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Abstrak :
Endometriosis adalah kelainan ginekologis yang dimanifestasikan dengan adanya kelenjar dan sel endometrium yang berkembang di luar uterus. Endometriosis merupakan penyakit multifaktorial dimana faktor genetik dan lingkungan berinteraksi menyebabkan timbulnya penyakit ini. Beberapa penelitian telah melaporkan bahwa endometriosis merupakan penyakit yang terkait dengan hormon estrogen. Mekanisme kerja estrogen ditentukan oleh kuantitas dan aktivitas reseptor estrogen. Namun demikian analisa variasi genetik, ekspresi dan aktivitas estrogen reseptor sampai saat ini belum banyak diketahui. Tujuan Penelitian ini adalah untuk menganalisa variasi genetik, ekspresi mRNA dan aktivasi ER pada jaringan endometriosis. Alel gen reseptor estrogen REα dan REβ dari 83 sampel penderita endometriosis dibandingkan dengan 76 kontrol menggunakan metoda PCR RFLP. Pengukuran ekspresi mRNA dari 18 jaringan penderita endometriosis dan 18 kontrol dilakukan dengan menggunakan metoda kuantitatif Real Time PCR (qRT-PCR). Pengukuran kadar estrogen serum (E2) dilakukan dengan metoda ELISA. Deteksi aktivasi ER dilakukan dengan uji fosforilasi reseptor estrogen β (serin 105) dengan metoda Western Blot. Hasil uji Chi-square ditemukan bahwa frekuensi alel A (normal) dan alel G (mutan) pada gen REα SNP rs9340799 dalam populasi berbeda bermakna (p=0,012) dan OR 1,772 dan kedua frekuensi alel dari hasil uji keseimbangan menurut Hardy-Weinberg berbeda bermakna (p = 0,003). Frekuensi alel (normal dan mutan) dalam populasi REα SNP rs2234693 tidak menunjukkan perbedaan bermakna dan seimbang dalam populasi. Frekuensi genotip pada SNP REβ rs4986938 pada endometriosis dibandingkan kontrol berbeda bermakna (p=0,015) dan OR 0,311 dengan populasi seimbang. Menurut keseimbangan Hardy-Weinberg dan frekuensi alel normal G dan alel mutan A juga berbeda bermakna (p=0,034) dan OR =0,438. Hasil pengukuran ekspresi mRNA menunjukkan terjadi peningkatan ekspresi ERβ 49,52 kali dibanding kontrol sedangkan REα tidak menunjukkan perbedaan dibandingkan kontrol. Kadar estradiol serum (E2) fase proliferasi tidak menunjukkan perbedaan bermakna dibanding kontrol. Hasil uji Spearman menunjukkan tidak ada korelasi kadar estradiol dengan ekspresi REα dan REβ (p>0,05). Fosforilasi ERβ pada Serin 105 menunjukkan penurunan pada kelompok endometriosis dibandingkan jaringan normal dengan perbandingan nilai intensitas pita yakni 0,1 pada endometriosis dan 4,2 pada kontrol. Sebagai kesimpulan, frekuensi alel A dan G gen REα berbeda bermakna pada SNP rs9340799 dan frekuensi alel di dalam populasi tidak seimbang. Distribusi genotip normal GG dan mutan AA serta frekuensi alel G dan alel A gen REβ berbeda bermakna pada SNP rs4986938. Ekspresi (mRNA) REβ lebih tinggi secara signifikans pada kelompok endometriosis dibandingkan kontrol. Ekspresi protein Fosforilasi ERβ pada Serin 105 menunjukkan penurunan pada endometriosis dibandingkan jaringan normal. ......Endometriosis is a gynecological disorder that is manifested by the presence of endometrium glands and cells that grow and develop outside the uterus. Endometriosis is a multifactorial with genetic and environmental factors interacting to cause this disease. Several studies have reported that endometriosis is a disease associated with the hormone estrogen. The mechanism of action of estrogen depends on the quantity and activity of estrogen receptors. However, genetic variation, expression and estrogen receptor activation in endometriois patients have not been fully characterized. The aim of this study was to analyze genetic variation, ER expression and determine ER activation in endometriosis patients. This study determined the alleles of the estrogen receptor gene REα and REβ from 83 blood samples from endometriosis patients compared with 76 controls using the RFLP PCR method. Quatitative Real time PCR was used to analyze mRNA expression of REβ genes from 18 tissues with endometriosis and 18 controls. Measurement of serum estrogen (E2) levels was carried out using the ELISA method. Furthermore, the phosphorylation test of estrogen receptor (serin 105) was carried out using the Western Immunobloting method. The results of the Chi-square test found that the frequencies of the A (normal) allele and G (mutant) allele in the REα SNP gene rs9340799 in the population were significantly different (p=0.012) and OR 1.772 and the two allele frequencies from the results of the balance test according to Hardy-Weinberg were significantly different. (p = 0.003). Allele frequencies (normal and mutant) in the REα SNP population of rs2234693 did not show significant and balanced differences in the population. The genotype frequency of SNP REβ rs4986938 in endometriosis compared to control was significantly different (p=0.015) and OR 0.311 with a balanced population. According to the Hardy-Weinberg balance, the frequencies of the normal G allele and the mutant A allele were also significantly different (p=0.034) and OR=0.438. Erβ expression showed 49,52 folds increase compared to control (p=0.00), whereas ERα did not show a significat different compared to control. There was no different in serum estradiol (E2) levels compared to controls. The results of the Spearman test showed that there was no correlation between serum estradiol levels and the expression of REβ and REβ (p>0.05). Phosphorylation Ser105 of ERβ showed a decrease in the endometriosis group compared to control with a comparison of values of 0.1 and 4 2. As a conclusion, The A and G allele frequencies of the RE gen gene were significantly different in SNP rs9340799 and the allele frequencies in the population were not balanced. The distribution of normal genotypes of GG and AA mutants and the frequency of G allele and A allele of REβ gene were significantly different at SNP rs4986938. REβ (mRNA) expression was significantly higher in the endometriosis group than the control group. Phosphorylated ERβ protein expression in Serin 105 showed a decrease in endometriosis compared to normal tissue.

