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185265769.Pdf View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Zagreb Medical School Repository SVEUČILIŠTE U ZAGREBU MEDICINSKI FAKULTET Emina Ejubović Povezanost koncentracije preovulacijskoga i postovulacijskoga progesterona u serumu i ishoda izvantjelesne oplodnje DISERTACIJA Zagreb, 2018. SVEUČILIŠTE U ZAGREBU MEDICINSKI FAKULTET Emina Ejubović Povezanost koncentracije preovulacijskoga i postovulacijskoga progesterona u serumu i ishoda izvantjelesne oplodnje DISERTACIJA Zagreb, 2018. Disertacija je izrađena u Klinici za ženske bolesti i porode Kliničkog bolničkog centra Zagreb i Medicinskog fakulteta Sveučilišta u Zagrebu. Voditelj rada: prof. dr. sc. Miro Kasum POSVETA Ovaj doktorat, s puno ljubavi i iskrene zahvalnosti, posvećujem svojim roditeljima Emiri i Nedžadu, te bratu Maliku, čija mi je podrška u svakom trenutku i u svakom pogledu davala dodatnu snagu da u ovome poslu istrajem do kraja. Isto tako ovaj doktorat, s iznimnim štovanjem i uvažavanjem, posvećujem dragoj prijateljici mr. sc. dr. Mirjani Bišćan, bez koje ove priče vjerojatno ne bi ni bilo, barem ne u ovom obliku. 3 ZAHVALE Prof. dr. sc. Miri Kasumu, mom mentoru, na stvaranju poticajnog ozračja, nesebičnim sugestijama, korisnim savjetima i kvalitetnom stručnom vodstvu, što je neprestano popravljalo retke ovog rada i učinilo da danas ovako izgleda. Stručnom povjerenstvu sastavljenom od vrsnih znalaca ginekološke endokrinologije, prof. dr. sc. Dinki Pavičić-Baldani, prof. dr. sc. Velimiru Šimuniću i prof. dr. sc. Krunoslavu Kuni, koji su svojim znanjem, opaskama i naputcima pridonijeli poboljšanju kvalitete ovog rada. Prof. dr. sc. Slavku Oreškoviću, predstojniku Klinike za ženske bolesti i porode Petrova, KBC Zagreb, koji je svojim autoritetom uvijek, kada je bilo potrebno, bio uz mene i omogućio mi nesmetano prikupljanje podataka u Ustanovi na čijem je čelu. Dr. sc. Josipu Jurasu na iznimno velikoj pomoći oko statističke obrade prikupljenih podataka. Petri Gverić Katana, prof. na lektoriranju rukopisa doktorata. Dr. sc. Patriku Staniću, embriologu, na pomoći pri angažiranju ispitanica za ovo istraživanje. Medicinskim sestrama Ireni, Jasni i Brigiti sa Klinike za ženske bolesti i porode Petrova, KBC Zagreb na tehničkoj pomoći pri radu s ispitanicama. 4 Istraživanje je registrirano u Registru kliničkih istraživanja Australije i Novog Zelanda (ANZCTR) na web stranici www.anzctr.org.au Identifikacijski broj istraživanja: ACTRN12615001315505 5 SADRŽAJ I. Kratice ....................................................................................................................................... iii II. Popis tablica, slika i grafikona .................................................................................................. vi 1. Uvod ...................................................................................................................................... 1 1.1. Definicija neplodnosti ........................................................................................................... 1 1.2. Epidemiologija i uzroci neplodnosti kod pacijentica u postupku izvantjelesne oplodnje ..... 1 1.2.1. Epidemiologija neplodnosti ................................................................................................... 1 1.2.2. Uzroci neplodnosti................................................................................................................. 2 1.3. Menstruacijski ciklus i ovulacija ........................................................................................... 4 1.3.1. Hipotalamus i hipofiza .......................................................................................................... 5 1.3.2. Endokrinologija menstruacijskoga ciklusa ............................................................................ 8 1.3.3. Faze menstruacijskoga ciklusa ............................................................................................ 15 1.4. Stimulacijski protokoli ........................................................................................................ 18 1.4.1. Gonadotropini ...................................................................................................................... 19 1.4.2. GnRH agonisti ..................................................................................................................... 19 1.4.3. GnRH-a u luteinskoj fazi ..................................................................................................... 20 1.4.4. "STOP" GnRH-a protokol ................................................................................................... 20 1.4.5. Učinak GnRH-a na sintezu FSH i LH („Flare up“ protokol) .............................................. 