Practical Approach to PCOS Women Wishing to Conceive

Practical Approach to PCOS Women Wishing to Conceive

Prof. Dr. Basil C. Tarlatzis

Unit for Human Reproduction

First Department of Obstetrics & Gynevology Aristotle University of Thessaloniki, Greece

Disclosures

•  

Vice President of the Board of Aristotle University of Thessaloniki, Greece

•  

Advisory Board, Consultations, lectures, traveling and research grants from MSD, Merck Serono, IBSA, Ferring and Ovascience

PCOS

Prevalence

n 

5-10% general female population

n 

Up to 30% of infertility population

ESHRE / ASRM PCOS Concensus Meeting, Rotterdam, May 2003

PCOS Diagnosis

- 2003 Rotterdam Consensus -

Hyperandrogenemia

Oligo/anovulation

PCOS

PCO

2^nd ESHRE/ASRM PCOS Consensus Meeting, Thessaloniki, 2007

PCOS: Management

n 

Life-style changes

n 

Ovulation induction

n 

Metformin and other insulin- sensitising drugs

n 

Laparoscopic ovarian surgery

n 

In Vitro Fertilization

3^rd ESHRE/ASRM PCOS Consensus Meeting,

Amsterdam, 2010

"

Adolescence

"

Hirsutism/acne/alopecia

"

Menstrual irregularity

"

Contraception

"

Quality of life

"

Pregnancy

"

Ethnic differences

"

Obesity

"

Insulin resistance/Metabolic Syndrome

"

Type 2 diabetes

"

Cardiovasc. disease markers and outcomes

"

Cancer risk

"

Menopause, general health

PCOS: Health Risks

PCOS Women: Approaches to Conceive

n 

Potential problems

n 

Management strategy

n 

Predictions

Obesity and PCOS

5 10 15 20

< 25 25-30 >30

Category of Average BMI

Obesity and PCOS

Teede et al 2010

Prevalence of PCOS

8600 Australian women followed longitudinally

Conclusions (agreement):

v  The prevalence of obesity is increasing and has an

important bearing on the phenotype of PCOS (level B).

v  Some studies suggest that higher BMI is associated with a greater prevalence of menstrual irregularity,

hyperandrogenemia, and hirsutism but more studies are required to confirm this (level B).

Obesity and PCOS

Insulin Resistance and

Metabolic Syndrome in PCOS

NHANES Control PCOS

~90%

~85%

~8

%

~60%

1%

~10%

0%

20%

40%

60%

80%

100%

NGT IGT DM

~16%

0%

*P<0.001

BMI (kg/m²)

25< 25-30 ≥30

1% 0%

12%

45%

68%

0%

20%

40%

60%

80%

100%

17%

PCOS

Leading Risk Factor Prediabetes & MetS

Ages 14 – 40 Years

Adapted from Legro et al. J Clin Endocrinol Metab 84:165-169, 1999 Palmert et al. J Clin Endocrinol Metab 87:1017-1023, 2002

Glucose Tolerance Metabolic Syndrome

~30%

Prevalence of impaired glucose tolerance (BMI matched)

Study or Subgroup Rajkhowa 1996 Yarali 2001 Dunaif 2001 Phy 2004 Faloia 2004

Sawathiparnich 2005 Diamanti-Kandarakis 2005 Alvarez-Blasco 2006 Attuoua 2008

Total (95% CI) Total events

Heterogeneity: Chi² = 9.97, df = 8 (P = 0.27); I² = 20%

Test for overall effect: Z = 3.22 (P = 0.001) Events

10 1 3 4 3 0 1 4 18

44

Total 72 30 14 7 50 6 29 32 107

347

Events 1 0 0 2 1 3 0 8 5

20

Total 39 30 12 18 20 6 22 72 100

319

Weight 6.9%

2.9%

2.5%

3.0%

8.3%

20.0%

3.3%

26.6%

26.5%

100.0%

M-H, Fixed, 95% CI 6.13 [0.75, 49.80]

3.10 [0.12, 79.23]

7.61 [0.35, 163.82]

10.67 [1.31, 86.93]

1.21 [0.12, 12.40]

0.08 [0.00, 1.96]

2.37 [0.09, 60.96]

1.14 [0.32, 4.11]

3.84 [1.37, 10.79]

2.54 [1.44, 4.47]

Year 1996 2001 2001 2004 2004 2005 2005 2006 2008

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

Moran et al 2010

Insulin Sensitivity in Ovulatory &

Anovulatory PCOS

0 100 200 300 400

control ovPCO anovPCO

0 50 100 150 200 250

control ovPCO anovPCO

Insulin area mU/l Insulin sensitivity mmol/l/min

(147-277)

