Hainan Reproduction vol.7 suppl.l pp.85-88, 1992

Indications for oocyte donation

P.N. Barri1, B. Coroleu, F. Martinez, N. Parera, A. Veiga, G. Calderdn, M. Boada, and I. Belil Service of Reproductive Medicine, Department of Obstetrics and Gynaecology, Institut Universitari Dexeus, Passeig Bonanova 67, 08017 Barcelona, Spain 'To whom correspondence should be addressed

Donated oocytes were transferred on 92 occasions to 87 women without gonadal function and 5 with functional ovaries. Twenty-three pregnancies were established (25% pregnancy rate), 9 after transfer of fresh embryos in 30 synchronous donor and recipient cycles and 14 after transfers of frozenthawed embryos in 62 asynchronous donor and recipient cycles. Twenty-two pregnancies were obtained in agonadal patients (253% pregnancy rate) and 1 in a gonadal woman (20% pregnancy rate). Pregnant women were younger than those who did not become pregnant, but the difference was not significant The pregnancy rate was higher when intra-Fallopian transfer was performed (46%) as compared with intrauterine transfer (21.5%) and when micronized progesterone was given intravaginally (pregnancy rate 30.3%) as compared to intramuscularly injected natural progesterone in oil (pregnancy rate 22%). Twenty healthy infants have been born including one set of twins; four pregnancies miscarried.

Key Words: Embryo transfer / intra-Fallopian transfer / intrauterine transfer / oocyte donation / ovarian failure

Introduction

Oocyte donation is a relatively recent development in the rapidly expanding field of in vitro fertilization (IVF) and embryo transfer and is the only way of producing a pregnancy for couples where oocytes are not available (Liitjen et al., 1984; Devroey et al., 1987; Rosenwaks, 1987). Oocyte donation involves egg retrieval from the donor, insemination with semen of the recipient's partner, in vitro culture, and transfer of cleaved embryos into the recipient's uterus. Different groups of patients may require egg donation to alleviate their infertility, including women without gonadal function, patients with repeated failures of assisted conception, and those with inheritable genetic problems (Devroey et al., 1989a; Hens et al., 1989). In this report, we describe our oocyte donation programme and analyze the factors which influence the success of ovum donation procedures. Materials and methods

Ninety-two cycles of ovum donation were studied in 177 pa© Oxford University Press

tients, with a mean (±SD) age of 34.0 (±4.1) years, who attended our Centre for Reproductive Medicine for alleviation of their infertility problems between September 1987 and December 1990. The mean duration of their infertility was 8.7 ± 4.2 years. The indication for treatment was primary ovarian failure in 159 patients (gonadal dysgenesis 27, premature menopause 77, and surgical or radiotherapy-induced castration 55). The remaining 18 women with functional ovaries were treated because of repeated failed attempts in the course of IVF cycles in 10, and the presence of genetic factors which may have been passed to their offspring in eight. The work-up of all patients consisted of a clinical, hormonal and cytogenetic evaluation. Routine assessment of the male partner included determinations of sperm concentration, motility and morphology, and the mixed antiglobulin reaction (MAR-test). Steroid replacement therapy of the agonadal recipients included oestradiol valerate (ProgynovaR, Schering, Berlin, FRG) administered orally in various concentrations (days 1-5, 1 mg; days 6-9, 2 mg; days 10-13, 6 mg; days 14-15, 2 mg; days 16-26, 4 mg; days 27-28, 2 mg) and two different regimens of progesterone, either natural progesterone in oil (Progesterone11, Lilly, Indianapolis, IN) (25 mg intramuscularly on days 13-14 and 50 mg daily from days 15 to 26), or intravaginal micronized progesterone (UtrogestanR, Besins-Iscovesco, Paris, France) day 14, 300 mg; days 15-16, 900 mg). The effectiveness of the steroid replacement therapy was assessed by taking an endometrial biopsy on day 21 and by measuring serum oestradiol (E2) and progesterone on days 16 and 24. In women with normal ovarian function, the embryos were replaced during a natural cycle. Oocytes were donated by IVF patients who agreed to donate extra oocytes, provided that no male factor infertility was present, by patients undergoing laparoscopic sterilization, and by volunteers brought by the recipients, i.e. relatives or friends of the patients were asked to donate to the programme thus creating a pool of oocytes which were used for other patients. All donors were between 18 and 40 years of age, had children, and were unknown to the recipient. The donors were assessed by interview for genetic and psychological factors. They were screened for hepatitis and HIV antibodies. All donors underwent ovarian stimulation with a gonadotrophin releasing hormone (GnRH) analogue (ProcrinR, Abbott Laboratories, Madrid, Spain) administered from day 22 of the cycle preceding the IVF treatment at a dose of 1 mg/day subcutaneously, and continued for 10 days. On the 3rd day of menstruation, a daily injection of 225 IU of human menopausal gonadotrophin (HMG) (PergonalR, Serono, S.A., Barcelona, Spain) was started, and continued for 7 days. The subsequent dose of HMG was determined according to follicular growth. The recipient started oestradiol valerate 2 days before the donor started HMG and was given progesterone on the same day that the donor received 10000 IU of human chorionic gonadotro-

