International Evidence Based Guidelines:

The role of insulin sensitizer in PCOS

Budi Wiweko

budi.wiweko01@ui.ac.id
budi.wiweko@gmail.com

Academic Health System Universitas Indonesia - Indonesian Medical Education and Research Institute
Faculty of Medicine Universitas Indonesia
Dr. Cipto Mangunkusumo General Hospital

Jakarta

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 ANOVULATION

In anovulatory women with polycystic ovaries, the antral stages of follicular development
are clearly abnormal and growth of these follicles is typically arrested at a diameter of 5–
8 mm
Webber et al. Formation and early development of follicles in the polycystic ovary. Lancet 2003

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 2 GnRH frequency

1 Insulin Resistance

Hypersecretion of LH

Theca cells 3 Low FSH

Hyperinsulinemia
Increase of IGF-1

HYPERANDROGEN
Decrease IGFBP-1

Increase Free Androgen

Decrease SHBG
Increase Free Estrogen
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Women with PCOS are under chronic inflammatory state in a long term, and may have increasingly risk of PCOS mediated by
upregulated androgen, insulin, LH, FSH, AGEs, IGF2, ROS, inflammatory cytokines, and downregulation of adiponectin and
SHBG.
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Polycystic Ovarian Syndrome (PCOS) likely has long-term effects
It is a disorder that typically has its onset early in life.

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1 Stein-Leventhal 1935

2 NIH 1990

5
3 Rotterdam 2003

4 Thessaloniki
Dec 2008

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 Diagnosis
1. Insulin resistance
2. Clinical hyperandrogenemia
3. Anti Mullerian hormone
4. Syndrome metabolic

Treatment
1. Insulin sensitizer
2. Anti androgen
3. Oral contraception
4. Anti obesity and bariatric surgery

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 International strategic advisor CRE PCOS
Bart Fauser Robert Norman

Screening and Life style Diagnostic Medical Infertility

risk assessment management assessment treatment management

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 Categories of the PCOS guideline recommendations Abbreviation
Evidence based recommendations: Evidence sufficient to EBR
inform a recommendation made by the guideline
development group.

Clinical Consensus Recommendations: In the absence of CCR

evidence, a clinical consensus recommendation has been
made by the guideline development group.

Clinical Practice Points: Evidence not sought. A practice point CPP

has been made by the guideline development group where
important issues arose from discussion of evidence-based or
clinical consensus recommendations.

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 Screening and
risk assessment

Health professionals and women with PCOS should be aware that, regardless of age, the
prevalence of gestational diabetes, impaired glucose tolerance and type 2 diabetes (5 fold
9 in Asia, 4 fold in the Americas and 3 fold in Europe) are significantly increased in
PCOS, with risk independent of, yet exacerbated by obesity.

A 75-g OGTT should be offered in all women with PCOS preconception when planning
pregnancy or seeking fertility treatment, given the high risk of hyperglycaemia and the
10 associated comorbidities in pregnancy. If not performed preconception, an OGTT should
be offered at < 20 weeks gestation, and all women with PCOS should be offered the test
at 24-28 weeks gestation.

Health professionals and women with PCOS should be aware of a two to six-fold
11 increased risk of endometrial cancer, which often presents before menopause; however
absolute risk of endometrial cancer remains relatively low.

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 Life style and
pharmacological

Healthy lifestyle behaviours encompassing healthy eating and regular physical activity
should be recommended in all those with PCOS to achieve and / or maintain healthy
1
weight and to optimise hormonal outcomes, general health, and quality
of life across the life course.

In combination with the COCP, metformin should be considered in women with PCOS
2 for management of metabolic features where COCP and lifestyle changes do not
achieve desired goals.

In combination with the COCP, metformin could be considered in adolescents with PCOS
3 and BMI ≥ 25 kg / m2 where COCP and lifestyle changes do not achieve desired goals.

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 Pharmacological

The COCP alone should be recommended in adult women with PCOS for management of
4 hyperandrogenism and / or irregular menstrual cycles.

In combination with the COCP, antiandrogens could be considered for the treatment of
5 androgen-related alopecia in PCOS.

Metformin in addition to lifestyle, could be recommended in adult women with PCOS,

6 for the treatment of weight, hormonal and metabolic outcomes.

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 Infertility

Letrozole should be considered first line pharmacological treatment for ovulation

induction in women with PCOS with anovulatory infertility and no other infertility
1
factors to improve ovulation, pregnancy and live birth rates.