(148-355)

(239-734)

p< 0.01 p< 0.01

Robinson et al, Clin Endocrinol 1993 39 351

Prevalence of metabolic syndrome in PCOS (BMI matched)

Study or Subgroup Faloia 2004

Alvarez-Blasco 2006 Shroff 2007b

Attuoua 2008 Gulcelik 2008

Total (95% CI) Total events

Heterogeneity: Chi² = 6.47, df = 4 (P = 0.17); I² = 38%

Test for overall effect: Z = 3.23 (P = 0.001) Events

10 8 6 17 20

61

Total 50 32 24 107 60

273

Events 3 19 4 4 7

37

Total 20 72 24 100 60

276

Weight 14.7%

37.6%

12.9%

14.9%

20.0%

100.0%

M-H, Fixed, 95% CI 1.42 [0.35, 5.80]

0.93 [0.36, 2.42]

1.67 [0.40, 6.87]

4.53 [1.47, 13.98]

3.79 [1.46, 9.82]

2.20 [1.36, 3.56]

Year 2004 2006 2007 2008 2008

PCOS Control Odds Ratio Odds Ratio

M-H, Fixed, 95% CI

0.001 0.1 1 10 1000

Lower risk for PCOS Higher risk for PCOS

Moran et al 2010

Goverde et al , Hum. Reprod 24, 710, 2009

PCOS Phenotypes and Metabolic

Disturbances

Conclusions (agreement):

v  Not all PCOS phenotypes have similar metabolic risk.

The combination of hyperandrogenemia and

oligomenorrhea signifies the most at risk group (level B).

v  It is critical for public health and for optimum design of long-term studies to stratify women with PCOS according to metabolic risk.

IR and MetS in PCOS

PCOS and type 2 diabetes

mellitus

Meta-analysis of studies reporting risk of T2D in women with PCOS

n 

IGT: OR 2.54 [1.44 - 4.47]

n 

T2D: OR 4.00 [1.97 - 8.10]

in BMI-matched groups

35 studies analysed

Moran et al Hum Reprod Update 2010 16 347-63

Gestational diabetes in women with PCOS

n  High prevalence (52%) of polycystic ovaries in women with history of GDM

n  Kousta et al, Clin Endocrinol 2000 53 501-7

n  Women with PCOS at increased risk of GDM (OR 2.94 (1.7 - 5.1)

n  Boomsma et al, Hum Reprod Update 2006 12 673-683 (meta-analysis)

n  High prevalence of GDM in women with PCOS (42% of 50 women)

n  Veltman-Verhulst et al, Hum Reprod 2010 (Epub, October)

PCOS and pregnancy outcome:

the role of hyperglycemia

20-30%

GDM in women with PCOS

1-14%

GDM in healthy women

Ben-Haroush , Diabet med 2004

Summary statement

pregnancy outcomes in PCOS

Outcome

Meta-

analysis1 ===

Boomsma, HRU’06

Meta-

analysis2 ===

Kjerulff, AJOG’11

Population based cohort ===

Roos, BMJ ’11

Gest. diabetes 2.9 2.8 2.3

Pre-eclampsia 3.5 4.2 1.5

Preterm birth 1.8 2.2 2.2

Fauser B , 2015

Conclusions (agreement):

v  PCOS is a major risk factor for developing IGT and T2D (level A).

v  Obesity (by amplifying IR) is an exacerbating factor in the development of IGT and T2D in PCOS (level A).

v  Diet and lifestyle are first choice in improving fertility and prevention of diabetes (level B).

PCOS and Type 2 Diabetes Melitus

Conclusions (agreement):

v  Screening for IGT and T2D should be performed by OGTT (75gr, 0 and 2h values). There is no utility for measuring insulin in most cases (level C).

v  Screening should be performed in the following conditions:

hyperandrogenism with anovulation, acanthosis nigricans, obesity (BMI > 30 kg/m2, or > 25 in Asian populations), in women with a family history of T2D or GDM (level C).

v  The increasing prevalence of obesity in the population

suggests that a further increase in diabetes in PCOS is to be expected.

PCOS and Type 2 Diabetes Melitus

Conclusions (agreement):

v  Diet and lifestyle are first choice in improving fertility and prevention of diabetes (level B).

v  Metformin may be used for IGT and T2D (level A). Avoid use of other insulin sensitizing agents, such as

thiazolidinediones (GPP).

