Hasta Dostu Tedaviler: Mümkün mü?

... konulu sunumlar: "Hasta Dostu Tedaviler: Mümkün mü?"— Sunum transkripti:

1 Hasta Dostu Tedaviler: Mümkün mü?
Doç. Dr. L. Cem Demirel Acıbadem Hastanesi Kadıköy - İstanbul xxxxxsedcrtfvgb jnkml,

2 İlk Test – Tüp Bebeği Doğal siklus Laparoskopik oosit toplanması
Tek matür oosit IVF 25 Temmuz 1978’de doğum.... Steptoe PC, Edwards RG (1978) “ Birth after the reimplantation of a human embryo” Lancet 2 (8085): 366 xxxxxsedcrtfvgb jnkml,

3 IVF Gebelik arzusu Ovarian stimülasyon ilaçların yan etkileri ve maliyetleri Daha fazla oosit OHSS riski Daha fazla embryo Kriyoprezervasyon Birden fazla embryo transferi Çoğul gebelikler Artmış gebelik şansı OHSS yi önleme için none veya minimal ovarian stimulation, çoğul gebeliği önleme için SET: dilemma will these measures result in lower pregnancy rates? Less embryos to transfer >>> need for fewer oocytes, less stimulation. xxxxxsedcrtfvgb jnkml,

4 Hasta dostu yaklaşım Basitleştirilmiş takip
Hiç ya da minimal stimülasyon Tek embryo transferi Doğal siklus IVF Minimal stimülasyon IVF IVM IVM ile kombine doğal siklus IVF xxxxxsedcrtfvgb jnkml,

5 Konvansiyonel Ovarian Stimülasyon
Yüksek dozda kullanılan gonadotropinlerin güvenilirliği? Gelecek için : kanser riski ? (Brinton 2004, Arthuis 2005) Şu an için: Doğal siklusa göre stimüle sikluslardaki kromozomal anomalilerde artış (Pellicer 2006) Oosit matürasyon defektleri ( de Ziegler 2006 ) Olumsuz endometrial etki (Devroey 2004, C. Simon 2007) Maximize the number of oocytes available Endometrial receptivity may be affected adversely by ovulation induction therapy. This may be due to advanced endometrial maturation and dysfunctional progesterone receptor activity. xxxxxsedcrtfvgb jnkml,

6 GnRH antagonist versus agonist
LH FSH Başlangıç flare-up etki yok Estrojen yoksunluk semptomları yok Agonist Pituitary Suppression Shorter treatment Azalmış gonadotropin kullanımı Esneklik Antagonist İnitial flare up: development of ovarian kists. Estrogen deprivation: headaches, hot flushes, vaginal dryness. In the current care, to achieve downregulation of endogenous gonadotropin secretion with a GnRH agonist a pretreatment period of 2 to 3 weeks is required. Furthermore, relatively high amounts of exogenous FSH are needed for adequate stimulation since during the whole period of stimulation endogenous FSH is deeply suppressed. Administration of the GnRH antagonist is only required during a short period of the stimulation, i.e. when a premature LH surge is likely to occur. GnRH antagonists do not induce initial stimulation of gonadotropin release. Furthermore a lower total dose of FSH is needed for stimulation, since with the use of a GnRH antagonist, FSH levels are only partly suppressed during the late follicular phase. Time xxxxxsedcrtfvgb jnkml,

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8 Single vs Multiple Dose
multiple single p dose dose PR /initiated cycle 23.7 % 23.3 % NS PR / ET 28 % % NS OHSS (severe) 0.7 % 0.8 % NS Olivennes, RBM Online, 2003 xxxxxsedcrtfvgb jnkml,

9 Tanımlar Terminoloji Hedef Metodoloji Doğal siklus IVF Tek oosit
İlaçsız takip Modifiye doğal siklus IVF Yalnızca hCG Antagonist & FSH add - back Mild stimulation IVF 2 – 7 oosit Düşük doz FSH & antagonist High stimulation IVF > 8 oosit Agonist / antagonist Konvansiyonel FSH dozu xxxxxsedcrtfvgb jnkml,

