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New insights and questions about glucocorticoid-suppressible hyperaldosteronism
VOLUME
The American
72
NUMBER
6
JUNE
1962
Journal of Medicine@ EDITORIAL
New Insights and Questions about Glucocorticoid-Suppressible Hyperaldosteronism ARUNABHA
G
lucocorticoid-suppressible (or dexamethasonesuppressible) hyperaklosteronism is a rare variant of primary aldosteronism first described by Sutherland and his colleagues [l] in 1966. Since then, few other patients with such disorder have been described [2-81. This particular variety of hyperaldosteronism (glucocorticoid-suppressible) distinguishes itself from primary aldosteronism caused by an aldosterone-producing adenoma or idiopathic adrenal hyperplasia by virtue of its familial occurrence and its responsiveness to glucocorticoid therapy with complete reversal of all the features of hyperaldosteronism including the hypertension. With glucocorticoid treatment, as the high plasma aldosterone concentration falls to low levels and blood pressure becomes normal, the previously suppressed plasma renin activity rises. Aldosterone secretion now becomes responsive to maneuvers that alter plasma renin activity such as upright posture or low-sodium diet [6,9, lo]. ACTH administration over a period of only a few days restores the hypertension [ 111, while infusion of aldosterone alone or of other conventional steroids fails to do so [ 111. The latter finding and the rapidity of the blood pressure response to ACTH raise the possibility of potentiation or synergism of aldosterone effect with some other unidentified steroid [ 7,8,11]. Although these patients show a gratifying response to glucocorticoids, they can also be treated with spironolactone or triamterene-thiazide combination [ 121. The latter forms of treatment are preferrable so that chronic suppression of the pituitary-adrenal axis can be avoided. Sutherland et al. [l] reported the disorder in a patient and his son. Most subsequent investigators have identified the condition in one or more of a proband’s firstdegree relatives. Most recently, however, we have
GANGULY,
M.D.
described [8] a family in which at least three members in successive generations were found to have the disorder, thereby strengthening the view of the heritability of the disorder. Additionally, we have extensively investigated various members of the family. HLA typing of members of the family including the affected subjects were carried out. Such a study did not indicate a linkage of HLA genotype and glucocorticoid-suppressible hyperaldosteronism. Our data are in agreement with another study of HLA typing [ 131 in two other families of patients with glucocorticoid-suppressible hyperaldosteronism, which also failed to establish a linkage. The mode of inheritance is compatible with an autosomal dominant pattern. The adrenal pathology in the majority of such patients is unknown. The adrenals from two patients who underwent operation revealed macronodular and micronodular hyperplasia of the adrenal cortex respectively [ 1,2]. Localizing procedures have not generally been undertaken. Adrenal venous catheterization with selective sampling of adrenal venous effluent has not been reported. An attempted adrenal venous catheterization in one of our patients was unsuccessful. A scintiscan with radiocholesterol in one patient after dexamethasone suppression showed no uptake of radioactivity in either gland [8], implying probable bilateral adrenal hyperplasia [ 141. Since these patients do so well with treatment, most investigators have chosen not to investigate them any further or subject them to operation. It is conceivable that some of the patients with presumed idiopathic adrenal hyperplasia who did not have a trial of glucocorticoid may in fact have had unrecognized glucocorticoid-responsive hyperaldosteronism. There have been several recent developments with regard to the pathophysiology of the disorder. If one
From the Department of Medicine, University of South Florida College of Medicine, and the James A. Haley Veterans Adminstration Hospital, Tampa, Florida. Reprint requests should be addressed to Dr. Arunabha Ganguly, University of South Florida College of Medicine, V.A. Hospital 7 11-M 13000 North 30th Street, Tampa, Florida 336 12.
