102006-2010 AÜTF data Genel Agonist Antagonist TOS 13.8 11 MII OOSİT 12.39.9Gn SÜREE MAX37962559TES2.962.69DOZ27603000GEBELİK (HCG)%49%42KL.GEBELİK%38İMPLANTASYON%22.4%19.1
112006-2010 AÜTF data NORMO Agonist Antagonist TOS 10.9 9.8 MII OOSİT 9.79Gn SÜRE9.9TES2.82.7E MAX25122248GEBELİK (HCG)%50.5KL.GEBELİK%43.5%45.3İMPLANTASYON%24.6%20.6
122006-2010 AÜTF data HİPER Agonist Antagonist TOS 19.2 17.8 MII OOSİT 17.3TES3.1E MAX54724349GEBELİK (HCG)%51%35KL.GEBELİK%42%30.2İMPLANTASYON%21.9%15.3
132006-2010 AÜTF data POOR Agonist Antagonist TOS 4.5 MII OOSİT 4.2 3.9 TES2.1E MAX861907GEBELİK (HCG)%30.7%33.3KL.GEBELİK%27%26İMPLANTASYON%20%15.8
14GnRH-a for Pituitary Control Genç normogonadotropik kadınlarda analog sikluslar da ovaryan stimülasyon için altın standart long GnRH-a protocoldür.Şeçim yapılmamış KOS siklus çalışmalarında GnRH-antagonist protokolün, agonist protokole üstün olduğunu gösteren kanıt yoktur.
20GnRH agonist n-=1117 GnRH antagonist n= 2865 P>1.5 ng/ml rFSH n= 138 % 8.7+LH n=979 % 8.1P>1.5 ng/mlrFSH n= 261 % 11.5+LH n=2594 % 5.2Nevertheless it is interestingto note that of 1117 IVF/ICSI cycles with a GnRH agonist long protocolthe progesterone level on the day of hCG administration wasabove 1.5 ng/ml in 8.7% of 138 treatment cycles using rFSH alonecompared with 8.1% of 979 treatment cycles using a stimulation protocol with LH activity. Of even more interest in 2855 patientsundergoing IVF/ICSI with a GnRH antagonist daily protocol the progesteronelevel on the day of hCG administration was above1.5 ng/ml in 11.5% of 261 cycles using rFSH alone compared with5.2% of 2594 cycles using a stimulation protocol with LH activity.
25Patients and methods: We reviewed the files of all consecutive patients undergoing COH with either GnRH-agonist or antagonist in our IVF unit during a 10-year period and who had theirpeak serum progesterone levels determined on the day of human chorionic gonadotropin(hCG) administration.Results: Of the 2244 IVF cycles evaluated, 2103 had peak progesterone level of 51.5 ng/mL(normal-P group) and 141 of41.5 ng/mL (high-P group) (6.28% of all the study population).Clinical pregnancy rate was significantly higher in the normal-P group (25.4% versus 16.6%;p50.006). Moreover, among the high-P group patients, the use of the long GnRH-agonistsuppressive protocol (GnRH-ag) was more prevalent in patients who conceived as compared tothose who did not (60.9% versus 39%, respectively; p50.05), with a tendency toward anincrease pregnancy rate in those using GnRH-ag compared with GnRH-antagonist protocol(GnRH-antag; p50.059) COH protocols.
26Conclusion: While subtle progesterone elevation in patients undergoing COH using GnRH-antag COH protocols, should dictate embryo cryopreservation and cancelation of the fresh transfer, inthose undergoing the GnRH-ag COH protocol, a fresh embryo transfer should be recommended.As expected [1,3], the high-P group had higher estradiol levelson the day of hCG administration and achieved a significantlyhigher oocytes yield. Moreover, patients in the high-P group whoconceived, also had higher oocyte yields, used more frequentlythe GnRH-ag rather than the GnRH-antag protocols. Theseaforementioned observations were also observed by Venetis et al. in the group of patients undergoing the GnRH-ag COHprotocol and were attributed to an excess number of follicles, eachone producing a normal, for the late follicular phase, amount ofprogesterone. As a result, the excess granulosa cells proliferatingleads to an increased progesterone production, independently ofLH exposure [1,4].
