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Results of tubal embryo transfer in premature ovarian failure
FERTILITY AND STERILITY
Vol. 54, No.2, August 1990
Copyright <> 1990 The American Fertility Society
Printed on acid-free paper in U.S.A.
Results of tubal embryo transfer in premature ovarian failure
Daniel A. Rotsztejn, M.D.* Jose Remohi, M.D.* Louis N. Weckstein, M.D.* Teri Ord*
Dean L. Moyer, M.D.t Jose P. Balmaceda, M.D.* Ricardo H. Asch, M.D.*:j:
University of California, Irvine, Orange, California, and University of Southern California, Los Angeles, California
Premature ovarian failure is usually defined by the triad of amenorrhea, estrogen (E) deficiency, and elevated concentration of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in women under the age of 40 years. It has been estimated that between 1 % and 3 % of the general population represents females with premature ovarian failure. Until recently, women suffering from premature ovarian failure were regarded as having untreatable sterility. This was challenged when the first successful pregnancy after in vitro fertilization and embryo transfer (IVF -ET) using donated oocytes into a primary ovarian failure recipient treated with steroid replacement was reported by an Australian team at Monash University. In 1986, we reported the first pregnancy obtained using gamete intrafallopian transfer (GIFT) with donated oocytes and husband's sperm in a premature ovarian failure patient. 1 This approach also has been corroborated by other groups showing an average pregnancy rate between 36% and 54% per treatment cycle. 2 Successful pregnancies in patients suffering from premature ovarian failure also have been established via nonsurgical recovery and transfer of donated embryos (ovum transfer Received December 27, 1989; revised and accepted April 13, 1990. * Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of California, Irvine. t Department of Pathology, Obstetrics and Gynecology, University of Southern California. :j: Reprint requests: Ricardo H. Asch, M.D., Department of Obstetrics and Gynecology, University of California, Irvine, 101 The City Drive, Orange, California 92668.
348
Rotsztejn et al.
Communications-in-brief
technique).3 Since tubal embryo transfer (TET) seems to be an excellent technique for treating infertile patients with patent fallopian tubes, 4 we were encouraged to offer this technique to premature ovarian failure patients. The purpose of this communication is to report the first series of TET performed in patients with premature ovarian failure, using donated oocytes.
MATERIALS AND METHODS Recipients
Eleven recipients were between 26 and 42 years of age (mean = 33.6). All the patients had longterm idiopathic premature ovarian failure developing between the ages of 20 and 37 years. Diagnosis of premature ovarian failure was based on clinical criteria (amenorrhea) and hormonal criteria (serum postmenopausal levels ofFSH and LH). Tubal patency was confirmed 3 to 6 months before TET by either laparoscopy with normal prompt tubal spillage of dye or normal hysterosalpingogram. All patients underwent an evaluation cycle on admission to the oocyte donation program, as previously described. 1 During the TET cycle, subjects received the same regimen of E replacement as in the evaluation cycle. They received the following steroid replacement: micronized 17.B-estradiol (E 2 ) orally (Estrace; Mead Johnson, Evansville, IN), 2 mg on days 3 to 8; 4 mg on days 9 to 11; and 6 mg on days 12 to 28. Progesterone injections were started on the day of transvaginal aspiration of the donated oocytes. After follicular aspiration, 00Fertility and Sterility
Table 1
Patient Characteristics and Results of Tubal Embryo Transfer
Case
Age"
No. embryos transferred
1 2 3 4 5 6 7 8 9 10
20 (26) 35 (37) 31 (37) 30 (37) 26 (33) 34 (37) 27 (32) 23 (24) 24 (32) 37 (42) 31 (34)
5 4 4 3 4 4 3 4 4 4 3
11
Pregnancy
Outcome no. gestational sacs
Comment
+ + + +
1 1 2 1
Singleton delivery Miscarriage Ongoing Miscarriage
" Age is given at time of premature ovarian failure; and current age is presented in ( ).