June 1982 The American Journal of Medicine
Volume 72
651
EDITORIAL-GANGULY
assumes all patients with glucocorticoid-suppressible hyperaldosteronism have adrenal hyperplasia, as revealed by the excised adrenal tissue from two patients, then pathologically this disorder resembles idiopathic adrenal hyperplasia. However, it is clear now that there are several differences between the two, other than the familial occurrence of glucocorticoid-suppressible hyperaldosteronism. Firstly, there is the distinctive finding that idiopathic adrenal hyperplasia is not amenable to long-term glucocorticoid therapy. The second finding is related to a urinary aldosterone-stimulating factor. Brown et al. [ 151 reported the presence of a new aldosterone-stimulating factor in the urine of a large proportion of patients with idiopathic adrenal hyperplasia. Such factor was not found by their assay in the urine of any of our patients with glucocorticoid-suppressible hyperaldosteronism in the two families [8]. Although it is unclear at present if such a factor can be pathogenetically linked to idiopathic adrenal hyperplasia, it may be a marker of the disorder. Its absence in glucocorticoid-suppressible hyperaldosteronism further supports the tenet that the latter is a distinct entity and not a subset of idiopathic adrenal hyperplasia. Thirdly, the postural response of plasma aldosterone appears to be useful in differentiating the two disorders. In normal persons, plasma aldosterone concentration rises during extended periods of standing after recumbency with increase of plasma renin activity. In aldosterone-producing adenoma, it falls [ 16,171, and this is thought to be due to the declining levels of ACTH. In idiopathic adrenal hyperplasia, plasma aldosterone concentration increases, like that in normal subjects [ 16,171 despite suppressed plasma renin activity and perhaps a very small increment of plasma renin concentration with upright posture. In glucocorticoid-suppressible hyperaldosteronism, on the other hand, plasma aldosterone level also falls, as in aldosteroneproducing adenoma under similar conditions [lo]. This latter finding therefore further distinguishes glucorcorticoid-suppressible hyperaldosteronism from idiopathic adrenal hyperplasia. Finally, another interesting feature in glucocorticoid-suppressible hyperaldosteronism is the effect of metoclopramide. A number of studies have suggested that a dopaminergic mechanism may be involved in aldosterone secretion. Metoclopramide, a dopamine antagonist, has been shown to increase aldosterone secretion consistently in humans. While the mechanism of its effect is not entirely clear, there seems to be no apparent involvement of the known physiologic mediators of aldosterone secretion in this effect, which has been observed also in anephric subjects as well as in patients with hypopituitarism [ 181. When patients with other forms of primary aldosteronism pretreated with dexamethasone were given me-
852
June 1882
The American Journal of Medicine
Volume 72
toclopramide intravenously, all such patients responded to it with a rise in plasma aldosterone concentration, but the patients with glucocorticoid-suppressible hyperaldosteronism showed no response [ 191. The last two observations raise important pathogenetic questions about the disorder. The pathogenesis of glucocorticoid-suppressible hyperaldosteronism, as of idiopathic adrenal hyperplasia, has remained elusive. In view of new observations in glucocorticoid-suppressible hyperaldosteronism, discussed in the preceding section, several possibilities can be entertained. The pathogenetic abnormality in this disorder may reside at the pituitary or the adrenal level. The fact that the hyperaldosteronism can be reversed by glucocorticoid therapy suggests involvement of a pituitary factor, unless such therapy affects the adrenals themselves. However, a direct effect of glucocorticoids on the adrenal in ameliorating the hyperaldosteronism is unlikely since the adrenals respond vigorously to exogenous ACTH even when pretreated with a glucocorticoid (unpublished observations). In view of the finding that patients with glucocorticoid-suppressible hyperaldosteronism show the same type of abnormal postural response in plasma aldosterone concentration [lo] as has been usually the hallmark of aldosterone-producing adenoma [ 16,171, a role for ACTH in aldosterone secretion in glucocorticoid-suppressible