SUMMARY OF DOCTORAL THESIS
Assisted fertilization Clinical studies with particular attention to ovarian stimulation, oocyte retrieval and transfer of gametes or embryos TOMTANBO From the Department of Obstetrics and Gynecology, Rikshospitalet, University of Oslo, Oslo, Norway, 1991
Acra Ohstet Gynecol Scand 1992; 71: 8&87
All procedures of assisted fertilization are dependent on a multifollicular recruitment and growth in response to controlled ovarian hyperstimulation (COH). An acceptable pregnancy rate can only be obtained by transferring numerous embryos or oocytes. However, a poor response to C O H , defined as few maturing follicles and low estradiol levels, is regularly observed, especially in patients in their late thirties, in ovarian endometriosis, and when there are extensive pelvic adhesions. On the other hand, in patients with the polycystic ovarian syndrome (PCOS), C O H often leads to excessive stimulation, with an increased risk of developing the ovarian hyperstimulation syndrome (OHSS). Retrieval of oocytes was previously performed by laparoscopy, but is now mostly performed by transvaginal ultrasound technique. In cases of tubal infertility, in vitro fertilization and transfer to the uterine cavity (IVF) have to be performed. However, when the Fallopian tubes are patent, several options exist, e.g. IVF, gamete intra-Fallopian transfer (GIFT), and tubal embryo stage transfer (TEST). The purposes of the present study were: -
-
-
to evaluate a method to predict a poor response outcome to C O H and to study the effect of a gonadotropin-releasing hormone (GnRH) agonist in previous stimulation failures; to study the effect of a G n R H agonist in PCOS; to compare laparoscopic oocyte retrieval under general anesthesia, with transvaginal ultrasoundguided retrieval in local analgesia; to compare various transfer procedures in infertile women with patent Fallopian tubes.
Acto Ohsrrr Gynecol Scund 71 (1992)
Most of our patients undergo C O H with a sequential clomiphene citrate (CC) / human menopausal gonadotropin (HMG) protocol. After 5 days of C C administration, FSH measurements were performed and the levels compared with the result of the following HMG stimulation. The results show that an elevated FSH response to CC predicted a poor response outcome in 90% in the cycle in question (1). Furthermore, a high cancellation rate was found in subsequent cycles, by using different stimulation protocols (2). In patients with repeated failed cycles, due either to poor response, spontaneous ovulation, o r simply failure to conceive, the use of a G n R H agonist in a long protocol prior to H M G stimulation was very effective in terms of a high pregnancy rate (3). In infertility related to PCOS, the results of gonadotropin stimulation are very poor compared with the results of H M G stimulation in normoprolactinemic amenorrhea. Elevated L H levels in PCOS induce increased androgen production in the theca cells and subsequent follicular atresia due to elevated androgen levels in the follicular fluid. Furthermore, elevated L H levels may lead to premature luteinization of growing follicles. In ovulatory women, G n R H agonists induce a hypogonadotropic hypogonadism due to a down-regulation effect on membrane receptors to G n R H in gonadotropic cells. If this was also the case in PCOS, a decrease in the LH level would be expected to reduce the ovarian androgen production and thereby decrease the process of atresia. G n R H agonist administration to 6 women with PCOS reduced the serum levels of LH, testosterone and androstenedione significantly (4). The time needed to suppress pituitary LH release,