10 Protocol for natural cycle IVF
hCG criteria: Lead follicle  18 mm E2  100 pg / mL No LH surge Start USG hCG + urinary LH kit every 6 hrs + E2, LH D9  14 mm  17 mm  18 mm If LH surge > OPU scheduled 33 hrs after the observation of a positive coloration with urinary testing. Urine test can identify LH concentaritons of 45 mIU / mL as an LH surge. With this protocol insidans of LH surge: around 30 %. LH surge olsa da timing of LH surge may allow oocyte retrieaval sometimes. Bu sikluslarda oosit recovery rate ortalama %

11 Use of GnRH antagonists in natural cycle IVF
Cetrorelix - Ganirelix 0.25 mg + 150 IU FSH / day start monitoring D8 E2  pg/mL Fol mm LH surge in natural cycle is defined as : serum LH  15 mIU / mL. (a plato or decrease in e2 levels and an increase in P levels are confirmatory. For LH surges.After ant, e2 drops drastically so fsh added.( although the decrease in e2 is not concern for a normal responder, it is posible that any decline in the bioavailable gonadotrpin has the potential to be problematic for the poor responder) Second ant inj 3 days after the first. In natural cycles ant administ.do not produce atresia of dominant folicule bu cause a decline in estradiol concenrations. With antagonists, cancellation rates due to LH surges are decreased in natural cycle IVF. Fakat bu yaklaşım poor responderlarda denenmedi. Main reason for cancellation in natural cycles is prematureLH surges.

12 Modifiye doğal siklus IVF için potansiyel endikasyonlar:
Uterine malformasyon (unikornuat uterus) Standard ovarian stimülasyona karşı kötü cevap Tekrarlayan implantasyon başarısızlıkları Ciddi OHSS öyküsü xxxxxsedcrtfvgb jnkml,

13 IRs: better endometrial growth in the natural cycle and avoidance of detrimental effects of hyperstimulation on endometrium. Or better quality of oocytes in natural cycles owing to the more fizyolojik metod of folicular development and recruitment. xxxxxsedcrtfvgb jnkml,

14 Poor responderlar için doğal versus modifiye – doğal siklus
doğal modifiye doğal p No siklus Yaş NS Oosit elde etme oranı (%) ET yapılan siklus oranı (%) Shulman et al, Fertil Steril 2002 Younger women (<40) in modified natural cycle group had significantly more cycles resulting in ET and pregnancy. Both groups were monitored by daily ultrasound follicular measurements and whenever a follicle larger than 13 mm was scaned daily assessment of E2, progesterone and LH levels were started. When the follicular diameter ? 17mm., 5000 IU of hCG were administered and OPU was performed. In group II, Cetrorelix (0.25mg) and hMG (150 IU) were administered when the domonant follicle reached a diameter of at least 14-mm. Follicular aspiration was performed as described above. 22 patients underwent 44 cycles in group I. 54 patients underwent 75 cycles in group II. Mean age at treatment was 39.7/4.6 and 38.5/5.6 years (NS) for groups I and II respectively. Spontaneous cycles with Cetrorelix were characterized by smaller rate of cancellations due to lesser events of premature LH surge and lower rates of arrested follicular development. Retrieval of mature oocytes was accomplished in 55% of group I and 78% of group II (p 0.04). Normal fertilization resulting in embryo transfer (ET) occurred in 22% and 49% of cycles for groups I and II, respectively (p 0.03). However, pregnancy rates per retrieval and per transfer did not differ significantly between both groups. Noteworthy, poor-responders treated by Cetrorelix (group II) who were younger than 40 years, were characterized by a higher rate of oocyte retrieval and significantly more cycles resulting in ET and pregnancy. Poor responders may benefit from spontaneous cycles combined with GnRH antagonists. The supplementation of Cetrorelix yielded a significant higher rate of cycles resulting in ovum pick-ups, oocyte retrieval, and embryo-transfer. xxxxxsedcrtfvgb jnkml,

15 Doğal siklus FSH > 12 mIU / mL ve tedaviye başlama yaşı > 38 olan poor responder hastalarda modifiye doğal siklus gerçekçi bir gebelik beklentisi sağlamamaktadır (0 / 98) Kolibianakis, 2004 Hum Reprod xxxxxsedcrtfvgb jnkml,

16 Neden “ mild stimulation” yapalım?
Elektif tek / çift embryo transferi planlanmakta ise, Az sayıda folikülün seçildiği kötü cevaplılar ile uğraşıyor isek, Azoospermi olan çiftlerde veya donör spermi kullanılacak ise..... xxxxxsedcrtfvgb jnkml,

