JOURNAL READING JARINGAN KOMPLEKS DARI BEBERAPA FAKTOR DALAM PATOGENESIS LEIOMIOMA UTERI

KEPANITERAAN KLINIK ILMU KEBIDANAN DAN KANDUNGAN

FAKULTAS KEDOKTERAN UKRIDA RUMAH SAKIT UMUM DAERAH TARAKAN

Nama Mahasiswa NIM Nama Pembimbing

: Mohd Asrul B. Che Rahim : 112012059 : Dr Harianto Wijaya, Sp.OG

Jaringan yang Kompleks dari beberapa faktor dalam Patogenesis Leiomioma Uteri Pendahuluan Leiomioma uteri(fibroids atau myomas) adalah satu-satunya tumor jinak uterus yang paling sering diindikasikan untuk di operasi hysterectomy. Leiomioma uteri secara klinikal timbul

pada 25% dari wanita dalam umur reproduktif dan menyebabkan morbiti seperti perdarahaan berat atau memanjang pada menstruasi,nyeri pada pelvic dan disfungsi reproduksi. Tatalaksana yang definitif untuk tumor fibroid adalah operasi, dan beberapa teknik invasif yang minimal. Estrogen dan Progesteron merupakan promoter pertumbuhan fibroid. Namun growth factor, cytokines dan chemokines juga diduga effektor yang potensial terhadap estrogen dan progestron. Tambahan pula perubahan genetik,mekanisme epigenetic dan komponen matriks extraselular diduga penting dalam inisiasi dan perumbuhan tumor ini.

Tumor uterus fibroid dan prevelensi ras. Prevelensi leimioma uteri adalah 3 kali lipat pada wanita berkulit hitam dari wanita berkulit putih.Faktor lain seperti menarche yang awal,umur(usia reproduktif yang

telat),keturunan,nulliparitas,obesitas,sindrom polikistik ovari,diabetis,hipertensi dan konsumsi alkohol mempunyai faktor meningkatkan risiko berkembangnya leiomioma uteri. Faktor genetik Leiomioma uteri adalah tumor yang indipenden dan monoclonal;pertumbuhan tumor berasal dari 1 sel miometrial yang mutasi. Defek keturunan dari gene fumarate hydratase (FH),Birt-HoggDube (BHD) dan tuberous sclerosis complex 2 akan mengkontribusi terhadap perkembangan tumor ini.Penelitian menunjukkan perbedaan pada perubahan genetik pada leimioma seperti delesi kromosom trisomy, translokasi kromosom dan monosomi kromosom Tambahan El Gharib et al .

menemukan kelainan kromosom klonal pada lima kromosom telah mengidentifikasi tiga loci pada

berbeda (2,7,8,12 dan 22) . Baru-baru ini Cha et al

kromosom 10q24.33,22q13.1, dan 11p15.5 yang berasosiasi dengan kerentanan terhadap uterine fibroid. Dengan konsistensi alterasi genetik kromosom dengan tempat yang tertentu,beberapa kandidat gene telah diidentifikasi HMGA2 sering diekspresi pada leiomioma uteri, dengan penyusunan kembali kromosom 12q15 ,yang mana target gene nya let -7 famili (microRNAs) . Tambahan pula RAD1L1, . Baru-baru ini ekspresi

(miRNAs) dan ditemukan disupresi oleh let-7 secara in-vitro adalah kandidat pasangan translokasi HMGA2 pada leiomioma

mRNA HMGA1 lebih tinggi telah diobservasi berbanding dengan tumor normal secara sitogenetik dengan alterasi 6p21 . Beberapa gene kandidat, seperti PCOLCE,ORC5L dan

LHFPL3,telah dipetakan pada interval kritikal pada kromosom 7q22

. Baru baru ini

penjelasan secara komprehensif terhadap alterasi genetik (mutasi MED12) pada leiomioma uteri telah dilaporkan oleh berbeda-beda kumpulan 45,46,47,48,49,50. Mediator Complex subunit 12 (MED12) adalah komponen mediator kompleks yang mempunyai peran regulator pada aktiviti RNA polimerase II. MED12 mempunyai prean pada aktivasi transkripsi dab represi dan terlibat pada banyak proses pekembangan. Makinen dan teman-teman menemukan bahwa gene MED12 telah bermutasi pada frekuensi tinggi (70%) pada leiomioma uteri didapat pada pasien yang berasal dari Finland (Caucasian). Semua mutasi ini berkluster pada exon 2, dengan lapan mutasi yang men codon 44. Pola yang sama mutasi MED12 exon 2 juga ditemukan pada pasien berasal dari Afrika Selatan. Baru-baru ini Je et al. menemukan studi tentang MED 12 pada 1862 sampel termasuk

