EVIDENCE-BASED MANAGEMENT OF PCOS

BUDI SANTOSO

HALAL BI HALAL- 17 JULI 2016

References

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

An Overview of the Magnitude of The Problem of PCOS

Prevalence~ 20%

ComplexPathophy-

siology

Diagnosis2003

Women’s HealthAspects

2011

Treatment & Outcome

2007

Three ESHRE/ASRM PCOS Consensus Workshops

Approximately 75% of PCOS women suffer from infertility due to anovulation.

EVIDENCE-BASED MANAGEMENT OF PCOS

Surgical• Laparoscopic Ovarian Drilling• Bariatric Surgery

Pharmacological• Clomiphene Citrate• Metformin• Aromatase inhibitors• Gonadotropins

Non PharmacologicalLife style modification

Lifestyle intervention (to optimise preconception health, fertility and long-term complications)

Lifestyle interventions include diet, exercise, behavioralmanagement techniques for modifying diet or exercise,or a combination of these.

1st Line Non Pharmacological management for Infertility

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 obese PCOS women, RCTs metformin + diet VS placebo + diet

Menstrual improvement : 4.3 vs 3.2 ( p= 0,017)No diff. in pregnancy rate

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

Balen Adam H. et.al. 2005 Polycystic ovary syndrome a guide to clinical management.

Lifestyle change is the first line treatment for womenwith PCOS who are over weight or obese, with as littleas 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

Clomiphene Citrate• 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

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.

1st line Pharmacological management 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.

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

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.

Table 1:RandomizedControlledTrials Comparing ClomipheneCitrate withMetformin inPCOS Women

Source: Costello & Ledger, 2012

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

MetforminClinical 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.

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

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

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

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

thought:

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

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

2nd line pharmacological/surgical management

3st line management could be other approriate intervension

1st line Non Pharmacological management for Infertility

Don’t use Aromatesinhibitor 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