cytes were inseminated; the embryos produced in vitro were transferred to the fallopian tubes as reported by Balmaceda et al. 5 If pregnancy was confirmed 14 days after TET by a positive ,a-human chorionic gonadotropin (,a-hCG) radioimmunoassay measurement, E 2 , and P were increased to 8 mgjd and 100 mgjd, respectively, until day 94 of gestation. Donors Four of the 11 donors were patients who underwent assisted conception techniques (IVF, GIFT, or TET). They agreed to donate their extra oocytes not used for transfer. A separate consent form was signed before the procedure by both the recipients and the donors. Four donors were patients undergoing diagnostic laparoscopies. Before laparoscopy, these patients agreed to a cycle of ovarian stimulation and to donate oocytes. In these 8 patients, the donation was anonymous and nonfinancially reimbursed. We selected recipients for oocyte donation who were within 12 to 14 days of E replacement from our waiting list. The selection of recipients was based primarily on the timing of their cycles and their ethnic similarities to the potential donors. Three of the 4 donors became pregnant during the cycle of assisted reproductive technique in which they donated extra oocytes. The remaining three donors were solicited by the recipients themselves; one was a patient's sister, and the other two donors were unrelated to the recipients. In these three nonanonymous donations, recipients started the hormone replacement on the second day of the donor's menstrual cycle. Donors received the following protocol for induction of follicular development: leuprolide acetate 1 mgjd subVol. 54, No.2, August 1990
+
Twins delivery
+ + + +
Ongoing Ongoing Ongoing Ongoing
1 1 2 2 b
One vanished gestational sac.
cutaneously (Lupron; TAP Pharmaceuticals, Chicago, IL) initiated between days 22 and 24 of a previous cycle; FSH (Metrodin; Serono Laboratories, Inc., Randolph, MA) 150 IU daily days 2 and 3 combined with human menopausal gonadotropin (hMG; Pergonal, Serono Laboratories, Inc.) 150IU daily from day 2 until two follicles were> 18 mm by transvaginal ultrasound (US) and E 2 1evels were at least 700 pgjmL. Human chorionic gonadotropin (Profasi; Serono Laboratories, Inc.) 10,000 IU intramuscularly was given, and 36 hours later, follicular aspiration under transvaginal US guidance was performed. RESULTS
Of the 11 patients treated, 9 became pregnant, giving a clinical pregnancy rate of 81.8% per transfer. We define clinical pregnancy when a gestational sac is visualized on US. Implantation rate was calculated by dividing the number of gestational sacs (n = 14) by the number of embryos transferred (n = 42); that represents a 33.3% chance that 1 embryo implanted will develop into a gestational sac. Two patients miscarried at 5 and 9 weeks, respectively, after TET (20%). One patient has already delivered a newborn by spontaneous vaginal delivery at 259 days after TET, and another patient delivered twins by cesarean section, for obstetrical indications at 256 days after TET. In both cases the infants were normal. Five patients have ongoing uneventful pregnancies: 3 singletons and 3 sets of twins (Table 1). DISCUSSION
This is the first report of a series with pregnancies and birth of normal children resulting from the Rotsztejn et al.
Communications-in-brief
349
donation of oocytes and TET in patients with premature ovarian failure. The results of the tubal embryo transfer procedure in this population have provided a novel approach for the treatment of infertility in couples previously considered to be irreversibly sterile. The clinical pregnancy rate of 81.8% obtained per transfer is markedly superior to that obtained with TET during stimulated cycles in regularly cycling women. Similarly, improved pregnancy rates in premature ovarian failure subjects have been also reported using GIFT and IVF -ET with donated oocytes. Some of the theories that could explain these improved results are related to the lack of hyperstimulation, hyperestrogenism, lack of premature luteinization, and their potential deleterious effect on endometrial receptivity. Furthermore, the implantation rates observed in this study are much greater than those reported previously in normal cycling women undergoing IVF -ET. This difference may be explained by: (1) exposure of the early embryo to the fallopian tube; (2) synchronous arrival to the uterine cavity before implantation; and (3) transfer to the tube, avoiding the potential mechanical problems associated with uterine transfer. Similarly, Yovich et a1. 6 found a significantly increased pregnancy rate in patients who receive TET when compared with matched subjects receiving IVF-ET. It appears from this small series of subjects that TET is an excellent technique for the treatment of premature ovarian failure subjects with patent fallopian tubes. Future randomized studies among GIFT, IVF -ET, and
350
Rotsztejn et a1.
