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"Pada perempuan nir-obese dengan SOPK perlu dicari tahu mengenai apa saja faktor yang berpengaruh terhadap patofisiologi terjadinya SOPK. Sejumlah faktor diketahui menjadi penyebab dalam patofisiologi terjadinya SOPK, termasuk faktor epigenetik. Namun, sampai saat ini belum ada yang menyatakan mengenai faktor yang menjadi penyebab utama serta korelasi sejumlah faktor tersebut, seperti metilasi DNA reseptor insulin dan juga kadar insulin, dengan Free Androgen Index (FAI) pada SOPK nirobese. Sehingga penelitian ini bertujuan untuk menilai korelasi antara gonadotropin, profil antropometri, metilasi DNA reseptor insulin, kadar insulin dengan Free Androgen Index (FAI) pada subjek dengan Sindrom Ovarium Polikistik (SOPK) nir-obese. Dilakukan studi potong lintang pada 43 perempuan nir-obese di Jakarta yang dibagi menjadi 2 kelompok, yaitu kelompok positif dengan SOPK dan kelompok tanpa SOPK. Pemeriksaan dilakukan pada sejumlah variabel seperti usia, IMT, lingkar pinggang, kadar FSH, kadar LH, level metilasi reseptor insulin, dan FAI, kemudian dianalisis secara statistik. Diperoleh level metilasi reseptor insulin yang berkorelasi positif dengan tingkat korelasi sedang ((p = 0.01, r = 0.53), juga pada nilai LH (p = 0.02, r = 0.5). Sementara nilai SHBG pada kelompok SOPK nir-obese menunjukkan korelasi negatif dengan tingkat korelasi sedang (p = 0.02, r = -0.5). Terdapat asosiasi signifikan antara kadar SHBG dengan FAI baik pada kelompok SOPK maupun kelompok kontrol, juga ditemukannya korelasi negatif pada kedua kelompok, serupa dengan yang terdapat pada nilai LH. Kondisi ini tanpa disertai hubungan bermakna dari insulin yang menunjukkan bahwa SHBG dan LH merupakan suatu faktor independen dari patofisiologi terjadinya SOPK. Korelasi negatif pada metilasi reseptor insulin menunjukkan terjadi silencing pada fungsi reseptor insulin, sehingga terjadi penurunan sensitivitas dari reseptor insulin dan berujung pada meningkatnya kadar FAI.

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Many factors that corresponding to pathophysiology of PCOS on lean women with PCOS. Some factors were still needed to be evaluated such as epigenetics, but until now no studies explaining about main cause and also correlation of those factors, including DNA methylation of insulin receptor and also insulin level, with Free Androgen Index (FAI) of lean PCOS. The aim of this study to evaluate the correlation between gonadotropin, anthropometric profile, DNA methylation of insulin receptor, insulin level, with Free Androgen Index (FAI) on Lean People with Polycystic Ovary Syndrome. A cross-sectional study included 43 lean women in Jakarta was done, and subjects were further classified into two groups, with PCOS and without PCOS. Several related variables such as age, body mass index (BMI), waist circumference, FSH level, LH level, DNA methylation of insulin receptor, insulin level, and FAI, were assessed and analyzed statistically. The DNA methylation of insulin receptor showed positive correlation with moderate correlation (p = 0.01, r = 0.53), and also to LH level (p = 0.02, r = 0.5). While SHBG level of lean PCOS group showed negative correlation with moderate correlation (p = 0.02, r = -0.5). Significance association was resulted between SHBG level and FAI of both groups, also found in LH level. This condition was found without significance association of insulin level which conclude that SHBG and LH level were independent factor of PCOS pathophysiology. Negative correlation of DNA methylation of insulin receptor showed silencing process of insulin receptor function, then decrease the sensitivity of insulin receptor which ended to increasing FAI level."