21 1.4.6. Učinak GnRH-a na sintezu FSH i LH s malim dozama agonista ........................................ 21 1.4.7. Kratki protokol .................................................................................................................... 22 1.4.8. Protokol s GnRH antagonistima (GnRH-ant)...................................................................... 23 1.5. Povišen preovulacijski progesteron i utjecaj na ishod trudnoće nakon postupka izvantjelesne oplodnje ......................................................................................................... 24 1.6. Strategije za prevenciju nepovoljnog djelovanja preovulacijskoga progesterona .............. 26 1.6.1. Blagi stimulacijski protokoli ............................................................................................... 26 i 1.6.2. Ranija primjena preovulacijskoga hCG-a ........................................................................... 26 1.6.3. Transfer zametaka 5. dana ................................................................................................... 27 1.6.4. Elekcijska krioprezervacija zametaka i odloženi transfer u prirodnome ciklusu ................ 28 1.7. Postovulacijski progesteron i lutealna potpora u postupku izvantjelesne oplodnje ............ 28 2. Hipoteza ............................................................................................................................... 30 3. Ciljevi rada .......................................................................................................................... 30 3.1. Opći cilj ............................................................................................................................... 30 3.2. Specifični ciljevi .................................................................................................................. 30 4. Ispitanice i metode ............................................................................................................... 32 4.1. Opis istraživanja .................................................................................................................. 32 4.2. Statistička obrada podataka ................................................................................................. 37 5. Rezultati ............................................................................................................................... 39 6. Rasprava .............................................................................................................................. 60 7. Zaključak ............................................................................................................................. 71 8. Sažetak ................................................................................................................................. 73 9. Summary.............................................................................................................................. 74 10. Popis literature ..................................................................................................................... 75 11. Kratak životopis................................................................................................................... 90 ii I. KRATICE ANZCTR - Australian New Zealand Clinical Trials Registry (Registar kliničkih istraživanja Australije i Novog Zelanda) SZO - Svjetska zdravstvena organizacija MPO - Medicinski pomognuta oplodnja IVF - In vitro fertilization (izvantjelesna oplodnja) GnRH - Gonadotropin-releasing hormone (gonadotropin oslobađajući hormon) FSH - Folikulostimulirajući hormon rFSH - Rekombinantni folikulostimulirajući hormon LH - Luteinizirajući hormon E1 - Estron E2 - Estradiol E3 - Estriol P4 - Progesteron SŽS - Središnji živčani sustav TSH - Tireostimulirajući hormon CRH - Corticotropin-releasing hormone (kortikotropin oslobađajući hormon) GHRH - Growth hormone–releasing hormone (oslobađajući hormon hormona rasta) SO - Supraoptička jezgra hipotalamusa SC - Suprakijazmatička jezgra hipotalamusa PV - Paraventrikularna jezgra hipotalamusa DM - Dorzomedijalna jezgra hipotalamusa VM - Ventromedijalna jezgra hipotalamusa PH - Stražnja hipotalamička jezgra PM - Premamilarna jezgra hipotalamusa LM - Lateralna mamilarna jezgra hipotalamusa iii MM - Medijalna mamilarna jezgra hipotalamusa ACTH - Adrenocorticotropic hormone (adrenokortikotropni hormon) GH - Growth hormone (hormon rasta) ADH - Antidiuretski hormon GPCR - G-protein-coupled receptor (G-protein receptor) hCG - Human Chorionic Gonadotropin (humani korionski gonadotropin) AMH - Anti-Müllerian hormone (Anti-Müllerov hormon) TGF-β - Transforming growth factor beta (transformirajući čimbenik rasta beta) PCOS - Polycystic ovary syndrome (sindrom policističnih jajnika) SHBG
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