27GnRH Antagonist ve İmplantasyon FSH ve GnRH Reseptörleri endometriumda gösterilmiştir.Gonadotropinlerin ve GnRH analoglarının endometrium üzerine direkt ya da indirekt etkisi olabilir.Yüksek serum E2 düzeyleri yada diğer hormonal değişiklikler endometriyumu olumsuz etkileyebilir.
34GnRH Antagonist ve İmplantasyon GnRH antagonistin endometrial GnRH reseptorlerine bağlanmasının implantasyon aşamasında rol alan post reseptör olaylar üzerinde olumsuz etkisi olabilir.Preovulatuar GnRH agonist verilmesi endometrial reseptörlerde GnRH antagonist ile yer değiştirip implantasyon için uygun postreseptör değişikliklerin oluşmasını sağlayabilirmi ??????
36GnRH Antagonist ve İmplantasyon Luteal fazda tek doz GnRH-agonist kullanımı implantasyon oranını hem GnRH-agonist hem de GnRH-antagonist protokollerde arttırır,Anlamlı klinik gebelik oran artışı sadece GnRH antagonist protokol ile tedavi edilen grupta izlenmiştir.Oliveira JB, Administration of single-dose GnRH agonist in the luteal phase in ICSI cycles:a meta-analysis. Reprod Biol Endocrinol 2010;8:107.
37GnRH Antagonist ve İmplantasyon GnRH antagonistlerinin implantasyona etkisi doz bağımlıdır.Ganirelix (0.5, 1, and 2 mg) dozları düşük implantasyon oranları göstermiştir.0.25-mg (21.9%)2-mg (1.5%),Doz artıkça abortus oranı artarIncontrast, when embryos were cryopreserved after an ovulationstimulation cycle in which high-dose GnRH antagonistswere used and later thawed and transfered, the implantationand pregnancy rates were unaffected by the use of GnRH antagonistduring the initial stimulation cycle (20, 25). Thesedata suggest an effect of GnRH antagonists on the endometriumand therefore an effect on endometrial receptivity.Ganirelix Dose-Finding Study Group. Hum Reprod 1998;13:3023–31.
38GnRH Antagonist ve İmplantasyon Endometrial gelişim histolojik olarak GnRH antagonist kullanılan sikluslarda, GnRH agonist sikluslara göre natürel sikluslara daha benzerdir.Simon C. Hum Reprod 2005;20: 3318–27.
39PINOPODE Y. Meng et al.Proteomics 2014, 14, 2350–2359 In our biopsies, we found developing, fully developed, andregressing pinopodes in each group which is the ultrastructuralmarkers of the implantation window [25, 26] (Fig. 1).In GnRH antagonists group (represented by “S”), the apicalsurfaces of cells were similar to agonists group (defined as“D”) and a little different from nonstimulated ones. It seemedthat there weremore fully developed pinopodes in natural cyclegroup (defined as “N”) and more regressing pinopodesin GnRH analogs treatment group. These results cannot suggesta different pattern of endometrial development in GnRHanalogs treatment group because of the limited sample sizein our study. But it confirmed that the endometrial datingwas corresponding to the putative window of implantation.Y. Meng et al.Proteomics 2014, 14, 2350–2359
41METHODS: Mid-luteal phase endometrial biopsies were obtained from oocyte donors undergoing ovarian stimulation and from control women with regular periods.Immunohistochemistry and real-time quantitative–polymerase chain reaction (QRT–PCR) were used to compareprotein and mRNA expression of progesterone receptor (PR), estrogen receptor a (ERa), estrogen receptor b(ERb), androgen receptor (AR), 3bHSD1, 3bHSD2, 17bHSD2 and 17bHSD5. RESULTS: Cetrorelix–rFSH treatmentcaused a mid-luteal suppression of PR protein expression in the endometrial stroma, surface epithelium andglands, although expression in the glands of control samples was variable. In contrast, the treatment caused anincrease in PR staining in perivascular cells. No other significant differences in protein expression were observedbetween the two groups. mRNA levels of AR, ERa, 3bHSD1 and 17bHSD2 were significantly reduced in the treatmentgroup. PR mRNA levels were also reduced by GnRH antagonist–rFSH treatment, but the difference was not significant.CONCLUSIONS: Changes in the expression of sex-steroid receptors and metabolizing enzymes may lead toalterations in the activity and intracellular availability of estrogens, progestogens and androgens in endometriumof women treated with Cetrorelix and rFSH. Their impact on embryo implantation merits further evaluation.
