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Pregnancy: a risk to initiation of leuprolide acetate during the luteal phase before controlled ovarian hyperstimulation*
FERTILITY AND STERILITY
Vol. 50, No. 2, August 1988 Printed in U.S.A.
Copyright 0 1988 The American Fertility Society
Pregnancy: a risk to initiation of leuprolide acetate during the luteal phase before controlled ovarian hyperstimulation*
Paulo Serafini, M.D. Joel Batzofin, M.D. John Kerin, M.D., Ph.D. Richard Marrs, M.D. Cedars-Sinai Medical Center, University of California at Los Angeles, and The Hospital of The Good Samaritan, Los Angeles, California
Selective gonadotropin hypophysectomy with analogs of gonadotropin-releasing hormone (GnRH) have recently been introduced for the management of ovulation induction. 1 Pituitary desensitization before controlled ovarian hyperstimulation (COH) with exogenous gonadotropins yields an improved ovarian response and pregnancy rate in women with induced ovulatory dysfunctions.2 Fraser and Sandow, 3 studying stumptailed macaque, suggested that therapy with GnRH analog (GnRHa) was more efficacious when started in the luteal phase. However, complications with initiation of leuprolide acetate in the luteal phase of the cycle may occur. This report will discuss complications with commencement of GnRHa therapy in women with long standing infertility secondary to tubal disease. CASE REPORTS Casel
A 35-year-old woman, gravida 2, para 0, ectopic 2, had previously undergone a right salpingectomy and a left salpingostomy. Hysterosalpingogram performed subsequent to the salpingostomy revealed minimal, delayed spillage of dye from the left tube. The patient was counseled about the risks and benefits of further surgery or in vitro fertilization (IVF) treatment. One mg (0.2 ml) ofleuprolide acetate (Lupron, TAP Pharmaceutical, North ChiReceived January 14, 1988; revised and accepted AprilS, 1988.
* Reprints not available. Vol. 50, No. 2, August 1988
cago, IL) was begun on day 24 of the menstrual cycle for pituitary desensitization before COH. Ovarian transvaginal ultrasonography performed on the day of GnRHa commencement was normal, and no cysts were visualized. In addition, serum estradiol (E 2) was 48 pg/ml. She returned for reevaluation 7 days after the beginning of leuprolide administration, and serum E 2 had risen to 178 pg/ml. Ovarian ultrasonography was unchanged. A week later, serum E 2 was 320 pg/ml, and the patient developed three ovarian cysts measuring 28, 23, and 17 mm in the largest diameters. Five days later, the patient was complaining of fatigue and pelvic pressure. Pelvic ultrasonography demonstrated an increase in size of the ovarian cysts, which measured 31 X 14, 25 X 24 and 21 X 15 mm. Serum E 2 and progesterone (P) levels were 300 pg/ml and 16.8 ng/ml, respectively. Vital signs were stable, no orthostatic changes were elicited, and the hematocrit was 36%. On the following day, the patient presented with low abdominal pain and stable vital signs and hematocrit, but ovarian ultrasound showed disappearance of two cysts and a reduction in size of the remaining cystic structure (19 X 18 mm). Furthermore, the cul-de-sac contained minimal amount of fluid (estimated <40 cc). A presumptive diagnosis of a ruptured functional ovarian cysts was entertained and since the patient was clinically stable, she was discharged with detailed instructions about follow-up. Two days later, the patient presented with severe abdominal pain, orthostatic changes on vital signs, and a hematocrit of 24%. An urgent exploratory laparotomy was Serafini et al. Communications-in-brief
371
performed and revealed a ruptured left ampullary pregnancy (18 X 15 mm). A left salpingectomy was performed, and the patient received four units of blood. Her postoperatorive recovery was uneventful. Case2
A 38-year-old woman, gravida 2, para 2, status post-bilateral tubal sterilization followed by failed tubal reconstructive surgery, was seen in our center for IVF treatment. The patient was placed on leuprotide acetate for pituitary desensitization with treatment beginning on day 24 of her cycle. Pelvic ultrasound was unremarkable, serum P was 12.63 ng/ml, and E 2 was 131 pg/ml. Ten days after the initiation of the analog treatment, ovarian ultrasound scan was normal, and pure follicle-stimulating hormone (300 IU/per day) was initiated concurrently with GnRHa. Four days later, serum E2 levels rose to 245 pg/ml, P was 19.67 ng/ml, and LH was 0.98 miU /ml. In view of increasing P levels, we considered the possibility of pregnancy, and a ~-hCG measurement was 1249 miU/ml. Exogenous gonadotropin therapy was discontinued, and ovarian scanning revealed arrest of follicle growth. Laboratory data on subsequent days are shown in Table 1. The ~-hCG levels dropped significantly, the patient remained clinically stable, and no surgical intervention was necessary. DISCUSSION
