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Exogenous progesterone for luteal support following gonadotropin-releasing hormone ovulation induction: case report
FERTILITY AND STERILITY Copyright c 1985 The American Fertility Society
Vol. 44, No.1, July 1985 Prinred in U.SA.
Exogenous progesterone for luteal support following gonadotropin-releasing hormone ovulation induction: case report
Nathan G. Berger, M.D.* Howard A. Zacur, M.D., Ph.D. Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology, The John Hopkins University School of Medicine, Baltimore, Maryland
Intravenous or subcutaneous pulsatile administration of gonadotropin-releasing hormone (GnRH) has been successfully used to induce ovulation in anovulatory women. This form of ovulation induction is more physiologic, more easily monitored, less likely to result in hyperstimulation or multiple gestations, and possibly less expensive than the use of menopausal gonadotropins. The postovulatory management of the luteal phase in women given GnRH has varied in previously reported clinical studies. Most commonly, either continuation of GnRH at the same dosage and frequency used to induce ovulation is given during the luteal phase, or discontinuation of GnRH followed by intramuscular human chorionic gonadotropin (hCG) has been us~d. A .case of primary infertility in which the WIfe eVIdenced anovulation unresponsive to clomiphene citrate (CC) therapy is presented. Successful ovulation induction by intermittent pulsatile subcutaneous GnRH administration followed by luteal phase support with vaginal progesterone (P) suppositories alone were provided. A midtrimester pregnancy is presently ongoing.
Received February 4, 1985; revised and accepted March 26, . 1985. *Reprint requests: Nathan G. Berger, M.D., Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology, The Johns Hopkins Hospital, B202 Park Building, Baltimore, Maryland 21205. Vol. 44, No.1, July 1985
CASE REPORT
In August, 1981, a 24-year-old married white women presented with complaints of primary infertility and secondary amenorrhea of 1% years' duration. She had discontinued oral contraceptives (OCs) after 4% years of usage and had experienced only one spontaneous menstrual flow since. Before OC use, she had had regular monthly menses since menarche at age 12. At the time of presentation, her last menses had been 6 months earlier, and she denied any headache, visual disturbance, significant weight loss or gain, change in body hair quantity or distribution, or galactorrhea. She had begun a vigorous exercise program composed of the use of Nautilus equipment (Nautilus Sports/Medical Industries, Deland, FL) and jogging during the previous year. Her husband was a healthy 26-year-old who had never fathered children. His semen analysis was normal. The patient's past medical and family histories were unremarkable. There was no history of pelvic surgery, inflammatory disease, or diethylstilbestrol exposure. Physical examination revealed a healthy white woman weighing 61 kg with a height of 158 cm. She was normotensive. Thyromegaly was not present. Breasts were at Tanner stage V of development without elicitable galactorrhea. Abdominal examination was unremarkable. Pelvic examination revealed normal external genitalia with normal female hair distribution. There was no Berger and Zacur Communications-in-brief
133
evidence of vaginal mucosal atrophy. Bimanual examination revealed a small midline uterus without adnexal enlargement. Withdrawal bleeding was induced after a progestin challenge test. Serum gonadotropins and prolactin (PRL) levels were normal (follicle-stimulating hormone, 6 mIU/ml; luteinizing hormone (LH), 10 mIU/ml; PRL, 5 ng/mI). A hypothalamic cause for the patient's amenorrhea was therefore suspected. Ovulation induction with CC was unsuccessful in dosages up to 200 mg/day for 5 days. CC followed by 5000 U ofhCG given intramuscularly on day 12 of therapy resulted in ovulation noted by biphasic basal body temperature (BBT) and a secretory endometrium at biopsy. This response was at best inconsistent initially and subsequently failed completely. Intermittent pulsatile subcutaneous administration of GnRH (Factrel, gonadorelin HCI, Ayerst Laboratories, New York, NY) was administered at a dosage of 15 f..Lg every 90 minutes via a portable pump (Auto Syringe, Auto Syringe Inc., Division of Travenol Laboratories, Hooksett, NH). The patient was monitored by weekly ultrasound evaluation of follicle growth and by recording her daily BBT. Development of a predominant follicle was noted on the 19th day of therapy. One week later, cul-de-sac fluid and collapse of the previously noted follicle were seen by ultrasound. BBT rose eight-tenths of a degree the following day; and on the third day of the sustained temperature rise, GnRH therapy was discontinued. Vaginal P suppositories (25 mg twice a day) were begun, and after 16 days of temperature elevation without vaginal bleeding, a positive serum l3-hCG titer was recorded. Ultrasound confirmed a single viable intrauterine pregnancy 3 weeks later. P was continued for 8 weeks. Presently the patient is in the midtrimester of an uncomplicated pregnancy.