"Latar belakang: Sindrom ovarium polikistik (SOPK) merupakan salah satu kelainan endokrin paling umum pada 7-15% wanita usia reproduksi yang menyebabkan infertilitas anovulatori. SOPK sering ditemukan pada wanita gemuk, sekitar 50-75% tetapi sindrom ini juga dapat ditemukan pada wanita kurus sebesar 5,5%. Penyebab dan patogenesis SOPK sampai sekarang masih diperdebatkan tapi hasil penelitian memperlihatkan hiperandrogen dan resistensi insulin terlibat dalam perkembangan perjalanan penyakit dan fenotip SOPK. Efek androgen dimediasi oleh reseptor androgen (AR) sedangkan efek insulin dimediasi oleh reseptor insulin (INSR). Ekspresi dan aksi dari kedua reseptor ini terutama pada sel granulosa ovarium dapat dipengaruhi oleh mekanisme epigenetik yang diduga terlibat dalam perkembangan penyakit SOPK ini. Tujuan: Mengetahui tingkat metilasi DNA pada gen reseptor androgen (AR) dan reseptor insulin (INSR) serta ekspresi mRNAnya pada sel granulosa subjek SOPK dan nir-SPOK. Metode: Penelitian ini merupakan penelitian deskriptif analitik dengan rancangan cross sectional. Sampel berupa sel granulosa dari folikel ovarium didapatkan dari wanita yang melakukan ovum pick up (OPU) di klinik Yasmin RSUPN Ciptomangunkusumo yang kemudian dilakukan isolasi DNA dan RNA. Pada isolat DNA dilakukan konversi bisulfit, Methyl Specifik PCR (MSP), elektroforesis dan analisis ketebalan pita dengan perangkat lunak ImageJ untuk mendapatkan data tingkat metilasi DNA. Pada isolat RNA dilakukan qPCR untuk mendapatkan ekspresi relatif mRNA gen AR dan INSR. Hasil: Analisis data dari 21 subjek SOPK dan 20 subjek nir SOPK menunjukkan terdapat perbedaan bermakna (p=0,00) tingkat metilasi DNA gen AR pada pasien SOPK (45.24 %±16,84) dibandingkan nir-SOPK (84,96±15,45). Analisis gen INSR, pada subjek SOPK 100% tidak terjadi metilasi pada promotor gen INSR tetapi pada subjek nir-SOPK 1 dari 21 wanita mengalami metilasi parsial ((37,82%±8,25). Dari penelitian juga didapatkan terjadinya peningkatan ekspresi relatif mRNA AR sebesar 2,459 kali dan 1,791 kali pada mRNA INSR. Tidak terdapat korelasi antara tingkat metilasi gen AR dan INSR dengan ekspresi mRNAnya. Kesimpulan: Penurunan tingkat metilasi DNA (hipometilasi) pada gen AR dan INSR dapat meningkatkan tingkat ekspresi mRNA AR dan INSR, yang kemudian berkontribusi terhadap kejadian hiperandrogen dan resistensi insulin pada fenotip subjek SOPK.

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Background: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in 7-15% of women of reproductive age who cause anovulatory infertility. PCOS is often found in obese women, around 50-75% but this syndrome can also be found in thin women at 5.5%. The causes and pathogenesis of PCOS is still debated but the results of the study show hyperandrogen and insulin resistance involved in the development of the disease course and the PCOS phenotype. The androgen effect is mediated by the androgen receptor (AR) while the effect of insulin is mediated by the insulin receptor (INSR). The expression and action of these two receptors, especially in ovarian granulosa cells can be influenced by epigenetic mechanisms that are thought to be involved in the development of PCOS.

Objective: To determine the level of DNA methylation in the androgen receptor gene (AR) and insulin receptor (INSR) and its mRNA expression in the SOPK and nir-SPOK granulosa cells.

Method: This study is a descriptive analytic study with a cross sectional design. Samples in the form of granulosa cells from ovarian follicles were obtained from women who performed ovum pick up (OPU) at the Yasmin clinic Ciptomangunkusumo Hospital which was then isolated from DNA and RNA. DNA isolates were carried out bisulfite conversion, Methyl Specific PCR (MSP), electrophoresis and tape thickness analysis with ImageJ software to obtain DNA methylation level data. QPCR was performed on RNA isolates to obtain the relative expression of the AR and INSR mRNA genes.

Results: Analysis of data from 21 SOPK subjects and 20 non-PCOS subjects showed significant differences (p = 0.00) of AR gene DNA methylation rates in PCOS patients (45.24% ± 16.84) compared to non-PCOS (84.96 ± 15 , 45). INSR gene analysis, in the subject of 100% PCOS there was no methylation of the INSR gene promoter but in non-PCOS subjects 1 out of 21 women had partial methylation ((37.82% ± 8.25). AR is 3.459 times and 2.791 times in INSR mRNA. There is no correlation between the rate of methylation of the AR and INSR genes with their mRNA expression.

