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Successful Induction of Ovulation with Synthetic Luteinizing Hormone-Releasing Hormone in Anovulatory Infertility
Vol. 23, No.9, September 1972
FERTILITY AND STERILITY
Copyright © 1972 by The Williams & Wilkin.s Co.
Printed in U.SA.
SUCCESSFUL INDUCTION OF OVULATION WITH SYNTHETIC LUTEINIZING HORMONE-RELEASING HORMONE IN ANOVULATORY INFERTILITY ARTURO zARATE, M.D., F.A.F.S.,* ELiAS,S. CANALES, M.D., F.A.F.S. ANDREW V. SCHALLY, PH.D., LUIS AYALA-VALDES, M.D., ABBA J. KASTIN, M.D.
Department of Gynecologic Endocrinology, Hospital Gineco-Obstetricia No.1, I.M.S.S. Mexico and Veterans Administration Hospital and Tulane University, New Orleans, Louisiana
It has been previously reported that luteinizing hormone-releasing hormone (LH-RH) purified from porcine hypothalami was able to induce ovulation 1 when infused intravenously for 24 hr. into a woman who was pretreated with human menopausal gonadotropin (HMG). Since synthetic LH-RH stimulates the release of follicle-stimulating hormone (FSH) in addition to LH,2 attempts were made to induce ovulation and pregnancy in subjects receiving only the synthetic decapeptide and without any previous pretreatment with HMG. The present communication reports our experience in the treatment of sterility in patients with suspected hypothalamic anovulation using synthetic LH-RH in various therapeutic modalities. MATERIAL AND METHODS
Synthetic LH-RH was prepared by solid phase method and repurified to be administered. 2 Clinical Material. Thirteen women with suspected hypothalamic anovulation were selected to receive LH-RH therapy. Two of these 13 patients had a syndrome of amenorrhea galactorrhea without sellar enlargement; one of them had the symptoms for 2 years which started after parturition (Chiari-Frommel syndrome); this patient failed to respond to clomiphene Received April 10, 1972; revised May 11, 1972. * Address requests for reprints to: Dr. Zarate, Hospital Gineco-Obstetricia No.1, Gabriel Mancera 222 Mexico 12, D.F.
therapy prior to this study. The other woman had primary sterility (Del Castillo syndrome), and no previous treatment. Low gonadotropin activity in urine as well as urinary estrogens was found in both cases. Five patients had polycystic ovarian disease or Stein-Leventhal syndrome. Bilaterally enlarged ovaries as proved by pelvineumography and endoscopy, secondary amenorrhea, and hirsutism established the working diagnosis. One of these 5 women became pregnant after clomiphene treatment 3 years before the present study. In all patients the urinary gonadotropin activity and total estrogens were within normal values or slightly above the upper normal limit. Six patients were diagnosed as "idiopathic secondary amenorrhea"; serum gonadotropins and gonadotropin activity in urine were either absent or in low levels; however a medium estrogenic effect was demonstrated in vaginal cytology and endometrium. Patients were observed during a 3-month period in order to verify the anovulatory stage. During this time, patients showed neither signs of ovulation nor menses. All women had tubal patency determined by hysterosalpinography, and a normal postcoital examination in all couples was also demonstrated. Women were considered to be infertile if conception attempts have been unsuccessful for a minimum of 2 years with apparently fertile males. Therapeutic Regimens. Three women received LH-RH by continuous intra-
672
September 1972
673
LUTEINIZING HORMONE-RELEASING HORMONE
TABLE 1. Results of Treatment of Sterility with Luteinizing Hormone-Releasing Hormone (LH-RH) LH-RH Case
Diagnosis
Previous therapy Intravenous
1 2 3 4
5 6 7 8 9 10 11 12 13
Secondary amenorrhea Stein-Leventhal Del Castillo Chiari-Frommel Stein-Leventhal Stein-Leventhal Stein-Leventhal Stein-Leventhal Stein-Leventhal Secondary amenorrhea Secondary amenorrhea Secondary amenorrhea Secondary amenorrhea
Intramuscular
Ovulation Ovulation No response No response to clomiphene Pregnancy with clomiphene
Ovulation Pregnancy No response No response No response No response Pregnancy No response Ovulation No response
No response to clomiphene
venous infusion. Five days after the onset of withdrawal bleeding from chlormadinone, a dose equivalent to 100 pg. of synthetic LH-RH was infused in saline solution for 8 hr. At the end of this time, an acute injection of the same quantity of LH-RH was given. After 10 days had elapsed, the infusion of 100 pg. of LH-RH over a period of 8 hr. was repeated without the supplemental injection of LH-RH. Coitus was advised immediately after the second infusion. Ten patients were given LH-RH by repeated intramuscular injections. Five days after a chlormadinone withdrawal bleeding, 50 /-Lg. of synthetic LH-RH were administered intramuscularly daily for 10 days. Coitus was indicated every other day starting on Day 8th of therapy. Since pregnancy was the main goal of treatment and the only unequivocal sign of ovulation, the results of therapy were analyzed in relation to the pregnancy rate. Presumptive ovulation was also determined on each mode of therapy; this was defined by a classical basal body temperature elevation of 14 ± 2 days, urinary pregnanediol levels above 1.5 mg./24 hr., increased urinary estrogens, and changes on cervical mucus and vaginal epithelium.
