Ovulation induction in oocyte donors Roma- September 2007 Dr. José Remohí Dr. Carmen Rubio Dr. Amparo Mercader Dr. Pilar Alama Dr. Marco Melo
Evolution of oocyte donation cycles 1500 1500 1000 58% 661 500 0 2000 2001 2002 2003 2004 2005 2006 Oocyte Donation Pregnancyes (days 3)
OOCYTE DONOR S PROTOCOLS We have analyzed with a P-R study, the influence in the use of agonist vs. antagonist of the GnRH in the ovarian stimulation in oocytes Donors. Parameters GnRHa Protocol Antagonist Protocol Prospective Randomized Number of cycles 1200 1200 ns BMI 23.5 24.1 ns Duration (days) 10.5 10.1 ns Gonadotrophin dose 2360 2245 ns E2 (hcg day) 2630 1520 <0.0505 P4 (hcg day) 0.9 0.8 ns Oocytes retrieved 19.4 18.6 ns Number of ET 2.09 2.01 ns Pregnancy rate (%) 58.2 56.1 ns Implantation ti rate (%) 33.8 31.6 ns Miscarriage rate (%) 11.3 12.1 ns
Different gonadotrophins- Long Protocol Using GnRH agonist we have analyzed different gonadotrophins protocols in a Prospective Randomized study Parameters hmg FSH FSH+LH Prospective Randomized Number of cycles 1000 1000 1000 ns BMI 23.1 22.5 23.7 ns Duration (days) 10.6 10.4 10.5 ns Gonadotrophin dose 2450 2500 2350 ns E2 (hcg day) 2850 2520 2710 ns P4 (hcg day) 0.9 1.01 0.9 ns Oocytes retrieved 19.3 18.7 19.5 ns Number of ET 2.01 1.9 2.0 ns Pregnancy rate (%) 57.2 56.8 59.1 ns Implantation rate (%) 32.1 33.5 33.33 ns Miscarriage rate (%) 11.1 11.7 11.3 ns
Low-dose hcg replacing the Gonadotrophins for Ovarian Stimulation 120 oocyte donors Group A (n= 30) Group B (n= 30) Group C (n= 30) Group D (n= 30) 200 FSH 100 FSH+100 hcg 50 FSH+200 hcg 200 hcg Start dose: 200 IU FSH When 1 follicle 14 mm, the gonadotrophin was changed according to the group
Low-dose hcg Protocol COH parameters A (n= 30) 200FSH B (n= 30) 100FSH+100hCG C (n= 30) 50FSH+200hC G D (n= 30) 200hCG Prospective Randomized Duration (days) 10.1 10.1 10.4 10.0 ns FSH dose (UI) 1797 ± 62 a,b 1488 ± 52 a 1428 ± 46 b 1218 ± 51 b a: p 0.001 b: p 0.0001 hcg dose (UI) - a 314 ± 18 a 588 ± 38 a 614 ± 25 a a: p 0.0001 E 2 - hcg day (pg/ml) 2493 ± 213 a,b 2853 ± 227 a,c 3149 ± 244 a,c 2269 ± 204 b,c b: p 0.04 a: p 0.01 c: p 0.01 P 4 - hcg day (ng/ml) 1.1 ± 0.2 1.1 ± 0.2 1.5 ± 0.3 1.0 ± 0.3 ns Number of oocytes retrieved 16.3 ± 1.5 a 19.1 ± 1.3 a 17.4 ± 1.6 a 12.3 ± 1.0 a a: p 0.04 We found lower E2 levels in te day of hcg administration in Group D. We also retrieved less oocytes in this Group
Low-dose hcg Protocol IVF outcome A (n= 41) B (n= 42) C (n= 31) D (n= 26) 200 FSH 100FSH+100hCG 50FSH+200hCG 200hCG Prospective Randomized Age (years) 39.9 ± 0.8 40.7 ± 0.6 39.4 ± 0.9 38.9 ± 0.9 ns Endometrium (mm) 9.4 ± 0.4 8.9 ± 0.3 9.1 ± 0.4 9.9 ± 0.9 ns Fertilization rate- ICSI (%) 72.0 ± 4.0 74.0 ± 3.0 75.0 ± 4.0 77.0 ± 4.0 ns Fertilization rate- FIV (%) 65.0 ± 80 8.0 67.0 ± 90 9.0 69.0 ± 10.00 85.0 ± 60 6.0 ns Number of embryos transferred 2,0 2,0 2,0 ± 0,1 2,0 ± 0,1 ns Pregnancy rate (%) 18/41 (44%) 20/ 42 (48%) 13/ 31 (42%) 19/ 26 (73%) p 0.01 Miscarriage rate (%) 3/ 18 (16.7%) 3/ 20 (15.0%) 2/ 13 (15.4%) 3/19 (15.8%) ns
For this part of the talk, we can conclude c that the young non sterile e donor women are going to have a very positive response to any ovarian stimulation protocol used