Conclusion: Decreasing levels of DNA methylation (hypomethylation) in AR and INSR genes can increase the level of expression of mRNA AR and INSR, which then contributes to the incidence of hyperandrogen and insulin resistance in the phenotype of the PCOS subject."

"Sindrom ovarium polikistik (SOPK) adalah kelainan endokrin yang paling banyak ditemukan dan memengaruhi 5–20% perempuan pada usia reproduksi. Kadar LH dan rasio LH dengan FSH lebih tinggi pada pasien SOPK nir-obese dibandingkan obese. Sekresi LH dan FSH dipengaruhi oleh pulsatilitas GnRH neuron GnRH di hipotalamus. Kisspeptin diduga sebagai regulator utama sekresi GnRH, sedangkan neurokinin B (NKB) dan dinorfin mengatur sekresi kisspeptin neuron KNDy. Namun, patofisiologi gangguan neuroendokrin pada pasien SOPK nir-obese belum dipahami sehingga diperlukan penelitian untuk mengetahui hubungan kadar kisspeptin, NKB dan dinorfin dengan rasio LH/FSH serta hubungannya dengan polimorfisme dan metilasi DNA gen KISS1. Penelitian ini menggunakan desain potong lintang di Klinik Yasmin, RSUPN dr. Cipto Mangunkusumo Kencana dan klaster Human Reproduction, Infertility and Family Planning IMERI UI pada bulan September 2021 sampai Januari 2023 dengan subjek penelitian 120 pasien SOPK nir-obese. Dilakukan pengukuran parameter komposisi tubuh, skor Ferriman-Gallwey dan pemeriksaan kadar FSH, LH, rasio LH/FSH, kisspeptin, NKB, dinorfin, leptin, adiponektin, AMH, glukosa darah puasa, insulin puasa, HOMA-IR, testosteron, dan SHBG. Dilakukan analisis polimorfisme rs4889 dan rs5780218 gen KISS1 danmetilasi DNA gen KISS1. Analisis bivariat dan analisis jalur dilakukan untuk mengetahui hubungan antarvariabel. Terdapat hubungan negatif antara dinorfin dengan kisspeptin, sedangkan kadar NKB tidak berhubungan dengan kisspeptin. Tidak ada hubungan kadar kisspeptin dengan rasio LH/FSH; namun, dinorfin berhubungan positif dengan rasio LH/FSH pada pada analisis bivariat maupun analisis jalur. Kadar AMH berhubungan dengan rasio LH/FSH baik pada kedua analisis. Pada analisis jalur, terdapat hubungan positif antara HOMA-IR dengan FAI dan antara FAI dengan AMH. Pada analisis polimorfisme gen KISS1tidak terdapat hubungan antara frekuensi genotipe maupun frekuensi alel rs4889 dan rs5780218 gen KISS1 SOPK nir-obese dengan kadar kisspeptin dan rasio LH/FSH. Tidak terdapat perbedaan bermakna antara metilasi DNA dengan kadar kisspeptin dan rasio LH/FSH. Terdapat hubungan antara peningkatan dinorfin dengan penurunan kadar kisspeptin. Hubungan dinorfin dengan rasio LH/FSH kemungkinan disebabkan oleh rendahnya kadar progesteron. Peningkatan AMH berhubungan dengan peningkatan rasio LH/FSH pada pasien SOPK nir-obese. AMH merupakan variabel perantara HOMA-IR dan FAI terhadap rasio LH/FSH. Tidak ada hubungan polimorfisme rs4889 dan rs5780218 gen KISS1 serta metilasi DNA gen KISS1 dengan kisspeptin dan rasio LH/FSH pada pasien SOPK nir-obese. Perlu penelitian lebih lanjut untuk mengetahui potensi terapi terhadap dinorfin dan AMH dalam tatalaksana pasien SOPK nir-obese.