DISCUSSION
Ovulation induction with GnRH may be successfully performed with intravenous, subcutaneous/ or nasal 2 routes of administration. Most clinical studies have employed either the intravenous or subcutaneous route. We have preferred to give GnRH subcutaneously on an outpatient basis because the potential risk of phlebitis, septicemia, or emboli is reduced. 134
Berger and Zacur Communications-in-brief
Whereas methods used to induce ovulation with GnRH have been established, treatment of the luteal phase after ovulation has varied. Discontinuation of pulsatile GnRH after ovulation without providing additional hormonal support can result in a high incidence of poor luteal function. 3 Continuation of GnRH in the luteal phase at the same dose and interval of administration as given before ovulation may not reproduce the same physiologic conditions seen in the natural cycle 4 and can result in inadequate luteal phase P production. 5 Intermittent supplementation with intramuscular hCG may support the luteal phase 3 but may increase the likelihood of multiple conceptions if the first dose is given close to the time of the GnRH-induced LH surge. 6 Use of hCG might theoretically increase the chance of ovarian hyperstimulation and also make the diagnosis of an early pregnancy difficult. When hCG is given, its use is frequently terminated after a diagnosis of pregnancy; and a high rate of early pregnancy loss (30% to 50%) has been noted in centers using hCG for luteal phase support. 1 , 6 Treatment of inadequate luteal function with P supplementation has been a standard of care in our institution for many years. Its use results in adequate progestational support of the endometrium, which can be readily continued until placental function suffices. Use of vaginal P suppositories provides direct endometrial hormone support, but their use will not necessarily reduce all GnRH-related abortion rates. The suppositories are easily administered, and the many problems found when hCG is given are avoided.
CONCLUSION
Intermittent pulsatile administration of GnRH results in orderly follicular development and ovulation in patients with hypothalamic amenorrhea. Luteal function is paramount for implantation and continued growth of a resultant gestation. P supplementation is effective and may be safer than other modes of corpus luteum support.
REFERENCES 1. Leyendecker G, Wildt L: Induction of ovulation with
chronic intermittent (pulsatile) administration of GnRH in women with hypothalamic amenorrhea. J Reprod Fertil 69:397, 1983
Fertility and Sterility
2. Phansey SA, Barnes MA, Williamson HO, Sagel J, Nair RMG: Combined use of clomiphene and intranasal luteinizing hormone-releasing hormone for induction of ovulation in chronically anovulatory women. Fertil Steril 34:448, 1980 3. Weinstein FG, Seibel MM, Tamyor ML: Ovulation induction with subcutaneous pulsatile gonadotropin-releasing hormone: the role of supplemental human chorionic gonadotropin in the luteal phase. Ferlil Steril 41:546, 1984 4. Reames N, Sauder SE: Pulsatile gonadotropin secretion during the human menstrual cycle: evidence for altered
Vol. 44, No.1, July 1985
frequency of gonadotropin-releasing hormone secretion. J Clin .Endocrinol Metab 59:328, 1984 5. Burger CW, Van Kessel H, Schoemaker J: Pulsatile LRH treatment in patients with menstrual dysfunction other than hypogonadotropic hypogonadism. In Brain and Pituitary Peptides II, Ferring Symposium, Edited by S Karger. Basel, Separatum, Publishers, 1983, p 113 6. Mason P, Adams J, Morris DV, Tucker M, Price J, Voulgaris Z, Van der Spuy ZM, Sutherland I, Chambers GR, White S, Wheeler MJ, Jacobs HS: Induction of ovulation with pulsatile luteinizing hormone-releasing hormones. Br Med J 288:181, 1984
Berger and Zacur Communications-in-brief
135
Vol. 44, No.1, July 1985 Prinred in U.SA.
