Egg donation in an in vitro fertilization program: an alternative approach to cycle synchronization and timing of embryo transfer

Transcription

1 FERTILITY AND STERILITY Copyright tl 1989 The American Fertility Society Printed on acid-free paper in U. S.A. Egg donation in an in vitro fertilization program: an alternative approach to cycle synchronization and timing of embryo transfer Isaac Ben-Nun, M.D.* Yehudit Ghetler, M.Sc. Arieh Gruber, M.D. Richard Jaffe, M.D. Moshe Fejgin, M.D. Department of Obstetrics and Gynecology "A ", In Vitro Fertilization Unit, Meir General Hospital and Sapir Medical Center, Kfar Saba, Israel In vitro fertilization (IVF) with embryo transfer (ET) and gamete intrafallopian transfer (GIFT), employing donated eggs, has become a well-established procedure for treatment of female infertility due to ovarian failure. 1,2 In most of the protocols, artificial endometrial cycles of the recipients have been created by giving ovarian steroids in sequential order and in incremental fashion in an effort to mimic the hormonal events of the normal menstrual cycle. 1 In 1987, Serhal and Crafe described a simplified hormone supplementation method for the recipient. They successfully induced receptive endometrium and achieved viable pregnancies using fixed estrogen and progesterone doses. However, due to the small number of reported cases and relatively limited experience of the various treatment centers, there remains a lack of consensus about the optimal method of hormonal management of the egg donation procedure. Herein, we present our own experience with a newly designed protocol for IVF and ET treatment using donated eggs. MATERIALS AND METHODS The treatment group consisted of seven women between 27 and 38 years of age. Two had premature Received February 1, 1989; revised and accepted June 16, * Reprint requests: Isaac Ben Nun, M.D., Department ofob stetrics and Gynecology "A", Sapir Medical Center, Kfar Saba 44281, Israel. menopause, two had surgically removed ovaries for benign conditions, and three had pure ovarian dysgenesis (streak ovaries with 46,XX kariotypes). The eggs were voluntarily donated by women who were undergoing IVF treatment. The women were stimulated with menotropins (human menopausal gonadotropins [hmg], Pergonal; Teva Ltd., Kfar Saba, Israel). Ten thousand units of human chorionic gonadotropin (hcg, Chorigon; Teva Ltd.) were given when three or more follicles were larger than 17 to 18 mm. The duration of the follicular phase varied between 8 and 12 days (mean, 8.8 days). Follicular aspiration was performed 32 to 34 hours later by either laparoscopy or transvaginal ultrasound-guided puncture. The starting points for the recipient and donor cycles were not synchronized, but only approximated with respect to the anticipated length of the follicular phase of the donor. During the proliferative phase, the recipients received a fixed dose of conjugated estrogens (Premarin; Dexxon Ltd., Haifa, Israel), 3.75 mg/d, divided into three daily 1.25-mg doses, for a variable period of time ranging from 9 to 14 days, to match the length of the follicular phase of the donor. The progesterone (P) administration, pure P in oil (Gestone, 50-mg ampoules; Paines and Byrne Ltd., Greenford, England; or Proluton, 25-mg ampoules; Schering A.G., Berlin Bergkamen, West Germany), administered intramuscularly, was started on the day that the egg-donating patients received hcg (Fig. 1). The hcg injection was given at 11:00 or 12:00 Ben-Nun et al. Communications-in-brief 683

2 EXPECTED ENDOMETRIAL DATING II I I I VARIABlE PAOli FERATlVE PHASE PROGESTERONE D 50mg o PREMARIN 1.25 mg I 1 HCG DONOR PREGNANCY TEST 1()'12 DAYS AFTER t OPU III f I PREGNANCY) CONT../ I T7 I 1/ II V Figure 1 Induction of artificial endometrial cycle of the recipient. P.M., about 10 hours after the first P injection (given around 2:00 P.M.). In all but one treatment cycle, the recipients received two daily doses of 50 mg P about 12 hours apart. One woman, Case No. 1 (one treatment cycle), was given three daily 25- mg P doses. This initial P dose was continued thereafter. Beginning on the first day of P supplementation, the daily estrogen dose was reduced to 1.25 to 2.5 mg/d until the day of ET. The initial estrogen dose of3.75 mg/d was resumed on the day of ET and then maintained at that level. Blood samples for 17{3-estradiol (E2) and P were taken on the day before the onset of P administration, daily until the day of ET, and thereafter three times per week. A blood test for {3-hCG was done 10 to 14 days after ET. In the conception cycles, the administration of estrogen, 3.75 mg/d, and P, 100 mg/d, were continued until the plasma E2 and P showed a sustained rise above the base level. First, the estrogen dose was gradually decreased and discontinued (Fig. 2). Approximately a week later, the P injections were Table 1 Clinical and Laboratory Data for 12 Treatment Cycles Discontinuation of steroid replacement Last day of Embryo transfer day after embryo Duration of proliferative- transfer proliferative phase No. of Case phase E 2" E2 pb embryos Outcome EC P d pg/ml pg/ml ng/ml d Id Singleton Twins Singleton Not pregnant 4' Singleton Not pregnant Not pregnant Not pregnant , Not pregnant Not pregnant Not pregnant Not pregnant " E 2, estradiol. ' Estrogen supplementation discontinued initially at day 43 b P, progesterone. and P at day 59. Resumed due to sharp fall in P level and vaginal C E, estrogen. bleeding. d Received P supplementation of 75 mg/d. 684 Ben-Nun et al. Communications-in-brief Fertility and Sterility

