Criteria*: oligo- or anovulation clinical and/or biochemical signs of hyperandrogenism polycystic ovaries on ultrasound *2003 Rotterdam PCOS consensus

1. EBM Management of
Polycystic Ovary
Dr. Marwan Alhalabi
Assistant Professor
in Faculty of medicine
Damascus University
And
Orient Hospital
Assisted Reproduction Center
Damascus – Syria

2. PCOS
- claims in the literature -
Prevalence
• 5-10% general female population
• Up to 30% of infertility population

3. PCOS
- diagnostic dillema’s -
Clinical features
hirsutism/acne
obesity
anovulation
Endocrine features
high androgens
high LH
insulin resistance
Polycystic ovaries
increased follicle #
increased stroma
increased ovarian volume

5. 5

6. 6

7. Rotterdam PCOS consensus workshop, May 2003
F&S, Jan 2004
HR, Jan 2004
PCOS diagnostic criteria
oligo and / or
anovulation
hyperandrogenemia
polycystic ovaries

8. 8
Polycystic ovary syndrome (PCOS)
Criteria*:
• oligo- or anovulation
• clinical and/or biochemical signs of hyperandrogenism
• polycystic ovaries on ultrasound
*2003 Rotterdam PCOS consensus

9. Maximal expression occurs in
preantral and small antral follicles1,2
Expression disappears in maturing
pre-ovulatory follicles (expression
restricted to GCs of the cumulus)2
1. Laven et al. J Clin Endocrinol Metab2004; 89: 318–323; 2. Weenen et al. Mol Hum Reprod 2004;10: 77–83;
3. Cook et al. Fertil Steril 2000; 73: 859–861; 4. La Marca et al. Hum Reprod 2004; 19: 2738–2741;
5. La Marca et al. Hum Reprod 2006; 21: 3103–3107
Anti-Müllerian hormone
(TGF-β superfamily: Müllerian duct regression in male embryos)

10. AMH
AMH is expressed in pre-
antral and small antral
follicles.
AMH is thus a good indicator
of the size of the ovarian
antral follicle pool.

11. AMH concentrations
AMH measured by Beckman-Coulter Gen II assay
Groups No AMH (pmol/l)
Controls 90 23.6 (15.0)*
PCOM 35 52.2 (35.0)**
PCOS 90 77.6 (61.0)***
P<0.05
P<0.001
PCOM vs PCOS
Controls vs PCOM
Controls vs PCOS

13. • Women with PCOS gain
regular menstrual cycles
when aging
• Menstrual cycle restored
in those with a smaller
follicle count
Elting et al, 2000, 2003
Effect of aging on PCOS

14. Anovulation
A excess LH +insulin
Multiple small follicles
AMH
FSH action
Anovulation progesterone

15. Increase In GnRH Pulsatility
ß
LH FSH
Increase Androgen
Synthesis
Inhibition of
folliculogenesis

16. Oligo/Anovulation
- hormone serum profile -
Normal
E2 (pg/ml)
FSH (IU/L)
10
High
Low
Normal
Low
1
40
10

17. Classification of Anovulatory
infertility
Serum Gonadotropins
&
Serum Estradiol levels
FSH & LH: Low
&
Estradiol: Low
FSH : Normal
LH: Normal / Elevated
&
Estradiol: Normal
FSH & LH: Elevated
&
Estradiol: Low
WHO I WHO II WHO III
Ovulation Induction
Gn-RH, FSH and LH
Eventually IVF
Ovulation Induction
CC and/or rFSH
Eventually IVF
Ovulation Induction ?
IVF ?
Egg Donation
10 % 10 %80 %

18. PCOS
- hyperandrogenemia -
• Testosterone
total or free (unbound)
• Free androgen index
(T x 100 / SHBG)
• Androstenedione
• Other androgens
• combination

19. Serum Endocrinology
• ­Fasting Insulin.
• ­Androgens(Testosteron and Androstendion).
• ­LH (Usually Normal FSH).
• ¯SHBG.
• ­Free Androgen index.
• ­Estradiol.
• ­Prolactine.

20. PCOS
- polycystic ovaries -
• Transabdominal versus transvaginal
• Few controlled studies
• Follicle number >12 mm
• Follicle size <10
• localisation??
• Ovarian stroma
objective???
• Ovarian volume
Balen, HRU 2003

21. Treatment
Irregular
bleeding
Hirsutism infertility
General
health risk
Oral
contraceptive
Medical
Ovulation
induction
Metformin
PCOS
Chronic anovulation
And androgen excess
Oral
Contraceptive and
spironolactone
If overweight, behavioral weight reduction

22. Ovarian stimulation
• Anovulation
• Single dominant
follicle development
• Normal cycle
• Multiple dominant
follicle development
Ovulation
induction
Ovarian
(hyper)stimulation

23. Elements of the Ideal Ovulation
Induction Protocol for PCOS
• Minimize amount of medication.
• Ease of compliance.
• No multiples (as high as 15%-20%)
• No OHSS (10%-15%)
• No cancellations (poor response/high
response or premature luteinization 10%-
40%)
• No miscarriages (30%-50% higher)

25. Type 1: Ovulation Failure
Type 2: Conception Failure
Type 3: Pregnancy loss ( Miscarriages )
PCOS
- Clomiphene Citrate Resistance -