Metformin could be used alone in women with PCOS, with anovulatory infertility and
2 no other infertility factors, to improve ovulation, pregnancy and live birth rates,
although women should be informed that there are more effective ovulation
induction agents.

Clomiphene citrate could be used in preference, when considering clomiphene citrate

3 or metformin for ovulation induction in women with PCOS who are obese (BMI is ≥ 30
kg / m2) with anovulatory infertility and no other infertility factors.

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 Infertility

If metformin is being used for ovulation induction in women with PCOS who are obese
4 (BMI ≥ 30kg / m2) with anovulatory infertility and no other infertility factors,
clomiphene citrate could be added to improve ovulation, pregnancy and live birth
rates.

Clomiphene citrate could be combined with metformin, rather than persisting with
clomiphene citrate alone, in women with PCOS who are clomiphene citrate-resistant,
5 with anovulatory infertility and no other infertility factors, to improve ovulation and
pregnancy rates.

Gonadotrophins could be used as second line pharmacological agents in women with

6 PCOS who have failed first line oral ovulation induction therapy and are anovulatory
and infertile, with no other infertility factors.

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 Infertility

Gonadotrophins could be considered as first line treatment, in the presence of

7 ultrasound monitoring, following counselling on cost and potential risk of multiple
pregnancy, in women with PCOS with anovulatory infertility and no other infertility
factors

Gonadotrophins, where available and affordable, should be used in preference to

8 clomiphene citrate combined with metformin therapy for ovulation induction, in women
with PCOS with anovulatory infertility, clomiphene citrate-resistance and no other
infertility factors, to improve ovulation, pregnancy and live birth rates.

Either gonadotrophins or laparoscopic ovarian surgery could be used in women with

9 PCOS with anovulatory infertility, clomiphene citrate-resistance and no other infertility
factors, following counselling on benefits and risks of each therapy.

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Conclusions:

There was a positive correlation between serum AMH and HOMA IR

levels. Serum AMH and HOMA IR levels were significantly different
across the four PCOS phenotypes; with the highest values were present
with phenotype 1.

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n = 125

Phenotype 1 shows significantly higher AMH levels

(Kruskal–Wallis, p < 0.05) than other phenotypes.

Wiweko et al. BMC Res Notes, 2018

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There was significant difference in fasting insulin and fasting glucose
levels among the four phenotypes (p = 0.014) based on the Kruskal –
Wallis test.

Wiweko et al. BMC Res Notes, 2018

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In the current study, we found an association between AMH and IR
(r = 0.52, p < 0.001).

Wiweko et al. BMC Res Notes, 2018

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Conclusion:

There was a significant decrease in the serum AMH level after

administration of either metformin or DLBS3233.

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THE EFFECT OF INSULIN SENSITIZER TO SERUM AMH

Wiweko et al. J Hum Reprod Sci, 2017

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CHARACTERISTICS OF
SUBJECTS

Wiweko et al. J Hum Reprod Sci, 2017

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Wiweko et al. J Hum Reprod Sci, 2017

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 Wiweko et al. J Hum Reprod Sci, 2017

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 Wiweko et al. J Hum Reprod Sci, 2017

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THE ROLE OF DLBS3233 IN THE MANAGEMENT OF
POLYCYSTIC OVARY SYNDROME (PCOS):

A RANDOMIZED, DOUBLE-BLIND, AND NON-

INFERIORITY STUDY

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Objectives
The objectives of the study were:

1. To evaluate the clinical and metabolic efficacy of DLBS3233 in women

with polycystic ovary syndrome compared with metformin as an active
control

2. To evaluate the efficacy of DLBS3233 in improving reproductive

parameters in women with polycystic ovary syndrome compared with
metformin as an active control

3. To evaluate the safety of DLBS3233 in women with polycystic ovary

syndrome compared with metformin

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Menstrual regularity rate

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 International evidence-based guideline for the assessment and management of
polycystic ovary syndrome 2018

SCREENING, DIAGNOSTIC ASSESSMENT, RISK ASSESSMENT

AND LIFE-STAGE

Comprehensive history and physical examination for clinical hyperandrogenism. Adults: acne, alopecia and
hirsutism and in adolescents severe acne and hirsutism.

Ultrasound should not be used for the diagnosis of PCOS in those with a gynaecological age of < 8 years (< 8
years after menarche), due to the high incidence of multi-follicular ovaries in this life stage

Use calculated free testosterone, free androgen index or calculated bioavailable testosterone in diagnosis.

