Polycystic ovary syndrome in young women –- new ideas

Disclosures

• Minor shareholder IVF clinic

• Grant support MSD, Merck and Ferring

• Grant support NHMRC

Perspective is everything in PCOS

http://www.wchfoundation.org.au/http://www.wchfoundation.org.au/

Peacock’s 2013

Polycystic ovary syndrome

• Unknown aetiology but familial elements

• Very diverse phenotype presenting to different practitioners

• Insulin resistance is very common

• Name implies this is a reproductive condition and medical aspects ignored.

Complex clinical syndrome

Norman et al Lancet 2007

A changing paradigm in PCOS

Human Reproduction 27:14-24 (2012)

Psychological features

Quality of life

Anxiety & depression

Poorbody

image

Psychosexual dysfunction

Eating disorders

Teede et al MJA 2011, Deeks et al Fertil Steril 2010

PCOS phenotypes across ethnicity

Africans:- High BMI levels- More metabolic

problems

Europeans:- Relatively mild phenotype

Middle Eastern / Mediterranean: - More hirsutism

East Asian:- High prevalence of metabolic

syndrome- Lower BMI- Mild hyperandrogenic phenotype

Hindustani:- More insulin resistance

South Asians:- high prevalence of

insulin resistance and metabolic syndrome

- high risk for type 2- diabetes mellitus- high central obesity

Surinam hindustani:- More insulin resistance

Ethnicity-specific guidelines for appropriate screening, diagnosis, treatment in high risk ethnic groups

(Louwers et al. JCEM 2014, courtesy Joop Laven)

NIH Group

AESGroup

RotterdamGroup

9% 10-12% 12-18%

PCOS prevalence

(March 2010; Boyle et al 2012)

LUCINA community prevalence study

N=728 women from retrospective cohort study

Representative population of all female births at QEH 1973-5

Different types of PCOS

Hyperandrogenism, oligo-anovulation, normal ultrasound (NIH)

Hyperandrogenism, normal cycles, PCO ultrasound

Normal androgens oligo-anovulation, PCO

16%

17%

7%

Hyperandrogenism, oligo-

anovulation, PCO ultrasound (NIH)

61%

N= 380Prevalence of PCO around 20%

Prevalence of PCOS 12-17%

Prevalence in Indigenous women 21%

PCOS and other conditions

Hart and Doherty JCEM 2015

PCOS and other conditions

Hart and Doherty JCEM 2015

Over nutrition reduces reproduction

Early puberty and menstrual abnormality

Anovulation and infertility

Increased androgens

Miscarriage

Gestational diabetes and other pregnancy disorders

•Reversal with caloric restriction

•Dependent on fat distribution

The prevalence of obesity in PCOS

Lim SS, Davies MJ, Norman RJ, Moran LJ. Hum Reprod Update. 2012 18:618-37.

Type 2 Diabetes Mellitus and PCOS

(Moran 2010)

Study or Subgroup

Dos Reis 1995

Rajkhowa 1996

Cibula 2000

Yarali 2001

Sir-Petermann 2004

Sawathiparnich 2005

Lo 2006

Alvarez-Blasco 2006

Leibel 2006

Marquez 2008

Shaw 2008

Bhattacharya 2009

Moini 2009

Total (95% CI)

Total events

Heterogeneity: Chi² = 26.82, df = 12 (P = 0.008); I² = 55%

Test for overall effect: Z = 33.93 (P < 0.00001)

Events

3

2

9

1

4

3

988

0

3

6

34

6

4

1063

Total

29

72

28

30

146

6

11035

32

36

50

104

264

273

12105

Events

0

0

60

0

0

0

1136

3

0

3

70

2

0

1274

Total

19

39

752

30

97

6

55175

72

21

70

286

116

276

56959

Weight

0.1%

0.2%

0.8%

0.1%

0.2%

0.1%

89.9%

0.6%

0.1%

0.6%

6.6%

0.7%

0.1%

100.0%

M-H, Fixed, 95% CI

5.15 [0.25, 105.59]

