0021 -972X/78/0046-0002$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society
Vol. 46, No. 2 Printed in U.S.A.
Role of Growth Hormone in the Regulation of Aldosterone Biosynthesis* ROBERT E. MCCAA.f JOSE M. MONTALVO, AND CONNIE S. MCCAA Department of Physiology and Biophysics, Department of Pediatrics, and Department of Biochemistry, University of Mississippi School of Medicine, Jackson, Mississippi ABSTRACT. Experimental evidence indicates that a non-ACTH pituitary hormone (s) is essential for a normal aldosterone response to ACTH and sodium deprivation in man and animals. The present study was designed to evaluate the role of somatotropin in the regulation of aldosterone biosynthesis in human beings. The aldosterone response to ACTH was determined in 8 intact human beings before and after dietary sodium restriction and compared with the aldosterone response observed in 3 patients with panhypopituitarism and 3 patients with isolated GH deficiency. Plasma aldosterone concentration, plasma cortisol concentration, and plasma renin activity were determined by radioimmunoassay. A normal aldosterone, cortisol, and renin response to dietary sodium restriction and ACTH was observed in the subjects with isolated GH deficiency. Plasma aldosterone concentration was normal under resting conditions in the patients with panhypopituitarism, but failed to increase in response to ACTH or sodium deprivation. A normal response of plasma renin
L
IEBERMAN and Luetscher (1) demoni strated that patients with pituitary insufficiency secrete normal amounts of aldosterone under resting conditions, but fail to respond with the usual acute rise in aldosterone secretion after administration of ACTH or sodium deprivation. Williams et al. (2) observed a normal aldosterone response to ACTH administration and sodium deprivation in patients maintained on glucocorticoid therapy to suppress endogenous pituitary secretion of ACTH. These observations suggest that chronic deficiency of some non-ACTH pituitary secretory factor (s) may reduce or abolish the adrenal aldosterone response to
* This investigation was supported by USPHS Grants HL 09921, HL 11678, and 5-MO-1-RR00626 from the National Institutes of Health and by a grant from The Mississippi Heart Association. t Address reprint requests to: Robert E. McCaa, Ph.D., Professor, Department of Physiology and Biophysics, University of Mississippi School of Medicine, 2500 North State Street, Jackson, Mississippi 39216.
activity to sodium deprivation was observed in the subjects with panhypopituitarism. A marked increase in the sensitivity of the adrenal glomerulosa to ACTH was observed in normal subjects and in subjects with isolated GH deficiency and panhypopituitarism during sodium deficiency. The subjects with isolated GH deficiency and panhypopituitarism were maintained on hGH replacement therapy for 12 months. All 6 subjects showed an increased growth rate, but GH replacement therapy failed to restore a normal aldosterone response to ACTH or sodium deprivation in the subjects with panhypopituitarism. Somatotropin is not the essential pituitary hormone required for a normal aldosterone response to ACTH or sodium deprivation since a normal aldosterone response was observed in subjects with isolated GH deficiency, and growth hormone replacement therapy failed to restore a normal aldosterone response in the subjects with panhypopituitarism. {J Clin Endocrinol Metab 46: 247, 1978)
sodium deprivation or ACTH in human beings. Several studies in experimental animals have demonstrated that some non-ACTH pituitary factor (s) may play a role in the regulation of aldosterone secretion. Ganong et al. (3) demonstrated that neither angiotensin II nor ACTH had a marked stimulatory effect on aldosterone secretion in chronically hypophysectomized dogs, whereas the aldosterone response to angiotensin II or ACTH in the intact dog chronically suppressed with dexamethasone was normal. Also, hypophysectomy abolished the aldosterone response to sodium depletion in the rat, whereas injections of extracts from whole pituitary glands partially restored the aldosterone response to sodium depletion (4). Other investigators (5) have observed that treatment of hypophysectomized rats with long-acting corticotropin failed to restore the adrenal in vitro production of aldosterone in response to dietary so-
247
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MCCAA ET AL.