TABLE 2. Results of Thempy with Synthetic
LH-RH in Hypothalamic Anovulation No. of ca...
Presumed ovulation
No. of conceptions
Intravenous infusion * Intramuscular Injectionst
3 10
2 4
0 2
Total
13
6
2
Type of therapy
* Two
8-hr. intravenous infusions, on Days 5th and 15th of the cycle. t Ten intramuscular injections, from Day 5th to 15th of the cycle.
RESULTS
Clinical data on the patients as well as the results of treatment are shown in Table 1. Two out of 3 patients who were given LH-RH by intravenous infusion had presumptive signs of ovulation but unsuccessful conception response~ Four of the 10 patients who received repeated intramuscular injections of LH-RH had presumptive signs of ovulation, and 2 of the 4 women who ovulated became pregnant. The 6 remaining patients injected intramuscularly responded only with increased urinary estrogens and an estrogenic effect upon the cervical mucus and vaginal epithelium. Table 2 summarizes the results
674
Vol. 23
ZARATE ET AL.
of treatment in both groups. It can be seen that a total of 6 patients apparently ovulated after LH-RH administration, and 2 became pregnant. At the time this communication is being written the 2 pregnancies are in progress. No adverse reactions were observed following LH-RH therapy. DISCUSSION
This preliminary study suggests that synthetic LH-RH can release enough FSH to induce follicular development and subsequently enough LH to result in ovulation. The results confirm the therapeutic role of LH-RH in certain cases of sterility. It was also shown that the intramuscular route of administration of LH-RH is effective in inducing ovulation, thus simplifying the mode of treatment with this synthetic hormone. One of the criteria for ovulation used in this report is based on the appearance of increased production of progesterone, and evidence indicates that this secretion may not always reflect true ovulation with ovum extrusion but may be associated only with extensive luteinization of ovarian stroma and follicles. 3 On the basis of presented data it may be concluded that treatment of anovulatory sterility with synthetic LH-RH seems to be effective; however, further studies with
larger groups of patients are necessary in order to assess the place of this therapy. SUMMARY
Thirteen patients with suspected hypothalamic anovulation were treated with synthetic luteinizing hormone-releasing hormone (LH-RH) in order to induce ovulation and pregnancy. Two out of 3 patients ovulated after LH-RH was administered by intravenous infusion for 8 hr. Four of the 10 patients ovulated after daily intramuscular injection of LH-RH for 10 days; 2 pregnancies were obtained in th~s group. This study suggests that synthetic LH-RH can release enough FSH and LH to induce follicular development as well as ovulation and confirms its potential usefulness in the treatment of some cases of sterility. REFERENCES
1. KASTIN, A. J., ZARATE, A., MIDGLEY, A. R., CANALES, E. S., AND SCHALLY, A. V. Ovulation confirmed by pregnancy after infusion of porcine LH-RH. J Clin Endocr 33:980, 1971. 2. SCHALLY, A. V., KASTIN, A. J., AND ARIMURA, A. The hypothalamus and reproduction. Amer J Obstet Gynec. In press, September 1972. 3. ZARATE, A., HERNANDEZ-AYup, S., AND RlOsMONTIEL, A. Treatment of anovulation in the Stein-Leventhal syndrome. Analysis of 90 cases. Fertil Steril 22:188, 1971.