2.80 [0.13, 59.82]

5.46 [2.37, 12.60]

3.10 [0.12, 79.23]

6.16 [0.33, 115.68]

13.00 [0.51, 330.48]

4.68 [4.28, 5.11]

0.31 [0.02, 6.09]

4.49 [0.22, 91.35]

3.05 [0.72, 12.82]

1.50 [0.92, 2.45]

1.33 [0.26, 6.67]

9.23 [0.49, 172.33]

4.43 [4.06, 4.82]

Year

1995

1996

2000

2001

2004

2005

2006

2006

2006

2008

2008

2009

2009

PCOS Control Odds Ratio Odds Ratio

M-H, Fixed, 95% CI

0.01 0.1 1 10 100

Lower risk for PCOS Higher risk for PCOS

PCOS greater prevalence of DM2 : OR 4.43 [4.06, 4.82]

Aetiology unknown

• Ovary

• Hypothalamic pituitary

• Insulin resistance

• Pregnancy

• Genetic

• Lifestyle

Serum AMH as a marker for PCOM

Australian and New Zealand Journal of Obstetrics and Gynaecology Volume 55, Issue 4, pages 384-389, 30 JUL 2015 DOI: 10.1111/ajo.12366

http://onlinelibrary.wiley.com/doi/10.1111/ajo.2015.55.issue-4/issuetoc

Primordial Small Preantral Large Preantral Antral (2-7 mm) Antral (8-12 mm) Preovulatory

ba

FSHAndrogens Estrogens

c

AMH

Role of AMH in Follicle Development

(Broekmans et al., Trends in Endocrin & Metab,2008)

AMH & GnRH neuron exitability

(Cimino et al., Nature Communications 2016)

Pathophysiology of Anovulation in PCOS

Progesterone

Hyperandrogenism

Anovulation

X

(Cimino et al., Nature Communications 2016; Blank et al., JCEM 2009)

0

0.2

0.4

0.6

0.8

1

MZT DZT

PCOS Oligomenorrhea

0

0.2

0.4

0.6

0.8

1

MZT DZT

Hirsutism Acne

Heritability index: of 0.76

(Vink et al., JCEM, 2006)

PCOS in twins

Discovery set: 744 cases; 895 controls

Replication 1: 2840 cases; 5012 controls

Replication 2: 498 cases; 780 controls

GWAS in Han Chinese PCOS women:

Genome Wide Association Studies (GWAS) in PCOS

(Chen et al., Nature genetics, 2011)

rsID SNP (chr:position) Eff. All. Freq. Nearest Gene Population.

rs13405728 2:48978159 0.94 THADA# Chinese Han

rs13429458 2:43638838 0.88 LHCGR Chinese Han

rs2268361 2:49201612 0.37 FSHR Chinese Han

rs4385527 9:97648587 0.60 C9orf3* Chinese Han

rs2479106 9:126525212 0.71 DENND1A Chinese Han

rs1894116 11:102070639 0.91 YAP1# Chinese Han

rs705702 12:56390636 0.68 RAB5B Chinese Han

rs2272046 12:66224461 0.97 HMGA2 Chinese Han

rs4784165 16:52347819 0.77 TOX3 Chinese Han

rs2059807 19:7166109 0.42 INSR Chinese Han

rs6022786 20:52447303 0.43 SUMO1P1 Chinese Han

rs11031006 11:30204731 0.15 KCNA4 /FSHB#European Ancestry

(G.H. et al)*

rs804279 8:11766130 0.74 GATA4 /NEIL2European Ancestry

(G.H. et al)*

rs2178575 2:213391766 0.15 ERRB4European Ancestry

(F.D. et al)#

rs13164856 5:131813204 0.73 IRF1/RAD50European Ancestry

(F.D. et al)#

rs1795379 12:75941042 0.24 KRR1European Ancestry

(F.D. et al)#

GWAS in European Descent Women with

(Hayes et al., Nature Communications, 2015; Day et al., Nature Communications, 2015)

