Current Update of PCOS Management in Indonesia

Budi Wiweko
[email protected]
[email protected]

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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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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 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
 2 GnRH frequency
1 Insulin Resistance

P COS
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
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.
Yan Li et al. Life Sciences, 2019
Fertil Steril, 2011

Anti-Mullerian hormone reduces follicle sensitivity to follicle-

stimulating hormone in human granulosa cells
Laura Pellatt, Suman Rice, Nafi Dilaver, Amira Heshri, Raymond Galea, Mark Brincat, Kristy Brown, Evan R. Simpson,
and Helen D. Mason

Design
Granulosa cells were exposed to AMH with and without gonadotropins for 48 hours

Results
The AMH decreased gonadotropin-stimulated aromatase expression
AMH also reduced FSH receptor mRNA expression

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 NORMAL PCOS
FSH
FSH treshold

FSH

FSH Inhibin B
FSH

Inhibin B
Aromatase
Aromatase

AMH
AMH

Androgens Androgens Jonard S. Hum Reprod Update, 2004

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Objective:

To determine whether the measurement of serum AMH can be used to diagnose PCOS and
as a tool to predict the prognosis of PCOS.

Wiweko et al. J Assist Reprod Genet, 2014

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The differences of basal hormone levels, age and BMI between PCOS and non-PCOS patients

n = 142

There were statistically significant differences between the PCOS and the control group in
median/ mean AMH, LH, and FSH levels.

Wiweko et al. J Assist Reprod Genet, 2014

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The AUC of AMH level was 0.870 (95 % CI 0.81–0.92) and optimal AMH cut-off level was 4.45 ng/ml,
yielding 76.1 % sensitivity and 74.6 % specificity.

Wiweko et al. J Assist Reprod Genet, 2014

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 ODDS RATIO OF EACH VARIABLE

n = 142

Patients with higher AMH levels ( ≥ 4.45 ng / mL) have 9.35 times higher possibility to suffer
from PCOS compared to patients with low AMH.

Wiweko et al. J Assist Reprod Genet, 2014

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 ROTTERDAM CRITERIA
2 out of 3 items

ANOV HA
Anovulation Hyperandrogen PCOS phenotype

1.Anov + HA + PCO
2.Anov + HA
PCO 3.Anov + PCO
Polycystic 4.HA + PCO

Which one is the most severe type ?

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 AMH levels of the four groups based on PCOS-related phenotypes

Indonesian people tend to be less hyperandrogenic compared to Caucasians

• Ovulatory PCOS patients had lower AMH levels compared to anovulatory PCOS patients
• Increased androgen levels have also been related with the increased production of AMH

Wiweko et al. J Assist Reprod Genet, 2014

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 Int. J. Mol. Sci. 2021

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 Int. J. Mol. Sci. 2021

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Objective: This study aimed to evaluate the correlation of anti-Müllerian hormone (AMH)
levels with the metabolic syndrome in patients with PCOS.

Wiweko et al. Int J Rep Med, 2020

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Wiweko et al. Int J Rep Med, 2020

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Wiweko et al. Int J Rep Med, 2020 Inspiring and empowering society
 Implantation-site vessels with endovascular trophoblast differed significantly among PCOS
phenotypes.

The overall incidence of microscopic placental lesions was significantly higher in the full-blown
and non-PCO phenotypes.

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Fertil Steril, 2010

Not all women diagnosed with PCOS share the same

cardiovascular risk profiles
Vuk P. Jovanovic, Enrico Carmina, and Rogerio A. Lobo

Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, New York;
Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy

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Background

The pathogenesis of PCOS is not fully understood, but one theory of anti-mullerian hormone
(AMH) has been proposed as one of the factor related to the degree of severity of PCOS.

However, there are no clear correlation between levels of AMH with the incidence of insulin
resistance in PCOS patients especially in Indonesia

Wiweko et al. BMC Res Notes, 2018

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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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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 Conclusion:
values were present with phenotype 1.
There was a significant decrease in the serum
AMH level after administration of either
metformin or DLBS3233.

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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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Menstrual regularity rate

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 Clin Exp Reprod Med. 2016

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AMH THRESHOLD DETERMINATION BASED ON
AUC AND PROBABILITY

Hestiantoro et al. Clin Exp Reprod Med. 2016

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High circulating luteinizing hormone (LH) level is a typical biochemical feature of
polycystic ovary syndrome (PCOS) whose pathophysiology is still unclear.

Certain mutations of LH and LH receptor (LHR) may lead to changes in bioactivity of these
hormones.

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 Poor responder
in PCOS patients

Suheimi, Wiweko et al.

IMERI - BMHS 2021

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Free Androgen Index and Ovarian Response

Suheimi, Wiweko et al. IMERI - BMHS 2021

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 AMH levels of the four groups
based on PCOS-related
phenotypes

Wiweko et al. J Assist Reprod Genet, 2014

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 Variants Beta LH and
Ovarian Response

Suheimi, Wiweko et al. IMERI - BMHS 2022

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Variants Beta LH and Ovarian Response

Suheimi, Wiweko et al. IMERI - BMHS 2022

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Variants Beta LH Sequencing

Suheimi, Wiweko et al. IMERI - BMHS 2022

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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. Evidence in PCOS relatively limited. With lifestyle, in adults should be considered for
weight, hormonal and metabolic outcomes and could
Should be considered in women with PCOS for Anti-androgens must be used with be considered in adolescents.
management of metabolic features, where COCP + contraception to prevent male fetal virilisation.
lifestyle does not achieve goals Most useful with BMI ≥ 25kg / m2 and in high risk
Can be considered with androgenic alopecia ethnic groups. Side-effects, including GI effects, are
Could be considered in adolescents with PCOS and BMI ≥ dose related and self-limiting
25kg / m2 where COCP and lifestyle changes do not Can be considered with androgenic alopecia
achieve desired goals. Consider starting low dose, with 500 mg increments 1-
2 weekly
Most beneficial in high metabolic risk groups including
those with diabetes risk factors, impaired glucose Metformin appears safe long-term. Ongoing
tolerance or high-risk ethnic groups monitoring required and has been associated with low
vitamin B12.

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

ASSESSMENT AND TREATMENT OF INFERTILITY

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Crosstalk between advanced glycation end products and vitamin D: A compelling paradigm
for the treatment of ovarian dysfunction in PCOS

Merhi. Moll Cell Endocrinol, 2018

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 High AMH PCOS

CC resistant
Metabolic syndrome

Insulin sensitizing agents (ISA)

Laparoscopic ovarian drilling (LOD)

VITAMIN D
LEPTIN

Decreasing serum AMH

Ovulation Decreasing risk of metabolic syndrome

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 TAKE HOME MESSAGES

1. Serum AMH can be used as diagnostic and prognostic biomarker of PCOS.

2. The prediction of obstetrics risk and metabolic syndrome in PCOS are correlated
with serum AMH.

3. The relationship between insulin resistance and serum AMH should be

investigated.

4. Serum AMH can be used for prediction of CC resistance in PCOS.

5. The correlation between variant beta LH in PCOS with ovarian response should be
elucidated further.

6. Vitamin D supplementation has potential role in management of PCOS patients.

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 Acknowledgement
Julianto Witjaksono, Ali Baziad, Andon Hestiantoro, Muharam Natadisastra, Kanadi Sumapraja,
Gita Pratama, Herbert Situmorang Eliza Mansyur, Tita Yuningsih, Dyah Pitha, Siti Mariam, Endang Kurdiningsih,
M Priangga, Valencia Yuwono, Nadia Safira, Lady Margaretha, Astrid Iskandar

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