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phin (HCG) (ProfasiR, Serono, S.A., Barcelona, Spain). Between 34 and 36 hours later, the oocytes were retrieved by laparoscopy (patients undergoing tubal sterilization) or ultrasound-guided transvaginal follicle puncture (IVF patients and volunteers). Thus, the fertilized ovum was replaced on the fourth to fifth day of progesterone administration (on days 17 and 18 of the artificial cycle). Donors received further treatment with GnRH analogue during the luteal phase in order to reduce the risk of hyperstimulation syndrome. In vitro fertilization and embryo culture were performed as described previously. Oocytes were cultured in Menezo B2 medium and inseminated with 100000 motile spermatozoa prepared by the swim-up technique or using Percoll gradients (Veiga el al., 1987). If more than three embryos were obtained they were frozen in early stages. When the cycles of the donor and recipient were synchronous, fresh embryos were transferred, otherwise frozen-thawed embryos were used. The method of transfer (intrauterine or intratubal) was determined by the state of the tubes. To maintain pregnancy in agonadal women, either 50-150 mg natural progesterone in oil (Progesterone1*, Lilly, Indianapolis, IN) or 300-900 mg intravaginal micronized progesterone (UtrogestanR, Besins-Iscovesco, Paris, France) together with 3-6 mg oestradiol valerate (ProgynovaR, Schering, Berlin, FRG) was given daily. Serum levels of oestradiol and progesterone were measured at 5-day intervals. The ovum donation programme was approved by the Ethical Committee of "Institut Universitari Dexeus". After careful counselling, written consent was obtained from donors and recipients. Results Of the 92 cycles of oocyte donation, 87 were done in patients without gonadal function (primary ovarian failure: Turner's syndrome 15, 46, XY karyotype 1; secondary ovarian failure: premature menopause 42, surgical or radiotherapy-induced castration 29) and 5 in patients with functional ovaries (failed IVF cycles 3, definitive carrier of an X-linked disease, 2). A total of 23 pregnancies were established (25% pregnancy rate) of which 22 were obtained in agonadal patients (25.3% pregnancy rate) and 1 in gonadal women (20% pregnancy rate) (Table I). Twenty healthy infants were delivered, including one set of twins. Four (17.4%) miscarriages occurred, all of them in agonadal women (primary ovarian failure 1, secondary ovarian failure 3). Pregnant women were younger than those who did not become pregnant (mean age, 34.7 ± 4.2 vs 35.6 ± 6.3 years), although the difference was not statistically significant. The source of the 117 donated oocytes were 70 patients from the assisted conception programme and 47 fertile volunteers. Nine pregnancies were attained after replacements of fresh embryos (mean, 2.7 ± 0.7 embryos per transfer) in 30 synchronous donor and recipient cycles (pregnancy rate 30%), whereas 14 pregnancies were established after transfers of frozen-thawed embryos (1.5 ± 0.5 embryos per transfer) in 62 asynchronous donor and recipient cycles (pregnancy rate 22.6%) (Table II). The pregnancy rate was higher when intra-Fallopian transfer was performed (6/13; 46%) as compared with intrauterine trans86

Table I. Establishment of 23 pregnancies in 92 cycles of oocyte donation Patients

No. pregnancies/ no. cycles

Pregnancy rate (%)

22/87 4/16 4/15 0/1 18/71 10/42 8/29 1/5 0/3 1/2

25.3% 25.0% 26.6%

Agonadal women Primary ovanan failure Turner's syndrome 46, XY karyotype Secondary ovarian failure Premature menopause Castration Gonadal women Failed IVF cycles Carrier of X-linked disease

25.3% 23.8% 27.5% 20.0% 50%

Table II. Oocyte Donation in Synchronous and Asynchronous Donor and Recipient Cycles Data

Donor and Recipient Cycles Synchronous Asynchronous

No. Donation cycles

30

62

Embryos per transfer

2.68±0.7

1.52±0.5

No. Pregnancies

9

14

Pregnancy rate (%)

