Seminar Evidence Based Obstetric & Gynecology POGI Cabang Surabaya 17 Juli 2016 - Pullman Hotel Surabaya

1. EVIDENCE-BASED
MANAGEMENT OF PCOS
BUDI SANTOSO
HALAL BI HALAL- 17 JULI 2016

2. References

4. Evidence-based guideline for the
assessment and management of
polycystic ovary syndrome
Developed 2011
Updated August 2015 - Section 7.4 Aromatase
inhibitors
Further update scheduled 2016/2017

5. An Overviewof the Magnitudeof The
Problemof PCOS
Prevalence
~ 20%
Complex
Pathophy-
siology
Diagnosis
2003
Women’s Health
Aspects
2011
Treatment &
Outcome
2007
Three ESHRE/ASRM PCOS
Consensus Workshops
Approximately 75% of PCOS women suffer from infertility due to anovulation.

6. EVIDENCE-BASEDMANAGEMENT OFPCOS
Surgical
• Laparoscopic Ovarian Drilling
• Bariatric Surgery
Pharmacological
• Clomiphene Citrate
• Metformin
• Aromatase inhibitors
• Gonadotropins
Non Pharmacological
Life style modification

7.  Lifestyle intervention (to optimise preconception
health, fertility and long-term complications)
 Lifestyle interventions include diet, exercise, behavioral
management techniques for modifying diet or exercise,
or a combination of these.
1st Line Non Pharmacological management for
Infertility

8. Lifestyle change
4 RCTs, (20, 21, 46 and 343 PCOS Obese/over weight
womens)  intervension groups VS lifestyle
Metformin only, CC only, Metformin + CC ( 24 – 28 weeks) VS
( diet only, diet + exercise, and diet + exercise + behavioral).
No significant different between Lifestyle VS pharmaceutical
in term of menstrual fuction, pregnancy rate
Pasquali,143 obesePCOS women,RCTs
metformin+diet VSplacebo+diet
Menstrualimprovement : 4.3vs3.2(p= 0,017)
Nodiff.inpregnancyrate

9. Secara singkat, bukti2 RCT tidak mendukung pengobatan
dengan induksi ovulasi seperti CC/metformin yang
mendahului treatment gaya hidup atau memulai
treatment gaya hidup yang dikombinasi dengan
pengobatan induksi ovulasi dibandingkan dengan tretmen
gaya hidup saja pada wanita obes infertil anovulatoar
dengan PCOS

10. Balen Adam H. et.al. 2005 Polycystic ovary syndrome a guide to clinical management.
Lifestyle change is the first line treatment for women
with PCOS who are over weight or obese, with as little
as 5-10 % weight loss improving psycological outcome,
reproductive features and metabolic features.
Amplification of sign and symtoms of PCOS with
Increasing obesity and insulin resistance

11. ClomipheneCitrate
• 1967
• as anti estrogenic and estrogenic
• competitive binding ER
• Studies with clomiphene citrate show
ovulation rates of 60%–85% and
pregnancy rates of 30%–50% after six
ovulatory cycles.
• The rates of twin 5%-7% and triplet
pregnancy 0.3%, respectively.
• The incidence of OHSS less than 1%
- Usadi, R, Fritz, M, Glob. libr. women's med., (ISSN: 1756-
2228) 2008; DOI 10.3843/GLOWM.10337
- Teede et al, Med J Australia 2011

12. Clomifene citrate
If ovulation cannot be achieved with clomifene citrate,
then the patient is said to have clomifene citrate
resistance. If pregnancy cannot be achieved after six
ovulatory cycles with clomifene citrate, then the patient is
described as having clomifene citrate failure.
Systematic review and meta-analysis 3 RCTs comparing
CC VS placebo, 3 trials 133 patients  CC improves ovulation
rate and pregnancy rate, but no publish CC VS placebo/ no
treatment examining live- birth as outcome.

13. 1st line Pharmacologicalmanagement for
Infertility
Teede et al, Med J Australia 2011
Evidence based recommendation:
CC should be fisrt line pharmacological therapy to improve
fertility No other infertility factor. CC is selective estrogen
receptor modulator with both estrogenic and anti estrogenic
properties.
Clinical practice point:
The risk of multiple pregnancy is increased with CC use and
therefore monitoring is recommended.

14. METFORMIN
 Biguanide
 Rationale as ISA to retore ovulation
 1994 as tretment for PCOS
 Adnistration metformin for PCOS many protocol : 1500 –
2550 mg.
 The most adverse reaction gastrointestinal symtoms

15. Metformin
o Metformin alone has been shown to improve ovulation and
clinical pregnancy rate but not live- birth rate.
o Metformin combined with clomifene citrate has a higher
ovulation, pregnancy and live-birth rate compared with
clomifene citrate alone only in clomifene citrate-resistant
(CCR) PCOS.