hyperaldosteronism has to be seriously considered. The possibility of participation of another pituitary factor similar to ACTH in its suppressibility by dexamethasone and its similarity of diurnal rhythm with ACTH cannot, however, be excluded. Indeed, Mulrow has recently proposed such a thesis. He and his associates [20] have already demonstrated that &lipotropin is capable of stimulating aldosterone secretion in the rat zona glomerulosa cells, He has suggested [21] that b-lipotropin, or a related peptide, therefore may be involved in the pathogenesis of glucocorticoid-suppressible hyperaldosteronism. Such a possibility definitely exists. The pituitary in a patient with glucocorticoid-suppressible hyperaldosteronism may even elaborate an abnormal ACTH analogue similar to that synthesized by Li et al. [22], capable of stimulating the zona glomerulosa cells to a much greater degree than the zona fasciculata cells. However, before fi-lipotropin and other related peptides can be incriminated in this disorder, certain questions have to be dealt with. One has to demonstrate that such a peptide is capable of stimulating the human adrenal, although a precursor opioid peptide has been shown to stimulate aldosterone release from the adrenal tissue of an aldosteronoma [23]. The studies of Matsuoka et al. [20] suggest that, on a mole per mole basis, the sensitivity of the rat glomerulosa cell to &lipotropin is
EDITORIAL-GANGULY
lower than that to ACTH [24]. However, in human blood, molar concentrations of P-lipotropin are lower than those of ACTH 1241. Therefore, unless human adrenal sensitivity to ,&iip&ropin is greater than that of the rat adrenal, patients with glucocorticoid-suppressible hyperaldosteronism have to have disproportionately greater amounts of ,8-lipotropin relative to ACTH for the former to be responsible for the hyperaldosteronism. The patients with glucocorticoid-suppressible hyperaldosteronism could have high ACTH levels. Unfortunately, the very limited data about the plasma ACTH levels in such patients are conflicting [2,9]. Alternatively, the abnormality in glucocorticoidsuppressible hyperaldosteronism may be in the adrenals. Long-term ACTH stimulation of the adrenal usually results in an initial increase in aldosterone secretion followed by a decline despite a continued stimulus of ACTH. The mechanism for this resuonse has not been clearly defined. In glucocorticoid-suppressible hyperaldosteronism, long-term stimulation by exogenous ACTH, unlike that in normal subjects and patients with other forms of primary aldosteronism, continues to evoke an increased aldosterone secretory response [l l]. If long-term adrenal stimulation by ACTH or possibly ,8-lipotropin is responsible for the hyperaldosteronism in glucocorticoid-suppressible hyperaldosteronism, we must assume that the normal inhibition of adrenal steroidogenesis does not occur in this disorder. The inhibitory effect of long-term ACTH stimulation in the adrenal could conceivably be mediated through the recently proposed dopaminergic mechanism 1251. If such a premise is correct, then the adrenals in the patients with glucocorticoid-suppressible hyperaldosteronism may lack the normal inhibitory dopaminergic control permitting chronic ACTH stimulation to sustain the high aldosterone secretory response in these patients [ 111. Other possibilities include increased numbers of ACTH receptors in the zona glomerulosa, which do not down-regulate with chronic ACTH stimulation. ACTH or fl-lipotropin action on the adrenal may be potentiated by the aminoterminal fragment of the ACTH precursor peptide [21,26]. We have found that adrenal responsiveness to low-dose ACTH infusion is significantly enhanced in glucocorticoid-suppressible hyperaldosteronism compared with that in normal subjects or in those with aldosteroneproducing adenoma or idiopathic adrenal hyperplasia (unpublished observations). Since the glucocorticoid secretion is generally normal in the patients with glucocorticoid-suppressible hyperaldosteronism, the adrenal abnormality, if present, has to be confined to the zona glomerulosa cells. In the light of all these observations and unanswered questions, clearly more work is needed to explain which
of the various possibilities is compatible pathophysiology of the disorder.
with the
ACKNOWLEDGMENT
The author wishes to thank Ms. Ruby Choquette for typing the manuscript.
REFERENCES 1.
2.
3.
8.
9.
10.
11.
12.
13.
14.
15.