Previous experience 4In oocyte donation cycles, we observed that younger women who produced a significantly higher number of oocytes with significantly lower doses of gonadotrophins produced d embryos with a significantly ifi higher chromosomal abnormality rate. Mean Age Gonadotrophin dose Oocytes retrieved E2 levels (pg/ml) Chromosomally abnormal embryos Chromosomally abnormal embryos (%) (%) DONORS 26,5 * 2418 ** 25,4 *** 3347 79/140 (56.4) * CONTROL 31,3 3616 14,8 2492 25/67(37.3) *(p=0,01) 01) **(p=0,02) 02) ***(p=0,001) 001) 4The pattern shown in the table associates high ovarian response with increased frequency of chromosomally abnormal embryos. (Reis Soares et al.,, Fertility and Sterility 2003)
ADDITIONAL CONTRIBUTING INFORMATION In the study by Munné et al., 2006 It was found that the rate of chromosome abnormalities was higher In the oocyte donor group than in the non-donor group (p<0.001) 001) This could be due to the fact that the oocyte donor group has a higher response.
Can the percentage of aneuplodies be reduced by lowering the dosages of gonadotrophins in order to lower the high ovarian response?
Baart et al., 2007 A very interesting ti study in response to this question. (December 2002-August 2005) Conventional ovarian stimulation - Pituitary down-regulation with GnRH agonist - Fixed daily dose of 225 IU recombinant FSH Mild stimulation Fixed dose of 150 IU recombinant FSH GnRH antagonist
Baart et al., 2007 Conventional Mild OOCYTES 484(121 (12.1, 57) 5.7) 459 (8.3, 4.7) N embryos obtained 271 260 N embryos suitable for biopsy 184 (68) 157 (60) N embryos diagnosed 159 (86) 143 (91) Proportion of embryos with normal morphology 35% Abnormal embryos/embryos diagnosed 63% 35% 51% 63% 45% P. 0.04 P 0.016 Normal embryo/patient 1.8 1.8 NS With mild stimulation, the percentage of abnormal embryos was lower than with conventional stimulation. However, the average number of chromosomally normal embryos per patient was the same.
When each group was analyzed separately A conventional group showed no significant correlation between the number of oocytes obtained and abnormalities. Conventional Mild However, there was a positive correlation in the mild group. Baart et al., 2007
We are running a study with 10 donors 4Inclusion criteria oocyte donors: bage: g 18-35 years bbmi: 18-25 kg/m2 b No history of recurrent miscarriage or implantation ti failure bno PCO DONOR 1st Stimulation Conventional Dose DONOR 2nd Stimulation Half Dose PGD PGD
10 DONORS DONOR 1st Stimulation Conventional dose DONOR 2nd Stimulation Half Dose Agonist of GnRH - FSH 225 IU - LH 75 IU Agonist of GnRH - FSH 112 IU - LH 37.5 IU
When we compared the 10 donors using conventional stimulation vs. half doses, we found that: Conventional Half p Nº cycles 10 10 - Nº oocytes 203 (20.6, 2.2) 116 (12.0, 1.0) <0.05 Fertilization rate 78.3 82.4 NS No embryos analyzed 102 58 NS Nº abnormal embryos (%) 55 (54.5) 28 (49.1) NS Nº blastocyst D5 (%) 69 (67.6) 44 (75.9) NS Nº normal bl. (%) 39 (38.2) 24 (41.4) NS With l ti l ti f t bt i d b t With lower stimulation fewer oocytes were obtained, but the percentage of aneuploidies remained virtually the same.