30

22.6

fer (17/79; 21.5%) The implantation rate was 25% for intratubal embryo replacement (mean ± 2SD, 2.2 ± 0.7 embryos per transfer) as compared to 17% for intrauterine embryo replacement (1.85 ± 0.7 embryos per transfer). Natural progesterone in oil was injected intramuscularly in 59 oocyte donation cycles and micronized progesterone was administered intravaginally in 33 cycles (Table III). Ten pregnancies were established after intravaginally administered micronized progesterone (n - 33 cycles; 2.75 ± 0.5 embryos per transfer, pregnancy rate 30.3%) and 13 after intramuscularly injected natural progesterone in oil {n - 59 cycles; 2 ± 0.7 embryos per transfer, pregnancy rate 22%). Two miscarriages occurred in each group. On the day of embryo transfer, mean levels of

Table III. Oocyte donation and regimen of progesterone administration Data

No. Donation cycles Oestradiol (pg/ml) Progesterone (ng/ml) Embryos per transfer No. Pregnancies (%) No. Miscarriages (%)

Route of progesterone administration Intramuscular Intravaginal 59 418.4± 151.5 20.9 ±8.1 2 ±0.7 13 (22) 2(15.3)

33 649.2 ±85.4 10.6± 1.3 2.75±0.5 10 (30.3) 2(20)

Indications for oocyte donation

oestradiol and progesterone were 649.2 ± 85.4 pg/ml and 10.6 ±1.3 ng/ml in patients treated with progesterone intravaginally and 418.4 ± 151.5 pg/ml and 20.9 ± 8.1 ng/ml, respectively, in patients given intramuscular progesterone. Discussion Although agonadal patients are the major candidates for oocyte donation, women with unsuccessful IVF attempts, in whom a poor response to ovarian stimulation has been related to an insufficient response to the clomiphene citrate challenge test, are becoming frequent candidates for ovum donation (Loumaye et ai, 1990; Barri et ai, 1991). In this series of 92 cycles of oocyte and embryo donation in infertile couples, a pregnancy rate of 25% was achieved. Patients with ovarian failure had similar pregnancy rates (25%) to those with intact ovaries (20%). A better outcome for patients with primary ovarian failure as compared to those with secondary ovarian failure was not found. Adequate receptivity of the endometrium was obtained after intramuscular injection or vaginal administration of micronized progesterone (Devroey et al., 1989b), although higher serum levels of progesterone were present after intramuscular injection. However, the use of vaginally administered progesterone is easier and represents a valuable increase in comfort for the patient, compared to the two to three daily intramuscular injections of progesterone in oil for several weeks. The success rate of oocyte donation was influenced by the method of transfer. Intra-Fallopian transfer provided better pregnancy rates (46.1%) than intrauterine transfer (21.5%), in agreement with Abdalla et al. 1990. An important factor in the success of an ovum donation programme is the synchronization of ovarian cycles in donor and recipient. Although the storage of embryos by cryopreservation avoids the need for synchronization and eliminates the time factor, cryopreservation has an important drawback, that is, the embryonic loss occurring after freezing and thawing (Veiga et ai, 1987; Salat-Baroux et ai, 1988). This should prompt adjustments to the synchronization technique (Devroey et al., 1989a). The combined use of GnRH analogues and HMG for ovarian stimulation provides an alternative means of synchronizing cycles in donor and recipient. It is also important to determine the number of weeks for which it is necessary to continue the steroid replacement therapy to maintain pregnancy. Ovarian steroid maintenance of pregnancy shifts to the placenta at about the 6th week of gestation for oestradiol and about the 8th week for progesterone (Navot et al., 1986, Liitjen et al., 1987; Laufer et al., 1987). In pregnant women with a complete absence of ovarian function, exogenous steroid hormones must be given until this shift. However, Devroey et al. (1989b) and Davis and Rosenwaks (1990) suggested that the shift may occur earlier at 5 weeks gestation. We recently obtained a successful triplet pregnancy in a woman in whom three embryos were transferred and, by mistake, steroid replacement was discontinued on day 10 after embryo replacement. Our centre respects the religious attitudes of the patients (Kemeter et ai, 1987; Schenker et ai, 1987) and excludes