Assisted fertilization however, was longer in PCOS patients than usually needed in ovulatory women. Stimulation with H M G or urinary FSH after 4 weeks’ administration of a G n R H agonist still resulted in multifollicular response, with two to three times as many oocytes obtained per oocyte retrieval as in ovulatory women. Moreover, the incidence of OHSS increased. However, the cleavage rate was no different from that in patients with ovulatory cycles (5). Despite a very low and declining L H level during FSH stimulation, the serum concentrations of testosterone and androstenedione rose significantly. This indicates that urinary FSH may have a direct effect on thecal androgen production and secretion, since the preparation is actually devoid of biological LH activity. The large number of oocytes obtained and a cleavage rate of 70% make surplus embryos available for cryopreservation. However, PCOS is a condition of anovulation and ovulation is necessary to induce secretory changes in the endometrium. Most of our patients did not ovulate while on C C medication, therefore the endometrial secretory response to cyclic estradiol and progesterone substitution was evaluated. The study showed that induction of secretory changes was possible and that transfer of frozen-thawed embryos in a substituted cycle resulted in implantation (6). The immediate change from laparoscopic oocyte retrieval under general anesthesia t o transvaginal ultrasound guided technique with local analgesia resulted in more oocytes obtained and more embryos replaced in the latter group. Although the study was not a prospective, randomized trial, the higher cleavage rate obtained with local analgesia and transvaginal retrieval might imply that general anesthesia or pneumoperitoneum may have a detrimental effect on the oocytes. To evaluate the possibly beneficial effect of the tubal environment on the process of fertilization and preimplantation embryo growth, a prospective, randomized study comparing IVF, GIFT and TEST in patients suffering from unexplained infertility, male infertility or minimal peritoneal endometriosis was performed. All patients had patent tubes confirmed by laparoscopy and hysterosalpingography . The implantation rates were similar in the IVF and TEST groups, and higher than in the GIFT group. This could be explained by the high incidence of fertilization failure in male and unexplained infertility.
87
Contrary to other retrospective comparisons of implantation rates after tubal versus uterine transfer of embryos, we were not able to show a supportive effect of the tubal environment on the processes of fertilization or implantation.
This thesis is based on the following papers: 1. Tanbo T, Dale PO, Abyholm T, Stokke KT. Folliclestimulating hormone as a prognostic indicator in clomiphene citrate/human menopausal gonadotropin-stimulated cycles for in-vitro fertilization. Hum Reprod 1989; 4: 647-50. 2. Tanbo T, Abyholm T, Bjoro T, Dale PO. Ovarian superstimulation in previous failures from in-vitro fertilization. Distinction of two groups of poor responders. Hum Reprod 1990; 5: 811-5. 3. Tanbo T, Dale PO, Abyholm T. Ovarian hyperstimulation for in vitro fertilization preceded by prolonged administration of a gonadotropin releasing hormone agonist. Acta Obstet Gynecol Scand 1990; 69: 333-7. 4. Tanbo T, Abyholm T, Magnus 0, Henriksen T . Gonadotropin and ovarian steorid production in polycystic ovarian syndrome during suppression with a gonadotropin-releasing hormone agonist. Gynecol Obstet Invest 1989; 28: 147-51. 5 . Tmbo T, Dale PO, Kjekshus E, Haug E, Abyholm T. Stimulation with human menopausal gonadotropin versus follicle-stimulating hormone after pituitatry suppression in polycystic ovarian syndrome. Fertil Steril 1990; 53: 798-803. 6. Dale PO, Tanbo T, Kjekshus E, Abyholm T. Pregnancy after transfer of cryopreserved ambryos in clomiphene citrate resistant polycystic ovarian syndrome. Fertil Steril 1990; 53: 3 6 2 4 . 7. Tanbo T, Henriksen T, Magnus 0 , Abyholm T . Oocyte retrieval in an IVF program. A comparison of laparoscopic and transvaginal ultrasound-guided follicular puncture. Acta Obstet Gynecol Scand 1988; 67: 243-6. 8. Tanbo T, Dale PO, Abyholm T. Assisted fertilization in infertile women with patent Fallopian tubes. A comparison of in-vitro fertilization, gamete intra-Fallopian transfer and tubal embryo stage transfer. Hum Reprod 1990; 5: 266-70. Address for correspondence:
Tom Tanbo, M.D. Department of Obstetrics and Gynecology Rikshospitalet N-0027 Oslo 1 Norway
Acra Obsrer Gynecol Scand 71 (1992)
