BUI DYC HIEN ANDROGEN VA VAI TRO CUA ANDROGEN DOI VI$I B§NH LY SUY SINH DQC B NAM GIOI HA NQI - 2010 LCf I CAM CiN Nlian dip hoan thanh khé›a luan nay, toi dupc to long biét on chan thanh vé sin sac tcii TItS. Dtro’ng TltJ Ly Hirong, nguéi thay da tan tinh lur6ng dan, chi bao tot trong qua trinh thuc hi(n, bo sung dong gé›p y kién clio toi hoan thien khoa 1ua(n nay. Co da day cho tfii phuong phap nghién cfni khoa hpc hieu qua va hon lhé niia la tinh than lam viec hét minh vi khoa hpc. TO Kin dupc bay to !ong biét on cac thay co gi:to trong bo mon Dupc ldc, truéng Dat hpc Duoc Ha Noi.
Cac thay co da tan tinh chi bao vé tao diéu kién cho tot trong théi gran hpc tap va tain khfia luan. Tfi i xin duoc bay to long b1€‘t on tcii céc thay co giao triréng Dat hpc Dupc Ha Noi. Cac thay co da truyén dat, trang bi cho tot nhiing kién thiic gut bau trong suot thol gian to dirpc hpc tap diréi mai truén g nay. Tfii xin dircic bay to long biét on sau sac nhat tcii cha me v:i gia dinh, nhiing ngiicn da J'éii thuong, nuoi nang, day bao va lufin bén Koi trong bat cu hoan canh nao.
Cuoi ciing toi xin chan thanh cain on su giup dé eua cac ban trong nhom nghien ctf u ciing nhir su dong vién chia sé ciia tat ca ban bé. Xin kinh chuc cac thay co, gia dinh va toan the c:ic ban sfic khoe va hanh phuc. H:i Noi, ngiiy 18 th:ing 5 nam 2010 Sinh vién But Duc Hién CHU GIAI CHP VIET TAT SSD Suy sinh due AR Androgen receptor ER Estrogen receptor sHBG Sex hormon binding globul in (globulin lien két voi hormon gici tinh) PDE5 Phosphodiesterase typ 5 DHT Di hydrotestosteron DHEA Dehydroepiandrosteron LH Luteinizing hormon FSH Follicle stimulating hormon GnRH Gonadotropin releasing hormon hCG Human chorionic gonadotropin NOS : N it‹ oxit synthase TAD Transactivation domain (viing diéu tiét sao chép) DBD. DNA-binding domain (viing lién két vcii DNA) I .RD Ligand-binding domain (vfing lién két vcii chat gan) DANH MUC CAC BANG STT Téii bring Trang 2.1 C:ic nguyén nhan c‹ b:in cua suy sinh duc nam 14 2.2 Cac test hormon dfing de chan dean suy sinh duc nam 20 Mot so thuoc testosteron thu rig dung trong diéu tri roi loan 3.1 40 ciiong duong DANH MUC CAC HINH STT Tén hinh Trang I.1 C:ie giai doan chuyén hoa tong hpp testosteron tai tinh hoiin 3 I .2 Cac androgen tu nhién a 1.3 Mot vat androgen dupc dung 4 1.4 So do chuJ én hoa cua androgen 6 J Tiic dung cua androgen thong qua cac receptor androgen va estrogen I .6 So dfi die“ u hoa chuyén hoa androgen Do thi biéu diéu nong do testosteron trong huyét thanh tu 1.7 bao thai den khi can tuoi 2.
1 Mau so s:inh kich thucic tinh hoan Prader 19 ph:ip ch:in doan suy sinh due nam 24 So do giii dinh cc ché diéu chinh biet hfia té bao ciia 36 androgen trong the hang 2.5 Se do qu:i trinh san sinh tinh triing 43 2.6 T:ic Kong cua androgen lén qua trinh sin xuat tinh triing 44 2.7 Can truc gen ciia androgen receptor 45 Can tr c gen cila AR va mot bién bat thiréirlg co ia , 46 lien quan dén vo sinh nam DA/ T VAN DE Khi xa hoi ngay cang phat trién thi d‹ii song tinh than cua con nguéi ngay cang dirpc quan tain chain soc. Trong do tinh duc la mot nhu cau tinh than chinh déng, da va dang dupc quan tain den mot cach da)c bi(t. Quan h( tinh dpc khfing chi dimg lai o muc dich duy tri nfii giong ma con dé›ng vai tro quan trpng trong doi song tinh than ciia ciic ca)p vp chong. Nhung ciing tain vcri st phiit trién ciia xa ho) i, con nguoi ugly céng phai doi mat véi cu6ng do viec cang thang dan t6i stress, m(t moi; tiép xiic nhiéu voi ciic hoa chat doc hai tir thqc pham va moi truéng.