June 1982
Sutherland DJA. Ruse JL, Laidlaw JC: Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J 1966; 95: 11091119. Miura K, Yoshinaga K. Goto K, et al.: A case of glucocorticoid-responsive hyperaldosteronism. J Clin Endocrinol Metab 1968; 28: 1807-1815. New MI. Siegal EJ, Peterson RE: Dexamethasone-suppressible hvperaldosteronism. J Clin Endocrinol Metab 1973; 37: ,j;_lOO. Giebink GS, Gotlin RW, Biglieri EG. Katz FH: A kindred with familiar glucocorticoid-suppressible aldosteronism. J Clin Endocrinol Metab 1973; 36: 715-723. Grim CE, Weinberger MH: Familial dexamethasone-suppressible, normokalemic hyperatdosteronism. Pediatrics 1980; 65:597-604. Oberfield SE, Levine LS, Stoner E, et al.: Adrenal glomerulosa function in patients with dexamethasone-suppressible hyperaldosteronism. J Clin Endocrinol Metab 1981; 53: 158-164. Gill JR, Bartter FC: Overproduction of sodium-retaining steroids by the zona glomerulosa is adrenocorticotropindependent and mediates hypertension in dexamethasonesuppressible aldosteronism. J Clin Endocrinol Metab 1981; 53: 331337. Ganguly A, Grim CE, Bergstein J, Brown RD, Weinberger MH: Genetic and pathophysiologic studies of a new kindred with glucocorticoid-suppressible hyperaldosteronism manifest in three generations. J Clin Endocrinol Metab 1981; 53: 1041-1046. Salti S, Stiefel M, Ruse JL, Laidlaw JC: Non-tumorous “primary” aldosteronism. I. Type relieved by glucocorticoid (glucocorticoid-remediable aldosteronism). Can Med Assoc J 1969; 10: l-10. Ganguly A, Grim CE, Weinberger MH: Anomalous postural aldosterone response in glucocorticoid-suppressible hyperaldosteronism. N Engl J Med 1981; 306 991-993. New MI, Peterson RE, Saenger P, Levine LS: Evidence for an unidentified ACTH-induced steroid hormone causing hypertension. J Clin Endocrinol Metab 1976; 43: 12831293. Ganguly A, Weinberger MH: Triamterene-thiazide combination: alternative therapy for primary aldosteronism. Clin Pharmacol Ther 1981; 30: 246-250. New MI, Oberfield SE, Levine LS, et al.: Autosomal dominant transmission and absence of HLA linkage in dexamethasone-suppressible hyperaldosteronism. Lancet 1980; I: 550-55 1. Conn JW, Cohen EL, Herwig KR: The dexamethasone modified adrenal scintiscan in hyporeninemic aldosteronism (tumor versus hyperplasia). A comparison with adrenal venography and adrenal venous aldosterone. J Lab Clin Med 1976; 88: 841-856. Brown RD, Wisgerhof M, Carpenter PC, et al.: Adrenal sensitivity to angiotensin II and undiscovered aldosterone
The American Journal of Medicine
Volume 72
853
EDITORIAL-GANGULY
16.
17.
18.
19.
20.
854
stimulating factors in hypertension. J Steroid Biochem 1979; 11: 1043-1050. Ganguly A, Dowdy AJ, Luetscher JA, Melada GA: Anomalous postural response of plasma aldosterone concentration in patients with aldosterone-producing adrenal adenoma. J Clin Endocrinol Metab 1973; 36: 401-404. Biglieri EG, Schambelan M, Brust N, Chang 8, Hogan M: Plasma aldosterone concentration: further characterization of aldosterone-producing adenomas. Circ Res 1974; 34 and 35 (suppl I): l-183-189. Pratt JH, Ganguly A, Parkinson CA, Weinberger MH: Stimulation of aldosterone secretion by metoclopramide in humans: apparent independence of renal and pituitary mediation. Metabolism 1981; 30: 129-134. Ganguly A, Pratt JH, Weinberger MH: A new distinctive feature of dexamethasone-suppressible hyperaldosteronism: lack of metoclopramide-induced increase in plasma aldosterone concentration. Clin Res 1981; 29: 291A. Matsuoka H, Mulrow PJ, France-Saenz R, Li CH: Effects of fi-lipotropinderived peptides on aldosterone production in the rat adrenal gland. J Clin Invest 1981; 68: 752759.
June 1982
The American Journal of Medicine
Volume 72
21.
22.
23.
24.
25.
26.
