pcos what’s new in diagnosis & treatment?€¦ · clear superiority of low-dose fsh over cc...
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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.
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