1. Ovulation Induction for PCOS
Roy Homburg
Barzilai Medical Center, Ashkelon, Israel
and Homerton University Hospital, London

2. Clomiphene Questions Spelling – clomiphene or clomifene?
Give hCG at mid-cycle?
Monitor CC cycles with ultrasound?
When to stop?
Is CC still the best first-line treatment?

3. Clomiphene n = 5268 Ovulation – 3858 (73%) Pregnancies – 1909 (36%)
Miscarriage – 20%
Multiple pregnancy rate – 10%
Single live-birth rate – 25%
Homburg, Hum Reprod, 2005

4. Should we give hCG in CC cycles?NO
Maybe
Yes
Agarwal & Buyalos, 1995
No improvement in conception rates
Deaton et al, 1997
No difference
Viahos et al, 2005
hCG may be beneficial
Kosmas et al, 2007 Meta-analysis
Favoured hCG but no significant difference
Brown et al, 2009, Cochrane review

5. Should we monitor clomiphene cycles with ultrasound?
No U/S or hCG
With U/S + hCG
150
105 n
34.7%
48%
Cumulative pregnancy rate
26.7%
35.6%
Deliveries 1
Multiple pregnancies
Konig, Homburg et al, ESHRE, 2009

6. Clomiphene Citrate Stopping… No ovulation with 150 mg/day
6 ovulatory cycles fail to yield a pregnancy
Endometrial thickness <7 mm at ovulation

7. Reasons for Clomiphene Failure
Failure to ovulate
FAI
BMI LH
Insulin
Ovulation
but no conception
Anti-estrogen effects
- Cervical mucus
- Endometrium
High LH

8. Aromatase Inhibitor Treatment:
Day 3-7 of Cycle ER ER ER ER E2
FSH AI
Figure 1. Administration of an aromatase inhibitor (AI) from days 3 to 7 results in suppression of ovarian estradiol secretion and reduction in estrogen negative feedback at the pituitary and mediobasal hypothalamus. Increased FSH secretion from the anterior pituitary results in stimulation of multiple ovarian follicle growth. Later in the follicular phase, the effect of the AI is reduced and estradiol levels increase as a result of follicular growth. Because AIs do not affect estrogen receptors (ER) centrally, the increased estradiol levels result in normal negative feedback on FSH secretion and follicles less than dominant follicle size undergo atresia, with resultant monofollicular ovulation in most cases.
Casper & Mitwally

9. Aromatase Inhibitors: Theoretical Advantages
Do not block estrogen receptors
No detrimental effect on endometrium
or cervical mucus
Negative feedback mechanism not
turned off—less chance of multiple
follicular development

10. Clomiphene Citrate TreatmentCC CC ER E2
FSH
Day 5 ER ER ER ER ER ER E2
FSH
Figure 2. Administration of clomiphene citrate (CC) from days 3 to 7 results in estrogen receptor (ER) depletion at the level of the pituitary and mediobasal hypothalamus. As a result, estrogen negative feedback centrally is interrupted and FSH secretion increases from the anterior pituitary leading to multiple follicular growth. By the late follicular phase, because of the long tissue retention of CC, there continues to be ER depletion centrally and increased estradiol secretion from the ovary is not capable of normal negative feedback on FSH. The result is multiple dominant follicle growth and multiple ovulation.
Day 10
Casper & Mitwally

11. Aromatase Inhibitor TreatmentER ER E2
FSH
Day 10 ER ER ER ER ER E2
FSH AI
Figure 1. Administration of an aromatase inhibitor (AI) from days 3 to 7 results in suppression of ovarian estradiol secretion and reduction in estrogen negative feedback at the pituitary and mediobasal hypothalamus. Increased FSH secretion from the anterior pituitary results in stimulation of multiple ovarian follicle growth. Later in the follicular phase, the effect of the AI is reduced and estradiol levels increase as a result of follicular growth. Because AIs do not affect estrogen receptors (ER) centrally, the increased estradiol levels result in normal negative feedback on FSH secretion and follicles less than dominant follicle size undergo atresia, with resultant monofollicular ovulation in most cases.
Day 5
Casper & Mitwally

12. Aromatase Inhibitor Questions
Do they work?
Better than CC for first-line treatment?
Safety?

13. Aromatase Inhibitors vs CC
Meta-analysis, 4 RCTs
Clear superiority of aromatase inhibitors in pregnancy rates (OR 2.0) and deliveries (OR 2.4)
Polyzos et al, Fertil Steril, 2008

14. Letrozole vs CC CC Letrozole Pregnancies 397 514
911 newborns in 5 centers
CC Letrozole
Pregnancies
Congenital (4.8%) 14 (2.7%)
malformations
Major malformations (3%) (1.2%)
Total cardiac anomalies % %
Tulandi et al, 2006

15. Aromatase Inhibitors Letrozole 2.5-10 mg/day, n=1102
Pregnancies (33.4%)
Miscarriages (26.9%)
Twins (0.5%)
Fetal anomalies 1 (0.2%)
Aghssa et al, 2007 (PCOS, eds Allahbadia, Agrawal)

16. Gonadotropin Treatment: Why Is PCOS Different?
Greater sensitivity to gonadotropin stimulation
Therefore, multiple (“explosive”) follicular development

17. Conventional Regimen With Gonadotropins75 75 75 5 5 5 5
Days

18. Results of Conventional Therapy: 14 Series, 1966-1984, WHO I & II
Conceived
46% (16-78)
Multiple preg.
34% (22-50)
Miscarriages
23% (12-30)
Severe OHSS
4.6% ( )
Hamilton-Fairley & Franks, 1990

