen M Hoeger MD MPH

Professor, Obstetrics and Gynecology

University of Rochester

June 18, 2016

International Joint Conference PCOS Society (India) and

AEPCOS

Disclosures

No conflicts of interest to disclose

2

Impact of Obesity on PCOS

Teede et al BMC Medicine 2010, Norman et al Lancet 2007, Teede et al MJA 2011

Courtesy Helena Teede MD

What is the prevalence of obesity in PCOS?

Rates vary by region/country

Influenced by environmental factors

Difficult to ascertain accurately--Biased populations who present

for evaluation/management

Obesity rates and PCOS, non selected population

BMI class N (%) PCOS (%)

<18.9 36 (5.3) 8.2

19-24.9 282 (41.8) 9.8

25-29.9 160(23.7) 9.9

30-34.9 87(12.9) 5.2

35-39.9 57(8.5) 12.4

>40 53(7.8) 11.5

Yildiz JCEM 2008

Obesity in PCOS

Lim SS, .. Moran Hum Reprod Update 2012

Australian Longitudinal Study on Women’s Health

0

2

4

6

8

10

12

14

16

BMI < 25 BMI 25-30 BMI > 30

Percentage with PCOS

n=5749

n=1522

n=723

498 women reported PCOS, 60% PCOS women were overweight, longitudinal data 9% inc risk PCOS for 1 unit BMI

Teede, Obesity 2013

Australian Longitudinal Study on Women’s Health

0

2

4

6

8

10

12

14

16

non PCOS PCOS

% Weight gain over 10 years

Teede, Obesity 2013

Impact of obesity on Phenotype

All women

NIH Rotterdam AE-PCOS

Total 100% 6.1% 19.9% 15.3%

Non-obese

90% 5.1% 19% 14.5%

Obese 10.2% 15% 30% 22.5%

Yildiz, Human Reprod 2012

Turkish government employees, prevalence of PCOS by BMI

Diet, Physical Activity and Obesity in PCOS

Looking at diet and exercise data from a cohort of women with

and without PCOS, investigators were able to examine the impact

of diet on the presence of obesity in these populations.

Although the BMI of the PCOS group was on average higher

than the controls, dietary choices and energy intake did not differ

in the overweight or obese groups.

Wright 2004

Diet, Physical Activity and Obesity in PCOS

More control women demonstrated moderate to vigorous

activity levels

Comparing normal weight PCOS to normal weight controls

the caloric intake of lean PCOS was significantly lower (1400

kcal/day compared to 1800 in the weight matched controls)

Wright 2004

Characteristics of women with PCOSAustralian population based study

PCOS Non PCOS p

age 33.5 33.7 0.01

BMI 29.3 25.6 <0.001

Sedentary behavior (h/day)

2.8 2.9 0.008

Kcal/day 2577 2265 0.004

12

Moran Hum Rep 2013

Impact of obesity on reproductive phenotype

Is there is evidence that the expression of reproductive features may

vary within BMI categories?

PCOS, infertility and BMI

Joham et al J Womens Health 2015

Pre

vale

nce o

f fe

rtili

ty c

on

cern

s (

%)

PCOS (n=309) Non-PCOS (4547)0

20

40

60

80PCOS (n=309)

Non-PCOS (4547)

BMI category

Pro

ble

ms w

ith

fert

ility

(%

)

25 25 30 > 300

10

20

30

40

50

60

70

80

90PCOS

Non-PCOS

PPCOS II study: PCOS reproductive phenotype by BMI

BMI <30

BMI 30-34.9

BMI 35-39.9

BMI >40 p

Hirsutism 14.4 17.1 18.3 18.9 <0.001

Antral follicle count

51.0 47.0 46.9 42.6 <0.001

Endometrialthickness

6.3 6.3 7.3 7.0 <0.001

AMH 10.0 9.1 7.5 5.7 <0.001

Total T 51.9 58.5 55.9 55.9 0.050

Legro F&S 2015

Obesity and sex steroids

Kiddy et al examined 263 women with PCOS

Compared to lean women, obese women with PCOS had higher rates of

hirsutism (73% vs 56%)

Free testosterone was significantly higher

Kiddy 1990

Geographic variation in obesity and metabolic parameters

Comparison of 210 women with PCOS from Delhi and Srinagar

Evaluated androgens, gonadotropins, cortisol, lipids, OGT and insulin

PCOS women from both communities had similar age, age of menarche,

height and blood pressure

17

Ganie et al Gynecol Endocrinol 2016 Feb 15:1-5

Geographic variation in obesity and metabolic parameters

0

5

10

15

20

25

30

35

40

BMI GI FG score HOMA IR

Delhi

Srinagar

%

Kg/m2

18

Ganie et al Gynecol Endocrinol 2016 Feb 15:1-5

Influence of Obesity on metabolic phenotype

Obesity has a detrimental impact on metabolic parameters in women

with PCOS

This is likely mediated via worsening insulin resistance seen with obesity

Published in: Evanthia Diamanti-Kandarakis; Andrea Dunaif; Endocrine Reviews 2012, 33, 981-1030.