Lifestyle changes

Lifestyle intervention and infertility

Number of

spontaneous

pregnancies

Spontaneous

ovulation

Average (kg)

weight loss

(Clark Hum Reprod 1995, 1998)

Months

34

5

2

1

0 1 2 3 4 5 6 9 12 15

100

8060

4020

0

6 month curriculum: Weekly group meetings

Modest dietary/exercise advice, social/psychological support

Study 1: n=13 (8 PCOS): 6.2 kg wt loss, 12/13 ovulation, 11/13 pregnancies

Study 2: n=67 (53 PCOS): 10.2 kg wt loss, 60/67 ovulation, 52/67 pregnancies

Start End

0-2-4

-6-8

-10

• • •

•

75

80

85

90

95

100

105

0 2 4 5 6

Week

Weig

ht

(kg

)

Wais

t cir

cu

mfe

ren

ce (

cm

)

Weight Waist circumference

0

2

4

6

8

10

12

14

16

0 2 4 6 8

Week

Ins

uli

n (

mU

/L)

Fre

e a

nd

ro

ge

n i

nd

ex

Insulin Free androgen index

Dietary interventions in PCOS

* Time p < 0.01

Mean±SD

8 weeks of energy restriction, dietary intake/day: 1167 kcal/day

Weight 5.6 kg

Waist circumference 6.1 cm

*

*

*

*

Insulin: 2.8 mU/L

Free androgen index: 3.1

86

(Moran AJCN 2006)

Improvement in

menstrual regularity or

ovulation for 57% of

women

Lifestyle modification improves fertility

Legro et al JCEM 2015

Prevention of weight gain

• Weight loss requires reduction 2-4 Mj (500-1000 kcals)/day to achieve 5-10% weight loss over 6 months

• Weight gain prevention requires 250kj (60kcals) per day less 250ml juice down to 100 ml

Logical, lower cost, more acceptable, small changes

What fertility options do we have?

WHO Group II anovulation

Clomiphene

Tamoxifen

Letrozole

Metformin

Gonadotropins

Laparoscopic Ovarian Drilling

Placebo/No treatment

Clomiphene + Metformin

Scientific question: Which is the most effective treatment option in WHO group II anovulation?

Results - Cumulative Rankograms -Clinical pregnancy Overall population

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

0.2

.4.6

.81

1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8

1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8

1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8

CC CC+Met FSH

LOD Let Met

Pla TamCum

ula

tive P

rob

ab

ilitie

s

RankGraphs by Treatment

1st

8th

SUrface under Cumulative RAnking(SUCRA)

CC+MetLet

Met

CC

Tam

FSH

Pla

0.2

.4.6

.8

SU

CR

A v

alu

es o

f low

er M

ultip

le P

reg

nanc

y

0 .2 .4 .6 .8 1SUCRA values of higher Clinical Pregnancy

Clustered Ranking Plot – Clinical & Multiple pregnancyby SUrface under Cumulative Ranking (SUCRA)

LOW risk of multiples

HIGH chance of pregnancy

Assisted reproduction

• Use of GnRH antagonist/agonist cycle to reduce OHSS

• In vitro maturation

• Single embryo transfer

Peacock’s 2013

Models of care for PCOS healthcare

Specialists:Endocrinologist

Gynaecologist

Dermatologist

Midwives

Allied Health:

Psychologist

Dietitian

Exercise Physiologist

Reputable education sources and consumer support group:

Websites, media, health

Primary care:Central to ongoing care

and co-ordination

Patient central to care and holds

management plan

is integration of best

research evidence with

clinical expertise and

patient values

Evidence Based Practice

Evidence from

research

Clinical judgment

Patient preference