FERTILITY AND STERILITY Copyright < 1976 The American Fertility Society
Vol. 27, No.6, June 1976 Printed in V.SA.
LUTEINIZING HORMONE-RELEASING HORMONE FOR INDUCTION OF FOLLICULAR MATURATION AND OVULATION IN WOMEN WITH INFERTILITY AND AMENORRHEA* SIMON R. HENDERSON, M.A., B.M., B.CR., M.R.C.O.G.,t JOHN BONNAR, M.D., F.R.C.O.G.J ANDREW MOORE, B.A., AND PAMELA C.B. MACKINNON, M.A., PH.D., M.B., B.S. Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, and Departments of Clinical Biochemistry and Human Anatomy, Oxford, England
Five patients with primary infertility and secondary amenorrhea who did not respond to clomiphene with a gonadotropin or estrogen surge were treated with 500 WI of luteinizing hormone, follicle-stimulating hormone-releasing hormone (LH-RH), self-administered subcutaneously every 8 hours for 14 days. Of four patients who responded to this treatment, three showed follicular maturation, ovulation, and menses, although the luteal phase was deficient; in the fourth patient, follicular maturation and menses occurred without evidence of ovulation. For their second course of treatment these four patients were given LH-RH with the addition of human chorionic gonadotropin when the urinary estrogen levels indicated follicular maturation. All four patients responded with ovulation, an adequate luteal phase, and menses, without clinical indication of ovarian hyperstimulation. These results suggest that LH-RH may be a better alternative to human menopausal gonadotropin in the treatment of anovulatory infertility.
Earlier reports of the use of luteinizing hormone, follicle-stimulating hormonereleasing hormone (LH-RH) in low doses to induce ovulation in anovulatory women have indicated limited success. I •3 However, there have been recent reports of follicular maturation, ovulation, and pregnancy in amenorrheic patients with anorexia nervosa following long-term treatment with LH-RH with or without the added stimulus of human chorionic gonadotropin (HCG).4, 5 The aim of this study was to examine the use of LH-RH alone and in comb iAccepted December 24, 1975. *Supported in part by Grant G 973/809/C from the Medical Research Council (to P. C. B. M.). tMedical Research Council Senior Clinical Research Fellow, Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford. :j:Present address: Rotunda Hospital, Dublin, Ireland.
621
nation with HCG for stimulating follicular maturation, ovulation, and normal luteal function in otherwise healthy but amenorrheic patients who complained of infertility. PATIENTS AND METHODS
Five involuntarily infertile women, ages 23 to 31, with amenorrhea of 2 to 7 years' duration were examined thoroughly for gynecologic, endocrinologic, and neurologic disease. X-ray examinations of the skull and pituitary fossa were normal. Serum thyroxine and triiodothyronine levels were normal, as were 24-hour urinary 17 -hydroxycorticosteroid and 17-ketosteroid determinations. Basal urinary estrogen and plasma 17.B-estradiol levels were low, and serum prolactin levels were normal (range, 10 to 24 ng/mD. After investigation, all five patients were given at
HENDERSON ET AL.
622
least one course of clomiphene (200 mg daily for 5 days), which failed to result in a significant elevation of plasma luteinizing hormone (LH) or folliclestimulating hormone (FSH) levels or a subsequent rise in basal body temperature (BBT), total urinary estrogens, or plasma 17,8-estradiol. Hormone Assays. LH and FSH were estimated by a double-antibody radioimmunoassay. Details of standards and quality controls used in this assay system have been reported previously.6 Plasma 17,8-estradiol and progesterone levels were also measured by radioimmunoassay using specific antisera. 7 Total urinary estrogens were measured, after extraction, by an automated spectrophotometric technique 8 ; the values just prior to ovulation ran~ed between 86 and 126 JLg/24 hours. With this method urinary estrogen values were generally 30 to 40% higher than those obtained with another technique. 9 LH-RH Regimen. The LH-RH test was performed on each patient following the diagnostic/therapeutic trial of clomiphene. An intravenous dose of 50 JLg of LH-RH (Hoechst Pharmaceuticals, Hounslow, Middlesex, United Kingdom) was given, and blood samples were obtained prior to injection and at various intervals thereafter. 10 The maximal plasma LH and FSH responses were calculated by determining the difference between the maximal postinjection and the mean preinjection concentrations of LH and FSH.