leiomioma,pelbagai carcinoma leukemia sarkoma dan tumor stromal lain-lain,yang mana ditemukan kadar frekuensi tinggi MED 12 tetapi hanya 1 pada tumor maligna. Temuan ini dan temuan sebelumnya menyarankan bahwa mutasi MED12 exon 2 mungkin tisu

spesifik terhadap leiomioma uteri.Namun baru-baru ini studi lain merekomendasi kan bahwa mutasi ini tidak hanya pada tumor jinak, pengkaji menemukan bahwa 11% tumor otot yang bepotensi maligna dan 20% leiomiosarkoma uteri ada mutasi MED12. Markawski et al .

. Mendemonstasikan bahwa mutasi MED 12 pada leiomioma uteri

kebanyakan diasosiasikan dengan karyotipe normal tumor. Kumpulan ini juga menemukan bahwa tumor dengan mutasi MED12 mengekspresikan mRNA WNT 4 pada kadar lebih tinggi,menunjukkan bahwa mutasi MED 12 mungkin terlibat dengan aktivasi jalur Wnt. Namun hasil imunohistokimia menunjukkan bahwa tidak ada asosiasi antara status MED 12 dan B-catenin nuclear/ lokalisasi sitoplasmik

Faktor epigenetik Epigenetik adalah semua perubahan diturunkan dalam ekpresi gen yang tidak dikodekan dalam urutan DNA DNA Methylation Deoxyribonucleci acid methylation berlaku pada karbon ke -5 cytosine,Metilasi ini berlaku dipelbagai proses perkembangan dengan menghilangkan,mengalih dan menstabilkan

gen.Ketidakseimbangan ekspresi DNA Metil transferase dijumpai pada leimioma uteri berbanding di miometrium yang sehat.

Modifikasi histone Modifikasi histone adalah faktor epigenetik kedua terpenting dalam peran meregulasi ekspresi gene. Protein histone bisa dimodifikasi dalam pelbagai cara pada N terminal,termasuk asetilasi,fosforilasi metilasi,deaminasi isomerisasi proline dan adenosinosine difosfat ribosilasi. Histone deasetilasi 6(HDAC6) adalah faktor regulator dalam jaringan pengangkutan endokrin dan mempunyai aktiviti deasetilasi histone. Menurut penelitian Wei et al. menguji

ekspresi HDCA6 dan peran patologi nya terhadap leiomioma uteri. Mereka menemukan pola peningkatan HDAC6 dan ekspresi ER- dalam sampel leiomioma. Dapat dikenalpasti bahawa modifikasi epigenetik diperlukan semasa perkembangan dan memainkan peran penting dalam diferensiasi selular dan tissue normal perkembangan menjadi dewasa. Namun sewaktu stadium penting dalam perkembangan,eksposur lingkungan boleh merubah keadaan genom yang terkait dengan program deferensiasi sel atau organ,dengan itu

mengalakkan kerentanan terhadap penyakit ini diwaktu kemudian kehidupan. Penelitian melaporkan melalui efek nongenomik terhadap program ulang pembentukan uterus,estrogen dari linkungan merekrut regulator epigenetik EZH2 dan mengurangkan kadar histone represif dalam kromatin dan mempromosikan tumorigenesis di uteri. Micro RNA Micro RNA adalah non protein coding yang meregulasi banyak proses biologi dengan merencanakan miRNA untuk pembelahan atau represi translasi . Penelitian menunjukkan

beberapa mRNA termasuk let7,miR-21,miR-93,miR 106b dan miR 200 dan target gene mereka secara signifikan di disregulasi pada leiomioma uteri berbanding miometrium normal. Pan et al. melaporkan bahawa miR-21 di ekspresikan berlebihan pada leiomioma, dengan peningkatan spesifik waktu fase sekretorik pada siklus menstruasi pada wanita yang menggunakan kontrasepsi oral. Zavadil et al meneliti korelasi pola global antara ekspresi miRNA yang diubah dengan predicted target genes pada leiomioma uteri dan miometria. Mereka menemukan jumlah miRNA didisregulasi secara korelasi terbalik dengan targetnya pada tingkat protein. Pola asosiasi terbalik miRNA dengan ekspresi pelbagai kandidat mRNA pada leiomioma uteri menunjukkan penglibatan