known donations. In the case of IVF patients, the patient donates to the programme one in three oocytes obtained from the 12th onwards. In conclusion, although we achieved a 25% pregnancy rate with oocyte donation, a further increase may be expected if more donors become available, if cryopreservation methods improve and if synchronization techniques are adjusted. Acknowledgement The authors are grateful to Marta Pulido, M.D. for editorial assistance and copy editing. References Abdalla, H.I., Baber, R., Kirkland, A., Leonard, T., Power, M., and Studd, J.W.W. (1990) A report on 100 cycles of oocyte donation; factors affecting outcome. Hum. Reprod., 5, 1018-1022. Barri, P.N., Coroleu, B., Calderon, G., Martinez, F., Maristany, P., Belil, I., Carrera, O., Boada, M., Aran, B. and Pascual, M.A. (1991) Influencia del protocolo de estimulacion en la evolucion de un ciclo de F1V. Proceedings del XIX Congreso de la Sociedat Espagfiola de Fertilidad. Edt. F.J. Rodriguez Escudero. San Sebastian (Spagfia), 1991. Davis, O.K. and Rosenwaks, S. (1990) The impact of IVF on the treatment of castrate women. Semin. Reprod. Endocrinoi, 8, 313-318. Devroey, P., Braeckmans, P., Camus, M, Khan, I., Smitz, J., Staessens, C, Van Der Abbeel, E., Van Waesberghe, L., Wisanto, A. and Van Steirteghem, A.C. (1987) Pregnancies after replacement of fresh and frozen-thawed embryos in a donation program. In Feichtinger, W. and Kemeter, P. (eds). Future Aspects in Human In Vitro Fertilization. Springer-Verlag, Berlin Heidelberg, pp. 133-137. Devroey, P., Camus, M., Van Den Abbeel, E., Van Waesberghe, L., Wisanto, A. and Van Steirteghem, A.C. (1989a) Establishment of 22 pregnancies after oocyte and embryo donation. Br. J. Obstet. Gynaecoi, 96, 900-906. Devroey, P., Palermo, G., Bourgain, C, Van Waesberghe, L, Smitz, J. and Van Steirteghem, A.C. (1989b) Progesterone administration in patients with absent ovaries. Int. J. Fertil. 34, 188-193. Hens, L., Devroey, P., Van Waesberghe, L., Bonduelle, M., Van Steirteghem, A.C. and Liebaers, I. (1989) Chromosome studies on fertility treatment in women with ovarian failure. Clin. Genet., 36, 81-91. Kemeter, P., Feichtinger, W. and Bernat, E. (1987) The willingness of infertile women to donate eggs. In Feichtinger, W. and Kemeter, P. (eds) Future Aspects in Human in Vitro Fertilization. SpringerVerlag, Berlin Heidelberg, pp. 145-153. Laufer, N., Navot, D., Rabinowitz, R., Lewin, A, Berkenfeld, A., Mangalioth, E.J. and Schenker, J. (1987) Pregnancies in the absence of ovaries - Parameters affecting outcome. In Feichtinger, W. and Kemeter, P. (eds). Future Aspects in Human In Vitro Fertilization. Springer-Verlag, Berlin Heidelberg, pp. 138-144. Loumaye, E., Psalti, I., Billion, J-M., Pensis, M., Mine, J-M. and Thomas, K. (1990) Prediction of individual response to controlled ovarian hyperstimulation by means of a clomiphene citrate challenge test. Fertil. Steril., 53, 295-301. Lfltjen, P., Trounson, A., Leeton, J., Findlay, J., Wood, C. and Renou, P. (1984) The establishment and maintenance of pregnancies using in vitro fertilization and embryo donation in a patient with primary ovarian failure. Nature, 307, 174-175.

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Lfltjen, P.J., Healy, D.L., Chan, C, Findlay, J.K., Kola, I. and Trounon, A.O. (1987) Oocyte and embryo donation in women with absent ovarian function. In Feichtinger, W. and Kemeter, P. (eds). Future Aspects in Human In Vitro Fertilization. Springer-Verlag, Berlin Heidelberg, pp. 125-132. Navot, D., Laufer, N., Kopolovic, J., Rabinowitz, R., Birkenfeld, A., Lewis, A., Granat, M., Margalioth, E.J. and Schenker, J.G. (1986) Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries. N. Engl. J. Med. 314, 806-811. Rosenwaks, Z. (1987) Donor eggs: their application in modem reproductive technologies. Fertil. Sterii, 47, 895-909. Salat-Baroux, J., Tibi, C, Cornet, D., Mandelbaum, J., Alvarez, S., Plachot, M. and Antoine, J.M. (1988) Pregnancies after replacement of frozen-thawed embryos in a donation program. Fertil. Sterii., 49, 817-821. Schenker, J.G. (1987) Religious aspects of gamete donation in in vitro fertilization and embryo transfer programs. In Feichtinger, W. and Kemeter. P. (eds). Future Aspects in Human In Vitro Fertilization. Springer-Verlag, Berlin Heidelberg, pp. 154-159. Veiga, A., Calderon, G., Barri, P.N. and Coroleu, B. (1987) Pregnancy after replacement of a frozen-thawed embryo with

Indications for oocyte donation.

Donated oocytes were transferred on 92 occasions to 87 women without gonadal function and 5 with functional ovaries. Twenty-three pregnancies were est...
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