Assisted fertilization Clinical studies with particular attention to ovarian stimulation, oocyte retrieval and transfer of gametes or embryos TOMTANBO From the Department of Obstetrics and Gynecology, Rikshospitalet, University of Oslo, Oslo, Norway, 1991
Acra Ohstet Gynecol Scand 1992; 71: 8&87
All procedures of assisted fertilization are dependent on a multifollicular recruitment and growth in response to controlled ovarian hyperstimulation (COH). An acceptable pregnancy rate can only be obtained by transferring numerous embryos or oocytes. However, a poor response to C O H , defined as few maturing follicles and low estradiol levels, is regularly observed, especially in patients in their late thirties, in ovarian endometriosis, and when there are extensive pelvic adhesions. On the other hand, in patients with the polycystic ovarian syndrome (PCOS), C O H often leads to excessive stimulation, with an increased risk of developing the ovarian hyperstimulation syndrome (OHSS). Retrieval of oocytes was previously performed by laparoscopy, but is now mostly performed by transvaginal ultrasound technique. In cases of tubal infertility, in vitro fertilization and transfer to the uterine cavity (IVF) have to be performed. However, when the Fallopian tubes are patent, several options exist, e.g. IVF, gamete intra-Fallopian transfer (GIFT), and tubal embryo stage transfer (TEST). The purposes of the present study were: -
-
-
to evaluate a method to predict a poor response outcome to C O H and to study the effect of a gonadotropin-releasing hormone (GnRH) agonist in previous stimulation failures; to study the effect of a G n R H agonist in PCOS; to compare laparoscopic oocyte retrieval under general anesthesia, with transvaginal ultrasoundguided retrieval in local analgesia; to compare various transfer procedures in infertile women with patent Fallopian tubes.
Acto Ohsrrr Gynecol Scund 71 (1992)
Most of our patients undergo C O H with a sequential clomiphene citrate (CC) / human menopausal gonadotropin (HMG) protocol. After 5 days of C C administration, FSH measurements were performed and the levels compared with the result of the following HMG stimulation. The results show that an elevated FSH response to CC predicted a poor response outcome in 90% in the cycle in question (1). Furthermore, a high cancellation rate was found in subsequent cycles, by using different stimulation protocols (2). In patients with repeated failed cycles, due either to poor response, spontaneous ovulation, o r simply failure to conceive, the use of a G n R H agonist in a long protocol prior to H M G stimulation was very effective in terms of a high pregnancy rate (3). In infertility related to PCOS, the results of gonadotropin stimulation are very poor compared with the results of H M G stimulation in normoprolactinemic amenorrhea. Elevated L H levels in PCOS induce increased androgen production in the theca cells and subsequent follicular atresia due to elevated androgen levels in the follicular fluid. Furthermore, elevated L H levels may lead to premature luteinization of growing follicles. In ovulatory women, G n R H agonists induce a hypogonadotropic hypogonadism due to a down-regulation effect on membrane receptors to G n R H in gonadotropic cells. If this was also the case in PCOS, a decrease in the LH level would be expected to reduce the ovarian androgen production and thereby decrease the process of atresia. G n R H agonist administration to 6 women with PCOS reduced the serum levels of LH, testosterone and androstenedione significantly (4). The time needed to suppress pituitary LH release,
