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The use of Synthetic Luteinizing Hormone-Releasing Hormone in Induction of Ovulation
Vol. 26, No. 12, December 1975 Printed in U.S A.
FERTILITY AND STERILITY Copyright c 1975 The American Fertility Society
THE USE OF SYNTHETIC LUTEINIZING HORMONE-RELEASING HORMONE IN INDUCTION OF OVULATION A. ARNALDO ACOSTA, M.D., VEASY C. BU'ITRAM, JR., M.D., L. RUSSELL MALINAK, M.D., PAIGE K. BESCH, PH.D., AND ROBERT R. FRANKLIN, M.D.
Department of Obstetrics and Gynecology, Baylor College of Medicine, and Reproductive Research Laboratory, St. Luke's Episcopal Hospital, Houston, Texas 77025
In 1971, Kastin et al. 1 reported the first successful use of luteinizing hormonereleasing hormone (LH-RH) in inducing ovulation in a human patient. The patient had received an infusion of purified porcine hypothalamic LH-RH following pretreatment with human menopausal gonadotropin. Since that time, several investigators have induced ovulation in anovulatory patients by using frequent serial injections of synthetic LH-RH, a synthetic decapeptide. 2 • 3 Keller 4 • 5 recently reported successful induction of ovulation with a single intravenous infusion of synthetic LH-RH following pretreatment with clomiphene. Using two intramuscular injections of LH-RH, he also succeeded in inducing ovulation in four patients pretreated with human menopausal gonadotropin (HMG). 4 The purposes ofthis study were to evaluate the effectiveness of synthetic LH-RH in inducing ovulation when used alone or in combination with other agents and to gain further information about the diagnostic value of the pituitary response to a single administration of LH-RH. MATERIALS AND METHODS
Patients Fourteen anovulatory patients were evaluated in the Clinical Research Center, Baylor College of Medicine, Houston, Received April!, 1974.
Texas, from February 1, 1973, to December 31, 1973. Each patient was evaluated by x-ray of the sella turcica and by determinations of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH), T3 and T 4 , 17-ketosteroids and 17-hydroxysteroids, plasma cortisol, and serum testosterone levels. In addition, pelvic endoscopy was performed in each case. Prior to evaluation, each patient had been treated with clomiphene in an unsuccessful attempt to induce ovulation. The clomiphene doses had reached 150 or 200 mg/day for at least 5 days/cycle in each case. Five patients had received therapy for a period of 3 months; nine patients had been treated for 6 to 18 months.
Administration of LH-RH LH-RH was administered alone in one cycle, then in conjunction with clomiphene in two consecutive cycles, and, finally (in four patients), in conjunction with human menopausal gonadotropin in a fourth cycle. Measurement of Gonadotropin Release following LH-RH Injection. In every cycle, plasma samples for LH and FSH determinations were obtained from each patient prior to, and 10, 20, 30, 45, 60, 90, 120, and 150 minutes after, intravenous injection of 150 1-Lg of synthetic LH-RH. The gonadotropin determinations were accomplished by a double-antibody radio-
1173
ACOSTA ET AL.
1174
Immunoassay method. 6 • 7 Gonadotropin response was classified as good when the maximal LH level was greater than 50 miU/ml; intermediate when the maximal level was greater than 25 miU/ml but less than 50 miU/ml; and poor when the LH level was less than 25 miU/ml. Attempts to Induce Ovulation. Menses were induced with progesterone or with estrogen plus progesterone when necessary. During each cycle, patients were followed for evidence of ovulatory response. Ovulation was determined on clinical grounds, i.e., symptoms, endometrial biopsy on the 28th day of the cycle, and biphasic basal body temperature charts. In the first cycle, a single intravenous injection of 150 p,g of synthetic LH-RH was administered on the 15th day of the induced menstrual cycle. Following the cycle in which LH-RH alone was administered, each patient received 150 mg of clomiphene orally for 10 days, beginning on day 5 of an induced cycle. A 150-p,g dose of synthetic LH-RH was then administered intravenously on the 17th day of the cycle. This clomiphene-LH-RH sequence was followed in two consecutive cycles. Four patients who did not ovulate with clomiphene-LH-RH were given two vials of HMG daily (Humegon; Organon, Inc., West Orange, N. J.) intramuscularly for 7 days, beginning on day 5 of an induced menstrual cycle. One hundred fifty micrograms of synthetic LH-RH were then administered in a single intravenous bolus on day 15, and each patient was followed for evidence of ovulation.
