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Ovarian response to human menopausal gonadotropin after therapy with the gonadotropin-releasing hormone agonist leuprolide
Ovarian response to human menopausal gonadotropin after therapy with the gonadotropin-releasing hormone agonist leuprolide Shahla Nader, MD, AlbertS. Berkowitz, PhD, and Craig A. Winkel, MD Houston, Texas Two of three patients receiving leuprolide, a gonadotropin-releasing hormone agonist, demonstrated a decreased ovarian response to gonadotropin stimulation that was consistent with that of an earlier report involving two cases. It would appear that this agonist has direct antigonadal actions. (AM J OesTET GYNECOL 1988;158:403-4.)
Key words: Gonadotropin-releasing hormone agonist, ovarian stimulation, human menopausal gonadotropins
Gonadotropin-releasing hormone agonists, especially buserelin (Hoechsi: AG, Wiesbaden, West Germany), have been used successfully, particularly in Europe, to increase the yield of oocytes and the fertilization and cleavage rates of oocytes obtained after gonadotropin treatment cycles in in vitro fertilization-embryo transfer programs. A recent study, involving two patients in whom another gonadotropin-releasing hormone agonist leuprolide (Lupron, TAP Pharmaceuticals, North Chicago, Ill.) was used, reported decreased ovarian response to human menopausal gonadotropin therapy after pretreatment with the gonadotropin-releasing hormone agonist. • We wish to report the use of leuprotide in three patients, two of whom demonstrated a dramatically decreased ovarian response to subsequent human menopausal gonadotropin therapy. This study was approved by the Committee for the Protection of Human Subjects at the University of Texas Health Science Center. Case reports Case no. I. A 34-year-old woman with ovulatory dysfunction was treated with human menopausal gonadotropin for three cycles because of failure to achieve pregnancy with clomiphene citrate. In two of these cycles, peak estradiol levels of 339 and 353 pg/ml were achieved together with the development of a dominant follicle. In the third cycle, a peak estradiol level of 552 pg/ml was attained. The woman required 16, 14, and 20 ampules of human menopausal gonadotropin (each From the Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Texas Health Science Center. Received for publication May 22, 1987; revised june 29, 1987; accepted August 14, 1987. Reprint requests: Shahla Nader, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, 6431 Fannin, Suite 3.204, Houston, TX 77030.
ampule contained 75 IU of follicle stimulating hormone and 75 IU of luteinizing hormone), respectively. To improve recruitment she was pretreated with leuprotide, 1 mg subcutaneously daily for 19 days (producing a serum luteinizing hormone concentration of 1.5 miU/ml), after which human menopausal gonadotropin therapy was commenced. Despite the administration of 21 ampules, the estradiol levels did not exceed 36 pg/ml and the treatment cycle was abandoned. Case no. 2. A 37-year-old woman with severe endometriosis and ovulatory dysfunction that was unresponsive to clomiphene citrate was treated with human menopausal gonadotropin for the purpose of in vitro fertilization-embryo transfer. A peak estradiol level of 417 pg/ml was achieved with 21 ampules of human menopausal gonadotropin, and one dominant and one secondary-sized follicle appeared. To improve follicular recruitment she was pretreated with leuprolide, initially 0.3 mg subcutaneously daily; subsequently the dosage was gradually increased to 0.75 mg daily to further reduce the luteinizing hormone levels. After a total of 39 days of leuprolide therapy (producing a serum luteinizing hormone concentration of2.0 miU/ml), human menopausal gonadotropin therapy was initiated. After.28 ampules of human menopausal gonadotropin an estradiol level of 113 pg/ml was achieved, and the cycle was abandoned. Case no. 3. A 30-year-old woman with polycystic ovary syndrome that was unresponsive to clomiphene citrate was treated with human menopausal gonadotropin on several occasions. She exhibited a multifollicular response, with many follicles and with peak estradiol levels exceeding 3000 pg/ml in three of these cycles. In an attempt to reduce the ovarian response she was pretreated with leuprolide 1 mg subcutaneously daily for 17 days (producing a luteinizing hormone concentration of 2.0 miU/ml). After treatment with doses of human menopausal gonadotropin similar to those in the previous cycles, she again exhibited a 403
Nader, Berkowitz, and Winkel
multifollicular ovarian response, with nine follicles> 10 mm diameter and with estradiol levels similar to those in previous cycles in which human menopausal gonadotropin alone had been administered. Comment The finding of reduced ovarian response to human menopausal gonadotropin stimulation in two of three patients receiving leuprolide is in agreement with the study of Barnes et al. 1 As in that study, our three patients continued on a regimen of leuprolide treatment during the period of human menopausal gonadotropin administration. The difference in response to human menopausal gonadotropin in cases 1 and 2, after leuprolide therapy, was not because of cycle-to-cycle variation in response since both patients had subsequent cycles of human menopausal gonadotropin therapy, after administration ofleuprolide had been discontinued for several weeks, and the usual response to human menopausal gonadotropin was observed. Leuprolide differs chemically from buserelin, the gonadotropin-releasing hormone agonist com"monly
February 1988 Am J Obstet Gynecol
used in Europe, and this might explain the differences in the response to human menopausal gonadotropin. Leuprolide, as well as desensitizing the pituitary and lowering gonadotropin levels, may well have a direct gonadal inhibitory effect in vivo. Consistent with this notion are the results of Tureck et al./ who demonstrated that a gonadotropin-releasing hormone agonist can inhibit progesterone secretion by cultured granulosa cells. The lack of effect of leuprolide on the ovarian response to human menopausal gonadotropin stimulation in case no. 3 presumably reflects individual differences in response.