June 1976
The first therapeutic regimen consisted of 500 JLg of LH-RH every 8 hours, self-administered subcutaneously into a skin fold below the umbilicus. In the second course of treatment, HCG (5000 IU) was given intramuscularly after urinary estrogen levels had increased (> 100 JLg/24 hours) for 2 days. Additional 3000-IU doses of HCG were then given twice weekly to maintain the luteal phase. During both regimens, plasma was assayed twice weekly for LH, FSH, 17,8-estradiol, and progesterone content, and total urinary estrogens were determined on almost a daily basis during LH-RH treatment. RESULTS
Treatment. Height, weight, mean basal LH and FSH levels, and LH and FSH responses at the time of the LH-RH test are shown in Table 1. All patients responded to LH-RH with a marked rise in plasma LH levels and with a smaller but significant rise in FSH. In two patients (patients 2 and 5) the basal plasma FSH values were higher than the LH levels, and the FSH increases were larger than those of the other patients. Results of the first course of treatment are shown in Table 2 and summarized in Table 3. Figure 1 (patient 1) shows the typical hormone and BBT patterns that occurred in three patients. The short duration of BBT elevation, prematurely low or undetectable levels of progesterone, and early onset of menses indicate
TABLE 1. Plasma Gonadotropin Levels before and after an Intravenous Injection of 50 p.g of LH-RH LH Patient
1 2 3 4 5
Height
Weight
em
kg
158 165 155 168 163
48.5 55.8 50.6 53.6 49.0
Basal
FSH Basal
Response"
Response"
mIUlml
9 4 11
15 3
51 38 49 155 32
"Maximal postinjection concentration minus basal concentration.
7 9 3 10 7
8 11
3 9 19
623
LH-RH'INDUCED FOLLICULAR MATURATION AND OVULATION
Vol. 27, No.6
TABLE 2. Induction of Follicular Maturation and Ovulation with LH-RH Peak urinary estrogen
Patient
Course
1
1 2 1 2 1 2 1 2 1
Day of cycle
Concentration
2 3 4 5
12 14
235 215 140 110 120 220 150 160 85
11
11 12 11 7
Duration of temperature rise
nglml
nglml
days
15.5 25.4 1.0 21.8 12.6 20.1 23.5 24.3 1.0
Vol. 27, No.6, June 1976 Printed in V.SA.
LUTEINIZING HORMONE-RELEASING HORMONE FOR INDUCTION OF FOLLICULAR MATURATION AND OVULATION IN WOMEN WITH INFERTILITY AND AMENORRHEA* SIMON R. HENDERSON, M.A., B.M., B.CR., M.R.C.O.G.,t JOHN BONNAR, M.D., F.R.C.O.G.J ANDREW MOORE, B.A., AND PAMELA C.B. MACKINNON, M.A., PH.D., M.B., B.S. Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, and Departments of Clinical Biochemistry and Human Anatomy, Oxford, England
Five patients with primary infertility and secondary amenorrhea who did not respond to clomiphene with a gonadotropin or estrogen surge were treated with 500 WI of luteinizing hormone, follicle-stimulating hormone-releasing hormone (LH-RH), self-administered subcutaneously every 8 hours for 14 days. Of four patients who responded to this treatment, three showed follicular maturation, ovulation, and menses, although the luteal phase was deficient; in the fourth patient, follicular maturation and menses occurred without evidence of ovulation. For their second course of treatment these four patients were given LH-RH with the addition of human chorionic gonadotropin when the urinary estrogen levels indicated follicular maturation. All four patients responded with ovulation, an adequate luteal phase, and menses, without clinical indication of ovarian hyperstimulation. These results suggest that LH-RH may be a better alternative to human menopausal gonadotropin in the treatment of anovulatory infertility.
Earlier reports of the use of luteinizing hormone, follicle-stimulating hormonereleasing hormone (LH-RH) in low doses to induce ovulation in anovulatory women have indicated limited success. I •3 However, there have been recent reports of follicular maturation, ovulation, and pregnancy in amenorrheic patients with anorexia nervosa following long-term treatment with LH-RH with or without the added stimulus of human chorionic gonadotropin (HCG).4, 5 The aim of this study was to examine the use of LH-RH alone and in comb iAccepted December 24, 1975. *Supported in part by Grant G 973/809/C from the Medical Research Council (to P. C. B. M.). tMedical Research Council Senior Clinical Research Fellow, Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford. :j:Present address: Rotunda Hospital, Dublin, Ireland.