December 1975
lated ovaries"-ovaries normal in size or slightly smaller, having a smooth, glistening surface without convolutions and having apparently few, if any, underlying follicles. Three of the patients had bilaterally enlarged polycystic ovaries and exhibited hirsutism, acne, and obesity, although they had no biochemical evidence of excess androgen. Gonadotropin Release following Injection of LH-RH Alone Five patients had a good gonadotropin release following LH-RH administration, two patients had an intermediate response, and seven patients had a poor response. Ovulatory Response to LH-RH Alone In no patient did administration of LH-RH alone result in ovulation even though, as indicated above, some females had a good LH response to LH-RH. The increase in serum FSH level was minimal, never rising above 10 miU/ml. Ovulatory Response to LH-RH Injection following Pretreatment with Clomiphene Eight patients ovulated in both cycles when LH-RH therapy followed pretreatment with clomiphene. One patient failed to ovulate in the first treatment cycle, but ovulated in the second treatment cycle (patient 9), and five patients did not ovulate with clomiphene-LH-RH.
Ovulatory Response to LH-RH in Patients Pretreated with Human The biochemical and radiographic tests Menopausal Gonadotropin performed to evaluate function of the Four patients, having failed to ovulate pituitary, thyroid, adrenal glands, and with clomiphene-LH-RH therapy, chose to ovaries indicated no significant abnormalundergo HMG pretreatment. One patient ity in any patient. In 11 patients, however, laparoscopy revealed "poorly stimu- ovulated. RESULTS
•
Vol. 26, No. 12
USE OF SYNTHETIC LH-RH IN INDUCTION OF OVULATION
Diagnostic Value of Pituitary Responsiveness to a Single Injection of LH-RH In Patients Pretreated with Clomiphene. Five patients had a good response to LHRH injection. Four of these ovulated in the clomiphene-LH-RH cycles, and pituitary response remained consistently good. The only patient in this group who did not ovulate demonstrated diminished pituitary response (good to intermediate) when LH-RH was administered in conjunction with clomiphene (patient 6). Two of the 14 patients had an intermediate response to the initial LH-RH infusion; both ovulated in subsequent clomiphene-LH-RH cycles. Seven patients demonstrated poor pituitary responsiveness to LH-RH injection. When both clomiphene and LHRH were administered in subsequent cycles, three of the seven patients showed improved pituitary response and they ovulated. Of the remaining four in this group, three had no improvement in pituitary responsiveness and one showed improvement from poor to intermediate (patient 4). None of the four ovulated when pretreated with clomiphene. Increase in FSH level was minimal in all cases, never rising above 10 miU/ml.
In Patients Pretreated with Human Menopausal Gonadotropin. The patient who ovulated had a poor pituitary response in all cycles but ovulated when pretreated with HMG. A second patient (patient 4) responded poorly to LH-RH alone, reached intermediate response in the clomiphene-LH-RH and HMG-LH-RH cycles, but did not ovulate in any cycle. The remaining two patients pretreated with HMG had a poor pituitary response to LH-RH, continued to respond poorly in the subsequent cycles, and never ovulated. The FSH levels remained below 10 miU/ml.
1175
DISCUSSION
An attempt was made to evaluate the effectiveness of synthetic LH-RH in inducing ovulation in anovulatory women who had not previously responded to high dosages of clomiphene. At the same time, results were examined for evidence that pituitary response to LH-RH is an effective predictor of subsequent ovulatory response to LH-RH in anovulatory patients pretreated with clomiphene or HMG. Administration ofLH-RH alone did not induce ovulation in any patient despite the good pituitary response in several. Possibly, ovulation failed to occur because adequate follicular maturation had not been achieved prior to LH-RH il\iection. In contrast, nine patients ovulated when pretreated with clomiphene, indicating that in these patients follicular maturation was sufficient for ovulation. Difficult to explain, however, is the patient who ovulated in the LH-RH-HMG cycle, even though her pituitary response in that cycle (as in all of the others) was poor. Whether the LH-RH is an important adjunctive stimulant is impossible to determine from the data. A study comparing responses to clomiphene in graduated doses, both with and without concurrent administration of LH-RH, is needed. The stimulative value of LH-RH is suggested by the fact that the patients observed had already been treated with fairly high dosages of clomiphene alone, some for long periods of time, and had not ovulated. It is also true, however, that the patients might have ovulated with continued high dosages of clomiphene alone, and the fact that the patients had had a 3-month rest period could have been a factor in ovulatory response. At the same time, it is possible that the injection ofLH-RH alone, although it did not induce ovulation, played a part in successful induction of ovulation in the succeeding cycle because of some cumulative effect. 4
ACOSTA ET AL.