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Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5–20% of reproductive age women. LH levels and LH/FSH ratios are higher in lean PCOS patients than in obese patients. LH and FSH secretion are influenced by GnRH pulsatility of GnRH neurons in the hypothalamus. Kisspeptin is thought to be the main regulator of GnRH secretion, whereas neurokinin B (NKB) and dynorphin regulate kisspeptin secretion in KNDy neurons. However, the pathophysiology of neuroendocrine disorders in lean PCOS patients is not well established. This study aims to determine the relationship between kisspeptin, NKB and dynorphin levels with the LH/FSH ratio and the relationship between polymorphism and DNA methylation of the KISS1 gene. This study used a cross-sectional design at the Yasmin Clinic, RSUPN dr. Cipto Mangunkusumo Kencana and the IMERI UI Human Reproduction, Infertility and Family Planning cluster from September 2021 to January 2023 with 120 lean PCOS patients as subjects. Body composition parameters, Ferriman-Gallwey score, FSH, LH, LH/FSH ratio, kisspeptin, NKB, dynorphin, leptin, adiponectin, AMH, fasting blood glucose, fasting insulin, HOMA-IR, testosterone, and SHBG were measured. Analysis of KISS1 gene polymorphisms of rs4889 and rs5780218 and DNA methylation were performed. Bivariate analysis and path analysis were performed to determine the relationship between variables. There was a negative relationship between dynorphin and kisspeptin, while NKB levels was not related to kisspeptin. There was no relationship between kisspeptin levels and the LH/FSH ratio; however, dynorphin was positively related to the LH/FSH ratio in both bivariate and pathway analysis. AMH levels was positively correlated with the LH/FSH ratio in both analyses. In path analysis, there is a positive relationship between HOMA-IR and FAI as well as between FAI and AMH. In the analysis of the KISS1 gene polymorphism, there was no significant difference between the genotype and allele frequencies of rs4889 and rs5780218 of the lean KISS1 gene with kisspeptin levels and the LH/FSH ratio. There was no significant difference between DNA methylation with kisspeptin levels and LH/FSH ratio. There is a relationship between the increased dynorphin and decreased kisspeptin levels. The association of dynorphins with the LH/FSH ratio may be due to low levels of progesterone. Increased AMH is associated with increased LH/FSH ratio in lean PCOS patients. AMH is an intermediary variable between HOMA-IR and FAI with the LH/FSH ratio. There is no relationship between the rs4889 and rs5780218 KISS1 gene polymorphisms and KISS1 gene DNA methylation with kisspeptin and the LH/FSH ratio in lean PCOS patients. Further research is required to determine the therapeutic potential of dynorphin and AMH in the management of lean PCOS patients."

"ABSTRAK Latar Belakang: Sindrom Ovarium Polikistik (SOPK) merupakan penyebab 40%infertilitas pada wanita usia reproduksi. Resistensi insulin sebagai salah satupatofisiolofi yang mendasari SOPK, berkaitan erat dengan jaringan adiposaviseral dan ditemukan pada 30-50% pasien SOPK dengan indeks masa tubuhnormal serta lingkar pinggang kurang dari 80 cm. Retinol Binding Protein-4(RBP-4) yang disekresi oleh jaringan adiposa viseral diketahui sebagai salah satuadipokin yang menyebabkan resistensi insulin. Pengukuran IMT dan lingkarpinggang tidak dapat mewakili akumulasi jaringan adiposa viseral pada SOPKdengan IMT normal serta lingkar pinggang kurang dari 80 cm. Dengandiketahuinya titik potong optimal kadar serum RBP-4 sebagai penanda jaringanadiposa viseral, diharapkan dapat memprediksi risiko kejadian resistensi insulinyang bermanfaat dalam menentukan penatalaksanaan kasus SOPK dengan IMTnormal terkait strategi pengurangan akumulasi jaringan adiposa viseral. Tujuan: Diketahuinya titik potong optimal kadar serum RBP-4 sebagai penandajaringan adiposa viseral untuk memprediksi risiko kejadian resistensi insulin padapenderita SOPK dengan IMT normal. Metode: Studi observasional dengan desain potong lintang selama periode Juli2014 hingga Maret 2015 di Poliklinik Yasmin, RSCM, Jakarta. Hasil: Sejumlah 40 subjek SOPK dengan IMT normal yang memenuhi kriteriainklusi didapatkan 16 subjek (40%) yang mengalami resistensi insulin dan 24subjek (60%) nir resistensi insulin. Sejumlah 23 subjek (57.5%) memiliki lingkarpinggang kurang dari 80 cm, dimana 6 subjek (26%) diantaranya mengalami resistensi insulin. Kadar serum RBP-4 pada kelompok resistensi insulin bermakna lebih tinggi dibandingkan nir resistensi insulin (p 0.008). Dengan analisis ROCdidapatkan AUC kadar serum RBP-4 78.8% (IK 95% -8445.59 ? -1447.98)dengan nilai p 0.002. Titik potong optimal kadar serum RBP-4 adalah 24133ng/mL dengan sensitivitas sebesar 75% dan spesifisitas sebesar 75%. Dengananalisis regresi logistik biner didapatkan pemeriksaan serum RBP-4 menambahnilai diagnostik dari parameter demografis dan klinis AUC 85.7% menjadi 91.1%. Kesimpulan: Kadar serum RBP-4 sebagai penanda jaringan adiposa viseral dapat digunakan untuk memprediksi risiko kejadian resistensi insulin pada penderita SOPK dengan IMT normal. ABSTRACT Background: Polycystic ovarian syndrome (PCOS) contributes to fourty percent