Mulrow PJ: Glucocorticoid-suppressible hyperaldosteronism: a clue to the missing hormone? N Engl J Med 1981; 305: 1012-1014. Li CH, Blake J, Cheng CHK: Adrenocorticotropin 56. Synthesis of (cy~~~)-2-ACTH-(1-26). Dissociation of aldosterone and corticosterone stimulating activity. Biochem Biophys Res Comm 1981; 102: 697-702. Lis M. Hamet P, Gutkowska J, et al.: Effect of N-terminal portion of pro-opiomelanocortin on aldosterone release by human adrenal adenoma in vitro. J Clin Endocrinol Metab 1981; 52: 1053-1056. Kreiger DT, Liotta AS, Suda T, Goodgold A, Condon E: Human plasma immunoreactive lipotropin and adrenocorticotropin in normal subjects and in patients with pituitary adrenal disease. J Clin Endocrinol Metab 1979; 48: 566-571. Carey RM, Thorner MO, Ortt EM: Effects of metoclopramide and bromocriptine on the renin-angiotensin aldosterone system in man: dopaminergic control of aldosterone secretion J Clin Invest 1979; 63: 727-735. Pedersen RC, Brownie AC, Ling N: Pro-adrenocorticotropin/ endorphinderived peptides: coordinate action on adrenal steroidogenesis. Science 1980; 208: 1044-1046.
The American
72
NUMBER
6
JUNE
1962
Journal of Medicine@ EDITORIAL
New Insights and Questions about Glucocorticoid-Suppressible Hyperaldosteronism ARUNABHA
G
lucocorticoid-suppressible (or dexamethasonesuppressible) hyperaklosteronism is a rare variant of primary aldosteronism first described by Sutherland and his colleagues [l] in 1966. Since then, few other patients with such disorder have been described [2-81. This particular variety of hyperaldosteronism (glucocorticoid-suppressible) distinguishes itself from primary aldosteronism caused by an aldosterone-producing adenoma or idiopathic adrenal hyperplasia by virtue of its familial occurrence and its responsiveness to glucocorticoid therapy with complete reversal of all the features of hyperaldosteronism including the hypertension. With glucocorticoid treatment, as the high plasma aldosterone concentration falls to low levels and blood pressure becomes normal, the previously suppressed plasma renin activity rises. Aldosterone secretion now becomes responsive to maneuvers that alter plasma renin activity such as upright posture or low-sodium diet [6,9, lo]. ACTH administration over a period of only a few days restores the hypertension [ 111, while infusion of aldosterone alone or of other conventional steroids fails to do so [ 111. The latter finding and the rapidity of the blood pressure response to ACTH raise the possibility of potentiation or synergism of aldosterone effect with some other unidentified steroid [ 7,8,11]. Although these patients show a gratifying response to glucocorticoids, they can also be treated with spironolactone or triamterene-thiazide combination [ 121. The latter forms of treatment are preferrable so that chronic suppression of the pituitary-adrenal axis can be avoided. Sutherland et al. [l] reported the disorder in a patient and his son. Most subsequent investigators have identified the condition in one or more of a proband’s firstdegree relatives. Most recently, however, we have
GANGULY,
M.D.
described [8] a family in which at least three members in successive generations were found to have the disorder, thereby strengthening the view of the heritability of the disorder. Additionally, we have extensively investigated various members of the family. HLA typing of members of the family including the affected subjects were carried out. Such a study did not indicate a linkage of HLA genotype and glucocorticoid-suppressible hyperaldosteronism. Our data are in agreement with another study of HLA typing [ 131 in two other families of patients with glucocorticoid-suppressible hyperaldosteronism, which also failed to establish a linkage. The mode of inheritance is compatible with an autosomal dominant pattern. The adrenal pathology in the majority of such patients is unknown. The adrenals from two patients who underwent operation revealed macronodular and micronodular hyperplasia of the adrenal cortex respectively [ 1,2]. Localizing procedures have not generally been undertaken. Adrenal venous catheterization with selective sampling of adrenal venous effluent has not been reported. An attempted adrenal venous catheterization in one of our patients was unsuccessful. A scintiscan with radiocholesterol in one patient after dexamethasone suppression showed no uptake of radioactivity in either gland [8], implying probable bilateral adrenal hyperplasia [ 141. Since these patients do so well with treatment, most investigators have chosen not to investigate them any further or subject them to operation. It is conceivable that some of the patients with presumed idiopathic adrenal hyperplasia who did not have a trial of glucocorticoid may in fact have had unrecognized glucocorticoid-responsive hyperaldosteronism. There have been several recent developments with regard to the pathophysiology of the disorder. If one
From the Department of Medicine, University of South Florida College of Medicine, and the James A. Haley Veterans Adminstration Hospital, Tampa, Florida. Reprint requests should be addressed to Dr. Arunabha Ganguly, University of South Florida College of Medicine, V.A. Hospital 7 11-M 13000 North 30th Street, Tampa, Florida 336 12.