Exogenous progesterone for luteal support following gonadotropin-releasing hormone ovulation induction: case report
Nathan G. Berger, M.D.* Howard A. Zacur, M.D., Ph.D. Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology, The John Hopkins University School of Medicine, Baltimore, Maryland
Intravenous or subcutaneous pulsatile administration of gonadotropin-releasing hormone (GnRH) has been successfully used to induce ovulation in anovulatory women. This form of ovulation induction is more physiologic, more easily monitored, less likely to result in hyperstimulation or multiple gestations, and possibly less expensive than the use of menopausal gonadotropins. The postovulatory management of the luteal phase in women given GnRH has varied in previously reported clinical studies. Most commonly, either continuation of GnRH at the same dosage and frequency used to induce ovulation is given during the luteal phase, or discontinuation of GnRH followed by intramuscular human chorionic gonadotropin (hCG) has been us~d. A .case of primary infertility in which the WIfe eVIdenced anovulation unresponsive to clomiphene citrate (CC) therapy is presented. Successful ovulation induction by intermittent pulsatile subcutaneous GnRH administration followed by luteal phase support with vaginal progesterone (P) suppositories alone were provided. A midtrimester pregnancy is presently ongoing.
Received February 4, 1985; revised and accepted March 26, . 1985. *Reprint requests: Nathan G. Berger, M.D., Department of Gynecology and Obstetrics, Division of Reproductive Endocrinology, The Johns Hopkins Hospital, B202 Park Building, Baltimore, Maryland 21205. Vol. 44, No.1, July 1985
CASE REPORT
In August, 1981, a 24-year-old married white women presented with complaints of primary infertility and secondary amenorrhea of 1% years' duration. She had discontinued oral contraceptives (OCs) after 4% years of usage and had experienced only one spontaneous menstrual flow since. Before OC use, she had had regular monthly menses since menarche at age 12. At the time of presentation, her last menses had been 6 months earlier, and she denied any headache, visual disturbance, significant weight loss or gain, change in body hair quantity or distribution, or galactorrhea. She had begun a vigorous exercise program composed of the use of Nautilus equipment (Nautilus Sports/Medical Industries, Deland, FL) and jogging during the previous year. Her husband was a healthy 26-year-old who had never fathered children. His semen analysis was normal. The patient's past medical and family histories were unremarkable. There was no history of pelvic surgery, inflammatory disease, or diethylstilbestrol exposure. Physical examination revealed a healthy white woman weighing 61 kg with a height of 158 cm. She was normotensive. Thyromegaly was not present. Breasts were at Tanner stage V of development without elicitable galactorrhea. Abdominal examination was unremarkable. Pelvic examination revealed normal external genitalia with normal female hair distribution. There was no Berger and Zacur Communications-in-brief
133
evidence of vaginal mucosal atrophy. Bimanual examination revealed a small midline uterus without adnexal enlargement. Withdrawal bleeding was induced after a progestin challenge test. Serum gonadotropins and prolactin (PRL) levels were normal (follicle-stimulating hormone, 6 mIU/ml; luteinizing hormone (LH), 10 mIU/ml; PRL, 5 ng/mI). A hypothalamic cause for the patient's amenorrhea was therefore suspected. Ovulation induction with CC was unsuccessful in dosages up to 200 mg/day for 5 days. CC followed by 5000 U ofhCG given intramuscularly on day 12 of therapy resulted in ovulation noted by biphasic basal body temperature (BBT) and a secretory endometrium at biopsy. This response was at best inconsistent initially and subsequently failed completely. Intermittent pulsatile subcutaneous administration of GnRH (Factrel, gonadorelin HCI, Ayerst Laboratories, New York, NY) was administered at a dosage of 15 f..Lg every 90 minutes via a portable pump (Auto Syringe, Auto Syringe Inc., Division of Travenol Laboratories, Hooksett, NH). The patient was monitored by weekly ultrasound evaluation of follicle growth and by recording her daily BBT. Development of a predominant follicle was noted on the 19th day of therapy. One week later, cul-de-sac fluid and collapse of the previously noted follicle were seen by ultrasound. BBT rose eight-tenths of a degree the following day; and on the third day of the sustained temperature rise, GnRH therapy was discontinued. Vaginal P suppositories (25 mg twice a day) were begun, and after 16 days of temperature elevation without vaginal bleeding, a positive serum l3-hCG titer was recorded. Ultrasound confirmed a single viable intrauterine pregnancy 3 weeks later. P was continued for 8 weeks. Presently the patient is in the midtrimester of an uncomplicated pregnancy.