of infertility?s issues on reproductive women. Insulin resistance as one of

important pathophysiology in PCOS, correlates with visceral adipose tissue and is

found on 30-50% PCOS patients with normal body mass index and waist

circumference less than 80 cm. Retinol Binding Protein-4 (RBP-4), which is

secreted by visceral adipose tissue, known as one of adipokines that cause insulin

resistance. The measurement of body mass index and waist circumference could

not represent visceral adiposity on PCOS with normal body mass index and waist

circumference less than 80 cm. Determination of serum RBP-4 cut off level as

visceral adipose tissue marker hopefully could predict the risk of insulin

resistance on polycystic ovarian syndrome with normal body mass index,

therefore it will be useful on its management related to reduction of visceral

adiposity.

Objective: To obtain serum RBP-4 cut off level as visceral adipose tissue marker

to predict the risk of insulin resistance on PCOS with normal body mass index.

Method: This was an observational study with cross sectional design conducted at

Yasmin Clinic, RSCM, Jakarta during a period of July 2014 until March 2015.

Result: Fourty PCOS patients with normal body mass index were participated on

this study. There were 16 subjects (40%) who were insulin resistance and 24

subjects (60%) who were not insulin resistance. There were 23 subjects (57.5%)

who had waist circumference less than 80 cm, where 6 of them (26%) were

insulim resistance. Serum RBP-4 level was significantly higher on insulin

resistance group (p 0.008). After ROC analysis was performed, AUC of serum

RBP-4 was 78.8% (CI 95% -8445.59 ? -1447.98, p 0.002). The cut off level of

serum RBP-4 was 24133 ng/mL with sensitivity 75% and specificity 75%. After

logistic regression analysis was performed, it was found that serum RBP-4 increase diagnostic value of demographic and clinical parameter with AUC 85.7% to 91.1%. ;Background: Polycystic ovarian syndrome (PCOS) contributes to fourty percent

of infertility?s issues on reproductive women. Insulin resistance as one of

important pathophysiology in PCOS, correlates with visceral adipose tissue and is

found on 30-50% PCOS patients with normal body mass index and waist

circumference less than 80 cm. Retinol Binding Protein-4 (RBP-4), which is

secreted by visceral adipose tissue, known as one of adipokines that cause insulin

resistance. The measurement of body mass index and waist circumference could

not represent visceral adiposity on PCOS with normal body mass index and waist

circumference less than 80 cm. Determination of serum RBP-4 cut off level as

visceral adipose tissue marker hopefully could predict the risk of insulin

resistance on polycystic ovarian syndrome with normal body mass index,

therefore it will be useful on its management related to reduction of visceral

adiposity.

Objective: To obtain serum RBP-4 cut off level as visceral adipose tissue marker

to predict the risk of insulin resistance on PCOS with normal body mass index.

Method: This was an observational study with cross sectional design conducted at

Yasmin Clinic, RSCM, Jakarta during a period of July 2014 until March 2015.

Result: Fourty PCOS patients with normal body mass index were participated on

this study. There were 16 subjects (40%) who were insulin resistance and 24

subjects (60%) who were not insulin resistance. There were 23 subjects (57.5%)

who had waist circumference less than 80 cm, where 6 of them (26%) were

insulim resistance. Serum RBP-4 level was significantly higher on insulin

resistance group (p 0.008). After ROC analysis was performed, AUC of serum

RBP-4 was 78.8% (CI 95% -8445.59 ? -1447.98, p 0.002). The cut off level of

serum RBP-4 was 24133 ng/mL with sensitivity 75% and specificity 75%. After

logistic regression analysis was performed, it was found that serum RBP-4 increase diagnostic value of demographic and clinical parameter with AUC 85.7% to 91.1%. "