June 1982 The American Journal of Medicine
Volume 72
651
EDITORIAL-GANGULY
assumes all patients with glucocorticoid-suppressible hyperaldosteronism have adrenal hyperplasia, as revealed by the excised adrenal tissue from two patients, then pathologically this disorder resembles idiopathic adrenal hyperplasia. However, it is clear now that there are several differences between the two, other than the familial occurrence of glucocorticoid-suppressible hyperaldosteronism. Firstly, there is the distinctive finding that idiopathic adrenal hyperplasia is not amenable to long-term glucocorticoid therapy. The second finding is related to a urinary aldosterone-stimulating factor. Brown et al. [ 151 reported the presence of a new aldosterone-stimulating factor in the urine of a large proportion of patients with idiopathic adrenal hyperplasia. Such factor was not found by their assay in the urine of any of our patients with glucocorticoid-suppressible hyperaldosteronism in the two families [8]. Although it is unclear at present if such a factor can be pathogenetically linked to idiopathic adrenal hyperplasia, it may be a marker of the disorder. Its absence in glucocorticoid-suppressible hyperaldosteronism further supports the tenet that the latter is a distinct entity and not a subset of idiopathic adrenal hyperplasia. Thirdly, the postural response of plasma aldosterone appears to be useful in differentiating the two disorders. In normal persons, plasma aldosterone concentration rises during extended periods of standing after recumbency with increase of plasma renin activity. In aldosterone-producing adenoma, it falls [ 16,171, and this is thought to be due to the declining levels of ACTH. In idiopathic adrenal hyperplasia, plasma aldosterone concentration increases, like that in normal subjects [ 16,171 despite suppressed plasma renin activity and perhaps a very small increment of plasma renin concentration with upright posture. In glucocorticoid-suppressible hyperaldosteronism, on the other hand, plasma aldosterone level also falls, as in aldosteroneproducing adenoma under similar conditions [lo]. This latter finding therefore further distinguishes glucorcorticoid-suppressible hyperaldosteronism from idiopathic adrenal hyperplasia. Finally, another interesting feature in glucocorticoid-suppressible hyperaldosteronism is the effect of metoclopramide. A number of studies have suggested that a dopaminergic mechanism may be involved in aldosterone secretion. Metoclopramide, a dopamine antagonist, has been shown to increase aldosterone secretion consistently in humans. While the mechanism of its effect is not entirely clear, there seems to be no apparent involvement of the known physiologic mediators of aldosterone secretion in this effect, which has been observed also in anephric subjects as well as in patients with hypopituitarism [ 181. When patients with other forms of primary aldosteronism pretreated with dexamethasone were given me-
852
June 1882
The American Journal of Medicine
Volume 72
toclopramide intravenously, all such patients responded to it with a rise in plasma aldosterone concentration, but the patients with glucocorticoid-suppressible hyperaldosteronism showed no response [ 191. The last two observations raise important pathogenetic questions about the disorder. The pathogenesis of glucocorticoid-suppressible hyperaldosteronism, as of idiopathic adrenal hyperplasia, has remained elusive. In view of new observations in glucocorticoid-suppressible hyperaldosteronism, discussed in the preceding section, several possibilities can be entertained. The pathogenetic abnormality in this disorder may reside at the pituitary or the adrenal level. The fact that the hyperaldosteronism can be reversed by glucocorticoid therapy suggests involvement of a pituitary factor, unless such therapy affects the adrenals themselves. However, a direct effect of glucocorticoids on the adrenal in ameliorating the hyperaldosteronism is unlikely since the adrenals respond vigorously to exogenous ACTH even when pretreated with a glucocorticoid (unpublished observations). In view of the finding that patients with glucocorticoid-suppressible hyperaldosteronism show the same type of abnormal postural response in plasma aldosterone concentration [lo] as has been usually the hallmark of aldosterone-producing adenoma [ 16,171, a role for ACTH in aldosterone secretion in glucocorticoid-suppressible