FERTILITY AND STERILITY
Copyright © 1972 by The Williams & Wilkin.s Co.
Printed in U.SA.
SUCCESSFUL INDUCTION OF OVULATION WITH SYNTHETIC LUTEINIZING HORMONE-RELEASING HORMONE IN ANOVULATORY INFERTILITY ARTURO zARATE, M.D., F.A.F.S.,* ELiAS,S. CANALES, M.D., F.A.F.S. ANDREW V. SCHALLY, PH.D., LUIS AYALA-VALDES, M.D., ABBA J. KASTIN, M.D.
Department of Gynecologic Endocrinology, Hospital Gineco-Obstetricia No.1, I.M.S.S. Mexico and Veterans Administration Hospital and Tulane University, New Orleans, Louisiana
It has been previously reported that luteinizing hormone-releasing hormone (LH-RH) purified from porcine hypothalami was able to induce ovulation 1 when infused intravenously for 24 hr. into a woman who was pretreated with human menopausal gonadotropin (HMG). Since synthetic LH-RH stimulates the release of follicle-stimulating hormone (FSH) in addition to LH,2 attempts were made to induce ovulation and pregnancy in subjects receiving only the synthetic decapeptide and without any previous pretreatment with HMG. The present communication reports our experience in the treatment of sterility in patients with suspected hypothalamic anovulation using synthetic LH-RH in various therapeutic modalities. MATERIAL AND METHODS
Synthetic LH-RH was prepared by solid phase method and repurified to be administered. 2 Clinical Material. Thirteen women with suspected hypothalamic anovulation were selected to receive LH-RH therapy. Two of these 13 patients had a syndrome of amenorrhea galactorrhea without sellar enlargement; one of them had the symptoms for 2 years which started after parturition (Chiari-Frommel syndrome); this patient failed to respond to clomiphene Received April 10, 1972; revised May 11, 1972. * Address requests for reprints to: Dr. Zarate, Hospital Gineco-Obstetricia No.1, Gabriel Mancera 222 Mexico 12, D.F.
therapy prior to this study. The other woman had primary sterility (Del Castillo syndrome), and no previous treatment. Low gonadotropin activity in urine as well as urinary estrogens was found in both cases. Five patients had polycystic ovarian disease or Stein-Leventhal syndrome. Bilaterally enlarged ovaries as proved by pelvineumography and endoscopy, secondary amenorrhea, and hirsutism established the working diagnosis. One of these 5 women became pregnant after clomiphene treatment 3 years before the present study. In all patients the urinary gonadotropin activity and total estrogens were within normal values or slightly above the upper normal limit. Six patients were diagnosed as "idiopathic secondary amenorrhea"; serum gonadotropins and gonadotropin activity in urine were either absent or in low levels; however a medium estrogenic effect was demonstrated in vaginal cytology and endometrium. Patients were observed during a 3-month period in order to verify the anovulatory stage. During this time, patients showed neither signs of ovulation nor menses. All women had tubal patency determined by hysterosalpinography, and a normal postcoital examination in all couples was also demonstrated. Women were considered to be infertile if conception attempts have been unsuccessful for a minimum of 2 years with apparently fertile males. Therapeutic Regimens. Three women received LH-RH by continuous intra-
672
September 1972
673
LUTEINIZING HORMONE-RELEASING HORMONE
TABLE 1. Results of Treatment of Sterility with Luteinizing Hormone-Releasing Hormone (LH-RH) LH-RH Case
Diagnosis
Previous therapy Intravenous
1 2 3 4
5 6 7 8 9 10 11 12 13
Secondary amenorrhea Stein-Leventhal Del Castillo Chiari-Frommel Stein-Leventhal Stein-Leventhal Stein-Leventhal Stein-Leventhal Stein-Leventhal Secondary amenorrhea Secondary amenorrhea Secondary amenorrhea Secondary amenorrhea
Intramuscular
Ovulation Ovulation No response No response to clomiphene Pregnancy with clomiphene
Ovulation Pregnancy No response No response No response No response Pregnancy No response Ovulation No response
No response to clomiphene
venous infusion. Five days after the onset of withdrawal bleeding from chlormadinone, a dose equivalent to 100 pg. of synthetic LH-RH was infused in saline solution for 8 hr. At the end of this time, an acute injection of the same quantity of LH-RH was given. After 10 days had elapsed, the infusion of 100 pg. of LH-RH over a period of 8 hr. was repeated without the supplemental injection of LH-RH. Coitus was advised immediately after the second infusion. Ten patients were given LH-RH by repeated intramuscular injections. Five days after a chlormadinone withdrawal bleeding, 50 /-Lg. of synthetic LH-RH were administered intramuscularly daily for 10 days. Coitus was indicated every other day starting on Day 8th of therapy. Since pregnancy was the main goal of treatment and the only unequivocal sign of ovulation, the results of therapy were analyzed in relation to the pregnancy rate. Presumptive ovulation was also determined on each mode of therapy; this was defined by a classical basal body temperature elevation of 14 ± 2 days, urinary pregnanediol levels above 1.5 mg./24 hr., increased urinary estrogens, and changes on cervical mucus and vaginal epithelium.
