PCOS – What’s new in Diagnosis & Treatment?

Roy Homburg

Maccabi Medical Services and Barzilai

Medical Centre, Ashkelon, Israel.

Antalya, October, 2009

PCOS diagnosis

- 1990 NIH criteria -

Hyperandrogenism

Chronicanovulation

PCOS

2 out of 3 criteria required

Oligo- and/or anovulation

i.e. oligomenorrhoea or amenorrhoea

Hyperandrogenism

- clinical and/or biochemical

Polycystic ovaries

Exclusion of other aetiologies

The Rotterdam ESHRE/ASRM Consensus Group

Revised 2003 Diagnostic Criteria for PCOS

Hum Reprod 2004; 19: 41-47. Fertil Steril, 2004; 81: 19-25.

1

Hyperandrogenemia

Oligo/anovulation(WHO 2 type)

PCOS

PCO

ESHRE/ASRM 2003 consensus

broader than NIH 1990 consensus

- Increases population base by ~ 20%

- Includes more women of normal weight

Belosi et al Human Reprod 2006; 21: 3108

- Concern about negative labelling of women with

“milder phenotype” and uncertainty of health risk

- Greater heterogeneity limits finding the unifying

diagnostic test or gene ….Azziz, JCEM 2006; 91: 781

Rotterdam additionsOligo/anovulation +

Hyperandrogenism +

PCO + +

n=165 vs Controls (n=284)

• LH, insulin, waist circumference, dyslipidemia

• FSH, SHBG

Norman et al, 1995; Dewailly et al 2006

“Clearly distinguishable from controls”. Welt et al, 2006

“Part of the spectrum of PCOS” Barber et al, 2007

Rotterdam additionsOligo/anovulation +

Hyperandrogenism +

PCO + +

n=165 vs O/A+PCO + HA (n=839)

• No difference in I, SHBG, gonadotrophins, similar

phenotypic features. Milder endocrine & metabolic

features

Norman et al, 1995; Welt et al, 2006; Dewailly et al 2006

“Part of the spectrum of PCOS” Barber et al, 2007

Rotterdam additionsOligo/anovulation +

Hyperandrogenism +

PCO + +

n=50 vs PCO + HA n=204

• Insulin lower in ovulatory, otherwise, very similar

Norman et al, 1995, Welt et al, 2006

•Milder metabolic abnormalities Dewailly et al 2006

• Less IR & HA but have dyslipidemia and elevated risk

markers in 38% vs 45%

• In ovulators: A & I, 17OHP response to GnRHa all raised

Carmina et al, 2005; Chang, 2000

Polycystic ovaries alone

• Behave exactly like full-blown PCOS

when stimulated.

• AMH – a possible new marker for PCO.

Rotterdam criteria:

• Recognize the broad spectrum of the syndrome

• Acknowledges that clinical & biochemical

features may vary in time.

Arguments against:

Clomiphene citrate

Clomiphene questions

• ? Give hCG at mid-cycle?

• ? Monitor CC cycles with ultrasound?

• ? Is CC still the best first-line treatment?

? Give hCG in CC cycles?

Agrawal & Buyalos, 1995

“ Routine addition of hCG at mid-cycle

does not improve conception rates”

Should we monitor clomiphene

cycles with ultrasound?Konig, Homburg et al, ESHRE, 2009

3 cycles of CC

• Group 1: N=105,

with U/S monitoring + hCG

• Group 2: N=150,

no U/S monitoring, no hCG

Should we monitor clomiphene

cycles with ultrasound?Konig, Homburg et al, ESHRE, 2009

With U/S + hCG No U/S or hCG

48% Cumulative conception rate 34.7%

35.6% Deliveries 26.7%

0 Multiple pregnancies 1

Anti-estrogen effect on

endometrium

• Endometrial thinning in 15-50%

(Gonen &Casper, 1990;Dickey et al, 1993)

• Causes ER downregulation and depletion.

• Suppresses pinopode formation (Creus et al, 2003)

• No pregnancies when endometrial thickness at

midcycle < 7mm

• Not dose related and recurs in repeat cycles

(Homburg et al, 1999)

Clomiphene

Homburg, Hum Reprod, 2005

n = 5268 patients

Ovulation - 3858 (73%)

Pregnancies - 1909 (36%)

Miscarriage - 827 (20.4%)

Multiple pregnancy rate - 10%

Konig, Homburg et al, ESHRE, 2009

95 pregnancies achieved with clomiphene

1 twin pregnancy only !!

Twin pregnancy rate with

clomiphene

Aromatase Inhibitor Treatment- day 3-7 of cycle

ER

ER

E2FSH

AI

Day 5

ER

ER

Casper & Mitwally

ER

ER

E2FSH

AI

Day 5

Aromatase Inhibitor Treatment

ER

ER

E2

FSH

Day 10

ER

ER

ER

ER

Casper & Mitwally

Aromatase inhibitors

Aghssa et al, 2007 (PCOS, eds Allahbadia,Agrawal)

• Letrozole 2.5-10mg/day, n=1102

• Pregnancies 368 (33.4%)

miscarriages 99 (27.3%)

twins 2 (0.5%)

fetal anomalies 1 (0.2%)