1176
That follicular growth and maturation can also be achieved with administration of human menopausal gonadotropin has been reported by others. L 4 In the present study the number of patients pretreated with HMG was so small that no conclusions can be drawn from the results. One patient pretreated with HMG ovulated after receiving a single injection ofLH-RH, but it is possible that the other three patients might have ovulated if given a higher dosage of HMG. Administration of LH-RH may well be more physiologic than administration of human chorionic gonadotropin in similarly pretreated patients and perhaps less likely to lead to hyperstimulation and multiple births. 8 Although Zarate et al. 2 • 3 and Keller4 induced ovulation in anovulatory patients by using frequent serial injections of LHRH-indicating that FSH was released in amounts sufficient to induce follicular maturation-the approach appears to be unphysiologic. 4 Moreover, it is impractical, expensive, and unnecessary if similar results can be obtained with the administration of a single dose of LH-RH to patients pretreated with clomiphene or HMG.
December 1975
The initial response to LH-RH alone may suggest a degree of susceptibility to ovulation induction in patients treated with LH-RH and clomiphene, but, within the limitations of the present study, gonadotropic response to LH-RH was not a consistently reliable predictor. Seven patients in our study had a poor pituitary response to LH-RH alone and might not have been expected to ovulate when treated with clomiphene-LH-RH. 5 Yet, three ovulated in the first clomipheneLH-RH cycle. Of the five patients who had a good response, four ovulated in the first clomiphene-LH-RH cycle, but one patient never ovulated. In the small number of patients under study, pituitary response to clomipheneLH-RH was a better predictor of ovulation than response to LH-RH alone (Table 1). Seven patients had a good response in the first clomiphene-LH-RH cycle; all seven ovulated. Three patients had a poor pituitary response; none ovulated. Limitation of quantity and the high cost of LH-RH and HMG continue to inhibit the amount of research done in this area. The number of anovulatory women is great but the number treated has
TABLE 1. Pituitary and Ovulatory Responses of 14 Anovulatory Patients to LH-RH Alone and to LH-RH Given in Conjunction with Clomiphene or HMG Patient
Intermenstrual interval
Ovulation
Pituitary response' Ovarian morphologyo
Clomiphene-LH-RH LH-RH
LH-RHHMG
Clomiphene-LH-RH LH-RH
1st cycle
2nd cycle
1st cycle
2nd cycle
G G G I p I G G I p I p G G
G G G I p I G G G p I p G G
+ + +
+ + +
LH-RHHMG
days
1 2 3 4 5 6 7
8 9 10 11
12 13 14
35-90 35-90 90-180 90-180 90-180 90-180 90-180 90-180 180 180 180 180 180 180
PSO PSO PSO PSO PSO POS POS POS PSO PSO PSO PSO PSO PSO
G G I p p G G G I p p p p P+
I p
+ + +
+ + +
+
+
+ +
+ +
p p
"PSO, Poorly stimulated ovaries; POS, polycystic ovary syndrome. bG, Good; P, poor; I, intermediate.
Vol. 26, No. 12
USE OF SYNTHETIC LH·RH IN INDUCTION OF OVULATION
necessarily been small. The reliability of a single injection of LH-RH as a test of pituitary function is not established, but the value of administration of LH-RH in anovulatory patients pretreated with clomiphene is fairly strongly indicated. SUMMARY
Each of 14 anovulatory patients received a single injection of 150 p,g of synthetic luteinizing hormone-releasing hormone (LH-RH) in one induced menstrual cycle. In two subsequent cycles, patients were pretreated with clomiphene before LH-RH injection. Four patients received LH7RH after pretreatment with human menopausal gonadotropin (HMG) in another cycle. In each cycle, gonadotropin release and ovulation were recorded. All patients had previously failed to ovulate when treated with large doses of clomiphene. No patient ovulated following injection of LH-RH alone, although five patients exhibited a good pituitary response. Nine patients ovulated when they received LH-RH after pretreatment with clomiphene, and one patient ovulated when pretreated with HMG. The diagnostic value of a single injection ofLH-RH is not clear. In the present study, gonadotropin response to LH-RH was not an entirely accurate predictor of a patient's ovulatory response in any of the four cycles. On the other hand, when clomiphene-LH-RH was administered, a good response was associated with ovulation in that cycle.