jalur,termasuk jalur extensive transcriptional

reprogramming,cell

proliferation control,mitogen activated protein kinase MAPK transforming growth factor (TGF),WNT, Janus Kinase/signal trasnduser dan activator of transcription signalling, remodelling perlekatan sel dan sel-sel dan sel-matrix contacts. Estrogen Estrogen mengeluarkan efek fisiologis terhadap target sel nya dengan mengikat ke Estrogen receptor (ER-)dan Estrogen receptor (ER-). Estrogen dan reseptornya memainkan peran

penting dalam fisiologi miometrium dan pertumbuhan leiomioma uteri. Beberapa kumpulan peneliti menemukan mRNA dan protein expression level of ER ( diekspresi lebih tinggi) dan ER- adalah lebih tinggi pada leiomima uteri berbanding miometrium normal. Penelitian terbaru menunjukkan estrogen boleh mempertahankan kadar Progestron receptor (PR) dan dengan demikian progestron melalui reseptornya dapat menggalakkan pertumbuhan leiomioma.

Estrogen secara signifikan mengurangkan ekspresi p53 ( protein supresor tumor). Estrogen dapat meransang proliferasi sel leiomioma dengan meregulasi ekspresi faktor pertumbuhan dan dengan mengaktivasi jalur sinyal. Estrogen juga mencetuskan pengaktifan cepat dan sementara jalur MAPK pada sel leiomioma. Estrogen juga menghasilkan fosforilasi protein tyrosine pada protein intraselular

Progesterone Progesteron bekerja dengan berinteraksi dengan reseptor progesterone dan reseptor reseptor (PR) Progesterene dan reseptornya memainkan peran dalam proses biologi leiomyoma dan miometrium. Penelitian menunjukkan kadar progesterone dan mRNA pada leiomioma lebih tinggi dari miometrium. Fujimoto et al. menemukan ekspresi mRNA PR relatif lebih pada permukaan leiomyoma.Ini menunjukkan ekspresi predominan PR-B pada bagian ini adalah fenotip aktif untuk proliferasi progestasi yang berkaitan dengan pertumbuhan leiomioma. Progesterone dapat menstimulasi pertumbuhan sel leiomioma dan ketahanan hidup sel dengan meningkatkan regulasi sel limfoma B ekspresi (Bcl)-2 protein dan menurunkan regulasi ekspresi tumor necrosis factor (TNF)

Growth factors Growth factor adalah protein atau peptida yang diproduksi oleh sel otot polos dan fibroblas yang turut berperan dalam beberapa aktivitas selelur seperti proliferasi, sintesis ECM dan angiogenesis yang penting untuk pertumbuhan leiomioma. Beberapa growth factors seperti EGF,Heparin binding EGF,PDGF,IGF, TGF- ,TGF- vascular endothelial growth factor (VEGF) , acidic firbroblast growth factor(FGF) dan reseptor masing-masing growth factors,dilaporkan memainkan peran dalam pertumbuhan leiomioma. Activin dan miostatin adalah protein yang diindentifikasi pada leiomioma dan miometrium. Sitokin Sitokin adalah protein yang dilepaskan oleh sel sistem imun . Sitokin menghantar sinyal intraselular dengan mengikat specific cell-surface receptor 151,152. Beberapa interleukin (IL) telah diidentifikasi dalam patofisiologi miometrium. Termasuk IL1,IL-, IL 11, dan IL 13,kerna ekspresi berlebihan sitokin berikut bertindak sebagai kunci regulator kepada subepithelial airway fibrosis. Terutama melalui interaksi dengan TGF-

156,157,158,159. Ekspresi sitokin tersebut lebih pada leiomioma berbanding miometrium. ILs menambah ekspresi TNF- yang ditemukan pada leiomioma relatif pada miometrium normal dan diturunkan regulasi oleh progesteron. Chemokines Chemokines adalah protein yang di ekspresi kan oleh hampir semua sel yang bernukleas. Chemokines adalah mediator angiogenesis,hematopoiesis dan fibrosis. Monocyte

chemoattractant protein 1 memainkan peran dalam respon inflamasi monosit dan makrofag.

