FERTILITY AND SrERIUTY Copyright © 1977 The American Fertility Society
Vol. 28. No.7. July 1977 Printed in U.SA.
THE EFFECT OF GONADOTROPIN-RELEASING HORMONE ON BLOOD GLUCOSE, INSULIN, LUTEINIZING HORMONE, AND FOLLICLE-STIMULATING HORMONE LEVELS
WILLIAM N. SPELLACY, M.D.* BERNARD CANTOR, M.D. PUSHPA S. KALRA, PH.D. WILLIAM C. BUHI, M.S. SHARON A. BIRK, R.N., B.S. Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida 32610
Sixteen women volunteers with menstrual irregularities were studied with an intravenous injection oflOO p.g ofgonadotropin-releasing hormone (GNRH). Serial blood samples were obtained for 2 hours after the injection and assayed for their concentration ofglucose, insulin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). There was a significant increase in the levels of both gonadotropins following the injection, with the peak for LH occurring at 30 minutes and the peak for FSH occurring at 90 minutes. There was a slight decrease in the glucose level at 45 minutes and in the insulin levels at 60 and 120 minutes. Because GNRH causes only minor changes in these parameters of carbohydrate metabolism, it would appear to be safe to use in women with ovulatory abnormalities secondary to diabetes mellitus.
strual irregularities varying from oligomenorrhea to secondary amenorrhea. They were brought to the metabolic laboratory at 8 A.M. after having fasted overnight. After they were weighed, each woman was seated for the remainder of the test. A catheter was inserted into an antecubital vein and kept patent with a saline-heparin solution. A fasting venous blood sample was obtained and the subject was then given an intravenous injection of 5 ml of water containing 100 p,g of GNRH (Lot CI-785, generously supplied by Parke, Davis & Co., Ann Arbor, Mich.). Repeat blood samples were than obtained 15, 30, 45, 60, 90, and 120 minutes after the injection. No adverse reactions were experienced by any of the women. Each blood sample was partitioned between plain containers and those containing heparin, and centrifuged; the serum and plasma were separated and frozen at - 20" C. The serum levels of FSH and LH were measured in duplicate by utilizing radioimmunoassay kits supplied by the National Institute of Arthritis, Metabolism and Digestive Diseases of the National Institutes of Health. 2 (Gonadotropin results are expressed in terms of the Second International Reference Preparation of human menopausal gonadotropin,
It has recently been shown that some hypothalamic polypeptides (e.g., somatostatin) have effects at tissues distant to the pituitary gland. 1 The systemic effects of these hypothalamic polypeptides are therefore important, for they are now being administered frequently for pituitary testing and/or treatment. The physician must know these sequelae since some of the persons receiving the compounds may have systemic diseases that could be adversely affected. In order to further our knowledge of the possible carbohydrate metabolic effects of gonadotropin-releasing hormone (GNRH) in women the following study was undertaken. The results show that GNRH does not markedly alter either blood glucose or plasma insulin levels while it does increase the serum gonadotropin concentrations. METHODS
Sixteen women volunteered for this study and each signed an informed consent. All had menReceived February 2, 1977; accepted February 23,1977. *Reprint requests: WilliamN. Spellacy, M.D., Department of Obstetrics and Gynecology, University of Florida College of Medicine, Box J-294 JHMHC, Gainesville, Fla. 32610.
733
SPELLACY ET AL.
734
July 1977 RESULTS
kindly supplied by the World Health Organization International Laboratory for Biological Standards, Holly Hill, London, England.) Plasma insulin levels were measured in duplicate by a modified solid-phase radioimmunoassay procedure. 3 • 4 (The human insulin used as a standard in these studies was Lot 516-734-B33, kindly supplied by Dr. Mary A. Root of the Lilly Research Laboratory, Indianapolis, Ind.) Blood glucose levels were measured in duplicate by the methods of Nelson5 and Somogyi. 6 All of the samples from one subject's complete test were assayed in the same radioimmunoassay procedure in order to eliminate interassay variation. All of these data were placed on punch cards and appropriately analyzed with the aid of a computer. Determinations were made of the means, standard errors of the mean, and matched-pair t-tests. The probability values were taken from two-tailed tables, and only values ofless than 0.05 were considered significant. The subjects' mean age was 22.6 ± 1.3 years and their mean weight was 117.2 ± 2.8 pounds. Five of the women had irregular menstrual periods and the remaining eleven women had secondary amenorrhea without apparent cause. AI~ of the women had sella turcica x-ray studies, which were normal. Their mean plasma progesterone concentration at the time of the test was 0.14 ± 0.03 nglml (all less than 1 nglml). Their mean serum estradiol level was 28.4 ± 4.5 pg/ml and ranged from 4.1 to 61.1 pglml. The mean serum prolactin level was 29.4 ± 10.0 ng/ml.