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18 Baart et al, Hum Reprod 2007 Hastalar < 38 yaş
Partner sperm: normozoospermi GnRH agonist rFSH : 225 IU / gün 40 hasta OPU 33 hasta PGD / AS 184 embryo PGD / AS % 28 normal embryolar GnRH antagonist rFSH : 150 IU / gün 56 hasta OPU 40 hasta PGD / AS 157 embryo PGD / AS % 39 normal embryolar Mild ovarian stimulation results in a reduced proportion of abnormal and mosaic embryos. Baart et al, Hum Reprod 2007 xxxxxsedcrtfvgb jnkml,

19 Mild Stimulation Standard uzun GnRH agonist protokolü ile CC ve GnRH antagonist co-treatment protokolü arasında benzer gebelik sonuçları Williams et al 2002, Fieder and Ludwig 2003, Lin et al 2006 xxxxxsedcrtfvgb jnkml,

20 Teramoto S, Kato O. RBMOnline 2007, 15: 134-48
Kato Ladies Clinic, , Nishishinjuku, Shinjuku, Tokyo , Japan Teramoto S, Kato O. RBMOnline 2007, 15: xxxxxsedcrtfvgb jnkml,

21 Embryo transfer sonuçları: oosit toplama başına kümülatif gebelik, düşük, ve ektopik gebelik oranları (dondurma – çözme siklusları da dahil olmak üzere) Administration of 50 mg clomiphene citrate is initiated on cycle day 3, and from day 8 patients receive 150 IU of FSH every other day. When the size of the dominant follicle and the oestradiol concentration reach the predefined values, gonadotrophin-releasing hormone agonist is administered to induce follicular maturation. Oocytes are then retrieved h later. Because the short half-life of enclomiphene (24 h) is of critical importance in this protocol, it is necessary to continue oral administration of clomiphene citrate until the day before maturation is triggered. Of all 43,433 cycles initiated, the rates for oocyte retrieval and embryo cleavage were 83 and 64% respectively. The mean number of oocytes retrieved was 2.2. The rates for live births, miscarriages, and ectopic pregnancies, in relation to initiated cycles, including cases of frozen-thawed transfer, were 11.1, 3.4 and 0.2% respectively. xxxxxsedcrtfvgb jnkml,

22 Heijnen et al, Lancet 2007 Mild stimülasyon N: 444 Standard tedavi
Ovarian stimülasyonun süresi (gün) 8.3 11.5 Enjeksiyonların süresi (gün) 8.5 25.3 Total FSH dozu (IU) 1307 1832 OPU başına düşen oosit sayısı 6.9 OHSS 1.4 % 3.7 % Minimal stimulation IVF: aim is to use the one dominant follicle that spontaneously develops in a natural cycle. GnRH antagonist is used to prevent LH surge Risk of OHSS is negligable. Mild in-vitro fertilisation (IVF) treatment might lessen both patients' discomfort and multiple births, with their associated risks. We aimed to test the hypothesis that mild IVF treatment can achieve the same chance of a pregnancy resulting in term livebirth within 1 year compared with standard treatment, and can also reduce patients' discomfort, multiple pregnancies, and costs. METHODS: We did a randomised, non-inferiority effectiveness trial. 404 patients were randomly assigned to undergo either mild treatment (mild ovarian stimulation with gonadotropin-releasing hormone [GnRH] antagonist co-treatment combined with single embryo transfer) or a standard treatment (stimulation with a GnRH agonist long-protocol and transfer of two embryos). Primary endpoints were proportion of cumulative pregnancies leading to term livebirth within 1 year after randomisation (with a non-inferiority threshold of -12.5%), total costs per couple up to 6 weeks after expected date of delivery, and overall discomfort for patients. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Clinical Trial, number ISRCTN FINDINGS: The proportions of cumulative pregnancies that resulted in term livebirth after 1 year were 43.4% with mild treatment and 44.7% with standard treatment (absolute number of patients=86 for both groups). The lower limit of the one-sided 95% CI was -9.8%. The proportion of couples with multiple pregnancy outcomes was 0.5% with mild IVF treatment versus 13.1% (p<0.0001) with standard treatment, and mean total costs were 8333 euros and euros, respectively (difference 2412 euros, 95% CI ). There were no significant differences between the groups in the anxiety, depression, physical discomfort, or sleep quality of the mother. INTERPRETATION: Over 1 year of treatment, cumulative rates of term livebirths and patients' discomfort are much the same for mild ovarian stimulation with single embryos transferred and for standard stimulation with two embryos transferred. However, a mild IVF treatment protocol can substantially reduce multiple pregnancy rates and overall costs. BACKGROUND: Milder stimulation protocols are being developed to minimize adverse effects of ovarian stimulation in in vitro fertilization (IVF) programs. A drawback is the possibility of an increased rate of insufficient ovarian response. This study aimed to develop a prognostic model for the prediction of cycle cancellation due to insufficient response to mild stimulation. METHODS: A total of 174 IVF patients aged<38 years and with a body mass index (BMI)<28 Kg/m2 were treated with mild ovarian stimulation using a fixed daily dose (150 IU) of recombinant follicle-stimulating hormone (rFSH) from cycle day 5 and GnRH antagonist from the late follicular phase. In women with mono- or bifollicular growth (17%), the cycle was cancelled and the treatment was adjusted in a second treatment cycle by starting rFSH on cycle day 2. RESULTS: In a multivariable logistic regression analysis, duration of infertility, menstrual cycle length, secondary infertility and BMI were included in the prediction model. The area under the receiver-operating characteristics curve of the model was A probability cut-off for cancellation of 0.3 yielded an expected sensitivity of 33% and specificity of 92%. Analysis of ovarian response in the subsequent treatment cycle showed an improved ovarian response and a significant reduction in the cancellation rate. CONCLUSIONS: With the presented model, it is possible to identify patients at risk for cycle cancellation, during mild ovarian stimulation, due to insufficient response. The contributing factors of the model suggest that ovarian aging and BMI are related to insufficient response to mild stimulation Heijnen et al, Lancet 2007 xxxxxsedcrtfvgb jnkml,