hyperaldosteronism has to be seriously considered. The possibility of participation of another pituitary factor similar to ACTH in its suppressibility by dexamethasone and its similarity of diurnal rhythm with ACTH cannot, however, be excluded. Indeed, Mulrow has recently proposed such a thesis. He and his associates [20] have already demonstrated that &lipotropin is capable of stimulating aldosterone secretion in the rat zona glomerulosa cells, He has suggested [21] that b-lipotropin, or a related peptide, therefore may be involved in the pathogenesis of glucocorticoid-suppressible hyperaldosteronism. Such a possibility definitely exists. The pituitary in a patient with glucocorticoid-suppressible hyperaldosteronism may even elaborate an abnormal ACTH analogue similar to that synthesized by Li et al. [22], capable of stimulating the zona glomerulosa cells to a much greater degree than the zona fasciculata cells. However, before fi-lipotropin and other related peptides can be incriminated in this disorder, certain questions have to be dealt with. One has to demonstrate that such a peptide is capable of stimulating the human adrenal, although a precursor opioid peptide has been shown to stimulate aldosterone release from the adrenal tissue of an aldosteronoma [23]. The studies of Matsuoka et al. [20] suggest that, on a mole per mole basis, the sensitivity of the rat glomerulosa cell to &lipotropin is
EDITORIAL-GANGULY
lower than that to ACTH [24]. However, in human blood, molar concentrations of P-lipotropin are lower than those of ACTH 1241. Therefore, unless human adrenal sensitivity to ,&iip&ropin is greater than that of the rat adrenal, patients with glucocorticoid-suppressible hyperaldosteronism have to have disproportionately greater amounts of ,8-lipotropin relative to ACTH for the former to be responsible for the hyperaldosteronism. The patients with glucocorticoid-suppressible hyperaldosteronism could have high ACTH levels. Unfortunately, the very limited data about the plasma ACTH levels in such patients are conflicting [2,9]. Alternatively, the abnormality in glucocorticoidsuppressible hyperaldosteronism may be in the adrenals. Long-term ACTH stimulation of the adrenal usually results in an initial increase in aldosterone secretion followed by a decline despite a continued stimulus of ACTH. The mechanism for this resuonse has not been clearly defined. In glucocorticoid-suppressible hyperaldosteronism, long-term stimulation by exogenous ACTH, unlike that in normal subjects and patients with other forms of primary aldosteronism, continues to evoke an increased aldosterone secretory response [l l]. If long-term adrenal stimulation by ACTH or possibly ,8-lipotropin is responsible for the hyperaldosteronism in glucocorticoid-suppressible hyperaldosteronism, we must assume that the normal inhibition of adrenal steroidogenesis does not occur in this disorder. The inhibitory effect of long-term ACTH stimulation in the adrenal could conceivably be mediated through the recently proposed dopaminergic mechanism 1251. If such a premise is correct, then the adrenals in the patients with glucocorticoid-suppressible hyperaldosteronism may lack the normal inhibitory dopaminergic control permitting chronic ACTH stimulation to sustain the high aldosterone secretory response in these patients [ 111. Other possibilities include increased numbers of ACTH receptors in the zona glomerulosa, which do not down-regulate with chronic ACTH stimulation. ACTH or fl-lipotropin action on the adrenal may be potentiated by the aminoterminal fragment of the ACTH precursor peptide [21,26]. We have found that adrenal responsiveness to low-dose ACTH infusion is significantly enhanced in glucocorticoid-suppressible hyperaldosteronism compared with that in normal subjects or in those with aldosteroneproducing adenoma or idiopathic adrenal hyperplasia (unpublished observations). Since the glucocorticoid secretion is generally normal in the patients with glucocorticoid-suppressible hyperaldosteronism, the adrenal abnormality, if present, has to be confined to the zona glomerulosa cells. In the light of all these observations and unanswered questions, clearly more work is needed to explain which
of the various possibilities is compatible pathophysiology of the disorder.
with the
ACKNOWLEDGMENT
The author wishes to thank Ms. Ruby Choquette for typing the manuscript.
REFERENCES 1.
2.
3.
8.
9.
10.
11.
12.
13.
14.
15.