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 Pharmacological treatment for non-fertility indications

In those with a clear PCOS diagnosis or in adolescents at risk of PCOS (with symptoms)

Education + lifestyle + first line pharmacological therapy for hyperandrogenism and irregular cycles

COCP FIRST LINE

Use lowest Consider natural Follow WHO general 35 micrograms Hirsutism requires Consider additional
effective oestrogen oestrogen preparations population guidelines ethinyloestradiol COCP and additional PCOS related risk
dose (20-30 balancing efficacy, for relative and plus cyproterone cosmetic therapy for factors such as high
micrograms ethinyl metabolic absolute acetate not first line at least 6 months BMI, hyperlipidemia
oestradiol or risk profile, side effects, contraindications and in PCOS due to and hypertension
equivalent) cost and availability risks increased adverse
effects

Second line pharmacological therapies

COCP + lifestyle + metformin COCP + anti-androgens Metformin + lifestyle

No COCP preparation is superior in PCOS.
Should be considered in women with PCOS for
management of metabolic features, where COCP +
lifestyle does not achieve goals
Could be considered in adolescents with PCOS and BMI ≥
25kg / m2 where COCP and lifestyle changes do not
achieve desired goals.
Most beneficial in high metabolic risk groups including
those with diabetes risk factors, impaired glucose
tolerance or high-risk ethnic groups
Evidence in PCOS relatively limited.
Anti-androgens must be used with
contraception to prevent male fetal virilisation.
Can be considered with androgenic alopecia
Can be considered with androgenic alopecia
With lifestyle, in adults should be considered for
weight, hormonal and metabolic outcomes and could
be considered in adolescents.
Most useful with BMI ≥ 25kg / m2 and in high risk
ethnic groups. Side-effects, including GI effects, are
dose related and self-limiting
Consider starting low dose, with 500 mg increments 1-
2 weekly
Metformin appears safe long-term. Ongoing
monitoring required and has been associated with low
vitamin B12.

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COCPs, metformin and other pharmacological treatments are generally offand
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in PCOS society
 International evidence-based guideline for the assessment and management of
polycystic ovary syndrome 2018

ASSESSMENT AND TREATMENT OF INFERTILITY

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 TAKE HOME MESSAGES (1)

NON - INFERTILITY MANAGEMENT

1. The prevalence of gestational diabetes, impaired glucose tolerance and type 2 diabetes (5 fold in
Asia, 4 fold in the Americas and 3 fold in Europe) are significantly increased in PCOS.

2. A 75-g OGTT should be offered in all women with PCOS preconception when planning pregnancy
or seeking fertility treatment

3. In combination with the COCP, metformin could be considered in adolescents with PCOS and BMI
≥ 25 kg / m2 where COCP and lifestyle changes do not achieve desired goals.

4. In combination with the COCP, metformin should be considered in women with PCOS for
management of metabolic features where COCP and lifestyle changes do not achieve desired
goals.

5. Metformin in addition to lifestyle, could be recommended in adult women with PCOS, for the
treatment of weight, hormonal and metabolic outcomes.

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 TAKE HOME MESSAGES (2)

INFERTILITY MANAGEMENT

1. Metformin could be used alone in women with PCOS, with anovulatory infertility and no other
infertility factors, to improve ovulation, pregnancy and live birth rates, although women should be
informed that there are more effective ovulation induction agents.

2. Clomiphene citrate could be used in preference, when considering clomiphene citrate or

metformin for ovulation induction in women with PCOS who are obese (BMI is ≥ 30 kg / m2) with
anovulatory infertility and no other infertility factors.

3. If metformin is being used for ovulation induction in women with PCOS who are obese (BMI ≥ 30 kg
/ m2) with anovulatory infertility and no other infertility factors, clomiphene citrate could be added
to improve ovulation, pregnancy and live birth rates.

4. Clomiphene citrate could be combined with metformin, rather than persisting with clomiphene
citrate alone, in women with PCOS who are clomiphene citrate-resistant, with anovulatory
infertility and no other infertility factors, to improve ovulation and pregnancy rates.

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 Acknowledgement
Ali Baziad, Andon Hestiantoro, Muharam Natadisastra, Kanadi Sumapraja,
Gita Pratama, Achmad Kemal, Herbert Situmorang Eliza Mansyur, Tita Yuningsih, Sarah Chairani, Siti Mariam,
Endang Kurdiningsih, M Priangga, Lewis, Elisia

Indonesian Reproductive Medicine

Research and Training Center
(INA – REPROMED)

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