Gonadotropins. The statistical studies of the serum gonadotropin concentrations are given in Table 1. The levels of both gonadotropins increased following the GNRH injection, and the increase for LH exceeded that for FSH. The time to peak mean concentration for LH was clearly at 30 minutes whereas the FSH peak was highest at 90 minutes, but there was little difference between the mean values from 30 to 120 minutes. The mean values are shown in Figure 1. Glucose. The statistical studies of the blood glucose levels are also given in Table 1. There was a slight but significant decrease in the glucose concentration 45 minutes after the injection of GNRH. All of the other values were unchanged from the fasting value. The mean values are shown in Figure 1. Insulin. The statistical studies of the plasma insulin values are given in Table 1. There was a significant decrease in the concentration of insulin at both 60 and 120 minutes after the GNRH was administered. The mean values are shown in Figure 1.
DISCUSSION
The purification and synthesis of GNRH has opened a new frontier in reproductive endocrinology.7 A more precise evaluation of the hypothalamic-pituitary axis is now possible by administering GNRH and measuring blood gonado-
TABLE 1. Statistical Studies of Blood Glucose and Plasma Insulin, LB, and FSH before and after an Intravenous Injection of 100118 of Gonadotropin-Releasing Hormone (N = 16) Time after injection
Parameter
LH (mIU/ml) Mean SEM t P FSH (mIU/ml) Mean SEM t P Glucose (mg/100 ml) Mean SEM t P Insulin 0-tU/ml) Mean SEM t P
aNS, Not significant.
Fasting control
15 min
30 min
45 min
60 min
90 min
120 min
20.9 3.5
93.7 22.2 3.73
Vol. 28. No.7. July 1977 Printed in U.SA.
THE EFFECT OF GONADOTROPIN-RELEASING HORMONE ON BLOOD GLUCOSE, INSULIN, LUTEINIZING HORMONE, AND FOLLICLE-STIMULATING HORMONE LEVELS
WILLIAM N. SPELLACY, M.D.* BERNARD CANTOR, M.D. PUSHPA S. KALRA, PH.D. WILLIAM C. BUHI, M.S. SHARON A. BIRK, R.N., B.S. Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, Florida 32610
Sixteen women volunteers with menstrual irregularities were studied with an intravenous injection oflOO p.g ofgonadotropin-releasing hormone (GNRH). Serial blood samples were obtained for 2 hours after the injection and assayed for their concentration ofglucose, insulin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). There was a significant increase in the levels of both gonadotropins following the injection, with the peak for LH occurring at 30 minutes and the peak for FSH occurring at 90 minutes. There was a slight decrease in the glucose level at 45 minutes and in the insulin levels at 60 and 120 minutes. Because GNRH causes only minor changes in these parameters of carbohydrate metabolism, it would appear to be safe to use in women with ovulatory abnormalities secondary to diabetes mellitus.