1177
The exact role of LH-RH in inducing ovulation is unclear, but the results of using LH-RH in conjunction with clomiphene are encouraging enough to warrant continued use and further study. Acknowledgments. We wish to thank Mrs. Loretta P. Brown, Mrs. Cheryl Belin, and Dr. D. M. Desiderio for their valuable contributions to this study. We also wish to thank St. Luke's Episcopal Hospital and Mr. Peter Maddeaux for their support of our studies. REFERENCES 1. Kastin AJ, Zarate A, Midgley AR Jr, Canales ES, Schally AV: Ovulation confirmed by pregnancy after infusion of porcine LH-RH. J Clin Endocrinol Metab 33:980, 1971 2. Zarate A, Canales ES, Schally AV, AyalaValdes L, Kastin AJ: Successful induction of ovulation with synthetic luteinizing hormonereleasing hormone in anovulatory infertility. Fertil Steril 23:672, 1972 3. Zarate A, Canales ES, Schally AV, Kastin AJ, Soria J: Induction of ovulation with synthetic luteinizing hormone-releasing hormone in suspected hypothalamic infertility. In Hypothalamic Hypophysiotropic Hormones, Edited by C Gaul, E Rosemberg. Amsterdam, Excerpta Medica Foundation, 1973, p 251 4. Keller PJ: Treatment of anovulation with synthetic luteinizing hormone-releasing hormone. Am J Obstet Gynecol 116:698, 1973 5. Keller PJ: Induction of ovulation by synthetic luteinizing-hormone releasing factor in infertile women. Lancet 2:570, 1972 6. Brown LP, Besch PK, Skelley DS, Buttram VC: Overnight radioimmunoassay of human follicle-stimulating hormone. Clin Chern 19:197, 1973 7. Brown LP, Skelley DS, Besch PK, Buttram VC, Fleischer NS: An overnight radioimmunoassay for human luteinizing hormone (abstr). Clin Chern 19:652, 1973 8. Taymor ML: Gonadotropin therapy. Possible causes and prevention of ovarian overstimulation. JAMA 203:362, 1968
FERTILITY AND STERILITY Copyright c 1975 The American Fertility Society
THE USE OF SYNTHETIC LUTEINIZING HORMONE-RELEASING HORMONE IN INDUCTION OF OVULATION A. ARNALDO ACOSTA, M.D., VEASY C. BU'ITRAM, JR., M.D., L. RUSSELL MALINAK, M.D., PAIGE K. BESCH, PH.D., AND ROBERT R. FRANKLIN, M.D.
Department of Obstetrics and Gynecology, Baylor College of Medicine, and Reproductive Research Laboratory, St. Luke's Episcopal Hospital, Houston, Texas 77025
In 1971, Kastin et al. 1 reported the first successful use of luteinizing hormonereleasing hormone (LH-RH) in inducing ovulation in a human patient. The patient had received an infusion of purified porcine hypothalamic LH-RH following pretreatment with human menopausal gonadotropin. Since that time, several investigators have induced ovulation in anovulatory patients by using frequent serial injections of synthetic LH-RH, a synthetic decapeptide. 2 • 3 Keller 4 • 5 recently reported successful induction of ovulation with a single intravenous infusion of synthetic LH-RH following pretreatment with clomiphene. Using two intramuscular injections of LH-RH, he also succeeded in inducing ovulation in four patients pretreated with human menopausal gonadotropin (HMG). 4 The purposes ofthis study were to evaluate the effectiveness of synthetic LH-RH in inducing ovulation when used alone or in combination with other agents and to gain further information about the diagnostic value of the pituitary response to a single administration of LH-RH. MATERIALS AND METHODS
Patients Fourteen anovulatory patients were evaluated in the Clinical Research Center, Baylor College of Medicine, Houston, Received April!, 1974.
Texas, from February 1, 1973, to December 31, 1973. Each patient was evaluated by x-ray of the sella turcica and by determinations of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH), T3 and T 4 , 17-ketosteroids and 17-hydroxysteroids, plasma cortisol, and serum testosterone levels. In addition, pelvic endoscopy was performed in each case. Prior to evaluation, each patient had been treated with clomiphene in an unsuccessful attempt to induce ovulation. The clomiphene doses had reached 150 or 200 mg/day for at least 5 days/cycle in each case. Five patients had received therapy for a period of 3 months; nine patients had been treated for 6 to 18 months.