248
dium restriction, but administration of somatotropin in combination with adrenal-maintaining doses of ACTH to chronically hypophysectomized rats partially restored the adrenal in vitro production of aldosterone and rise of aldosterone secretory rate in response to dietary sodium restriction. The present study was designed to evaluate the role of GH in the regulation of aldosterone secretion in human beings. The aldosterone response to ACTH administration and dietary sodium restriction was determined in normal intact human subjects and compared with the response observed in 3 subjects with isolated GH deficiency and in 3 subjects with panhypopituitarism. The aldosterone response to sodium deprivation and ACTH administration was determined in the same human subjects with isolated GH deficiency or panhypopituitarism after they had been maintained for 1 year on human pituitary GH replacement therapy. Methods All experimental procedures used in this study were approved by the Committee on Human Investigation of the University of Mississippi School of Medicine and were performed in the Clinical Research Center at the University Medical Center. Informed consent was obtained from all of the human subjects, none of whom suffered adverse effects or complained of any unusual symptoms during the study. The aldosterone and cortisol response to corticotropin, a 1-24, [Cortrosyn, 250 /ig i.v. (Organon, Inc., West Orange, N.J.)] was determined in 14 human beings before and after dietary sodium restriction. Plasma renin activity was measured in all of the subjects before and after sodium deprivation. Eight human subjects between the ages of 16 and 27 years with no known disease served as intact controls for this study. Also, 3 human subjects with isolated GH deficiency, 2 subjects with craniopharyngiomas, and 1 subject with empty sella syndrome were used in the study. All of the patients were males between the ages of 6 and 11 years, and all subjects were known to have had pituitary disorders for 3 years before the investigation. Anterior pituitary function studies performed in the patients with isolated GH deficiency indicated that all of the pituitary secretions were normal except GH secretion. Plasma GH was undetectable by
JCR&M • 1978 Vol 46 • No 2
radioimmunoassay and infusion of insulin and arginine failed to stimulate GH secretion in these subjects. The subjects with isolated GH deficiency were not taking any medication. Anterior pituitary function studies were performed in the patients with craniopharyngiomas and empty sella syndrome. The results from these studies are provided in Table 1. These human subjects were maintained on replacement therapy consisting of cortisone and thyroxine. Medication was stopped during the period of testing. Experimental protocol The following.experimental protocol was used for the ACTH study. Each of the subjects was admitted to the Clinical Research Center on the evening before the study. The ACTH stimulatory test was performed on the following morning at 0800 after the subjects had remained supine overnight and before breakfast. The subjects were required to remain recumbent during the study. Control blood samples were collected for determination of plasma aldosterone concentration, plasma cortisol concentration, and plasma renin activity, and 250 /xg corticotropin, a 1-24 (Cortrosyn) were administered i.v. Blood samples were then collected at 15-min intervals for 1 h after the injection. The subjects were then maintained on dietary sodium restriction (10 mEq Na+/day) for 10 days. Total 24-h urinary output was collected daily for determination of urinary sodium excretion. After 10 days, the ACTH stimulatory test was repeated in the manner described above. The patients with isolated GH deficiency, craniopharyngiomas, and empty sella syndrome were maintained on hGH replacement therapy for the next 12 months. hGH was provided by the Distribution Center of the National Pituitary Hormone Agency. All 6 patients responded to GH replacement therapy with an increased growth rate. These 6 patients were admitted to the Clinical Research Center for re-evaluation of aldosterone and cortisol response to ACTH by the procedure described above. Collection and analysis of blood samples Blood samples for the determination of plasma aldosterone concentration and plasma cortisol concentration were collected in disposable syringes. A portion was transferred to tubes pretreated with ethylenediamine tetra-acetate (EDTA) and centrifuged for 20 min at 4°C. A portion of each blood sample drawn for the control sample before and after sodium restriction was used for the determi-
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CONTROL OF ALDOSTERONE SECRETION
249
TABLE 1. Anterior pituitary function studies on three human beings with panhypopituitarism Anterior Pituitary Function Patient No.