REFERENCES 1. Barnes RB, Scommegna A, Schreiber JR. Decreased ovarian response to human menopausal gonadotropin caused by subcutaneously administered gonadotropin-releasing hormone agonist. Fertil Steril 1987;47:512. 2. Tureck RW, Mastroianni L, Blasco L, StraussjF.1nhibition of human granulosa cell progesterone secretion by a gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab 1982;54:1078.
Sonographic detection of fetuses with trisomies 13 and 18: Accuracy and limitations Beryl R. Benacerraf, MD, Wayne A. Miller, MD, and Fredric D. Frigoletto, Jr., MD Boston, Massachusetts Nine fetuses having trisomy 13 and 15 fetuses with trisomy 18 were diagnosed by cytogenetic studies and also underwent a sonogram between 15 and 40 weeks. All nine fetuses with trisomy 13 had been prospectively identified as having sonographic findings suggestive of trisomy 13. Twelve of the 15 fetuses with trisomy 18 had sonographic abnonnalities compatible with trisomy 18. Findings included abnormalities of the face and head, extremities, and diaphragmatic hernia. This report examines criteria for the ultrasound diagnosis of trisomies 13 and 18 and describes the accuracy of prenatal sonography for these diagnoses. (AM J 0BSTET GYNECOL 1988;158:404-9.)
Key words: Trisomy 13 and 18, sonography Sonographically determined morphologic features associated with fetuses who have trisomies 13 and 18
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, and the Department of Radiology, Brigham and Women's Hospital, Haroard Medical School, and the Department of Pediatrics (Genetics), Massachusetts General Hospital, Haroard Medical School. Received for publication june I, 1987; revised july 27, 1987; accepted August 30, 1987. Reprint requests: Beryl Benacerraf, MD, 333 Longwood Avenue, Boston, MA 02115.
404
have been described, •·s but the rate of prenatal identification of trisomies 13 and 18 in a general obstetric ultrasound laboratory has not been reported. This report examines the accuracy and limitations of prenatal sonography to identify fetuses with trisomies 13 and 18 and establishes the most common sonographic abnormalities associated with these chromosomal defects. Material and methods From the six cytogenetic laboratories that receive the specimens from the patients scanned in our laboratory,
Key words: Gonadotropin-releasing hormone agonist, ovarian stimulation, human menopausal gonadotropins
Gonadotropin-releasing hormone agonists, especially buserelin (Hoechsi: AG, Wiesbaden, West Germany), have been used successfully, particularly in Europe, to increase the yield of oocytes and the fertilization and cleavage rates of oocytes obtained after gonadotropin treatment cycles in in vitro fertilization-embryo transfer programs. A recent study, involving two patients in whom another gonadotropin-releasing hormone agonist leuprolide (Lupron, TAP Pharmaceuticals, North Chicago, Ill.) was used, reported decreased ovarian response to human menopausal gonadotropin therapy after pretreatment with the gonadotropin-releasing hormone agonist. • We wish to report the use of leuprotide in three patients, two of whom demonstrated a dramatically decreased ovarian response to subsequent human menopausal gonadotropin therapy. This study was approved by the Committee for the Protection of Human Subjects at the University of Texas Health Science Center. Case reports Case no. I. A 34-year-old woman with ovulatory dysfunction was treated with human menopausal gonadotropin for three cycles because of failure to achieve pregnancy with clomiphene citrate. In two of these cycles, peak estradiol levels of 339 and 353 pg/ml were achieved together with the development of a dominant follicle. In the third cycle, a peak estradiol level of 552 pg/ml was attained. The woman required 16, 14, and 20 ampules of human menopausal gonadotropin (each From the Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Texas Health Science Center. Received for publication May 22, 1987; revised june 29, 1987; accepted August 14, 1987. Reprint requests: Shahla Nader, MD, Department of Obstetrics, Gynecology, and Reproductive Sciences, 6431 Fannin, Suite 3.204, Houston, TX 77030.