Administration of LH-RH LH-RH was administered alone in one cycle, then in conjunction with clomiphene in two consecutive cycles, and, finally (in four patients), in conjunction with human menopausal gonadotropin in a fourth cycle. Measurement of Gonadotropin Release following LH-RH Injection. In every cycle, plasma samples for LH and FSH determinations were obtained from each patient prior to, and 10, 20, 30, 45, 60, 90, 120, and 150 minutes after, intravenous injection of 150 1-Lg of synthetic LH-RH. The gonadotropin determinations were accomplished by a double-antibody radio-
1173
ACOSTA ET AL.
1174
Immunoassay method. 6 • 7 Gonadotropin response was classified as good when the maximal LH level was greater than 50 miU/ml; intermediate when the maximal level was greater than 25 miU/ml but less than 50 miU/ml; and poor when the LH level was less than 25 miU/ml. Attempts to Induce Ovulation. Menses were induced with progesterone or with estrogen plus progesterone when necessary. During each cycle, patients were followed for evidence of ovulatory response. Ovulation was determined on clinical grounds, i.e., symptoms, endometrial biopsy on the 28th day of the cycle, and biphasic basal body temperature charts. In the first cycle, a single intravenous injection of 150 p,g of synthetic LH-RH was administered on the 15th day of the induced menstrual cycle. Following the cycle in which LH-RH alone was administered, each patient received 150 mg of clomiphene orally for 10 days, beginning on day 5 of an induced cycle. A 150-p,g dose of synthetic LH-RH was then administered intravenously on the 17th day of the cycle. This clomiphene-LH-RH sequence was followed in two consecutive cycles. Four patients who did not ovulate with clomiphene-LH-RH were given two vials of HMG daily (Humegon; Organon, Inc., West Orange, N. J.) intramuscularly for 7 days, beginning on day 5 of an induced menstrual cycle. One hundred fifty micrograms of synthetic LH-RH were then administered in a single intravenous bolus on day 15, and each patient was followed for evidence of ovulation.
December 1975
lated ovaries"-ovaries normal in size or slightly smaller, having a smooth, glistening surface without convolutions and having apparently few, if any, underlying follicles. Three of the patients had bilaterally enlarged polycystic ovaries and exhibited hirsutism, acne, and obesity, although they had no biochemical evidence of excess androgen. Gonadotropin Release following Injection of LH-RH Alone Five patients had a good gonadotropin release following LH-RH administration, two patients had an intermediate response, and seven patients had a poor response. Ovulatory Response to LH-RH Alone In no patient did administration of LH-RH alone result in ovulation even though, as indicated above, some females had a good LH response to LH-RH. The increase in serum FSH level was minimal, never rising above 10 miU/ml. Ovulatory Response to LH-RH Injection following Pretreatment with Clomiphene Eight patients ovulated in both cycles when LH-RH therapy followed pretreatment with clomiphene. One patient failed to ovulate in the first treatment cycle, but ovulated in the second treatment cycle (patient 9), and five patients did not ovulate with clomiphene-LH-RH.
Ovulatory Response to LH-RH in Patients Pretreated with Human The biochemical and radiographic tests Menopausal Gonadotropin performed to evaluate function of the Four patients, having failed to ovulate pituitary, thyroid, adrenal glands, and with clomiphene-LH-RH therapy, chose to ovaries indicated no significant abnormalundergo HMG pretreatment. One patient ity in any patient. In 11 patients, however, laparoscopy revealed "poorly stimu- ovulated. RESULTS
•
Vol. 26, No. 12
USE OF SYNTHETIC LH-RH IN INDUCTION OF OVULATION
Diagnostic Value of Pituitary Responsiveness to a Single Injection of LH-RH In Patients Pretreated with Clomiphene. Five patients had a good response to LHRH injection. Four of these ovulated in the clomiphene-LH-RH cycles, and pituitary response remained consistently good. The only patient in this group who did not ovulate demonstrated diminished pituitary response (good to intermediate) when LH-RH was administered in conjunction with clomiphene (patient 6). Two of the 14 patients had an intermediate response to the initial LH-RH infusion; both ovulated in subsequent clomiphene-LH-RH cycles. Seven patients demonstrated poor pituitary responsiveness to LH-RH injection. When both clomiphene and LHRH were administered in subsequent cycles, three of the seven patients showed improved pituitary response and they ovulated. Of the remaining four in this group, three had no improvement in pituitary responsiveness and one showed improvement from poor to intermediate (patient 4). None of the four ovulated when pretreated with clomiphene. Increase in FSH level was minimal in all cases, never rising above 10 miU/ml.