42GnRH Antagonist /Adezyon molekülleri Muc-1 antiadheziv özellik gösteren bir moleküldür. Farelerde embriyonun tutunmasından önce endometrium epitelinde down-regüle olduğu gösterilmiştir. Buna karşılık insanda reseptif dönemde ekspresyonda artış olmaktadır. Ancak dikkatle incelendiğinde embriyonun bulunmasının Muc-1 yapımını epitelyumda yakınlaşma safhasında arttırdığı, ancak adezyon safhasında embriyonun bulunmasının implantasyon sahasındaki Muc-1 konsantrasyonunu azalmasını indüklediği gösterilmiştir
43GnRH antagonist /Adezyon molekülleri integrin β3leukaemia-inhibitory factor (LIF)Comparedwith the PMSG alone protocol, OS with GnRH agonistco-treatment showed elevated expression levels of endometrialintegrin β3 subunit and LIF and a higher embryonic implantationrate, suggesting that OS with GnRH agonist co-treatment,but not with GnRH antagonist co-treatment, may potentiallyimprove uterine receptivity, and this improvement of uterinereceptivity in mice might be partially through the restoration ofphysiologically endometrial secretion changed in the OS cycle
46Patient(s): Nineteen subjects were included: 12 subjects underwent controlled ovarian hyperstimulation with recombinantFSH and used either a GnRH antagonist or a GnRH agonist; seven control subjects underwent naturalcycles.Intervention(s): Pipelle endometrial biopsies were obtained 11 days after hCG administration or spontaneous LHsurge in untreated cycles, respectively. Immunohistochemistry was used to assess HOXA10 protein expression inendometrial glands and stroma.Main Outcome Measure(s): Endometrial HOXA10 protein expression.Result(s): HOXA10 expression was significantly decreased in endometrial stromal cells in GnRH antagonist–treated cycles compared with GnRH agonist–treated cycles or natural cycle control subjects. There was no significantdifference in glandular cell HOXA10 expression among the three groups.Conclusion(s): Use of GnRH antagonists may be associated with impaired HOXA10 expression in endometrialstromal cells and thus may affect endometrial receptivity.
47Study design: This study was conducted at the Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Thirty-five volunteers were recruited into this prospective, self-controlled study, which was divided into two cycles, the first a natural control cycle and the second a GnRH antagonist-treated cycle. The two cycles were separated by one resting cycle. In the GnRH antagonist-treated cycle, when the leading follicle was 15 mm, ganirelix (Orgalutran1) 0.25 mg was administered daily. In both cycles, ovulation was induced when the largest follicle reached 18 mm in diameter. Finally, endometrial biopsy was performed on day 6 after documented ovulation, which corresponds to the window of implantation. Endometrial HOXA10 protein expression, a marker of endometrial receptivity, was analyzed by immunohistochemistry. The protein expression was compared between the two cycles regarding their percentage of immunostained cells and IHC-scores (percentage of stained cells intensity of nuclear staining).
50SonuçEldeki verilere göre implantasyon açısından GnRH agonistleri daha iyi gözükmektedir.İndirekt etkiler olabileceği gibi, endometriumda bulunan GnRH reseptörleri burada direkt etken olabilir.Yüksek progesteron seviyelerinde embriyo freezing önerilmelidir.Dual trigger ve freeze all stratejisi ile bu olumsuzluk giderilebilir.