Sozen et al. menemukan chemokine lebih tinggi pada miometrium berbanding leiomioma. Apabila sel leiomioma diterapi dengan anti-MCP-1 neutralizing antibody,didapati berlaku proliferasi.Tambahan lagi pada sel leiomioma E2 dan progestin sendiri dan pada kombinasi mengurangkan kadar MCP-1. Hasil ini menunjukkan MCP-1 mempunyai sifat antineoplastik pada leiomioma. IL-8 dan reseptor IL-8 tipe A telah diidentifikasi dengan peningkatan ekspresi pada miometrium berbanding leiomioma dan inhibisi proliferasi sel diobservasi apabila IL-8 diblok oleh antibodi neutral,ini menunjukkan potensi peran IL-8 dalam pertumbuhan tisu miometrium. Tambahan pula beberapa chemokines dan reseptor chemokines termasuk macrophage inflammatory protein (MIP)-1, MIP-1, RANTES, eotaxin, eotaxin-2, IL-8, chemokine (cc-motif) receptor 1 (CCR1), CCR3, CCR5, chemokine (cxc-motif) receptor 1 (CXCR1), and CXCR2 mRNA, telah diidentifikasi pada miometrium dan tisu leiomioma,lebih rendah daripada miometrium. Komponen ECM Leiomioma uteri dikarakterisasi oleh kuantiti dan kualitas abnomaliti pada komponen ECM, terutama kolagen, fibronectin, and proteoglycans. Leiomioma mengandungi 50% lebih daripada miometrium bersamaan dan berfungsi sebagai reservoir untuk growth factors,sitokin chemokines angiogenic dan mediator respon inflamasi dan proteases yang diproduksi oleh sel tumor. Kolagen adalah komponen major pada ECM yang berkontribusi kepada stabilisasi dan mempertahankan integriti struktur tisu. Namun struktur dan orientasi fibrin kolagen yang

abnormal ditemukan pada leiomioma. Disamping itu ekpresi relatif berlebihan pada mRNA kolagen tipe I dan III pada leiomioma berbanding miometrium disebelahnya. Tambahan pula peningkatan ekspresi kolagen tipe I dan V pada tingkat protein ditemukan pada leiomioma

berbanding miometrium yang normal.

Malik et al. menguji beberapa seri kolagen subtipe

COL1A1, 4A2, 6A1, 6A2, 7A1, dan 16A1 diekspresikan lebih banyak pada leiomioma berbanding pada miometrium. Leiomioma uteri pada manusia yang berasal dari fibroblas dapat menstimulisasi proliferasi sel leiomioma uteri dengan peningkatan produksi kolagen tipe type I, IGFBP-3, VEGF, EGF, bFGF, PDGF-A and B, TGF-1, and TGF-3 dan dapat juga mengaktifkan reseptor tyrosine kinase dan reseptor sinyal TGF-. Penemuan ini menunjukkan bahawa pertumbuhan leiomioma dapat dimediasi oleh mekanisme autokrin atau parakrin. Tumor yang berasal dari fibroblas dan atau sel leiomioma uteri dapat menggalakkan sintesis growth factors dan mengaktif kan jalur sinyalnya yang penting dalam menstimulasi proliferasi sel tumor dan produksi komponen ECM. Penelitian menunjukkan perubahan pada ECM dapat memodifikasi stress mekanikel pada sel yang menyebabkan aktivasi internal mechanical signaling dan menyumbang pada pertumbuhan leiomioma. Telah dilaporkan sel leiomioma yang terpajan pada beban mekanikal dan menunjukkan fitur struktural dan biokimia yang konsisten dengan aktivasi solid state signalling.Walaupun fitur leiomioma meningkatkan stress mekanikal sel leiomioma menunjukkan respons melemah pada isyarat mekanikal berbanding pada sel miometrium. Berdasarkan persoalan ini, Malik et al. mengkarakterisasi integrin dan laminin kepada sinyal pada sel leimioma.Hasil eksperimen mereka menunjukkan hasil bahwa sinyal mekanikal yang dilemahkan pada sel leiomioma diikuti oleh peningkatan ekspresi dan ketergantungan pada sinyal integrin 1 pada sel leiomioma berbanding daripada sel miometrium. Dermatopontin, protein ekstraselular yang mengikat kepada molekul kecil demantan sulfate dan decorin, diekspresikan pada leiomioma,namum kadar ekspresi berkurang pada leiomioma berbanding daripada miometrium.Mengingat Leiomioma dan keloid adalah penyakit fibrotik dan berkongsi kesamaan epidemiologik, kaitan molekular telah dibina antara kedua kondisi