621
nation with HCG for stimulating follicular maturation, ovulation, and normal luteal function in otherwise healthy but amenorrheic patients who complained of infertility. PATIENTS AND METHODS
Five involuntarily infertile women, ages 23 to 31, with amenorrhea of 2 to 7 years' duration were examined thoroughly for gynecologic, endocrinologic, and neurologic disease. X-ray examinations of the skull and pituitary fossa were normal. Serum thyroxine and triiodothyronine levels were normal, as were 24-hour urinary 17 -hydroxycorticosteroid and 17-ketosteroid determinations. Basal urinary estrogen and plasma 17.B-estradiol levels were low, and serum prolactin levels were normal (range, 10 to 24 ng/mD. After investigation, all five patients were given at
HENDERSON ET AL.
622
least one course of clomiphene (200 mg daily for 5 days), which failed to result in a significant elevation of plasma luteinizing hormone (LH) or folliclestimulating hormone (FSH) levels or a subsequent rise in basal body temperature (BBT), total urinary estrogens, or plasma 17,8-estradiol. Hormone Assays. LH and FSH were estimated by a double-antibody radioimmunoassay. Details of standards and quality controls used in this assay system have been reported previously.6 Plasma 17,8-estradiol and progesterone levels were also measured by radioimmunoassay using specific antisera. 7 Total urinary estrogens were measured, after extraction, by an automated spectrophotometric technique 8 ; the values just prior to ovulation ran~ed between 86 and 126 JLg/24 hours. With this method urinary estrogen values were generally 30 to 40% higher than those obtained with another technique. 9 LH-RH Regimen. The LH-RH test was performed on each patient following the diagnostic/therapeutic trial of clomiphene. An intravenous dose of 50 JLg of LH-RH (Hoechst Pharmaceuticals, Hounslow, Middlesex, United Kingdom) was given, and blood samples were obtained prior to injection and at various intervals thereafter. 10 The maximal plasma LH and FSH responses were calculated by determining the difference between the maximal postinjection and the mean preinjection concentrations of LH and FSH.
June 1976
The first therapeutic regimen consisted of 500 JLg of LH-RH every 8 hours, self-administered subcutaneously into a skin fold below the umbilicus. In the second course of treatment, HCG (5000 IU) was given intramuscularly after urinary estrogen levels had increased (> 100 JLg/24 hours) for 2 days. Additional 3000-IU doses of HCG were then given twice weekly to maintain the luteal phase. During both regimens, plasma was assayed twice weekly for LH, FSH, 17,8-estradiol, and progesterone content, and total urinary estrogens were determined on almost a daily basis during LH-RH treatment. RESULTS
Treatment. Height, weight, mean basal LH and FSH levels, and LH and FSH responses at the time of the LH-RH test are shown in Table 1. All patients responded to LH-RH with a marked rise in plasma LH levels and with a smaller but significant rise in FSH. In two patients (patients 2 and 5) the basal plasma FSH values were higher than the LH levels, and the FSH increases were larger than those of the other patients. Results of the first course of treatment are shown in Table 2 and summarized in Table 3. Figure 1 (patient 1) shows the typical hormone and BBT patterns that occurred in three patients. The short duration of BBT elevation, prematurely low or undetectable levels of progesterone, and early onset of menses indicate
TABLE 1. Plasma Gonadotropin Levels before and after an Intravenous Injection of 50 p.g of LH-RH LH Patient
1 2 3 4 5
Height
Weight
em
kg
158 165 155 168 163
48.5 55.8 50.6 53.6 49.0
Basal
FSH Basal
Response"
Response"
mIUlml
9 4 11
15 3
51 38 49 155 32
"Maximal postinjection concentration minus basal concentration.
7 9 3 10 7
8 11
3 9 19
623
LH-RH'INDUCED FOLLICULAR MATURATION AND OVULATION
Vol. 27, No.6
TABLE 2. Induction of Follicular Maturation and Ovulation with LH-RH Peak urinary estrogen
Patient
Course
1
1 2 1 2 1 2 1 2 1
Day of cycle
Concentration
2 3 4 5
12 14
235 215 140 110 120 220 150 160 85
11
11 12 11 7
Duration of temperature rise
nglml
nglml
days
15.5 25.4 1.0 21.8 12.6 20.1 23.5 24.3 1.0