ampule contained 75 IU of follicle stimulating hormone and 75 IU of luteinizing hormone), respectively. To improve recruitment she was pretreated with leuprotide, 1 mg subcutaneously daily for 19 days (producing a serum luteinizing hormone concentration of 1.5 miU/ml), after which human menopausal gonadotropin therapy was commenced. Despite the administration of 21 ampules, the estradiol levels did not exceed 36 pg/ml and the treatment cycle was abandoned. Case no. 2. A 37-year-old woman with severe endometriosis and ovulatory dysfunction that was unresponsive to clomiphene citrate was treated with human menopausal gonadotropin for the purpose of in vitro fertilization-embryo transfer. A peak estradiol level of 417 pg/ml was achieved with 21 ampules of human menopausal gonadotropin, and one dominant and one secondary-sized follicle appeared. To improve follicular recruitment she was pretreated with leuprolide, initially 0.3 mg subcutaneously daily; subsequently the dosage was gradually increased to 0.75 mg daily to further reduce the luteinizing hormone levels. After a total of 39 days of leuprolide therapy (producing a serum luteinizing hormone concentration of2.0 miU/ml), human menopausal gonadotropin therapy was initiated. After.28 ampules of human menopausal gonadotropin an estradiol level of 113 pg/ml was achieved, and the cycle was abandoned. Case no. 3. A 30-year-old woman with polycystic ovary syndrome that was unresponsive to clomiphene citrate was treated with human menopausal gonadotropin on several occasions. She exhibited a multifollicular response, with many follicles and with peak estradiol levels exceeding 3000 pg/ml in three of these cycles. In an attempt to reduce the ovarian response she was pretreated with leuprolide 1 mg subcutaneously daily for 17 days (producing a luteinizing hormone concentration of 2.0 miU/ml). After treatment with doses of human menopausal gonadotropin similar to those in the previous cycles, she again exhibited a 403
Nader, Berkowitz, and Winkel
multifollicular ovarian response, with nine follicles> 10 mm diameter and with estradiol levels similar to those in previous cycles in which human menopausal gonadotropin alone had been administered. Comment The finding of reduced ovarian response to human menopausal gonadotropin stimulation in two of three patients receiving leuprolide is in agreement with the study of Barnes et al. 1 As in that study, our three patients continued on a regimen of leuprolide treatment during the period of human menopausal gonadotropin administration. The difference in response to human menopausal gonadotropin in cases 1 and 2, after leuprolide therapy, was not because of cycle-to-cycle variation in response since both patients had subsequent cycles of human menopausal gonadotropin therapy, after administration ofleuprolide had been discontinued for several weeks, and the usual response to human menopausal gonadotropin was observed. Leuprolide differs chemically from buserelin, the gonadotropin-releasing hormone agonist com"monly
February 1988 Am J Obstet Gynecol
used in Europe, and this might explain the differences in the response to human menopausal gonadotropin. Leuprolide, as well as desensitizing the pituitary and lowering gonadotropin levels, may well have a direct gonadal inhibitory effect in vivo. Consistent with this notion are the results of Tureck et al./ who demonstrated that a gonadotropin-releasing hormone agonist can inhibit progesterone secretion by cultured granulosa cells. The lack of effect of leuprolide on the ovarian response to human menopausal gonadotropin stimulation in case no. 3 presumably reflects individual differences in response.
REFERENCES 1. Barnes RB, Scommegna A, Schreiber JR. Decreased ovarian response to human menopausal gonadotropin caused by subcutaneously administered gonadotropin-releasing hormone agonist. Fertil Steril 1987;47:512. 2. Tureck RW, Mastroianni L, Blasco L, StraussjF.1nhibition of human granulosa cell progesterone secretion by a gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab 1982;54:1078.
Sonographic detection of fetuses with trisomies 13 and 18: Accuracy and limitations Beryl R. Benacerraf, MD, Wayne A. Miller, MD, and Fredric D. Frigoletto, Jr., MD Boston, Massachusetts Nine fetuses having trisomy 13 and 15 fetuses with trisomy 18 were diagnosed by cytogenetic studies and also underwent a sonogram between 15 and 40 weeks. All nine fetuses with trisomy 13 had been prospectively identified as having sonographic findings suggestive of trisomy 13. Twelve of the 15 fetuses with trisomy 18 had sonographic abnonnalities compatible with trisomy 18. Findings included abnormalities of the face and head, extremities, and diaphragmatic hernia. This report examines criteria for the ultrasound diagnosis of trisomies 13 and 18 and describes the accuracy of prenatal sonography for these diagnoses. (AM J 0BSTET GYNECOL 1988;158:404-9.)
Key words: Trisomy 13 and 18, sonography Sonographically determined morphologic features associated with fetuses who have trisomies 13 and 18
From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, and the Department of Radiology, Brigham and Women's Hospital, Haroard Medical School, and the Department of Pediatrics (Genetics), Massachusetts General Hospital, Haroard Medical School. Received for publication june I, 1987; revised july 27, 1987; accepted August 30, 1987. Reprint requests: Beryl Benacerraf, MD, 333 Longwood Avenue, Boston, MA 02115.
404
have been described, •·s but the rate of prenatal identification of trisomies 13 and 18 in a general obstetric ultrasound laboratory has not been reported. This report examines the accuracy and limitations of prenatal sonography to identify fetuses with trisomies 13 and 18 and establishes the most common sonographic abnormalities associated with these chromosomal defects. Material and methods From the six cytogenetic laboratories that receive the specimens from the patients scanned in our laboratory,