DISCUSSION
Ovulation induction with GnRH may be successfully performed with intravenous, subcutaneous/ or nasal 2 routes of administration. Most clinical studies have employed either the intravenous or subcutaneous route. We have preferred to give GnRH subcutaneously on an outpatient basis because the potential risk of phlebitis, septicemia, or emboli is reduced. 134
Berger and Zacur Communications-in-brief
Whereas methods used to induce ovulation with GnRH have been established, treatment of the luteal phase after ovulation has varied. Discontinuation of pulsatile GnRH after ovulation without providing additional hormonal support can result in a high incidence of poor luteal function. 3 Continuation of GnRH in the luteal phase at the same dose and interval of administration as given before ovulation may not reproduce the same physiologic conditions seen in the natural cycle 4 and can result in inadequate luteal phase P production. 5 Intermittent supplementation with intramuscular hCG may support the luteal phase 3 but may increase the likelihood of multiple conceptions if the first dose is given close to the time of the GnRH-induced LH surge. 6 Use of hCG might theoretically increase the chance of ovarian hyperstimulation and also make the diagnosis of an early pregnancy difficult. When hCG is given, its use is frequently terminated after a diagnosis of pregnancy; and a high rate of early pregnancy loss (30% to 50%) has been noted in centers using hCG for luteal phase support. 1 , 6 Treatment of inadequate luteal function with P supplementation has been a standard of care in our institution for many years. Its use results in adequate progestational support of the endometrium, which can be readily continued until placental function suffices. Use of vaginal P suppositories provides direct endometrial hormone support, but their use will not necessarily reduce all GnRH-related abortion rates. The suppositories are easily administered, and the many problems found when hCG is given are avoided.
CONCLUSION
Intermittent pulsatile administration of GnRH results in orderly follicular development and ovulation in patients with hypothalamic amenorrhea. Luteal function is paramount for implantation and continued growth of a resultant gestation. P supplementation is effective and may be safer than other modes of corpus luteum support.
REFERENCES 1. Leyendecker G, Wildt L: Induction of ovulation with
chronic intermittent (pulsatile) administration of GnRH in women with hypothalamic amenorrhea. J Reprod Fertil 69:397, 1983
Fertility and Sterility
2. Phansey SA, Barnes MA, Williamson HO, Sagel J, Nair RMG: Combined use of clomiphene and intranasal luteinizing hormone-releasing hormone for induction of ovulation in chronically anovulatory women. Fertil Steril 34:448, 1980 3. Weinstein FG, Seibel MM, Tamyor ML: Ovulation induction with subcutaneous pulsatile gonadotropin-releasing hormone: the role of supplemental human chorionic gonadotropin in the luteal phase. Ferlil Steril 41:546, 1984 4. Reames N, Sauder SE: Pulsatile gonadotropin secretion during the human menstrual cycle: evidence for altered
Vol. 44, No.1, July 1985
frequency of gonadotropin-releasing hormone secretion. J Clin .Endocrinol Metab 59:328, 1984 5. Burger CW, Van Kessel H, Schoemaker J: Pulsatile LRH treatment in patients with menstrual dysfunction other than hypogonadotropic hypogonadism. In Brain and Pituitary Peptides II, Ferring Symposium, Edited by S Karger. Basel, Separatum, Publishers, 1983, p 113 6. Mason P, Adams J, Morris DV, Tucker M, Price J, Voulgaris Z, Van der Spuy ZM, Sutherland I, Chambers GR, White S, Wheeler MJ, Jacobs HS: Induction of ovulation with pulsatile luteinizing hormone-releasing hormones. Br Med J 288:181, 1984
Berger and Zacur Communications-in-brief
135