June 1982
Sutherland DJA. Ruse JL, Laidlaw JC: Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J 1966; 95: 11091119. Miura K, Yoshinaga K. Goto K, et al.: A case of glucocorticoid-responsive hyperaldosteronism. J Clin Endocrinol Metab 1968; 28: 1807-1815. New MI. Siegal EJ, Peterson RE: Dexamethasone-suppressible hvperaldosteronism. J Clin Endocrinol Metab 1973; 37: ,j;_lOO. Giebink GS, Gotlin RW, Biglieri EG. Katz FH: A kindred with familiar glucocorticoid-suppressible aldosteronism. J Clin Endocrinol Metab 1973; 36: 715-723. Grim CE, Weinberger MH: Familial dexamethasone-suppressible, normokalemic hyperatdosteronism. Pediatrics 1980; 65:597-604. Oberfield SE, Levine LS, Stoner E, et al.: Adrenal glomerulosa function in patients with dexamethasone-suppressible hyperaldosteronism. J Clin Endocrinol Metab 1981; 53: 158-164. Gill JR, Bartter FC: Overproduction of sodium-retaining steroids by the zona glomerulosa is adrenocorticotropindependent and mediates hypertension in dexamethasonesuppressible aldosteronism. J Clin Endocrinol Metab 1981; 53: 331337. Ganguly A, Grim CE, Bergstein J, Brown RD, Weinberger MH: Genetic and pathophysiologic studies of a new kindred with glucocorticoid-suppressible hyperaldosteronism manifest in three generations. J Clin Endocrinol Metab 1981; 53: 1041-1046. Salti S, Stiefel M, Ruse JL, Laidlaw JC: Non-tumorous “primary” aldosteronism. I. Type relieved by glucocorticoid (glucocorticoid-remediable aldosteronism). Can Med Assoc J 1969; 10: l-10. Ganguly A, Grim CE, Weinberger MH: Anomalous postural aldosterone response in glucocorticoid-suppressible hyperaldosteronism. N Engl J Med 1981; 306 991-993. New MI, Peterson RE, Saenger P, Levine LS: Evidence for an unidentified ACTH-induced steroid hormone causing hypertension. J Clin Endocrinol Metab 1976; 43: 12831293. Ganguly A, Weinberger MH: Triamterene-thiazide combination: alternative therapy for primary aldosteronism. Clin Pharmacol Ther 1981; 30: 246-250. New MI, Oberfield SE, Levine LS, et al.: Autosomal dominant transmission and absence of HLA linkage in dexamethasone-suppressible hyperaldosteronism. Lancet 1980; I: 550-55 1. Conn JW, Cohen EL, Herwig KR: The dexamethasone modified adrenal scintiscan in hyporeninemic aldosteronism (tumor versus hyperplasia). A comparison with adrenal venography and adrenal venous aldosterone. J Lab Clin Med 1976; 88: 841-856. Brown RD, Wisgerhof M, Carpenter PC, et al.: Adrenal sensitivity to angiotensin II and undiscovered aldosterone
The American Journal of Medicine
Volume 72
853
EDITORIAL-GANGULY
16.
17.
18.
19.
20.
854
stimulating factors in hypertension. J Steroid Biochem 1979; 11: 1043-1050. Ganguly A, Dowdy AJ, Luetscher JA, Melada GA: Anomalous postural response of plasma aldosterone concentration in patients with aldosterone-producing adrenal adenoma. J Clin Endocrinol Metab 1973; 36: 401-404. Biglieri EG, Schambelan M, Brust N, Chang 8, Hogan M: Plasma aldosterone concentration: further characterization of aldosterone-producing adenomas. Circ Res 1974; 34 and 35 (suppl I): l-183-189. Pratt JH, Ganguly A, Parkinson CA, Weinberger MH: Stimulation of aldosterone secretion by metoclopramide in humans: apparent independence of renal and pituitary mediation. Metabolism 1981; 30: 129-134. Ganguly A, Pratt JH, Weinberger MH: A new distinctive feature of dexamethasone-suppressible hyperaldosteronism: lack of metoclopramide-induced increase in plasma aldosterone concentration. Clin Res 1981; 29: 291A. Matsuoka H, Mulrow PJ, France-Saenz R, Li CH: Effects of fi-lipotropinderived peptides on aldosterone production in the rat adrenal gland. J Clin Invest 1981; 68: 752759.
June 1982
The American Journal of Medicine
Volume 72
21.
22.
23.
24.
25.
26.
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