The occurrence of an ectopic pregnancy in one patient and a preclinical gestation in the second woman with longstanding infertility due to tubal disease clearly illustrate the risk of pregnancy in women initiating GnRHa in the luteal phase of the cycle. The administration of the GnRHa patients with significant tubal disease in addition to the ovarian stimulation followed by cyst formation, which occurs in up to 35% of women receiving leuprotide acetate at a dose of 1 mg daily for pituitary desensitization, hindered the physicians' ability to consider the diagnostic possibility of ectopic pregTable 1 Serum Levels of E 2 (pg/ml), LH (miU/::nl), P (ng/ml), and ,8-hCG (miU/ml) after the Fourth Day of Exogenous Gonadotropin Administration (Case 2)"
E2 LH p ,8-hCG
Day4
5
6
7
9
11
245 0.98 19.67 1,249
355 1.10 7.30 526
530 1.51 5.76 319
652 0.83 1.78 174
0.65 1.45 102
0.66 1.22 12.3
• The RIA used to measure LH was obtained from Serono Laboratories (Maia Clone, Norwell, MA). 372
Serafini et al.
Communications-in-brief
nancy. The clinical and ultrasonographic findings contributed to the delay in the diagnosis and surgical intervention in this patient. This procrastination contributed to the necessity of laparotomy and blood transfusion, since early diagnosis could have possibly enabled endoscopic resection of a tubal gestation, which is a much less invasive procedure, and the risks of hematinic transfusion might have been avoided. Just as important are the potential risks of exposing embryos or fetuses, in a normally implanted pregnancy, to GnRHa. The analogs of GnRH are known to be luteolytic in some animal species and may predispose to abortion. 4 Although previous studies have shown that GnRHa failed to induce abortion in early human pregnancy,5 information in this regard is still scant. Furthermore, the effects of GnRHa on early human pregnancy remain unknown. Sopelak and Hodgen 6 have shown that· agonistic analogs can easily cross the placenta barrier and cause a reduction in neonatal testicular weight of rhesus monkeys. Therefore, counseling the patient on continuation or termination of pregnancy becomes an extremely difficult task. Vaginal barrier contraceptives or spermicides should be utilized in the periovulatory time of a cycle in which GnRHa will be administered in the early or mid-luteal phase. Furthermore, serum progesterone levels ~5 ng/ml or increasing concentrations after initial GnRHa therapy should alert the clinician to the possibility of pregnancy. Acknowledgment: We thank Mrs. Hazel Myers for her skillful assistance in the preparation of this manuscript.
REFERENCES 1. Fleming R, Coutts JRT: Induction of multiple follicular growth in normally menstruating women with endogenous gonadotropin suppression. Fertil Steril 45:226, 1986 2. Serafini P, Stone B, Kerin J, Batzofin J, Quinn P, Marrs R: An alternate approach to controlled ovarian hyperstimulation (COH) in poor responders: pretreatment with a GnRH analog (GnRHa). Fertil Sertil 49:90, 1988 3. Fraser HM, Sandow J: Suppression of follicu~ar maturation by infusion of a luteinizing hormone-releasing hormone agonist starting during the last luteal phase in the stumptailed macaque monkey. J Clin Endocrinol Metab 60:579, 1985 4. Arimura A, Pedroza E, Vilchez-Martinez JA, Schally AV: Prevention of implantation by D-Trp6 -LHRH in the rat: Comparative study with the effects of large doses of hCG on pregnancy. Endocr Res Commun 4:354, 1977 5. Skarin G, Nillius SJ, Wide L: Failure to induce abortion of early human pregnancy by high doses of a superactive LRH agonist. Contraception 26:457, 1982 6. Sopelak VM, Hodgen GD: Infusion of gonadotropin-releasing hormone agonist during pregnancy: maternal and fetal responses in primates. Am J Obstet Gynecol 156:755, 1987 Fertility and Sterility
Vol. 50, No. 2, August 1988 Printed in U.S.A.