Metyrapone Response, Urinary 170HC (mg/24Hir) Age (yr,
— T4
Control
Day 1
Day 2
GH (ng/ml) Peak Response to:
TV 11
A
(jug/100
TSH
Insulin
Skeletal Age (yr)
Arginine
ml) 1 2 3
9 11 6
1.54 1.44 0.66
1.32 1.80 0.83
3.87 3.30 0.67
nation of plasma renin activity. The plasma samples from each patient were frozen until the experiment was complete, and all samples from the same patient were analyzed during the same assay period. Plasma renin activity was determined by the radioimmunoassay method of Haber et al. (6). Plasma cortisol concentration was determined by the competitive protein-binding procedure reported by Murphy (7). Plasma aldosterone concentration was determined using a previously described modification (8) of the radioimmunoassay method of Mayes et al. (9). Statistical method Each of the patients used in this investigation was evaluated on 2 separate occasions. Student's t test for paired observations was used to compare each experimental period with the average of the control period.
Results Response of plasma aldosterone concentration and plasma renin activity to dietary sodium restriction in normal human beings and patients with isolated GH deficiency or panhypopituitarism The responses of plasma renin activity and plasma aldosterone concentration to dietary sodium restriction (10 mEq Na + /day) for 10 days in intact control human subjects, patients with isolated growth hormone deficiency, and patients with panhypopituitarism are illustrated in Fig. 1. In 8 intact control human subjects, plasma renin activity increased from 0.65 ± 0.21 to 2.89 ± 0.53 ng/ml/h (P < 0.001) and plasma aldosterone concentration increased from 7.6 ± 2.1 to 41.3 ± 7.1 ng/dl (P < 0.001) in response to dietary sodium restriction. A normal increase in plasma renin activity (P < 0.001) and plasma aldosterone concen-
6.7 5.4 3.6
2.0 1.3
Vol. 46, No. 2 Printed in U.S.A.
Role of Growth Hormone in the Regulation of Aldosterone Biosynthesis* ROBERT E. MCCAA.f JOSE M. MONTALVO, AND CONNIE S. MCCAA Department of Physiology and Biophysics, Department of Pediatrics, and Department of Biochemistry, University of Mississippi School of Medicine, Jackson, Mississippi ABSTRACT. Experimental evidence indicates that a non-ACTH pituitary hormone (s) is essential for a normal aldosterone response to ACTH and sodium deprivation in man and animals. The present study was designed to evaluate the role of somatotropin in the regulation of aldosterone biosynthesis in human beings. The aldosterone response to ACTH was determined in 8 intact human beings before and after dietary sodium restriction and compared with the aldosterone response observed in 3 patients with panhypopituitarism and 3 patients with isolated GH deficiency. Plasma aldosterone concentration, plasma cortisol concentration, and plasma renin activity were determined by radioimmunoassay. A normal aldosterone, cortisol, and renin response to dietary sodium restriction and ACTH was observed in the subjects with isolated GH deficiency. Plasma aldosterone concentration was normal under resting conditions in the patients with panhypopituitarism, but failed to increase in response to ACTH or sodium deprivation. A normal response of plasma renin
L
IEBERMAN and Luetscher (1) demoni strated that patients with pituitary insufficiency secrete normal amounts of aldosterone under resting conditions, but fail to respond with the usual acute rise in aldosterone secretion after administration of ACTH or sodium deprivation. Williams et al. (2) observed a normal aldosterone response to ACTH administration and sodium deprivation in patients maintained on glucocorticoid therapy to suppress endogenous pituitary secretion of ACTH. These observations suggest that chronic deficiency of some non-ACTH pituitary secretory factor (s) may reduce or abolish the adrenal aldosterone response to
* This investigation was supported by USPHS Grants HL 09921, HL 11678, and 5-MO-1-RR00626 from the National Institutes of Health and by a grant from The Mississippi Heart Association. t Address reprint requests to: Robert E. McCaa, Ph.D., Professor, Department of Physiology and Biophysics, University of Mississippi School of Medicine, 2500 North State Street, Jackson, Mississippi 39216.