Abstrak :
Endometriosis merupakan penyakit ginekologi umum yang dipicu terjadinya peradangan kronis yang ditandai dengan produksi beberapa sitokin pro-inflamasi, salah satu yang terbanyak yaitu TNF-α. Di sisi lain, sitokin anti-inflamasi, seperti IL-10, dapat mengakhiri proses inflamasi berlanjut ini. Propolis adalah bahan bioaktif alami produk lebah, sebagai imunomodulator dan efek anti-inflamasi yang dapat menekan proliferasi sel-sel patologis. Penelitian ini bertujuan untuk menentukan pengaruh pemberian propolis terhadap tumor necrosis factor alpha dan interleukin 10. Penelitian ini menggunakan desain uji klinis dengan alokasi acak dan double-blinded. 24 wanita dengan terapi Levonorgestrel (LNG) karena endometriosis secara acak ditugaskan untuk menerima propolis yang mengandung 17,5 mg flavonoid per tetes atau plasebo. Intervensi diberikan dua kali sehari, pada pagi dan malam hari, dengan dosis 1 tetes/10 kg berat badan (kgBB) per kali. Sampel darah dan penilaian gizi diambil pada kunjungan pertama dan 30 hari setelahnya. Hasil penelitian menunjukkan bahwa kadar tumor necrosis factor alpha dan interleukin 10 tidak memiliki perbedaan yang signifikan antara kedua kelompok (p>0,05). Kadar tumor necrosis factor alpha mengalami penurunan yang lebih besar pada kelompok propolis sebesar 4,17 (44,36-50,05) pg/mL dibandingkan dengan kelompok plasebo. Kadar IL-10 menunjukkan peningkatan sebesar 344,94 setelah 30 hari diberikan intervensi. Pemberian flavonoid dalam propolis tidak menghasilkan perubahan yang signifikan dalam kadar Tumor Necrosis Factor Αlpha dan Interleukin 10 selama periode intervensi 30 hari. ......Endometriosis is a common gynecological disease triggered by chronic inflammation characterized by the production of several pro-inflammatory cytokines, one of which is TNF-α. On the other hand, anti-inflammatory cytokines, such as IL-10, can end this ongoing inflammatory process. Propolis are natural bioactive ingredients contained in bee products, as immunomodulators and anti-inflammatory effects that can suppress the proliferation of pathological cells. This study aimed to determine the effect of propolis supplementation on tumor necrosis factor alpha and interleukin 10. This study used clinical trial design with random allocation and double- blinded. 24 women with Levonorgestrel (LNG) therapy due to endometriosis were randomly assigned to receive propolis-contained 17.5 mg of flavonoids per drop or placebo. The intervention given two times a day,in the morning and at night, with a dose of 1 drop /10 kg body weight (kgBW) per time. Blood samples and nutritional assessment were taken at the first time of visit and 30 days thereafter. The results showed that the levels of tumor necrosis factor alpha and interleukin 10 did not differ significantly between the two groups (p>0.05). Tumor necrosis factor alpha levels experienced a greater decrease in the propolis group by 4.17 (44.36-50.05) pg/mL compared to the placebo group. IL-10 levels showed an increase of 344.94 after 30 days of intervention. The administration of propolis supplementation did not result in significant changes in the levels of Tumor Necrosis Factor Αlpha and Interleukin 10 during the 30- day intervention period.