Copyright 0 1988 The American Fertility Society
Pregnancy: a risk to initiation of leuprolide acetate during the luteal phase before controlled ovarian hyperstimulation*
Paulo Serafini, M.D. Joel Batzofin, M.D. John Kerin, M.D., Ph.D. Richard Marrs, M.D. Cedars-Sinai Medical Center, University of California at Los Angeles, and The Hospital of The Good Samaritan, Los Angeles, California
Selective gonadotropin hypophysectomy with analogs of gonadotropin-releasing hormone (GnRH) have recently been introduced for the management of ovulation induction. 1 Pituitary desensitization before controlled ovarian hyperstimulation (COH) with exogenous gonadotropins yields an improved ovarian response and pregnancy rate in women with induced ovulatory dysfunctions.2 Fraser and Sandow, 3 studying stumptailed macaque, suggested that therapy with GnRH analog (GnRHa) was more efficacious when started in the luteal phase. However, complications with initiation of leuprolide acetate in the luteal phase of the cycle may occur. This report will discuss complications with commencement of GnRHa therapy in women with long standing infertility secondary to tubal disease. CASE REPORTS Casel
A 35-year-old woman, gravida 2, para 0, ectopic 2, had previously undergone a right salpingectomy and a left salpingostomy. Hysterosalpingogram performed subsequent to the salpingostomy revealed minimal, delayed spillage of dye from the left tube. The patient was counseled about the risks and benefits of further surgery or in vitro fertilization (IVF) treatment. One mg (0.2 ml) ofleuprolide acetate (Lupron, TAP Pharmaceutical, North ChiReceived January 14, 1988; revised and accepted AprilS, 1988.
* Reprints not available. Vol. 50, No. 2, August 1988
cago, IL) was begun on day 24 of the menstrual cycle for pituitary desensitization before COH. Ovarian transvaginal ultrasonography performed on the day of GnRHa commencement was normal, and no cysts were visualized. In addition, serum estradiol (E 2) was 48 pg/ml. She returned for reevaluation 7 days after the beginning of leuprolide administration, and serum E 2 had risen to 178 pg/ml. Ovarian ultrasonography was unchanged. A week later, serum E 2 was 320 pg/ml, and the patient developed three ovarian cysts measuring 28, 23, and 17 mm in the largest diameters. Five days later, the patient was complaining of fatigue and pelvic pressure. Pelvic ultrasonography demonstrated an increase in size of the ovarian cysts, which measured 31 X 14, 25 X 24 and 21 X 15 mm. Serum E 2 and progesterone (P) levels were 300 pg/ml and 16.8 ng/ml, respectively. Vital signs were stable, no orthostatic changes were elicited, and the hematocrit was 36%. On the following day, the patient presented with low abdominal pain and stable vital signs and hematocrit, but ovarian ultrasound showed disappearance of two cysts and a reduction in size of the remaining cystic structure (19 X 18 mm). Furthermore, the cul-de-sac contained minimal amount of fluid (estimated <40 cc). A presumptive diagnosis of a ruptured functional ovarian cysts was entertained and since the patient was clinically stable, she was discharged with detailed instructions about follow-up. Two days later, the patient presented with severe abdominal pain, orthostatic changes on vital signs, and a hematocrit of 24%. An urgent exploratory laparotomy was Serafini et al. Communications-in-brief
371
performed and revealed a ruptured left ampullary pregnancy (18 X 15 mm). A left salpingectomy was performed, and the patient received four units of blood. Her postoperatorive recovery was uneventful. Case2
A 38-year-old woman, gravida 2, para 2, status post-bilateral tubal sterilization followed by failed tubal reconstructive surgery, was seen in our center for IVF treatment. The patient was placed on leuprotide acetate for pituitary desensitization with treatment beginning on day 24 of her cycle. Pelvic ultrasound was unremarkable, serum P was 12.63 ng/ml, and E 2 was 131 pg/ml. Ten days after the initiation of the analog treatment, ovarian ultrasound scan was normal, and pure follicle-stimulating hormone (300 IU/per day) was initiated concurrently with GnRHa. Four days later, serum E2 levels rose to 245 pg/ml, P was 19.67 ng/ml, and LH was 0.98 miU /ml. In view of increasing P levels, we considered the possibility of pregnancy, and a ~-hCG measurement was 1249 miU/ml. Exogenous gonadotropin therapy was discontinued, and ovarian scanning revealed arrest of follicle growth. Laboratory data on subsequent days are shown in Table 1. The ~-hCG levels dropped significantly, the patient remained clinically stable, and no surgical intervention was necessary. DISCUSSION