23 Weghofer, FS, 2004: Minimal stimulation in advanced age women
Minimal stimulation FSH + GnRH antagonist vs uzun protokol: siyah (başlanılan siklus) – gri (embryo transferi başına) Patients on the long protocol underwent standard cycle monitoring and stimulation. In contrast, women with minimal stimulation had transvaginal sonography initiated on day 8 of the menstrual cycle and at a follicle size of 13 mm. We administered 0.25 mg of GnRH antagonist and 75 IU recombinant FSH daily until ovulation induction. Result(s): Minimal stimulation cycles resulted in a clinical pregnancy rate of 8.2% per started cycle and 10% per embryo transfer (ET), whereas the control group yielded a clinical pregnancy rate of 10.6% per started cycle and of 10.7% per ET (not statistically significant). Conclusion(s): In women aged 40 and above with abnormal FSH levels, minimal stimulation protocol achieves similar pregnancy rates to a standard protocol, and thus represents a cost-effective alternative. (Fertil Steril 2004;81:1002– 6. Weghofer, FS, 2004: Minimal stimulation in advanced age women xxxxxsedcrtfvgb jnkml,

24 Clinical outcome of IVM in PCOS
About 30 – 35 % of infertile women with PCOS who undergo IVM treatment achieve clinical pregnancies. In recent years, in vitro maturation (IVM) of human oocytes for assisted reproductive technologies has attracted an ever growing attention in such a way that its clinical use is quickly expanding for a variety of conditions. Though it is a procedure that needs further improvement in terms of implantation and pregnancy rates. In clinical practice IVM has largely been reserved for patients having either polycystic ovarian syndrome (PCOS) or polycystic looking ovaries (PCO) in an effort to avoid the risks of ovarian hyperstimulation syndrome and to minimize gonadotropin use. This category of patients seems to be ideal candidates for the application of IVM technology because of high oocyte yield with immature oocyte retrieval and high risk of OHSS with gonadotropin use. Several studies in the literature report good and aceeptable rates of implantation (ranging between 5.5 to 34.5 %) and pregnancy per embryo transfer (ranging between 21.9 to 52.9 %) with IVM in PCOS or PCO patients. Fsh and hcg priming (FSH 75 – 150 IU / 3 ile 6 gün arası). xxxxxsedcrtfvgb jnkml,