activity to sodium deprivation was observed in the subjects with panhypopituitarism. A marked increase in the sensitivity of the adrenal glomerulosa to ACTH was observed in normal subjects and in subjects with isolated GH deficiency and panhypopituitarism during sodium deficiency. The subjects with isolated GH deficiency and panhypopituitarism were maintained on hGH replacement therapy for 12 months. All 6 subjects showed an increased growth rate, but GH replacement therapy failed to restore a normal aldosterone response to ACTH or sodium deprivation in the subjects with panhypopituitarism. Somatotropin is not the essential pituitary hormone required for a normal aldosterone response to ACTH or sodium deprivation since a normal aldosterone response was observed in subjects with isolated GH deficiency, and growth hormone replacement therapy failed to restore a normal aldosterone response in the subjects with panhypopituitarism. {J Clin Endocrinol Metab 46: 247, 1978)
sodium deprivation or ACTH in human beings. Several studies in experimental animals have demonstrated that some non-ACTH pituitary factor (s) may play a role in the regulation of aldosterone secretion. Ganong et al. (3) demonstrated that neither angiotensin II nor ACTH had a marked stimulatory effect on aldosterone secretion in chronically hypophysectomized dogs, whereas the aldosterone response to angiotensin II or ACTH in the intact dog chronically suppressed with dexamethasone was normal. Also, hypophysectomy abolished the aldosterone response to sodium depletion in the rat, whereas injections of extracts from whole pituitary glands partially restored the aldosterone response to sodium depletion (4). Other investigators (5) have observed that treatment of hypophysectomized rats with long-acting corticotropin failed to restore the adrenal in vitro production of aldosterone in response to dietary so-
247
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MCCAA ET AL.
248
dium restriction, but administration of somatotropin in combination with adrenal-maintaining doses of ACTH to chronically hypophysectomized rats partially restored the adrenal in vitro production of aldosterone and rise of aldosterone secretory rate in response to dietary sodium restriction. The present study was designed to evaluate the role of GH in the regulation of aldosterone secretion in human beings. The aldosterone response to ACTH administration and dietary sodium restriction was determined in normal intact human subjects and compared with the response observed in 3 subjects with isolated GH deficiency and in 3 subjects with panhypopituitarism. The aldosterone response to sodium deprivation and ACTH administration was determined in the same human subjects with isolated GH deficiency or panhypopituitarism after they had been maintained for 1 year on human pituitary GH replacement therapy. Methods All experimental procedures used in this study were approved by the Committee on Human Investigation of the University of Mississippi School of Medicine and were performed in the Clinical Research Center at the University Medical Center. Informed consent was obtained from all of the human subjects, none of whom suffered adverse effects or complained of any unusual symptoms during the study. The aldosterone and cortisol response to corticotropin, a 1-24, [Cortrosyn, 250 /ig i.v. (Organon, Inc., West Orange, N.J.)] was determined in 14 human beings before and after dietary sodium restriction. Plasma renin activity was measured in all of the subjects before and after sodium deprivation. Eight human subjects between the ages of 16 and 27 years with no known disease served as intact controls for this study. Also, 3 human subjects with isolated GH deficiency, 2 subjects with craniopharyngiomas, and 1 subject with empty sella syndrome were used in the study. All of the patients were males between the ages of 6 and 11 years, and all subjects were known to have had pituitary disorders for 3 years before the investigation. Anterior pituitary function studies performed in the patients with isolated GH deficiency indicated that all of the pituitary secretions were normal except GH secretion. Plasma GH was undetectable by
JCR&M • 1978 Vol 46 • No 2