In Patients Pretreated with Human Menopausal Gonadotropin. The patient who ovulated had a poor pituitary response in all cycles but ovulated when pretreated with HMG. A second patient (patient 4) responded poorly to LH-RH alone, reached intermediate response in the clomiphene-LH-RH and HMG-LH-RH cycles, but did not ovulate in any cycle. The remaining two patients pretreated with HMG had a poor pituitary response to LH-RH, continued to respond poorly in the subsequent cycles, and never ovulated. The FSH levels remained below 10 miU/ml.
1175
DISCUSSION
An attempt was made to evaluate the effectiveness of synthetic LH-RH in inducing ovulation in anovulatory women who had not previously responded to high dosages of clomiphene. At the same time, results were examined for evidence that pituitary response to LH-RH is an effective predictor of subsequent ovulatory response to LH-RH in anovulatory patients pretreated with clomiphene or HMG. Administration ofLH-RH alone did not induce ovulation in any patient despite the good pituitary response in several. Possibly, ovulation failed to occur because adequate follicular maturation had not been achieved prior to LH-RH il\iection. In contrast, nine patients ovulated when pretreated with clomiphene, indicating that in these patients follicular maturation was sufficient for ovulation. Difficult to explain, however, is the patient who ovulated in the LH-RH-HMG cycle, even though her pituitary response in that cycle (as in all of the others) was poor. Whether the LH-RH is an important adjunctive stimulant is impossible to determine from the data. A study comparing responses to clomiphene in graduated doses, both with and without concurrent administration of LH-RH, is needed. The stimulative value of LH-RH is suggested by the fact that the patients observed had already been treated with fairly high dosages of clomiphene alone, some for long periods of time, and had not ovulated. It is also true, however, that the patients might have ovulated with continued high dosages of clomiphene alone, and the fact that the patients had had a 3-month rest period could have been a factor in ovulatory response. At the same time, it is possible that the injection ofLH-RH alone, although it did not induce ovulation, played a part in successful induction of ovulation in the succeeding cycle because of some cumulative effect. 4
ACOSTA ET AL.
1176
That follicular growth and maturation can also be achieved with administration of human menopausal gonadotropin has been reported by others. L 4 In the present study the number of patients pretreated with HMG was so small that no conclusions can be drawn from the results. One patient pretreated with HMG ovulated after receiving a single injection ofLH-RH, but it is possible that the other three patients might have ovulated if given a higher dosage of HMG. Administration of LH-RH may well be more physiologic than administration of human chorionic gonadotropin in similarly pretreated patients and perhaps less likely to lead to hyperstimulation and multiple births. 8 Although Zarate et al. 2 • 3 and Keller4 induced ovulation in anovulatory patients by using frequent serial injections of LHRH-indicating that FSH was released in amounts sufficient to induce follicular maturation-the approach appears to be unphysiologic. 4 Moreover, it is impractical, expensive, and unnecessary if similar results can be obtained with the administration of a single dose of LH-RH to patients pretreated with clomiphene or HMG.