PCOS and Type 2 Diabetes Melitus

PCOS: Management

n 

Life-style changes Diet

Exercise

Intervention strategies

Weight

Weight change %

Insulin with GTT

Moran et al Cochrane 2010

Weight Loss in PCOS: Results of RCT

Control

(n=84)

Intervention

(n=87)

Weight loss (kg)

1.3 (0.2) 4.7 (0.3)

Pregnancies at 18months

18

(21.4%)

53 (61%)

Miscarriage 3

(16.6%)

6 (11.3%)

ART

pregnancies

9% 37%

Spontaneous pregnancies

11% 24%

*

*

* p<0.001

*

*

Moran et al, 2003

Lifestyle changes in women with PCOS

n  Lifestyle intervention improves body composition, hyperandrogenism (high male hormones and clinical effects) and insulin resistance in women with PCOS.

n  There was no evidence of effect for lifestyle intervention on improving glucose tolerance or lipid profiles and no literature assessing clinical reproductive outcomes,

quality of life and treatment satisfaction

Moran et al, Cochrane Dtabase Syst Rev 2011

n 

Lifestyle management better than drugs

n 

Few randomised trials

n 

Dropouts major problem

n 

Almost impossible to maintain

n 

No evidence for one type of diet

n 

Metformin addition has no benefit for weight

n 

Bariatric surgery may be required

(Avoid pregnancy during rapid weight loss)

Intervention strategies

PCOS: Management

n 

Life-style changes

n 

Ovulation induction

n 

Metformin and other insulin- sensitising drugs

n 

Laparoscopic ovarian surgery

n 

In Vitro Fertilization

PCOS: Management

n 

Ovulation induction Clomiphene citrate Aromatase inhibitors

Gonadotropins +/- GnRH analogues

Imani B et al. Fertil Steril 77:91, 2002

FAI

0

5

10

Chance of ovulation (%)

95 90 80 70 60 50 40 30 20

oligomenorrhea

20 30 40

amenorrhea

20 30 40

Required screening information - Amenorrhea or oligomenorrhea - BMI (kg/m²)

- FAI (T x 100/SHBG) - Age (y)

BMI

Chance of ovulation (%) ₁₀₀

80 60 40 20

Chance of a live birth (%)

(95% CI)

5 ( 1-16) 10 ( 5-20) 20 (14-30) 30 (24-40) 40 (33-49) 50 (42-59) 60 (52-69) 80 (70-88)

amenorrhea

20 25 30 35 40

oligomenorrhea

20 25 30 35 40

Age

Prediction of Ovulation Induction Outcome

Imani et al., Fertil Steril, 2002  

PCOS: Management

n 

Life-style changes

n 

Ovulation induction

n 

Metformin and other insulin- sensitising drugs

n 

Laparoscopic ovarian surgery

n 

In Vitro Fertilization

Surgical management of polycystic ovary syndrome

Multiple ovarian puncture performed either by diathermy or by laser is well known as “Ovarian drilling”

Gjonnaess 1984

Ovarian drilling is a modification of ovarian wedge resection but less invasive

Surgical laparoscopic removal of ovarian tissue was introduced by Palmer and De Brux in 1967

Laparoscopic Ovarian Surgery for Ovulation Induction in Anovulatory PCOS Women: Live Births

Farquahar et al, Cochrane Database Syst Rev 2012

Laparoscopic Ovarian Surgery for Ovulation Induction in Anovulatory PCOS Women: Multiples

Farquahar et al, Cochrane Database Syst Rev 2012

PCOS: Management

Conclusions

Ovulation Induction in PCOS:

Conclusions

Before initiation of infertility treatment, it is necessary to assess the risk factors associated with PCOS

Life-style modifications should be advised before ovulation induction in obese PCOS women and weight

loss is recommended as first-line therapy in obese women with PCOS seeking pregnancy

It is important to make prediction of poossible success

for the various treatment options

Laparoscopic ovarian drilling is as effective as

gonadotropins for ovulation induction and achievement of pregnancy but with significantly less multiples

Ovulation Induction in PCOS:

Conclusions

First Department of Obstetrics & Gynecology Medical School

Aristotle University of Thessaloniki, Greece Professor B.C. Tarlatzis

Acknowledgments E.M. Kolibianakis D.G. Goulis

G. Grimbizis G. Pados H. Bili

K.A. Toulis G. Mintziori C.A. Venetis J. Bosdou L. Zepiridis

Thank you !

Thank you !