19. Problems With Conventional Gonadotropin Therapy for PCOS
Multiple follicle development
- Multiple pregnancies
- OHSS

20. Low-Dose rFSH IU IU
50-75 IU 14 7 7
Days

21. Low-Dose Gonadotropins: Summary of Results
Patients , Cycles 2472
Updated from Homburg & Howles, 1999

22. 50 IU starting dose; increments of 25 or 50 IU
Incremental Dose Rise
50 IU starting dose; increments of 25 or 50 IU
n=158 1 8 15 22 29 35
150 IU daily
100 IU daily
125 IU daily
75 IU daily
7 days
50 IU daily
Start day 3 of
menses
250 IU daily
200 IU daily
150 IU daily
7 days
100 IU daily
7 days
7 days
50 IU daily
7 days
7 days 1 8 15 22 29 36
Days of treatment
FSH increments: Only allowed when no follicle 12 mm
hCG: 1 follicle 18 mm
Cancellation: 3 follicles 15 mm
Leader et al, 2006

23. Higher cancellation rate with 50 IU increments
P=0.009
P=0.009
Higher cancellation rate with 50 IU increments
Duration and pregnancy rate - same
Leader et al, 2006

24. Only Minimal Dose Increment Needed
Incremental dose rise of 8.3 IU each week
N=25, PCOS, CC failures, 69 cycles
64.6 IU
58.3 IU
50 IU
Days
Orvieto & Homburg, 2008

25. Only Minimal Dose Increment Needed
Treatment days – 10.8 ± 4.3
Total dose of FSH (IU) – 622 ± 286
Cycle cancellation – 1/69
1 follicle only >16 mm – 82.6%
Clinical pregnancies – 20/25 (29% of cycles)
Live births – 16/25 patients
Twins – 1
OHSS – 0
Orvieto & Homburg, 2008

26. Low-Dose rFSH in Vietnamese Women With PCOS
N=183, PCOS, CC failure, normal or low BMI
75 IU
Puregon
50 IU
25 IU
Days
Lan et al, RBM Online, 2009

27. Low-Dose rFSH in Vietnamese Women With PCOS
Duration (± 4.8) days
Total FSH dose (± 257) IU
Ovulation rate %
Mono-ovulation %
Pregnancy
– Clinical %
– Ongoing %
Multiple pregnancy 0
Mild OHSS 1
Lan et al, RBM Online, 2009

28. Duration of Initial Dose: 14 or 7 Days?
14 days days
N=50, 107 cycles
FSH required
- Amps
- Days
1 large follicle/cycle % %
E2 (pmol/L)
Pregnancies (40%) (56%)
OHSS
Multiple pregnancies /14
Homburg, 1999

29. Extended Study Multiple pregnancies 14 days 0/10 7 days 6/29
Homburg, 1999

30. How long does it take?
With a starting dose of 75 IU FSH, unchanged for a minimum of 14 days, 90% will get to the criteria for hCG within 14 days
Homburg & Howles, 1999

31. Comparison of Results: CC vs FSH – 100 Women34 25
Single live births 2 3
Twins
BUT…….
Low-dose FSH has only been given to
clomiphene failures!
Homburg, Hum Reprod, 2005; Homburg & Howles, HR Update, 1999

32. If we started with FSH…. Projection/100 women
Starting with
CC rFSH
Singleton live births 25 50
Multiples 3 3
Projection/100 women

33. CC or low-dose FSH for first-line treatment?
Treatment-naive PCOS
Randomization
CC Low-dose FSH
3 cycles
Homburg et al, Hum Reprod, In press

34. M-L. Hendriks
T. Konig
CB. Lambalk
P. Hompes
A. Martinez
R. Rueda-Saenz
T. D’Hooghe
M. Welkenhuysen
R. Anderson
M. Rajkhowa
A. Balen
T. Child
M. Davis
M. Brincat

35. FSH CC Randomized N=302 Allocated N=143 Allocated N=159 Drop-outs N=20
Analyzed
N=123
Analyzed
N=132
Per-protocol

36. CC or low-dose FSH for first-line treatment?
1st cycle, 50 mg/day
If no ovulation, dose increased by 50 mg
in subsequent cycles
FSH (Puregon)
100 IU
75 IU
50 IU
hCG – when at least 1 follicle >17 mm.

37. Results CC FSH P Patients per protocol 123 132 Cycles 310 288
Pregnancies (44%) (58%)
Miscarriage rates (9%) (9%)
Multiple pregnancies (3%)
Pregnancies/cycle % %
Live births (39%) (52%)
Homburg et al, Hum Reprod, In press

38. Cumulative Live-Birth Rates
Cycles
After 3 cycles - CC 36%, FSH 47% (P=0.03)

39. Summary Clear superiority of low-dose FSH over CC for
first-line treatment of anovulatory PCOS
×2 chance of clinical pregnancy in 1st cycle
30% vs 14.6% (P=0.003)
After 2nd cycle, 50.7% vs 32.5% (P=0.003)
Shorter treatment to pregnancy time
Homburg et al, Hum Reprod, In press

40. Can low-dose FSH replace CC?
CC FSH
+ Ease of administration
Cost
= Monitoring =
Treatment - pregnancy time +
Chances for pregnancy +
Single live birth +

41. 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