patologik dengan melihat berkurangnya ekspresi dermatopontin (kolagen pengikat protein) dan struktur fibril kolagen. Disamping itu beberapa analisa mikroarray menunjukkan penurunan regulasi dermtopontin pada leiomioma berbanding dengan miometrium. Proteoglikan adalah protein glikosilasi yang terikat secara kovalen pada glikoaminoglikan sulfat dan bagian penting kepada struktur leiomioma. David et al. menemukan kadar glikoaminglikan dan versican ( proteoglikan ECM besar) yang tinggi pada fibroid uteri,namun kadar dekorin yang relatif rendah pada fibroid uteri dan keloid berbanding tisu normal. Penemuan ini konsisten dengan penemuan sebelumnya yang berkaitan dengan ikatan molekular antara kedua jenis penyakit fibrotik ini. Tambahan pula beberapa penelitian menunjukkan kadar ekspresi versican adalah lebih tinggi pada leiomioma berbanding daripada miometrium. Pelbagai ekspreis

glikosaminoglikan dan proteoglikan juga ditemukan pada leiomioma dan miometrium. Fibronectin adalah glikoprotein ECM yang mengikat kolagen kepada integrin.Terdapat Kadar ekspresi mRNA fibronectin pada pelbagai patofisiologi miometrium. Stewart et al. menemukan tidak ada perbedaan yang signifikan atara leiomioma dan miometrium pada apa pun tahap pada siklus menstruasi.Namun Arici and Sozen menemukan peningkatan kadar ekspresi fibronectin pada leiomioma berbanding daripada autologous miometrium. Menariknya, kumpulan ini turut melaporkan bahwa TGF-3 menginduksi ekspresi fibronectin pada leiomioma dan secara lansung menstimulasi sel miometrium dan leiomioma pada kultur berpoliferasi. Tissue remodelling yang melibatkan ECM turnover memainkan peran penting pada regresi leiomioma,dimana diregulasi oleh kombinasi aksi oleh matriks

pertumbuhan dan

metalloproteinase (MMP) (protein yang memecahkan ECM) dan tissue inhibitor of MMPs (TIMPs). Khususnya beberapa bentuk dari mRNA MMPs dan TIMPs dan protein telah

ditemukan diekspresikan secara berbeda pada miometrium dan leiomioma. Baru-baru ini analisis mikroarray menunjukkan perubahan pada array secara meluas pada MMP pada tisu leiomioma. Sel Kandidat untuk perkembangan dan pertumbuhan fibroid Dengan mempertimbangkan bahwa fibroid uteri adalah sangat lazim dan mempengaruhi wanita pada usia reproduksi (adanya siklus menstruasi) menambahkan lagi kepercayaan bahwa cedera yang berhubungan dengan dengan mens dapat menyebabkan respon inflasmasi yang tidak benar, ini membawa kepada pembentukan fibroid uteri. Kontraksi miometrium pada akhir

perdarahan menstruasi dapat menginduksi cedera iskemi atau cedera iskemi-reperfusi pada otot polos miometrium yang mungkin menjadi kandidat untuk sel progenitor dari fibroid uteri. Untuk mendukung hipotesis ini, sel apoptotik positif , sel positif p53 dan sel positif 21 telah ditemukan hanya pada fase folikuler pada siklus menstruasi. Namum sel positif Ki-67 yang dilihat terutama pada fase luteal siklus menstruasi. Hasil ini memberi kesan bahwa majoriti dari sel yang rusak kelihatan dieliminasi pada fase folikuler siklus menstruasi, dieliminasi sebagai sel apoptotik , tetapi beberapa sel yang rusak bisa bertahan hidup dengan menerima mekanisme pertahanan terhadap stress oxidatif dan apoptosis. Sel ini mungkin adalah progenitor kepada fibroid uteri. Bahkan sel leiomioma uteri menpunyai mekanisme proteksi terhadap stress mekanisme yang mengekspresi manganase superoxide dismutase (MnSOD) dan terhadap apoptosi Bcl-2, PEP-19(protein sel Purkinje 4 PCP4) dan secreted frizzled related protein1 (sFRP1) Telah dipersetujui bahwa menstruasi ovulasi dan parturitas menyebabkan kecederaan fisiologi yang mencetuskan reaksi inflamasi pada uterus. Sel Miofibroblas diaktifkan oleh inflamasi dan transformasi selular inilah yang menjadi peristiwa penting untuk pemulihan homeostasis tisu dan

proses

penyembuhan

luka.