Communications-in-brief
TET will be necessary to prove whether there is any significant difference among these techniques in the success rate for agonadal patients in which oocyte donation is indicated. SUMMARY
The transfer of embryos generated in vitro to the fallopian tubes in 11 cases of premature ovarian failure resulted in 9 clinical pregnancies. This approach may have theoretical advantages over GIFT and IVF-ET in agonadalpatients. Acknowledgment. We thank Mrs. Toula Batshoun for her collaboration in this study. REFERENCES 1. Borrero C, Remohi J, Ord T, Balmaceda JP, Rojas F, Asch RH: A program of oocyte donation and gamete intrafallopian transfer. Hum Reprod 4:275, 1989 2. Serhal PF, Craft IL: Oocytes donation in 61 patients. Lancet 1:1195, 1989 3. Sauer MV, Macaso TM, Ishida EH, Giudice L, Marshall JR, Buster JE: Pregnancy following nonsurgical donor ovum transfer to a functionally agonadal women. Fertil Steril48:324, 1987 4. Devroey P, Staessen C, Camus M, DeGrauwe E, Wisanto A, Van Steirteghem AC: Zygote intrafallopian transfer as a successful treatment for unexplained infertility. Fertil Steril 52:246, 1989 5. Balmaceda JP, Gastaldi C, Remohi J, Borrero C, Ord T, Asch RH: Tubal embryo transfer as a treatment for infertility due to male factor. Fertil Steril50:476, 1988 6. Yovich JL, Blackledge DG, Richardson PA, Matson PL, Turner SR, Draper R: Pregnancies following pronuclear stage tubal transfer. Fertil Steril48:851, 1987
Fertility and Sterility
Vol. 54, No.2, August 1990
Copyright <> 1990 The American Fertility Society
Printed on acid-free paper in U.S.A.
Results of tubal embryo transfer in premature ovarian failure
Daniel A. Rotsztejn, M.D.* Jose Remohi, M.D.* Louis N. Weckstein, M.D.* Teri Ord*
Dean L. Moyer, M.D.t Jose P. Balmaceda, M.D.* Ricardo H. Asch, M.D.*:j:
University of California, Irvine, Orange, California, and University of Southern California, Los Angeles, California
Premature ovarian failure is usually defined by the triad of amenorrhea, estrogen (E) deficiency, and elevated concentration of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in women under the age of 40 years. It has been estimated that between 1 % and 3 % of the general population represents females with premature ovarian failure. Until recently, women suffering from premature ovarian failure were regarded as having untreatable sterility. This was challenged when the first successful pregnancy after in vitro fertilization and embryo transfer (IVF -ET) using donated oocytes into a primary ovarian failure recipient treated with steroid replacement was reported by an Australian team at Monash University. In 1986, we reported the first pregnancy obtained using gamete intrafallopian transfer (GIFT) with donated oocytes and husband's sperm in a premature ovarian failure patient. 1 This approach also has been corroborated by other groups showing an average pregnancy rate between 36% and 54% per treatment cycle. 2 Successful pregnancies in patients suffering from premature ovarian failure also have been established via nonsurgical recovery and transfer of donated embryos (ovum transfer Received December 27, 1989; revised and accepted April 13, 1990. * Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of California, Irvine. t Department of Pathology, Obstetrics and Gynecology, University of Southern California. :j: Reprint requests: Ricardo H. Asch, M.D., Department of Obstetrics and Gynecology, University of California, Irvine, 101 The City Drive, Orange, California 92668.
348
Rotsztejn et al.