Assisted fertilization however, was longer in PCOS patients than usually needed in ovulatory women. Stimulation with H M G or urinary FSH after 4 weeks’ administration of a G n R H agonist still resulted in multifollicular response, with two to three times as many oocytes obtained per oocyte retrieval as in ovulatory women. Moreover, the incidence of OHSS increased. However, the cleavage rate was no different from that in patients with ovulatory cycles (5). Despite a very low and declining L H level during FSH stimulation, the serum concentrations of testosterone and androstenedione rose significantly. This indicates that urinary FSH may have a direct effect on thecal androgen production and secretion, since the preparation is actually devoid of biological LH activity. The large number of oocytes obtained and a cleavage rate of 70% make surplus embryos available for cryopreservation. However, PCOS is a condition of anovulation and ovulation is necessary to induce secretory changes in the endometrium. Most of our patients did not ovulate while on C C medication, therefore the endometrial secretory response to cyclic estradiol and progesterone substitution was evaluated. The study showed that induction of secretory changes was possible and that transfer of frozen-thawed embryos in a substituted cycle resulted in implantation (6). The immediate change from laparoscopic oocyte retrieval under general anesthesia t o transvaginal ultrasound guided technique with local analgesia resulted in more oocytes obtained and more embryos replaced in the latter group. Although the study was not a prospective, randomized trial, the higher cleavage rate obtained with local analgesia and transvaginal retrieval might imply that general anesthesia or pneumoperitoneum may have a detrimental effect on the oocytes. To evaluate the possibly beneficial effect of the tubal environment on the process of fertilization and preimplantation embryo growth, a prospective, randomized study comparing IVF, GIFT and TEST in patients suffering from unexplained infertility, male infertility or minimal peritoneal endometriosis was performed. All patients had patent tubes confirmed by laparoscopy and hysterosalpingography . The implantation rates were similar in the IVF and TEST groups, and higher than in the GIFT group. This could be explained by the high incidence of fertilization failure in male and unexplained infertility.
87
Contrary to other retrospective comparisons of implantation rates after tubal versus uterine transfer of embryos, we were not able to show a supportive effect of the tubal environment on the processes of fertilization or implantation.
This thesis is based on the following papers: 1. Tanbo T, Dale PO, Abyholm T, Stokke KT. Folliclestimulating hormone as a prognostic indicator in clomiphene citrate/human menopausal gonadotropin-stimulated cycles for in-vitro fertilization. Hum Reprod 1989; 4: 647-50. 2. Tanbo T, Abyholm T, Bjoro T, Dale PO. Ovarian superstimulation in previous failures from in-vitro fertilization. Distinction of two groups of poor responders. Hum Reprod 1990; 5: 811-5. 3. Tanbo T, Dale PO, Abyholm T. Ovarian hyperstimulation for in vitro fertilization preceded by prolonged administration of a gonadotropin releasing hormone agonist. Acta Obstet Gynecol Scand 1990; 69: 333-7. 4. Tanbo T, Abyholm T, Magnus 0, Henriksen T . Gonadotropin and ovarian steorid production in polycystic ovarian syndrome during suppression with a gonadotropin-releasing hormone agonist. Gynecol Obstet Invest 1989; 28: 147-51. 5 . Tmbo T, Dale PO, Kjekshus E, Haug E, Abyholm T. Stimulation with human menopausal gonadotropin versus follicle-stimulating hormone after pituitatry suppression in polycystic ovarian syndrome. Fertil Steril 1990; 53: 798-803. 6. Dale PO, Tanbo T, Kjekshus E, Abyholm T. Pregnancy after transfer of cryopreserved ambryos in clomiphene citrate resistant polycystic ovarian syndrome. Fertil Steril 1990; 53: 3 6 2 4 . 7. Tanbo T, Henriksen T, Magnus 0 , Abyholm T . Oocyte retrieval in an IVF program. A comparison of laparoscopic and transvaginal ultrasound-guided follicular puncture. Acta Obstet Gynecol Scand 1988; 67: 243-6. 8. Tanbo T, Dale PO, Abyholm T. Assisted fertilization in infertile women with patent Fallopian tubes. A comparison of in-vitro fertilization, gamete intra-Fallopian transfer and tubal embryo stage transfer. Hum Reprod 1990; 5: 266-70. Address for correspondence:
Tom Tanbo, M.D. Department of Obstetrics and Gynecology Rikshospitalet N-0027 Oslo 1 Norway
Acra Obsrer Gynecol Scand 71 (1992)