December 1975
The initial response to LH-RH alone may suggest a degree of susceptibility to ovulation induction in patients treated with LH-RH and clomiphene, but, within the limitations of the present study, gonadotropic response to LH-RH was not a consistently reliable predictor. Seven patients in our study had a poor pituitary response to LH-RH alone and might not have been expected to ovulate when treated with clomiphene-LH-RH. 5 Yet, three ovulated in the first clomipheneLH-RH cycle. Of the five patients who had a good response, four ovulated in the first clomiphene-LH-RH cycle, but one patient never ovulated. In the small number of patients under study, pituitary response to clomipheneLH-RH was a better predictor of ovulation than response to LH-RH alone (Table 1). Seven patients had a good response in the first clomiphene-LH-RH cycle; all seven ovulated. Three patients had a poor pituitary response; none ovulated. Limitation of quantity and the high cost of LH-RH and HMG continue to inhibit the amount of research done in this area. The number of anovulatory women is great but the number treated has
TABLE 1. Pituitary and Ovulatory Responses of 14 Anovulatory Patients to LH-RH Alone and to LH-RH Given in Conjunction with Clomiphene or HMG Patient
Intermenstrual interval
Ovulation
Pituitary response' Ovarian morphologyo
Clomiphene-LH-RH LH-RH
LH-RHHMG
Clomiphene-LH-RH LH-RH
1st cycle
2nd cycle
1st cycle
2nd cycle
G G G I p I G G I p I p G G
G G G I p I G G G p I p G G
+ + +
+ + +
LH-RHHMG
days
1 2 3 4 5 6 7
8 9 10 11
12 13 14
35-90 35-90 90-180 90-180 90-180 90-180 90-180 90-180 180 180 180 180 180 180
PSO PSO PSO PSO PSO POS POS POS PSO PSO PSO PSO PSO PSO
G G I p p G G G I p p p p P+
I p
+ + +
+ + +
+
+
+ +
+ +
p p
"PSO, Poorly stimulated ovaries; POS, polycystic ovary syndrome. bG, Good; P, poor; I, intermediate.
Vol. 26, No. 12
USE OF SYNTHETIC LH·RH IN INDUCTION OF OVULATION
necessarily been small. The reliability of a single injection of LH-RH as a test of pituitary function is not established, but the value of administration of LH-RH in anovulatory patients pretreated with clomiphene is fairly strongly indicated. SUMMARY
Each of 14 anovulatory patients received a single injection of 150 p,g of synthetic luteinizing hormone-releasing hormone (LH-RH) in one induced menstrual cycle. In two subsequent cycles, patients were pretreated with clomiphene before LH-RH injection. Four patients received LH7RH after pretreatment with human menopausal gonadotropin (HMG) in another cycle. In each cycle, gonadotropin release and ovulation were recorded. All patients had previously failed to ovulate when treated with large doses of clomiphene. No patient ovulated following injection of LH-RH alone, although five patients exhibited a good pituitary response. Nine patients ovulated when they received LH-RH after pretreatment with clomiphene, and one patient ovulated when pretreated with HMG. The diagnostic value of a single injection ofLH-RH is not clear. In the present study, gonadotropin response to LH-RH was not an entirely accurate predictor of a patient's ovulatory response in any of the four cycles. On the other hand, when clomiphene-LH-RH was administered, a good response was associated with ovulation in that cycle.
1177
The exact role of LH-RH in inducing ovulation is unclear, but the results of using LH-RH in conjunction with clomiphene are encouraging enough to warrant continued use and further study. Acknowledgments. We wish to thank Mrs. Loretta P. Brown, Mrs. Cheryl Belin, and Dr. D. M. Desiderio for their valuable contributions to this study. We also wish to thank St. Luke's Episcopal Hospital and Mr. Peter Maddeaux for their support of our studies. REFERENCES 1. Kastin AJ, Zarate A, Midgley AR Jr, Canales ES, Schally AV: Ovulation confirmed by pregnancy after infusion of porcine LH-RH. J Clin Endocrinol Metab 33:980, 1971 2. Zarate A, Canales ES, Schally AV, AyalaValdes L, Kastin AJ: Successful induction of ovulation with synthetic luteinizing hormonereleasing hormone in anovulatory infertility. Fertil Steril 23:672, 1972 3. Zarate A, Canales ES, Schally AV, Kastin AJ, Soria J: Induction of ovulation with synthetic luteinizing hormone-releasing hormone in suspected hypothalamic infertility. In Hypothalamic Hypophysiotropic Hormones, Edited by C Gaul, E Rosemberg. Amsterdam, Excerpta Medica Foundation, 1973, p 251 4. Keller PJ: Treatment of anovulation with synthetic luteinizing hormone-releasing hormone. Am J Obstet Gynecol 116:698, 1973 5. Keller PJ: Induction of ovulation by synthetic luteinizing-hormone releasing factor in infertile women. Lancet 2:570, 1972 6. Brown LP, Besch PK, Skelley DS, Buttram VC: Overnight radioimmunoassay of human follicle-stimulating hormone. Clin Chern 19:197, 1973 7. Brown LP, Skelley DS, Besch PK, Buttram VC, Fleischer NS: An overnight radioimmunoassay for human luteinizing hormone (abstr). Clin Chern 19:652, 1973 8. Taymor ML: Gonadotropin therapy. Possible causes and prevention of ovarian overstimulation. JAMA 203:362, 1968