Communications-in-brief
technique).3 Since tubal embryo transfer (TET) seems to be an excellent technique for treating infertile patients with patent fallopian tubes, 4 we were encouraged to offer this technique to premature ovarian failure patients. The purpose of this communication is to report the first series of TET performed in patients with premature ovarian failure, using donated oocytes.
MATERIALS AND METHODS Recipients
Eleven recipients were between 26 and 42 years of age (mean = 33.6). All the patients had longterm idiopathic premature ovarian failure developing between the ages of 20 and 37 years. Diagnosis of premature ovarian failure was based on clinical criteria (amenorrhea) and hormonal criteria (serum postmenopausal levels ofFSH and LH). Tubal patency was confirmed 3 to 6 months before TET by either laparoscopy with normal prompt tubal spillage of dye or normal hysterosalpingogram. All patients underwent an evaluation cycle on admission to the oocyte donation program, as previously described. 1 During the TET cycle, subjects received the same regimen of E replacement as in the evaluation cycle. They received the following steroid replacement: micronized 17.B-estradiol (E 2 ) orally (Estrace; Mead Johnson, Evansville, IN), 2 mg on days 3 to 8; 4 mg on days 9 to 11; and 6 mg on days 12 to 28. Progesterone injections were started on the day of transvaginal aspiration of the donated oocytes. After follicular aspiration, 00Fertility and Sterility
Table 1
Patient Characteristics and Results of Tubal Embryo Transfer
Case
Age"
No. embryos transferred
1 2 3 4 5 6 7 8 9 10
20 (26) 35 (37) 31 (37) 30 (37) 26 (33) 34 (37) 27 (32) 23 (24) 24 (32) 37 (42) 31 (34)
5 4 4 3 4 4 3 4 4 4 3
11
Pregnancy
Outcome no. gestational sacs
Comment
+ + + +
1 1 2 1
Singleton delivery Miscarriage Ongoing Miscarriage
" Age is given at time of premature ovarian failure; and current age is presented in ( ).
cytes were inseminated; the embryos produced in vitro were transferred to the fallopian tubes as reported by Balmaceda et al. 5 If pregnancy was confirmed 14 days after TET by a positive ,a-human chorionic gonadotropin (,a-hCG) radioimmunoassay measurement, E 2 , and P were increased to 8 mgjd and 100 mgjd, respectively, until day 94 of gestation. Donors Four of the 11 donors were patients who underwent assisted conception techniques (IVF, GIFT, or TET). They agreed to donate their extra oocytes not used for transfer. A separate consent form was signed before the procedure by both the recipients and the donors. Four donors were patients undergoing diagnostic laparoscopies. Before laparoscopy, these patients agreed to a cycle of ovarian stimulation and to donate oocytes. In these 8 patients, the donation was anonymous and nonfinancially reimbursed. We selected recipients for oocyte donation who were within 12 to 14 days of E replacement from our waiting list. The selection of recipients was based primarily on the timing of their cycles and their ethnic similarities to the potential donors. Three of the 4 donors became pregnant during the cycle of assisted reproductive technique in which they donated extra oocytes. The remaining three donors were solicited by the recipients themselves; one was a patient's sister, and the other two donors were unrelated to the recipients. In these three nonanonymous donations, recipients started the hormone replacement on the second day of the donor's menstrual cycle. Donors received the following protocol for induction of follicular development: leuprolide acetate 1 mgjd subVol. 54, No.2, August 1990
+
Twins delivery
+ + + +
Ongoing Ongoing Ongoing Ongoing
1 1 2 2 b
One vanished gestational sac.