16. Table 1:
Randomized
Controlled
Trials Comparing
Clomiphene
Citrate with
Metformin in
PCOS Women
Source: Costello &
Ledger, 2012

17. Metformin
o Fertility outcomes are improved with the addition of
clomifene citrate to metformin compared with
metformin alone in obese PCOS women (BMI >= 30
kg/m2).
o There is no improvement in fertility outcomes when
metformin is combined with laparoscopic ovarian
drilling, gonadotropin ovulation induction with timed
intercourse, or IVF. However, metformin
coadministration with IVF results in a 70 –80% lower risk
of OHSS

18. Metformin
Clinical question. In women with PCOS, is metformin effective for improving fertility
outcomes?
Teede et al, Med J Australia 2011
Evidence-based recommendations
Metformin should be combined with clomiphene citrate to improve fertility outcomes
rather than persisting with further treatment with clomiphene citrate alone in women
with PCOS who are clomiphene citrate resistant, anovulatory and infertile with no
other infertility factors.

19. Gonadotrophins
 Gonadotrophins are often used as second-line therapy in
anovulatory PCOS women with CCR (Clomiphene Citrate
Resistance) and CCF (Clomiphene Citrate Failure).
 Recent randomized evidence suggests that gonadotropin
therapy may be more effective than clomifene citrate in therapy-
naive PCOS women. Low dose Gonadotropin 70%
monofollicular, PR per ovulatory 15-20%, cumulatif PR 55-70%.
 Increased risk of multiple pregnancy and OHSS 1%  A low-
dose “step up” protocol
 The duration gonadotropin therapy should not exceed 6 ovulatory
cycles
Teede et al, Med J Australia 2011

20. Gonadotrophins
 Cohcrane systemic review rFSH and uFSH no different,
in OR, PR, MP and MCR in treatment CCR women with
PCOS
 2 RCTs FSH induction ovulation VS CC in treatment 76
women with PCOS  Improvement in pregnancy rate,
no different in live birth, no different in OR, and no Diff
in MP.
 The second RCT low dose step up of FSH VS CC in 255
women PCOS  FSH higher PR and LBR
But > cost and inconvinient
SECOND LINE TREATMENT

21.  Aromatase inhibitors were proposed as ovulation-inducing
agents in 2001.
 Letrozole and anastrozole are the most commeonly in IO
Aromatase Inhibitors
 Aromase Inhibitor === biosyntesa estogen (interfering H/P)
increasing FSH
Growing Follicle
 The effectiveness of letrozole is not better than CC
 There is conflicting published data on the potential teratogenic
effect of letrozole when used as an ovulation induction agent.
D

22. LAPAROSCOPI OVARIAN DRILLING
 Laparoscopic ovarian “driling” was first
described in
1984
 Mechanisms underpinning hormonal
changes
and resumption of ovulation remain
poorly
understood.
 Result 6 month : OR 54-76%, PR 28-
76%,
12 month: OR: 33-88%, PR: 54-
70%
 Laparoscopic ovarian drilling in PCOS is

23. LOD When Recommended?
 Second line Tx. CC resistence
in PCOS Patients, alternative
gonadotropin equal in efficacy
but lower of MP and Cost
 Hypersecretion LH
 Who need laparoscopy?
 Who live too far from
hospital  intensive
monitoring during
gonadotropin tx

24. Bariatric Surgery
• Bariatric/ Weight surgery result in aproximally 15-30% weight
loss
• A Cohrane review -> conventional Tx in obesity reduce DM,
Hypertension based on 3 RCTs, did not assess fertility
outcome
• There not any published RCTs assesing the effectiveness of
bariatric surgery specifically in PCOS women.
• Another systemic review based in reproductive outcome 
improve fertility and reduction obstetric complication ( DM in
pregnancy, macrosomia, hypertension disorder), but IUGR
increase.
• A recent study reported that bariatric surgeryis a potential
future tratment option for obese PCOS women, the criteria
still large debateble and more scientific research is required

25. 2ndlinepharmacological/surgicalmanagement
3st line management could be other approriate intervension
1st line Non Pharmacological
management for Infertility
Don’t use Aromates
inhibitor as First Tx. (B)
LOD (B)
Under caution
CC+Met (A)
Management of Infertility in women with PCOS
Gonadotropin (B)
Metformin, if BMI <=35
(B)
Bariatric surgery (CR)
Arom Inhibit (D)
Only women CC rest,
anovulatoar, infertil with no
other fertility factor
Lifestyle intervension
(C)
1st Line Pharmacological
managent for Infertility
Clomiphen C (A)
Only for adult who are anovulatory and
have a BMI >= 35 kr/m2 and who remain
infertile despiter undertaking an intensive
structured lifestyle management program
for minimum of 6 months