The occurrence of an ectopic pregnancy in one patient and a preclinical gestation in the second woman with longstanding infertility due to tubal disease clearly illustrate the risk of pregnancy in women initiating GnRHa in the luteal phase of the cycle. The administration of the GnRHa patients with significant tubal disease in addition to the ovarian stimulation followed by cyst formation, which occurs in up to 35% of women receiving leuprotide acetate at a dose of 1 mg daily for pituitary desensitization, hindered the physicians' ability to consider the diagnostic possibility of ectopic pregTable 1 Serum Levels of E 2 (pg/ml), LH (miU/::nl), P (ng/ml), and ,8-hCG (miU/ml) after the Fourth Day of Exogenous Gonadotropin Administration (Case 2)"
E2 LH p ,8-hCG
Day4
5
6
7
9
11
245 0.98 19.67 1,249
355 1.10 7.30 526
530 1.51 5.76 319
652 0.83 1.78 174
0.65 1.45 102
0.66 1.22 12.3
• The RIA used to measure LH was obtained from Serono Laboratories (Maia Clone, Norwell, MA). 372
Serafini et al.
Communications-in-brief
nancy. The clinical and ultrasonographic findings contributed to the delay in the diagnosis and surgical intervention in this patient. This procrastination contributed to the necessity of laparotomy and blood transfusion, since early diagnosis could have possibly enabled endoscopic resection of a tubal gestation, which is a much less invasive procedure, and the risks of hematinic transfusion might have been avoided. Just as important are the potential risks of exposing embryos or fetuses, in a normally implanted pregnancy, to GnRHa. The analogs of GnRH are known to be luteolytic in some animal species and may predispose to abortion. 4 Although previous studies have shown that GnRHa failed to induce abortion in early human pregnancy,5 information in this regard is still scant. Furthermore, the effects of GnRHa on early human pregnancy remain unknown. Sopelak and Hodgen 6 have shown that· agonistic analogs can easily cross the placenta barrier and cause a reduction in neonatal testicular weight of rhesus monkeys. Therefore, counseling the patient on continuation or termination of pregnancy becomes an extremely difficult task. Vaginal barrier contraceptives or spermicides should be utilized in the periovulatory time of a cycle in which GnRHa will be administered in the early or mid-luteal phase. Furthermore, serum progesterone levels ~5 ng/ml or increasing concentrations after initial GnRHa therapy should alert the clinician to the possibility of pregnancy. Acknowledgment: We thank Mrs. Hazel Myers for her skillful assistance in the preparation of this manuscript.
REFERENCES 1. Fleming R, Coutts JRT: Induction of multiple follicular growth in normally menstruating women with endogenous gonadotropin suppression. Fertil Steril 45:226, 1986 2. Serafini P, Stone B, Kerin J, Batzofin J, Quinn P, Marrs R: An alternate approach to controlled ovarian hyperstimulation (COH) in poor responders: pretreatment with a GnRH analog (GnRHa). Fertil Sertil 49:90, 1988 3. Fraser HM, Sandow J: Suppression of follicu~ar maturation by infusion of a luteinizing hormone-releasing hormone agonist starting during the last luteal phase in the stumptailed macaque monkey. J Clin Endocrinol Metab 60:579, 1985 4. Arimura A, Pedroza E, Vilchez-Martinez JA, Schally AV: Prevention of implantation by D-Trp6 -LHRH in the rat: Comparative study with the effects of large doses of hCG on pregnancy. Endocr Res Commun 4:354, 1977 5. Skarin G, Nillius SJ, Wide L: Failure to induce abortion of early human pregnancy by high doses of a superactive LRH agonist. Contraception 26:457, 1982 6. Sopelak VM, Hodgen GD: Infusion of gonadotropin-releasing hormone agonist during pregnancy: maternal and fetal responses in primates. Am J Obstet Gynecol 156:755, 1987 Fertility and Sterility