cutaneously (Lupron; TAP Pharmaceuticals, Chicago, IL) initiated between days 22 and 24 of a previous cycle; FSH (Metrodin; Serono Laboratories, Inc., Randolph, MA) 150 IU daily days 2 and 3 combined with human menopausal gonadotropin (hMG; Pergonal, Serono Laboratories, Inc.) 150IU daily from day 2 until two follicles were> 18 mm by transvaginal ultrasound (US) and E 2 1evels were at least 700 pgjmL. Human chorionic gonadotropin (Profasi; Serono Laboratories, Inc.) 10,000 IU intramuscularly was given, and 36 hours later, follicular aspiration under transvaginal US guidance was performed. RESULTS
Of the 11 patients treated, 9 became pregnant, giving a clinical pregnancy rate of 81.8% per transfer. We define clinical pregnancy when a gestational sac is visualized on US. Implantation rate was calculated by dividing the number of gestational sacs (n = 14) by the number of embryos transferred (n = 42); that represents a 33.3% chance that 1 embryo implanted will develop into a gestational sac. Two patients miscarried at 5 and 9 weeks, respectively, after TET (20%). One patient has already delivered a newborn by spontaneous vaginal delivery at 259 days after TET, and another patient delivered twins by cesarean section, for obstetrical indications at 256 days after TET. In both cases the infants were normal. Five patients have ongoing uneventful pregnancies: 3 singletons and 3 sets of twins (Table 1). DISCUSSION
This is the first report of a series with pregnancies and birth of normal children resulting from the Rotsztejn et al.
Communications-in-brief
349
donation of oocytes and TET in patients with premature ovarian failure. The results of the tubal embryo transfer procedure in this population have provided a novel approach for the treatment of infertility in couples previously considered to be irreversibly sterile. The clinical pregnancy rate of 81.8% obtained per transfer is markedly superior to that obtained with TET during stimulated cycles in regularly cycling women. Similarly, improved pregnancy rates in premature ovarian failure subjects have been also reported using GIFT and IVF -ET with donated oocytes. Some of the theories that could explain these improved results are related to the lack of hyperstimulation, hyperestrogenism, lack of premature luteinization, and their potential deleterious effect on endometrial receptivity. Furthermore, the implantation rates observed in this study are much greater than those reported previously in normal cycling women undergoing IVF -ET. This difference may be explained by: (1) exposure of the early embryo to the fallopian tube; (2) synchronous arrival to the uterine cavity before implantation; and (3) transfer to the tube, avoiding the potential mechanical problems associated with uterine transfer. Similarly, Yovich et a1. 6 found a significantly increased pregnancy rate in patients who receive TET when compared with matched subjects receiving IVF-ET. It appears from this small series of subjects that TET is an excellent technique for the treatment of premature ovarian failure subjects with patent fallopian tubes. Future randomized studies among GIFT, IVF -ET, and
350
Rotsztejn et a1.
Communications-in-brief
TET will be necessary to prove whether there is any significant difference among these techniques in the success rate for agonadal patients in which oocyte donation is indicated. SUMMARY
The transfer of embryos generated in vitro to the fallopian tubes in 11 cases of premature ovarian failure resulted in 9 clinical pregnancies. This approach may have theoretical advantages over GIFT and IVF-ET in agonadalpatients. Acknowledgment. We thank Mrs. Toula Batshoun for her collaboration in this study. REFERENCES 1. Borrero C, Remohi J, Ord T, Balmaceda JP, Rojas F, Asch RH: A program of oocyte donation and gamete intrafallopian transfer. Hum Reprod 4:275, 1989 2. Serhal PF, Craft IL: Oocytes donation in 61 patients. Lancet 1:1195, 1989 3. Sauer MV, Macaso TM, Ishida EH, Giudice L, Marshall JR, Buster JE: Pregnancy following nonsurgical donor ovum transfer to a functionally agonadal women. Fertil Steril48:324, 1987 4. Devroey P, Staessen C, Camus M, DeGrauwe E, Wisanto A, Van Steirteghem AC: Zygote intrafallopian transfer as a successful treatment for unexplained infertility. Fertil Steril 52:246, 1989 5. Balmaceda JP, Gastaldi C, Remohi J, Borrero C, Ord T, Asch RH: Tubal embryo transfer as a treatment for infertility due to male factor. Fertil Steril50:476, 1988 6. Yovich JL, Blackledge DG, Richardson PA, Matson PL, Turner SR, Draper R: Pregnancies following pronuclear stage tubal transfer. Fertil Steril48:851, 1987
Fertility and Sterility