10 DONORS High Responders 20 oocytes > 3000 pg/ml of E2 DONOR 1st Stimulation Conventional dose 5 women DONOR 2nd Stimulation Half Dose Normal Responders Agonist of GnRH - FSH 225 IU - LH 75 IU 5women go st o G Agonist of GnRH - FSH 112 IU - LH 37.5 IU
High Responders RESULTS Conventional Half p Nº cycles 5 5 - No. oocytes (mean, SEM) 125 (25.6,2.9) * 55 (11.6,1.5) * <0.05 Fertilization rate 84.8 80.5 NS No. embryos analyzed 63 29 - No. abnormal embryos (%) 32 (50.8) * 10 (34.5) * <0.05 No. blastocyst D5 (%) 46 (73.0) 24 (82.8) NS No. normal bl. (%) 27 (42.8) 16 (55.2) NS The results of high responders showed, that we significantly reduced the number of oocytes by almost half by lowering the doses. There was a significant decrease in chromosomal abnormalities with half stimulation protocols.
Normal Responders RESULTS Conventional Half p Nº cycles 5 5 - No. oocytes (mean, SEM) 76(152 (15.2, 1.1) 11) 62(12413) (12.4,1.3) NS Fertilization rate 69.2 84.0 NS No. embryos analyzed 38 28 - No. abnormal embryos (%) 23 (60.5) 18 (64.3) NS No. blastocyst D5 (%) 23 (59.0) 20 (69.0) NS No. normal bl. (%) 12 (31.6) 8 (28.6) NS The results for normal responders show that the number of oocytes is similar for the two types of stimulation. The number of chromosomal abnormalities is also similar for the two protocols. The number of normal blastocysts available from the tranfer is also similar
CONCLUSIONS 4This indicates that high responders react differently than normal responders when doses are lowered. 4In other words, there are fewer chromosomal abnormalities in this group.
Natural cycle In another study along these lines, which is extremely interesting, we studied the abnormal alterations in the embryos resulting from 15 donors without stimulation. - That means the Natural cycle. 15 DONORS 8 DONORS z 1 st 2 nd NATURAL CONVENTIONAL In 8 of them, we have completed a second cycle. This time with Conventional stimulation. Labarta et al., (unpublished data)
RESULTS Natural Conventional p Nº cycles 15 8 - Nº oocytes MII 15 (1.0, 0) 121 (18, 5) - Fertilization rate 100 66.1 NS No embryos analyzed 15 53 NS Nº abnormal embryos (%) 6 (40%) 24 (45.28) NS Nº normal bl. (%) 9 (60%) 27 (50.94) NS Surprisingly, the results show that in the natural cycle there was a high percentage of abnormal embryos (40%) which is similar to the percentage found in the conventional cycles (45,28%). But the number of normal blastocysts was much greater in the Conventional cycles. Labarta et al., (unpublished data)
RESULTS Natural Conventional p Nº Cycles 15 8 P Aneuploidies rate 40% 45,28% NS Clinical pregnancy rate 11,1% 71,4% 0,001 Implantation rate per ET 22,2% 66,6% 0,035 The clinical results further show that the pregnancy rate was much hhigher h in the conventional cycle than in the natural cycle. The implantation rate per embryo transfer was also much higher. Labarta et al., (unpublished data)
The current trend in IVF treatments is to stimulate ovulation as mildly as possible and the natural cycle is considered to be the most physiological. CONCLUSION Our clinical results for the natural cycle oblige us to use ovarian stimulation, but to also keep in mind that high responders may benefit from milder doses.