26. PCOS
- Therapeutic Plan -

27. Management of clomiphene resistance (1)
Weight
Reduction
Persistently
poor
Ceevical
mucus and
endometrial
response
Raised
Serum
DHEAS or
testosterone
Raised
Serum
prolactin
Fasting Serum
insuline >25IU
Fasting blood
sugar : insuline
ratio >4.5
Tamoxifen
20mg/day
from day 2-
5X5 days
Gonadortopins
Letrozole
2.5-5mg/day
from day 2-
5X5 days Dexamethasone 0.5mg/day
Prednisolone 5g/day
Continuously or in follicular phase
Bromocriptine 2.5mg b.d or t.d.s
Carbogoline 0.5 3mg/week
Surgical
ovulation
induction
Metformin 1500mg/day
Rosiglitazone 45mg/day
Pioglitazone 4mg/day
D-chiro inositol 1200 mg/day
One time
treatment
No
monitoring
required
No
hyperstimula
tion

28. Management of clomiphene resistance (2)
Persistent
luteinized
unruptured
follicle
GnRH antagonist added along
with FSH from Day7to
suppress LH surge
Gonadotropins with
clomiphene
Clomiphene
for 7-10 Days
Raised LH
Inj. HCG 5000-10000IU
when follicle is 18-20 mm
Clomiphene 100mg from day
2-6
FSH 150 IU Day 6 onwards
Ovarian
Suppression
GnRH
agonist
Oral
Contraceptives
Combined treatment
Greater LH Suppression
No estrogen deficiency

29. Ovarian stimulation
by interference with
E feedback
• Clomiphene citrate
• Tamoxifen
• Other SERMs ?
• Aromatase inhibitors

30. Why is PCOS different?
Greater sensitivity to gonadotrophin
stimulation
therefore:
Multiple (“explosive”) follicular
development

31. Why multifollicular response to
gonadotrophins?
• Insulin, growth factor, binding protein
ratios
• VEGF
• Androgens in follicular fluid
• Too many antral follicles

32. Low dose protocols
• Step-down
(Fauser)
• Sequential
step-up/step-
down (Hugues)

33. 100
75
If <10mm
10mm
3 days hCG
50
50
75
100
14 days
21
1
Step-up
Step-down

34. Conclusions 1
• Step-up safer and more efficient than step-down
- lower rate of overstimulation
- higher rate of monofollicular cycles
- higher ovulation rate
Christin-Maitre & Hugues

36. Technique of Ovarian drilling
ÜLaparoscopy
Ü3-4 port technique
ÜIrrigation
ÜAvoid the hilum and the ovarian ligament
ÜPunctures under vision ,do not loose sight of
the needle
ÜRecommended 4 diathermy points per ovary,
4 secs and 40 W

37. Laparoscpic Ovarian Drilling
4 4 40Armeretal

38. Ovulation after LOD in relation to the number
of punctures
69
72717374
88
77
66
90
80
70
60
50
40
30
20
10
0
>2 3 4 5 6 7 8 <8

39. Indication of LOD
1. Clomifene resistance.
2. Persistent hypersecretion of LH.
3. Combined with pelvic assessment.
4. Gonadotropin resistance.
5. Persistent overstimulation.

40. Advantages
ÜHigh prevalence of mono-follicular growth
ÜLower multiple pregnancies
ÜReduction in miscarriages
ÜSuccessful “One Off” procedure”
ÜLower OHSS
ÜIf ovulation does not occur in 2-3 months ,
then using the same earlier medication,
ovaries are more responsive

41. Etiology

42. PCOS Management
Oligo/anovulation
+
PCOS
clomifene
x4-6 ovulatory
cycles or no response
Pregnancy
Weight loss
± metformin
Clomiphene failure
+ metformin
Low-dose FSH
x4-6 ovulatory cycles
Pregnancy
Laparoscopic
ovarian drilling
(± CC or FSH)
IVF/ET Pregnancy
Letrozol

43. High responders- why antagonist?
• A shorter duration of stimulation with GnRH
antagonist
• Gonadotrophin requirements are decreased
compared to GnRH agonists
• OHSS incidence decreased
• Allows the use of an agonist trigger.

44. FSH
hCG
FSH
hCG
0.25mg/day antagonist
Day 5 , 6 or 7 antagonist start
FIXED
0.25mg/day antagonist
day 8/9
Follicle size 14mm- start antagonist
Flexible regime

45. FSH
GnRH agonist
FSH
0.25mg/day antagonist
Day 5 , 6 or 7 antagonist start FIXED
0.25mg/day antagonist
day 8/9
Follicle size 14mm- start antagonist
Flexible
GnRH agonist

46. GnRH agonist trigger vs hCG
• Produces an endogenous LH surge similar to a
natural cycle.
• Smaller amplitude than hCG
• Much shorter half-life.
• Releases less VEGF

47. FSH
GnRH agonist
0.25mg/day antagonist
Day 5 start
FIXED
Luteal phase support possibilities:
1. Massive doses Progesterone (i/m 50mg/day) +E2
2. 1500 IU hCG on day OPU (Humaidan 2009)
3. Freeze all embryos and transfer in natural cycle

48. FSH
GnRH agonist
0.25mg/day antagonist
Day 5 start
FIXED
Luteal phase support:
1500 IU hCG on day OPU
(Humaidan 2009)
No significant difference in outcome compared with hCG trigger

49. Advice
• If >25 follicles >11mm
Freeze all !

50. Metformin in IVF
• Short term co-treatment with metformin
for PCOS in IVF/ICSI :
• Does not improve response to stimulation
• Improves pregnancy rates ?
• Reduces the risk of OHSS
Tang, Bart & Balen, 2005

51. Thank you...

52. Thank you