Miofibroblas

dikarekterisasi

oleh

pertambahan

proliferasi,kebolehan bermigrasi, produksi sitokin dan kapasitas untuk menghasilkan matriks interstitial. Namun fungsi miofiblas yang tidak tepat telah ditunjukkan dapat menyebabkan fibrosis,oleh kerana memiliki sifat ketidakmampuan regenerasi tisu,selalu menghasilkan kolagen kolagen dan parut kaku.. Transformasi miofibroblas dapat berlaku dari sel berbeda tipe,kerna miometrium mengandungi sel otot polos , jaringan ikat fibroblas,stem sel,sel vascular dan progenitor sel berasal dari sumsum tulang. Baru- baru ini penelitian mengenai stem sel telah membuka kemungkinan baru untuk memahami pertumbuhan uterine fibroid. Kesimpulan dan perspektif masa hadapan. Uterine fibroid umumnya berhubungan dengan perdarahan menstruasi yang memanjang, berat dan nyeri pelvis. Namun tumor ini juga mempunyai efek negatif terhadap fertilitas dan hasil kehamilan untuk pasien yang ingin mengikuti assisted reproductive technology (ART). Namun literatur berkaitan dengan leiomioma uteri dan kesan nya kepada ART adalah membingungkan. Tambahan pula prevelensi tinggi leiomioma uteri dan pengaruh potensinya yang merugikan terhadap ART dan fungsi reproduksi. Ini menjamin penelitian yang dirancang teliti diteruskan untuk memastikan etiologi,terapi optimal dan terapi baru yang kurang morbiditasnya. Perbedaan ras dan faktor risiko lain,faktor genetik,mekanisme epigenetik, estrogen, progesteron, growth factors,sitokin,chemokines. Dan komponen ECM telah dikenalpasti memberi kesan kepada biologi miometium dan leiomioma. Beberapa dari faktor tersebut boleh dipertimbangkan untuk membina strategi terapi untuk menghalang transformasi miometium dan/ atau

pertumbuhan miometrium. Sehingga sekarang terapi yang mungkin telah diuji secara klinikal dan beberapa masih sedang dikaji pada biologi leiomioma.

Untuk menimbang perubahan genetik pada leiomioma berbanding miometrium,terapi gene dapat menjanjikan target untuk menghentikan pembentukan leiomioma.Laporan telah menunjukkan terapi dengan adenovirus mediated herpes simplex virus thymidine

kinase/ganciclovir menginhibisi proliferasi petumbuhan leiomioma pada manusia dan tikus dan mengurangkan volume fibroid uteri pada model tikus Eker. Tambahan pula, Ad- mediated delivery of a DNER (dominant negative E receptor) gene juga mengecilkan tumor leiomioma uteri pada tikus Eker. Selain faktor genetik,pemahaman tentang status metilasi DNA dan modifikasi histone pada patogenesis leiomioma uteri adalah kritikal dalam mengembangkan terapi epigenetik yang akan memulihkan modifikasi reguler pola epigenetik dengan menginhibisi enzim epigenetik modifier ( DNA methltransferases, demethylases, and histone deacetylases). Dengan munculnya miRNA sebagai kunci regulator kepada kestabilan ekspesi gene,ini akan lebih menarik untuk diselidiki tentang potensi peran regulasi miRNAs terhadap target gene terpilih.yang dimana produknya dapat mempengaruhi pertumbuhan leiomioma. Dengan mempertimbangkan peran paling penting hormon seks steroid pada pertumbuhan leiomioma, GnRH agonis telah diluluskan oleh US Food and Drug Administration kerana mengurangkan volume fibroid dan simptom yang terkait. US Food and Drug Administration juga telah meluluskan alat intrauterine levenorgestrel-releasing intrauterine system (Mirena) (Bayer Schering Pharma, Germany) sebagai tambahan untuk merawat perdarahan berat pada pengguna alat sahaja.Tambahan lagi beberapa terapi yang mungkin terutama antiprogestin (mifepristone) dan selective Progesterone receptor modulators (asoprisnil, CDB-2914, and CDB4124) telah menunjukkan hasil teraputik yang efesien dan sekarang diuji klinis (www.fda.gov).