radioimmunoassay and infusion of insulin and arginine failed to stimulate GH secretion in these subjects. The subjects with isolated GH deficiency were not taking any medication. Anterior pituitary function studies were performed in the patients with craniopharyngiomas and empty sella syndrome. The results from these studies are provided in Table 1. These human subjects were maintained on replacement therapy consisting of cortisone and thyroxine. Medication was stopped during the period of testing. Experimental protocol The following.experimental protocol was used for the ACTH study. Each of the subjects was admitted to the Clinical Research Center on the evening before the study. The ACTH stimulatory test was performed on the following morning at 0800 after the subjects had remained supine overnight and before breakfast. The subjects were required to remain recumbent during the study. Control blood samples were collected for determination of plasma aldosterone concentration, plasma cortisol concentration, and plasma renin activity, and 250 /xg corticotropin, a 1-24 (Cortrosyn) were administered i.v. Blood samples were then collected at 15-min intervals for 1 h after the injection. The subjects were then maintained on dietary sodium restriction (10 mEq Na+/day) for 10 days. Total 24-h urinary output was collected daily for determination of urinary sodium excretion. After 10 days, the ACTH stimulatory test was repeated in the manner described above. The patients with isolated GH deficiency, craniopharyngiomas, and empty sella syndrome were maintained on hGH replacement therapy for the next 12 months. hGH was provided by the Distribution Center of the National Pituitary Hormone Agency. All 6 patients responded to GH replacement therapy with an increased growth rate. These 6 patients were admitted to the Clinical Research Center for re-evaluation of aldosterone and cortisol response to ACTH by the procedure described above. Collection and analysis of blood samples Blood samples for the determination of plasma aldosterone concentration and plasma cortisol concentration were collected in disposable syringes. A portion was transferred to tubes pretreated with ethylenediamine tetra-acetate (EDTA) and centrifuged for 20 min at 4°C. A portion of each blood sample drawn for the control sample before and after sodium restriction was used for the determi-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 15 November 2015. at 04:22 For personal use only. No other uses without permission. . All rights reserved.
CONTROL OF ALDOSTERONE SECRETION
249
TABLE 1. Anterior pituitary function studies on three human beings with panhypopituitarism Anterior Pituitary Function Patient No.
Metyrapone Response, Urinary 170HC (mg/24Hir) Age (yr,
— T4
Control
Day 1
Day 2
GH (ng/ml) Peak Response to:
TV 11
A
(jug/100
TSH
Insulin
Skeletal Age (yr)
Arginine
ml) 1 2 3
9 11 6
1.54 1.44 0.66
1.32 1.80 0.83
3.87 3.30 0.67
nation of plasma renin activity. The plasma samples from each patient were frozen until the experiment was complete, and all samples from the same patient were analyzed during the same assay period. Plasma renin activity was determined by the radioimmunoassay method of Haber et al. (6). Plasma cortisol concentration was determined by the competitive protein-binding procedure reported by Murphy (7). Plasma aldosterone concentration was determined using a previously described modification (8) of the radioimmunoassay method of Mayes et al. (9). Statistical method Each of the patients used in this investigation was evaluated on 2 separate occasions. Student's t test for paired observations was used to compare each experimental period with the average of the control period.
Results Response of plasma aldosterone concentration and plasma renin activity to dietary sodium restriction in normal human beings and patients with isolated GH deficiency or panhypopituitarism The responses of plasma renin activity and plasma aldosterone concentration to dietary sodium restriction (10 mEq Na + /day) for 10 days in intact control human subjects, patients with isolated growth hormone deficiency, and patients with panhypopituitarism are illustrated in Fig. 1. In 8 intact control human subjects, plasma renin activity increased from 0.65 ± 0.21 to 2.89 ± 0.53 ng/ml/h (P < 0.001) and plasma aldosterone concentration increased from 7.6 ± 2.1 to 41.3 ± 7.1 ng/dl (P < 0.001) in response to dietary sodium restriction. A normal increase in plasma renin activity (P < 0.001) and plasma aldosterone concen-
6.7 5.4 3.6
2.0 1.3