25 Clinical outcome of IVM in women with normal ovaries
As expected, the average number of oocytes retrieved from women with PCO and PCOS is higher than that obtained from women with normal ovaries (12.1 vs. 5.1, respectively). Antral follicle counts (AFC) strongly correlated with the number of immature oocytes retrieved IVM has also been tried in other patient populations. The aim is to have a less coastly and more friendly IVF treatment. One group of a such patient population is those patients whose infertility is solely male factor infertility. In such cases, the women may apt not to undergo vigourous ovarian stimulation for a reason not related to her health directly. The outcome of IVM in such women with normal looking ovaries is reported in the literature to be much worse in terms of implantation (ranging between 1.5 to 22.6 %) and pregnancy rates (ranging between 4 to 33.3 %) as compared to PCOS patients Better prognosis if AFC > 7 xxxxxsedcrtfvgb jnkml,

26 IVM as an alternative to prevent OHSS
If > 20 follicles with a diameter > 10 mm after at least 5 days of gonadotropin stimulation: over responder and risk of OHSS hCG when leading follicle 12-14mm Immature oocyte retrieval 36 hrs post hCG xxxxxsedcrtfvgb jnkml,

27 IVM as an alternative to prevent OHSS
Number of cases at risk of OHSS 56 Mean dose of gonadotropin used during COH IU Mean number of oocytes retrieved per patient 15.6 % of MII oocytes at retrieval 24. 6 % Maturation rate within 48 hrs 76 % Fertilization rate 81.6 % Clinical pregnancy rate 46.4 % Lim et al, Fertil Steril, 2005; 84: S84-5 xxxxxsedcrtfvgb jnkml,

28 IVM as an alternative to prevent OHSS
Number of cases at risk of OHSS 56 Mean dose of gonadotropin used during COH IU Mean number of oocytes retrieved per patient 15.6 % of MII oocytes at retrieval 24. 6 % Maturation rate within 48 hrs 76 % Fertilization rate 81.6 % Clinical pregnancy rate 46.4 % No case of severe OHSS This study suggests that IVM after interruption of COH may be a solution to the management of patients with high risk of OHSS during COH, without lowering the pregnancy rate. These studies illustrate the potential role of IVM as an alternative to cancellation of IVF in high responders. It is not known how IVM in these circumstances would compare with other options, such as coasting or triggering ovulation with a GnRH agonist. Lim et al, Fertil Steril, 2005; 84: S84-5 xxxxxsedcrtfvgb jnkml,

29 European IVF Monitoring
yılları arasında Avrupa’da transfer edilecek embryo sayısı 3’den 2’e indirildi. Üçüz doğum oranı % 3.6’dan % 1.2’e indi. İkiz doğum oranlarında marjinal bir azalma izlendi (% 24) Should twin rates be reduced? Yes. Can we reduce the twin rate without reducing the pregnancy rate? And how ? –eSET in selected patients. xxxxxsedcrtfvgb jnkml,

30 Tanımlar SET: single embryo transfer
SET ve kriyoprezervasyon için embryo olmaması eSET: elective single embryo transfer En azından iki tane iyi kalitede embryo varlığında iyi kalitedeki tek bir embryonun transferi SET ve dondurulabilecek en azından bir embryo varlığı xxxxxsedcrtfvgb jnkml,

31 eSET: Hasta Seçimi Yaş < 36 Birinci veya ikinci siklus
Endikasyon: TESE olmayacak Oosit sayısı: Poor responder olmayacak xxxxxsedcrtfvgb jnkml,

32 eSET: Embryo Seçimi Blastomer sayısı Multinucleated blastomer sayısı
Fragmantasyon : < % 20 Eşit blastomer boyutu Erken bölünme Bölünme hızı xxxxxsedcrtfvgb jnkml,

33 Kuzey Avrupa’da ART sonrası doğum, çoğul gebelik ve SET oranları
Karlström, 2006 xxxxxsedcrtfvgb jnkml,

34 DET vs SET Dört çalışma – Cochrane Review
Fresh siklusda DET, hasta başına daha yüksek canlı doğum oranları vermektedir. Fakat dondurulmuş bir embryonun müteakkip transferi sonrası eş – benzer canlı doğum oranlarına ulaşılmaktadır. Pandian Z, Hum Reprod 2005, 20: 2681 We need improved embryo selection criteria, improved cryopreservation, reimbursement of ART, longer storage of cryopreserved embryos, xxxxxsedcrtfvgb jnkml,