Karena sistesis estrogen aromatase dan diekspresi berlebihan pada leiomioma berbanding miometrium pada African American relatif kepada Caucasian American dan wanita jepang beberapa aromatase inhibitors (letrozole, anastrozole, and fadrozole)telah diuji terhadap leiomioma. Sehingga sekarang, trial klinik (fase 1) terhadap letrozole telah ditarik. Namun trial klinikal fase III terhadap anastrozole telah direkrut. Namun beberapa terapi medikal (GnRH antagonists, raloxifene, cabergoline, danazol gestrinone, and lanreotide) telah gagal dalam mencapai efektifitasnya terhadap regresi fiboid dan simptom yang berkatian dengan firboid. Terbukti bahwa growth factor, sitokin dan kemokin dipertimbangkan sebagai efektor potensial estrogen dan progesteron terhadap pertumbuhan leiomioma. Growth factor, sitokin dan kemokin mengawal beberapa proses biologi seperti proliferasi sel,remodelling ECM,angiogenesis dan apoptosis,yang mana merupakan penting dalam pertumbuhan leiomioma. Oleh itu adalah jelas bahwa growth factor, sitokin dan kemokin boleh dipetimbangkan sebagai target major dalam mengawal pertumbuhan leiomioma, Karena EGF telah ditunjukkan dapat memediasi kerja estrogen dan memainkan peran dalam meregulasi pertumbuhan leiomioma. AG1478 dan TKS050 (EGFR blocker) telah ditunjukkan efektif dalam memhentikan pertumbuhan sel leiomioma.TGF-B juga mempunyai peran kritikal terhadap pertumbuhan sel leiomioma. Bukti dari model hewan coba yang rentan secaa genetik juga menunjukkan bahwa Sinyal TGF-B adalah kritikal untuk mempertahankan penyakit ini. Oleh kerna itu telah ditemukan bahwan inhibitor selektif terhadap TGF-RI menurunkan jumlah insidens dan saiz dari tumor ini. Dengan mempertimbangkan bahwa leiomioma dikarekterisasi oleh pertambahan proliferasi sel dan tisu fibrosi, antiproliferasi dan atau agen anti fibrotik boleh menjadi target untuk terapi

leiomioma. Awalnya beberapa campuran

termasuk pirfenidone (235), CP8947 (236),

rosiglitazone (237), ciglitizone (238), halofuginone (239), tranilast semua-trans retinoic acid 242, 243, heparin (244), isoliquiritigenin (245), curcumin 246, 247 dan vitamin D 248, 249, 250,telah menunjukkan efek antiproliferatif dan efek antifibrotik terhadap sel leiomioma. Dari semua ini trial klinik fase 2 terhadap perfenidone telah selesai. Vitamin D menunjukkan hasil yang baik terhadap efektifitas terapi. Vitamin D menginhibisi proliferasi sel leiomioma melalui supresi terhadap COMT. Polimorfisme COMT dan asosiasinya terhadap uterine fibroid adalah lebih tinggi pada African American berbanding wanita berkulit putih atau wanita hispanik Tambah3an lagi defisiensi vitamin D adalah lebih banyak pada African American berbanding European American. Vitamin D juga mengurangkan ekspresi gene TGF3 induced fibrosis related pada sel leiomioma. Tambahan lagi vitamin D mengecilkan saiz tumor pada model tikus Eker. Epigallocatechin gallate yang ditemukan pada teh hijau (Camellia sinensis),secara invitro menunjukkan berlaku apoptosis dan efek inhibisi terhadap proliferasi sel leiomioma.

Eksperimen in vivo menunjukkan bahwa epigallocatechin gallate mengurangkan volume dan berat tumor pada tikus percobaan. Trial klinik rehadap epigallocatechin gallate juga telah selesai. Masih didalam investigasi bahwa leiomioma adalah hasil daripada respon inflamasi yang tidak benar,oleh itu anti-inflamasi (alami atau sintetik) adalah agen efektif untuk tumor jinak ini.

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