3 E, Pg/ml '800 '600 '000 '200 ' Figure 2 Estradiol measurements during the early pregnancy period. Circles indicate discontinuation of the estrogen supplementation '00 '0 5 0 '0 ' a '00 DAYS FROM reduced to 50 mgjd and then stopped (Fig. 3). At that time, each patient received one intramuscular injection of 500 mg Proluton Depo (Schering A.G.). In one case, the daily P injections and estrogen supplementation were renewed for an additional 10 days after the patient started to bleed vaginally and P blood levels fell sharply (Table 1). RESULTS The seven treated women had a total of 12 cycles with ET, resulting in four term pregnancies. Table 1 presents pertinent clinical and laboratory data on the treatment cycles. DISCUSSION The results of this and a previous study3 clearly demonstrate that a properly receptive endometrium can be induced without simulation of hormonal dynamics of the spontaneous menstrual cycle. As shown recently, sufficient proliferation of a dormant endometrium and adequate secretory transformation can be produced, even after such a brief period as 10 days of estrogen administration. 4 Conversely, the flexibility of the current protocol permits extension of the proliferative phase, if some additional time is required for cycle synchronization with the donor cycle. In this respect, our approach for induction of endometrial growth and proliferation is in agreement with the concept proposed by Serhal and Craft.3 While in a standard IVF -ET treatment, conceptuses are being transferred 2 days after follicle aspiration; variable timing of ET has been reported in cases with donated eggs. In a cumulative study of 102 treatment cycles, Rozenwaks 1 noted that no conceptions were achieved when ET was carried out after day 20 ofthe idealized recipient's endometrial cycle, whereas the highest success rate has been recorded when ET was performed between days 17 and Croxatto et al. 5 have shown that in spontaneous cycles, embryo implantation probably takes place about 5 to 7 days after ovulation. At this time, the histological dating of the endometrium should correspond to day 19 to 21 of the 28-day cycle. There- Ben-Nun et al. Communications-in-brief 685

4 Prog. ng I ml ~ DA YStPREMAAIN Figure 3 Progesterone measurements during the early pregnancy period. Circles indicate discontinuation of the progesterone supplementation. In case 4, the progesterone administration was resumed "R," shortly after the discontinuation. (Interrupted cycle) About 10 days later, P administration was finally stopped (thickened circle).. fore, we began to administer P 4 days before the expected date of ET, in an effort to mimic the natural endometrial development. Meanwhile, we made allowances for a decline in the serum E2 levels from the onset of the P supplementation until the day of ET. This step was empirically taken in the belief that a reduced estrogen availability might enhance the progestative effect on the endometrium. Csapo and co-workers 6 have shown that the luteal placental hormonal takeover occurs at about 7 to 8 weeks' gestational age. Our study indicates that, apparently, in this respect, there is no difference between the pregnancies in agonadal and those of normally cycling women. In the case of the twin pregnancy, however, significant elevations of E2 and P were detected earlier than anticipated. It would be logical to assume that the augmented steroidogenesis in this case was caused by the presence of a larger placental mass. As a precaution, we administered one Depo progesterone injection at the time of hormonal support withdrawal. However, the sharp drop in P level observed in Case No. 4 calls into question the potential of this preparation to produce adequate levels of P serum. The success rate for the present treatment protocol compares well with previous reports, l even though additional studies are required for a better understanding ofthe process, and for a wider comparison of different protocols. SUMMARY A new flexible protocol for the induction of recipient endometrial cycles is presented. For stimulation of endometrial growth, a fixed dose of conjugated estrogens, 3.75 mg/d was employed. The duration of the proliferative phase varied from 9 to 14 days, thus being adjusted to match the length of the follicular phase of the donor. Embryo transfer was performed on the fifth day of progesterone administration. Four term pregnancies resulted from 12 treatment cycles. In the conception cycles, the hormonal support was continued until the luteal placental shift occurred, regardless of gestational age. Acknowledgment. We are indebted to Mrs. Sally Esakov for her assistance in the preparation of this manuscript. REFERENCES 1. Rosenwaks Z: Donor eggs: their application in modern reproductive technologies. Fertil Steril4 7:895, Ben-Nun et al. Communications-in-brief Fertility and Sterility

5 2. Asch RH, Balmaceda JP, Ord T, Borrero C, Cefalu E, Gastaldi C, Rojos F: Oocyte donation and gamete intrafallopian transfer in premature ovarian failure. Fertil Steril 49:263, Serhal PF, Craft IL: Ovum donation-a simplified approach. Fertil Steril48:265, Boyers SP, Thatcher SS: Endometrial histology and serum estradiol (E 2), progesterone (P), follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels during 28 versus 24-day programmed replacement cycles in patients with premature ovarian failure (POF). (Abstr.) Presented at the 44th Annual Meeting of The American Fertility Soci- ety, Atlanta, Georgia, October 10 to 13, Published by The American Fertility Society in the 1988 Abstracts of Scientific Paper and Poster Sessions, 1988, p S2 5. Croxatto HB, Diaz S, Fuentealba B, Croxatto HD, Carrillo D, Fabres C: Studies on the duration of egg transport in the human oviduct. I. The time interval between ovulation and egg recovery from the uterus of normal women. Fertil Steril 23:447, Csapo AI, Pulkinnen KO, Weist WG: Effects of luteetectomy and progesterone replacement therapy in early pregnant patients. Am J Obstet Gynecol 115:759, 1973 Ben-Nun et al. Communications-in-brief 687