da khién so nguoi mac ciic b(nh man tinh va nan y ngay cang gia tang, trong do co b(nh trén chuc niing tinh duc. Suy sinh duc nam la benh ly cé› the xuat hi(n ci bat giai doan phiit trién nao cua con ngucii, tit théi ky bao thai cho dén khi chét. B(nh gay ra nhiing rot loan chuc nang, tha)m chi lam mat hoan toan kha nang trong hoat dong tinh duc va kha néng sinh sén ciia nam gioi. Hi(n nay suy sinh due nam la b(nh ly ducic quan tain bac nhat trong b(nh hpc tinh duc nam.
Nhfmg tién bo cua khoa hpc ky thuat da giup y hpc hiéu diing hon ve nguyén nhan ciing nhu co the dna ra c:ie phirong phap chan doén va diéu tri hi(u qua hon. Androgen la hormon quan trpng nhat cua sinh dpc va sinh situ nam gioi, thiéu hut androgen ciing la tiéu chuan véng de chan doén suy sinh due nam. M(ac dii vay, hi(n nay van dé sir dung androgen trong diéu tri. suy sinh duc nam van chua co dirpc sir quan tain thich dang.
Vi v a)y khoa lua(n “Androgen hien véii muc dich: 1. Tong hpp diriyc c:ie kien thfrc lién quan den androgen. Phfi n tich dirt c vat tro cfia androgen dci v6i b(nh ly suy sinh due fr nam gi6i, tbfing qua c:ie b rig chfrng tien firm sang va lfim sling. TONG QUAN VE ANDROGEN Androgen la nhfmg hormon steroid, co tac dqng kich thich hoac kiém soat su pliat ti ten va duy tri cac dac tinh nam thii ph:it cua dong vat co xuong song.
Androgen cung chinh I:i nhfing steroid dong hoa goc va la tién than cua tat ca c:ic estrogen [2 l ]. Androgen chinh va dupc biét den nhiéu nh:it la testosteron. Nguoa goc androgen Trong cc thé, testosteron dirpc bai tlet chu yéu tit té bao Leydig ciia tinh hoan (95%). Ngoai ra mot pllan nho testosteron con diroc bai tiét fi nhiirig not ngoai tinh hoan nhu vo thupng than (4%), buong trfmg, nhau thai.
[I ] C:ic té bao Leydig tong h pp androgen tfr cholesterol va acetyl-CoA, trong do con duérg tong hpp tir cholesterol la cliinh. Theo kinh diéu, can den 5 loai men de bién dc›i i‘: cholesterol thanh testosteron. Trong qu:i trinh bién doi nay, chuoi bén ciia cholesterol dupe cat é 2 diem de gram tit 27 xuong cfin 19 carbon vfi vong A cua steroid dirpc oxy hoa thanh dang A4-3-ceto (hinh l. 1) Ngoai testosteron cac té béo Leydig con tong hpp mot lupng nho estradiol (7(tg/ngay).
Cac estrogen tir nhién trong cc thé bao goin 17§- estradiol (E2), estron (El ) va estriol (E3), Bién d c›i c:ie androgen thanh estrogen l:i bucic bién doi cuoi ciing va dupc xuc tae boi phiic hpp enzym P,›o aroinatase monooxygenase (cé› mat trong he thong l iréii not nguyén sinh va thuc hi(n chfrc nang cat nhom methyl). Cau tao hoa hpc vé cac giai doan chuyén hfia tong hpp androgen dircic mo I:i trong so do diroi day [74J: tac dung trong 2 tuan [74]. Mfit mui tiém testosteron undecanoat co the duy tri tac dung toi mol th:ing [97]. Testosteron este hoa tan trong dau tot hon testosteron.
Testosteron alkyl hcia thuéng sfi dung qua dirérig uong, co tac dung yen hon testosteron va co toc do chuyén hoa qua gan chain hon testosteron. Testosteron alkyl hoa co the gay doc gan (lay 1. Chuyen ho:i ngoai vi cua c:ie androgen Testosteron la mot tién hormon sinh duc nam. Trong cci the, tai trio dicli testosteron co the chuyén lioa thanh 2 hormon khac con heat tinh la dihydrotestosteron vé estradiol duéi tac dung cua 2 enzym tuong Brig la 5o- reductase vii aromatase [74].