TABLE 2. Results of Thempy with Synthetic
LH-RH in Hypothalamic Anovulation No. of ca...
Presumed ovulation
No. of conceptions
Intravenous infusion * Intramuscular Injectionst
3 10
2 4
0 2
Total
13
6
2
Type of therapy
* Two
8-hr. intravenous infusions, on Days 5th and 15th of the cycle. t Ten intramuscular injections, from Day 5th to 15th of the cycle.
RESULTS
Clinical data on the patients as well as the results of treatment are shown in Table 1. Two out of 3 patients who were given LH-RH by intravenous infusion had presumptive signs of ovulation but unsuccessful conception response~ Four of the 10 patients who received repeated intramuscular injections of LH-RH had presumptive signs of ovulation, and 2 of the 4 women who ovulated became pregnant. The 6 remaining patients injected intramuscularly responded only with increased urinary estrogens and an estrogenic effect upon the cervical mucus and vaginal epithelium. Table 2 summarizes the results
674
Vol. 23
ZARATE ET AL.
of treatment in both groups. It can be seen that a total of 6 patients apparently ovulated after LH-RH administration, and 2 became pregnant. At the time this communication is being written the 2 pregnancies are in progress. No adverse reactions were observed following LH-RH therapy. DISCUSSION
This preliminary study suggests that synthetic LH-RH can release enough FSH to induce follicular development and subsequently enough LH to result in ovulation. The results confirm the therapeutic role of LH-RH in certain cases of sterility. It was also shown that the intramuscular route of administration of LH-RH is effective in inducing ovulation, thus simplifying the mode of treatment with this synthetic hormone. One of the criteria for ovulation used in this report is based on the appearance of increased production of progesterone, and evidence indicates that this secretion may not always reflect true ovulation with ovum extrusion but may be associated only with extensive luteinization of ovarian stroma and follicles. 3 On the basis of presented data it may be concluded that treatment of anovulatory sterility with synthetic LH-RH seems to be effective; however, further studies with
larger groups of patients are necessary in order to assess the place of this therapy. SUMMARY
Thirteen patients with suspected hypothalamic anovulation were treated with synthetic luteinizing hormone-releasing hormone (LH-RH) in order to induce ovulation and pregnancy. Two out of 3 patients ovulated after LH-RH was administered by intravenous infusion for 8 hr. Four of the 10 patients ovulated after daily intramuscular injection of LH-RH for 10 days; 2 pregnancies were obtained in th~s group. This study suggests that synthetic LH-RH can release enough FSH and LH to induce follicular development as well as ovulation and confirms its potential usefulness in the treatment of some cases of sterility. REFERENCES
1. KASTIN, A. J., ZARATE, A., MIDGLEY, A. R., CANALES, E. S., AND SCHALLY, A. V. Ovulation confirmed by pregnancy after infusion of porcine LH-RH. J Clin Endocr 33:980, 1971. 2. SCHALLY, A. V., KASTIN, A. J., AND ARIMURA, A. The hypothalamus and reproduction. Amer J Obstet Gynec. In press, September 1972. 3. ZARATE, A., HERNANDEZ-AYup, S., AND RlOsMONTIEL, A. Treatment of anovulation in the Stein-Leventhal syndrome. Analysis of 90 cases. Fertil Steril 22:188, 1971.