1. Diagnosis and Treatment of PCOS
Nick Macklon
University Medical Centre
Utrecht
The Netherlands

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

4. PCOS diagnosis - 1990 NIH criteria -
Hyperandrogenemia
PCOS
Chronic
anovulation

5. Epidemiology of PCOS Population/ethnicity sample size PCOS reference
Greek Island, Lesbos NIH Diamanti, JCEM 99
17-45 yrs %
Caucasian, reproductive age NIH Asuncion, JCEM 00
Blood donors, Spain %
Preemployment physical, US NIH Azziz, JCEM 04
18-45 yrs (223 black, 166 white) % Knochenhauer, JCEM 98

6. Why Revisit the NIH Criteria?
First step to standardizing diagnosis
Based on Questionnaire
PCOS -broader spectrum of ovarian dysfunction
-regular cycles and hyperandrogenism and/or PCO
-PCO without hyperandrogenism
May not be suitable for trials of clinical outcomes

7. ESHRE / ASRM endorsed PCOS Consensus Meeting Rotterdam, The Netherlands
Azziz
Laven
Bouchard
Dewailly
Legro
Nestler
Diamanti
Pasquali
Ibanez
Balen
Dahlgren
Homburg
Wild
Norman
Franks
Wild
Tan
Dunaif
Devoto
Strauss
Taylor
Pugeat
Filicori
Magoffin
Fauser
Tarlatzis
Rotterdam, May 2003

8. Revised Diagnostic Criteria for PCOS
1999 NIH Criteria (both 1 and 2)
1. Chronic anovulation
2. Clinical and/or biochemical signs of hyperandrogenism
Exclusion of other aetiologies
Revised 2003 Rotterdam Criteria (2 and of 3)
1. Oligo- and/or anovulation
2. Clinical and/or biochemical signs of hyperandrogenism
3. Polycystic ovaries
Exclusion of other aetiologies

9. PCOS diagnostic criteria
Exclusion of other causes of androgen excess
Cushing, 21 hydroxylase deficiency
androgen producing tumours
Exclusion of other causes of anovulation
Hypogonadotropic hypogonadism
Premature ovarian failure
Hyperprolactinaemia
Often obesity (but not required)
Often elevated LH (but not required)
Often hyperinsulinemia (but not required)

10. PCOS - hyperandrogenemia -
Clinical:
Acne
Hirsutism
Biochemical:
Testosterone total or free (unbound)
Free androgen index (T x 100 / SHBG)
Androstenedione?
DHEAS?
combination
Normative data lacking
Subjective
May be less prevalent in East Asian Women
Variable laboratory methods
Wide variability in normal population
Normative ranges not well established in well characterized control populations

11. PCOS - polycystic ovaries -
Presence of 12 or more follicles (2-9mm) per ovary. Location not important.
Ovarian volume >10mls
0.5 x length x width x thickness
Ovarian stroma objective?
One ovary sufficient for diagnosis
Scan early follicular phase
Balen,
HRU 2003

12. 1
PCOS
Hyperandrogenemia
Oligo/anovulation
(WHO 2 type)
PCO

13. PCOS phenotypes Oligo/anovulation + + + Hyperandrogenemia + + +
NIH Rotterdam
additions
Oligo/anovulation
Hyperandrogenemia
PCO

15. TREATMENT OF PCOS

16. Ovulation Induction Type of ovarian stimulation aimed at
restoring normal fertility
by inducing single dominant follicle selection,
ovulation and hence normo-ovulatory cycles.

17. Ovulatory infertility and Obesity
Mulders et al. Hum Reprod Update 2003

18. Impact of obesity of clinical, hormonal and
metabolic features of PCOS
Hoeger K, Clin Obstet Gynecol, 2007

19. Ovulation Induction Step 1: Lose weight
(Guzick et al., Fertil Steril, 1994)
Treatment
Controls
Total T
SHBG
SHBG - T
Insuline
Glucose 90 .9 16 90
120 80 .8 14 80
110 70 .7 12 70
100 60 .6 10 60 90 50 .5 8 50 40 .4 6 40
Pre
Post
Pre
Post
Pre
Post
Pre
Post
Pre
Post

22. Ovulation Induction Non-steroidal estrogen antagonist
Step 2: Clomiphene Citrate
Non-steroidal estrogen antagonist
Blocks negative feedback of E2 at pituitary
50-150mg from day 2-5 of cycle
FSH  %
70-80% ovulate
22% conception rate per cycle
Cheap & effective

23. Ovulation Induction Step 3: Metformin? Step 3: Aromatase inhibitors?
Step 3: Electrocautery of ovaries?
Step 3: Gonadotropins?

24. Ovulation Induction 626 women with PCOS Step 3: Add Metformin?
Combination of
metformin and CC
50-150mg CC plus placebo
from cycle day 3-7
500 mg-2000 mg Metformin
plus placebo
Up to 6 months treatment
Obesity not an exclusion
Legro et al, NEJM

25. Ovulation Induction
Step 3: Add Metformin?
Legro et al, NEJM 2007

26. Ovulation Induction Step 3: Add Metformin?
Tarlatzis etal, Hum Rep 2007

27. Aromatase Inhibitors E2 E2 FSH FSH AI Day 5 Day 10 ER ER ER ER ER
Halflife: hours

28. Aromatase Inhibitors Few RCTS: Badawy et al; No advantage over CC
Outstanding questions
Impact of low intrafollicular estradiol levels?
Impact of intrafollicular androgen accumulation?
: positive (via increase in FSH receptors)
: negative: androgen excess
Impact on oocyte quality?
Few RCTS: Badawy et al; No advantage over CC
Teratogenicity issues?

29. Gonadotropin regimens
hCG
FSH levels
FSH dose
STEP-UP Protocol
window
10mm
FSH levels
FSHdose
hCG
STEP-DOWN Protocol
menses

30. Cumulative pregnancy rates after
ovulation induction 1
0.8
0.6
Ongoing Singleton Pregnancy Rate
Resulting in Live Birth
0.4
0.2 3 6 9 12 15 18 21 24
Follow-up (months)
Eikemans et al, Hum Reprod 2003

31. Electrocautery of ovaries

32. Ovulation Induction
Step 3: Electrocautery of ovaries

33. Step 4: IVF

34. IVF in PCOS: Ovarian Stimulation
The ‘classical’ long protocol
hCG
FSH / HMG
Luteal support OC
GnRH agonist
The ‘antagonist’ protocol
hCG/GnRHa
FSH / HMG
GnRH antag
Luteal support
Cycle day 1

35. IVF outcomes in women with PCOS (458) vs Controls (694)
A meta-analysis. Heijnen et al, Hum Reprod Update, 2006
WMD for number oocytes per ovum pick up
WMD for number of oocytes fertilised
OR for chance of cancellation
OR for chance of live birth per started cycle
OR for chance of miscarriage per started cycle

36. Pregnancy outcomes in PCOS
Meta-analysis: 720 women with PCOS vs 4505 controls
OR 95% CI
Gestational Diabetes:
Pregnancy induced hypertension:
Pre-eclampsia
Pre-term birth
Peri-natal mortality

37. Conclusions Need for uniform definition Lifestyle as therapy
Clomiphene still first line?
Gonadotropins versus Laparoscopic electrocautery?
Ovulation Induction works!
IVF effective- and with appropriate care: safe
Role of in-vitro oocyte maturation?