Hat hormon nay tac dong lén 2 loai receptor khac nhau tai cac trio dich khac nhau de diéu hoa cac hoat dong lien quan den chuc nang sinh duc — sinh san nam gioi. Testosteron cling bi chuyén hoa mat hoat tinh tar gan de tao thanh androsteron va etiocholanolon va dao thai qua than. Moi ngay co iiiot niia firing testosteron Hi tong hpp dirpc thfii qua nucic tiéu ducii dang 17- cetosteroid (chu yéu la androsteron va etiocholanol on) va iriot niia con lai dupc dao thai dufii dang diol, triol va cac dan xuat két hop. Do thanh lpc cua testosteron t¿ do tar gan rat cao va nua d’cii ciia testosteron trong huyét tuong la 12 phut [1].
Ch yén ho Chuyén h ho tie hogt tinh AN RDSTERON HO rMuctase TESTOSTERO CYP1 romatase) ETIOCHOLANOLO * C dgng to drogen trong ord Testosteron thong oong huyét tuong phdn bén J‹ét protein (W7°Z»), va in Iphén cliii ii dang tp dO (2-3‘Jo) 8 o hat lom protein huyét én két v‹n testosteron globuliir Testosteron Inn két thi long léo con lién ket globulin tbi ch8t ché hon nhiéu Ai ciia globulin 6i hormon steroid l6n 0‘-10’ lan :ii luc ciia albumin. Ph testosteron tp do va phdii lien ket long léo vdi albumin cé tbé khuéch tlin in:ing té bao ggi chung- testosteron he sinh hoc (t›io lién két ché vdi obulio (sex hormon-bindio obulin viét :i SHB phén kbong ho hoc testosteron. Phdn testosteron lién ket vdi SHB 7 ciiiem kho:ing 40° «, phan lién két véi albumin chiem ichn:ing 60°f« tong lu9ng Testosteron to n ph n [74]. T:ie dung v± cii ché tire dung cua androgen C:ic androgen the“ hien tiic dung thong qua lién ket véi receptor tirong Testosteron co the trpc tiép tac dung lén androgen receptoT (AR) ho? ac gi:in tiep throng qua DHT ( in u$r» ct lién két in hon véi AR[74]), ciing cc the I:ic dong lén estrogen receptor (ER) thong qua con dirérig aroma‹s×e de ta.n th:inh estradiol (hinh 1.5) TESTOSTERO YP19 romatase red ) Estradiol Co quan sinh due ngoéi Co quan sinh dqc Xirong trong: - T6ng m$t d§ xtrong - L8m c9c d8u x rong d8y thi Co, x‹zong gin nhau - G8y 6$nh tuyén tién Ji$t - Tung khai lizpng vd d0 d4i trong Sén sinh, phét trién, véo giai doan trué'ng thdntl nuoi d«ang tinh trung thdi Nang ldng/téc Tao hong cau " T:ic dq ng ciia androgen Androgen tac d“c›ng kich thlch hoac kiém soat sir phét trién vfi duy iri cac da(c tinh nam thir ph:it.
Song trong nhfing giai doan khac nhau thi androgen co nhfmg t:ic dung cu the kh:ic nhau. Tufi kj biro thai. Testosteron co chuc nang quyét dinh céc dac diem sinh duc cua thai bao gom c:i qu:i trinh hinh thanh d irong va) t va bao tinh he:in. Testosteron ciing quyét d nh sq hinh thanh v:i phat trlén cua tuyén tién li(t v:i ong dan tinh [74].
Trong hat thang cuoi cua thai ky tinh hoan tiet mot lupng thich hpp testosteron dé dira tinh ho:in tit khoang bung di chuyén xuong bao tinh hoan. T/i‹ii kfi #ny f/ii rii trir itg f/min/i: San day thl, testosterOn kich thiCl4 tain tall g kich thiroc cua dirong v I, tinh hoan va bao tinh hoan. Testosteron kich thich hinh thénh cite d(ac diem sinh duc thfi cép tir khi bat dau da(y thi den khi thanh thuc tinh duc can cti vao nhiiiig da)c diem ve sinh due thu cap va ca quan sinh due de phan bi(t nam va nu.