Metformin + Letrozole

or + CC

Sohrabvand et al, 2006

N=59 given metformin for 6-8 weeks

Letrozole 2.5mg CC 100mg

Metformin + Letrozole

or + CC

34.5 %

10 %

0

10

20

30

40

Letrozole group Clomiphene citrate group

Full-term pregnancies in letrozole - metformin group vs

clomiphene citrate - metformin group

Sohrabvand et al, 2006

Letrozole induction of ovulation in women

with CC–resistant PCOS… (Elnashar et al, 2006)

• Ovulation- 24/44 cases (54.6%)

• Clinical pregnancy- 6/44 cases

(25%of ovulators)

Resistance to CC 100mg

Begum et al, 2008

N=64 PCOS resistant to 100mg CC

Letrozole 7.5mg CC 150mg

Resistance to CC 100mg

Letrozole CC 150mg

Ovulation 20 (62.5%) 12 (37.50%)

E2 dhCG (pg/mL) 448 817.75

Endometrial thickness

on dhCG 10.37 mm 9.03 mm

Pregnancies 13 (40.6%) 6 (18.75%)

Begum et al, 2008

Treatment scheme for

anovulatory PCOS

Clomiphene citrate

50-150mg/day for

5 days

Ovulation No ovulation

x6 on 150mg/day

No pregnancy

Low-dose FSH

Clomifene or low-dose FSH for

the first-line treatment of

anovulatory PCOS.

A randomized, prospective, study

The COFFI group

(10 centres in 7 countries)

R.Rueda-Saenz

A.Martinez

A.Balen

T.Child

M.Davis

M-L.Hendriks

T.Konig

CB.Lambalk

P.Hompes

T.D’HoogheM.Welkenhuysen

R.Anderson

M.Rajkhowa

M.Brincat

Clomifene

Homburg, Hum Reprod, 2005

n = 5268 patients

Ovulation - 3858 (73%)

Pregnancies - 1909 (36%)

Miscarriage - 20%

Multiple pregnancy rate - 10%

Single live-birth rate – 25%

Low dose gonadotrophins

75-112.5 IU50-75 IU

100-150 IU

14 7 7

Days

Low Dose Gonadotropins

Summary of ResultsPatients - 841, Cycles 1556

Pregnancies 320 (40%)

Fecundity/cycle 20%

Uniovulation 70%

OHSS 0.14%

Multiple pregs. 5.7%

Updated from Homburg & Howles, 1999

Comparison of results

CC vs FSH – 100 womenCC FSH

25 Single live births 34

3 Twins 2

BUT…….Low dose FSH has only been given to

clomiphene failures!

If we started with FSH….

Starting withCC rec-FSH

Singleton live births 25 50

Multiples 3 3

Projection / 100 women

CC or low-dose FSH for first-line

treatment?

Treatment-naïve PCOS

Randomization

CC Low-dose FSH

3 cycles

CC or low-dose FSH for first-line

treatment?

• CC - 1st cycle, 50mg/day.

- If no ovulation, dose increased by 50mg

in subsequent cycles.

• FSH (Puregon)

50 IU

100 IU75 IU

1 7 14 21

hCG – when at least 1 follicle >17mm.

Power calculation

• Assuming an absolute difference of 15%

in pregnancy rates in favour of FSH,

80% power and P<0.05, 150 subjects

needed in each arm.

Randomized

N=268

Allocated

N=130Allocated

N=138

Drop-outs

N=24

Drop-outs

N=18

Analysed

N=114

Analysed

N=112

CC FSH

Per-protocol

Results

CC FSH P

Patients per protocol 112 114

Cycles 287 249

Pregnancies 46 (41%) 64 (56%) 0.02

Miscarriage rates 15% 12.5%

Multiple pregnancies 0 2 (3%)

Results

CC FSH P

Pregnancies/cycle 16% 26% 0.006

Live births 40 (35.7%) 56 (49%) 0.03

Cumulative conception rates

0%

10%

20%

30%

40%

50%

60%

70%

80%

CC

FSH

Cycle 1 2 3

After 3 cycles - CC 48%, FSH 72%

Cumulative live-birth rates

0%

10%

20%

30%

40%

50%

60%

70%

CC

FSH

Cycle 1 2 3

After 3 cycles - CC 42%, FSH 62%

With CC – 46 With FSH – 64 (P=0.02)

Cycle 1 32.6% 54.6% (P=0.003)

Cycle 1+2 71.7% 90% (P=0.005)

Of pregnancies achieved…..

Can low-dose FSH

replace CC?

CC FSH

+ Ease of administration

+ Cost

= Monitoring =

Treatment - pregnancy time +

Chances for pregnancy +

Single live birth +

CC vs low-dose FSH as first-

line therapy for PCOS

Lopez et al, 2004 Single centre RCT

• Subjects, CC – 38, FSH - 38

• Cycles, CC – 104, FSH – 91

• Pregnancy rates RR 1.78 (0.92-1.46)

• Live birth rates RR 1.83 (0.79-4.40)

in favour of FSH

Summary

Clear superiority of low-dose FSH over CC for first line treatment of anovulatory PCOS.

Absolute difference -

• of 24% in CCR over 3 cycles.

• of 10% in pregnancy rates/cycle.

• of 20% in cumulative live birth rates.

• More than x2 chance of conception in 1st cycle.

• Shorter treatment to pregnancy time.

Conclusions

• Differences in cost and convenience may

limit the choice of low-dose FSH as first-

line treatment.

But….• This study provides “real-life” results to

enable judgment of this option, according

to individual countries and circumstances.