DOI: 10.1210/er.2011-1034

Copyright © 2012

Published in: Evanthia Diamanti-Kandarakis; Andrea Dunaif; Endocrine Reviews 2012, 33, 981-1030.

DOI: 10.1210/er.2011-1034

Copyright © 2012

Published in: Evanthia Diamanti-Kandarakis; Andrea Dunaif; Endocrine Reviews 2012, 33, 981-1030.

DOI: 10.1210/er.2011-1034

Copyright © 2012

Insulin Resistance in PCOS

WHO criteria for IR<25th centile on clamp studies

65% Obese controls75% lean PCOS

95% obese PCOS women

Overall 85% IR in PCOS

Stepto, Teede Human Reprod 2013

DM2 prevalence in PCOS

Moran L J et al. Hum. Reprod. Update 2010

PPCOS II study: PCOS metabolic phenotype by BMI

BMI <30

BMI 30-34.9

BMI 35-39.9

BMI >40 p

Fasting glucose

82.5 85.7 87.6 88.8 <0.001

Fasting insulin

8.4 16.4 26.3 28.0 <0.001

HDL Chol 41.9 37.7 36.2 34.7 <0.001

TG 92.9 128.3 127.5 128.1 <0.001

MS (%) 9.8 42.5 42.1 49.8 <0.001

Legro F&S 2015

Treatment of PCOS in the setting of obesity

Given the high prevalence of obesity seen in PCOS, what additional

impact does it have on the success of treatments commonly used for

PCOS?

Little data exist for the most common treatment for patients not

seeking fertility—oral contraceptives

26

OCP Normal weight vs Obese PCOS(NGT, DSG,GTD)

Mean age 25.4, BMI 20.3 n=28

Pre Post Δ

Acne 2.38 1.46 -0.92p=0.05

FG 9.1 6.9 -2.17p=0.01

T 2.72 1.44 -1.28p=0.001

SHBG 73.0 150.3 77.3p=0.001

Mean age 23.5, BMI 32.3 n=15

Pre Post Δ

Acne 1.67 0.79 -0.88NS

FG 9.8 7.2 -2.58NS

T 2.91 1.65 -1.26p=0.05

SHBG 51.0 105.5 54.5p=0.01

NormalObese

Cibula, Hum Reprod 2001

Oral contraceptive risk and PCOS

No clear indication that PCOS increases the risks of OC use

However obesity may increase the thrombotic risk in OC use

28

OCP Risks in PCOS

No clear data on whether OCs have increased risk of DVT in PCOS

There may be independent association of thrombotic risk and PCOS due

to a prothrombotic state and increase activity of PAI-1

• Prevalence of VTE 374.3 vs 193.8/100,000 in PCOS vs controls

irrespective of OC use (Okoroh Am J Obstet Gynecol 2012)

• On OCs PCOS higher 23.7 vs 10.9/10,000 (RR 2.12) (Byrd CMAJ 2013)

29

Impact of obesity on fertility treatments

30

Ovulation Induction with CC and obesity

201 women with oligo-ovulation undergoing ovulation induction with

clomid

Best predictors of failure to respond

• Free androgen index

• BMI

Mean BMI of non-responders was 30

Imani 1998

Obesity and FSH ovulation induction Several studies suggest gonadotropin dosing for ovulation induction in PCOS is related to weight

Hamilton-Fairley et al retrospectively examined 100 women with PCOS

Comparison of overweight versus normal weight

Increased dose of FSH required for ovulation but pregnancy rates did not differ

Increased rates of SAB were noted in the heavier group—60% vs 27%

Hamilton-Fairley 1992

Legro RS et al. N Engl J Med 2007;356:551-566.

PPCOS I:Clomiphene, Metformin or Both

Legro RS et al. N Engl J Med 2014;371:119-129.

PPCOS II: Clomiphene versus Letrozole

Obesity and intercourse compliance in PCOS

Conclusions

Women with PCOS demonstrate different phenotypes based on BMI

which may vary considerably by geography

Obesity has a significant impact on the metabolic and reproductive

consequences of PCOS

Women with PCOS who are obese demonstrate lower success with

infertility treatments

36

37