strual irregularities varying from oligomenorrhea to secondary amenorrhea. They were brought to the metabolic laboratory at 8 A.M. after having fasted overnight. After they were weighed, each woman was seated for the remainder of the test. A catheter was inserted into an antecubital vein and kept patent with a saline-heparin solution. A fasting venous blood sample was obtained and the subject was then given an intravenous injection of 5 ml of water containing 100 p,g of GNRH (Lot CI-785, generously supplied by Parke, Davis & Co., Ann Arbor, Mich.). Repeat blood samples were than obtained 15, 30, 45, 60, 90, and 120 minutes after the injection. No adverse reactions were experienced by any of the women. Each blood sample was partitioned between plain containers and those containing heparin, and centrifuged; the serum and plasma were separated and frozen at - 20" C. The serum levels of FSH and LH were measured in duplicate by utilizing radioimmunoassay kits supplied by the National Institute of Arthritis, Metabolism and Digestive Diseases of the National Institutes of Health. 2 (Gonadotropin results are expressed in terms of the Second International Reference Preparation of human menopausal gonadotropin,
It has recently been shown that some hypothalamic polypeptides (e.g., somatostatin) have effects at tissues distant to the pituitary gland. 1 The systemic effects of these hypothalamic polypeptides are therefore important, for they are now being administered frequently for pituitary testing and/or treatment. The physician must know these sequelae since some of the persons receiving the compounds may have systemic diseases that could be adversely affected. In order to further our knowledge of the possible carbohydrate metabolic effects of gonadotropin-releasing hormone (GNRH) in women the following study was undertaken. The results show that GNRH does not markedly alter either blood glucose or plasma insulin levels while it does increase the serum gonadotropin concentrations. METHODS
Sixteen women volunteered for this study and each signed an informed consent. All had menReceived February 2, 1977; accepted February 23,1977. *Reprint requests: WilliamN. Spellacy, M.D., Department of Obstetrics and Gynecology, University of Florida College of Medicine, Box J-294 JHMHC, Gainesville, Fla. 32610.
733
SPELLACY ET AL.
734
July 1977 RESULTS
kindly supplied by the World Health Organization International Laboratory for Biological Standards, Holly Hill, London, England.) Plasma insulin levels were measured in duplicate by a modified solid-phase radioimmunoassay procedure. 3 • 4 (The human insulin used as a standard in these studies was Lot 516-734-B33, kindly supplied by Dr. Mary A. Root of the Lilly Research Laboratory, Indianapolis, Ind.) Blood glucose levels were measured in duplicate by the methods of Nelson5 and Somogyi. 6 All of the samples from one subject's complete test were assayed in the same radioimmunoassay procedure in order to eliminate interassay variation. All of these data were placed on punch cards and appropriately analyzed with the aid of a computer. Determinations were made of the means, standard errors of the mean, and matched-pair t-tests. The probability values were taken from two-tailed tables, and only values ofless than 0.05 were considered significant. The subjects' mean age was 22.6 ± 1.3 years and their mean weight was 117.2 ± 2.8 pounds. Five of the women had irregular menstrual periods and the remaining eleven women had secondary amenorrhea without apparent cause. AI~ of the women had sella turcica x-ray studies, which were normal. Their mean plasma progesterone concentration at the time of the test was 0.14 ± 0.03 nglml (all less than 1 nglml). Their mean serum estradiol level was 28.4 ± 4.5 pg/ml and ranged from 4.1 to 61.1 pglml. The mean serum prolactin level was 29.4 ± 10.0 ng/ml.
Gonadotropins. The statistical studies of the serum gonadotropin concentrations are given in Table 1. The levels of both gonadotropins increased following the GNRH injection, and the increase for LH exceeded that for FSH. The time to peak mean concentration for LH was clearly at 30 minutes whereas the FSH peak was highest at 90 minutes, but there was little difference between the mean values from 30 to 120 minutes. The mean values are shown in Figure 1. Glucose. The statistical studies of the blood glucose levels are also given in Table 1. There was a slight but significant decrease in the glucose concentration 45 minutes after the injection of GNRH. All of the other values were unchanged from the fasting value. The mean values are shown in Figure 1. Insulin. The statistical studies of the plasma insulin values are given in Table 1. There was a significant decrease in the concentration of insulin at both 60 and 120 minutes after the GNRH was administered. The mean values are shown in Figure 1.
DISCUSSION
The purification and synthesis of GNRH has opened a new frontier in reproductive endocrinology.7 A more precise evaluation of the hypothalamic-pituitary axis is now possible by administering GNRH and measuring blood gonado-
TABLE 1. Statistical Studies of Blood Glucose and Plasma Insulin, LB, and FSH before and after an Intravenous Injection of 100118 of Gonadotropin-Releasing Hormone (N = 16) Time after injection
Parameter
LH (mIU/ml) Mean SEM t P FSH (mIU/ml) Mean SEM t P Glucose (mg/100 ml) Mean SEM t P Insulin 0-tU/ml) Mean SEM t P
aNS, Not significant.
Fasting control
15 min
30 min
45 min
60 min
90 min
120 min
20.9 3.5
93.7 22.2 3.73
