1. No category

Dexamethasone-suppressible hyperaldosteronism. Adrenal transition cell hyperplasia?
J M Connell, C J Kenyon, J E Corrie, R Fraser, R Watt and A F Lever
Hypertension. 1986;8:669-676
doi: 10.1161/01.HYP.8.8.669
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1986 American Heart Association, Inc. All rights reserved.
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Dexamethasone-Suppressible Hyperaldosteronism
Adrenal Transition Cell Hyperplasia?
JOHN M.C.
CONNELL, CHRISTOPHER J. KENYON, JOHN E.T.
CORRIE, ROBERT FRASER,
R U B Y W A T T , AND ANTHONY F. LEVER
SUMMARY Dexamethasone-suppressible hyperaldosteronism is a rare familial syndrome in which
hypokalemia, suppression of plasma renin concentration, and elevated aldosterone secretion are
corrected by treatment with glucocorticoids. Regulation of adrenocortical function and body electrolytes was studied in two affected brothers. Both were hypertensive (210/128 and 160/106 mm Hg) with
hypokalemia (3.3 and 3.5 mM) and low plasma renin concentrations. Aldosterone was elevated
intermittently with levels as high as 45 ng/dl (normal range, 4-16 ng/dl). Cortisol concentrations were
normal but were correlated with aldosterone levels (r = 0.9 and 0.7). Concentrations of 11-deoxycorticosterone (19 and 21 ng/dl; normal range, 4-16 ng/dl) and 18-hydroxycortisol (1000 and 950 ng/dl;
normal range, 34-150 ng/dl) were elevated, and diurnal changes in both were the same as those seen
with aldosterone. Infusion of adrenocorticotropic hormone,_24 (ACTH) caused exaggerated increases
of aldosterone, 11-deoxycorticosterone, and 18-hydroxycortisol; cortisol response was normal. A
4-week trial of dexamethasone normalized blood pressure and caused a natriuresis, a fall in aldosterone, and a rise in plasma renin. Administration of ACTH after dexamethasone treatment again caused
exaggerated increases of aldosterone. Aldosterone did not respond to angiotensin II before dexamethasone therapy (r = 0.01), but it showed a normal response after therapy (r = 0.8, p<0.01). Neither
administration of dopamine (1 /xg/kg/min) nor long-term therapy with bromocriptine (2.5 mg t.i.d.
for 4 weeks) affected aldosterone biosynthesis. Thus, loss of dopaminergic inhibition of mineralocorticoid biosynthesis does not account for hyperaldosteronism in this condition. The abnormal pattern of
steroid secretion in these brothers is consistent with a population of adrenocortical transition-type
cells that secrete aldosterone in response to ACTH but not to angiotensin II and have biosynthetic
characteristics of both zona glomerulosa and zona fasciculata cell types. These properties would
explain the excess synthesis of 18-hydroxycortisol from a cell type that can uniquely hydroxylate
steroid at both the 17 and 18 positions. (Hypertension 8: 669-676, 1986)
KEY WORDS • hyperaldosteronism • cortisol
11-deoxycorticosterone * corticosterone
•
18-hydroxycortisol
hypertension itself, remains a matter for speculation. 5 6
We studied two brothers with this condition and
examined the effect of dexamethasone therapy on body
sodium and potassium content. We also examined the
effects of ACTH and angiotensin II (ANG II) on adrenal function before and after dexamethasone treatment, as it seems likely that the disorder represents a
primary or secondary abnormality of steroidogenesis.
It has been proposed that in this condition, hyperaldosteronism is caused by a lack of normal tonic adrenocortical inhibition by dopamine, 7 and this was investigated by measuring responsiveness to ACTH with and
without concomitant dopamine infusions and by longterm treatment with the dopamine agonist bromocriptine. In addition to measurement of 11-deoxycorticosterone, corticosterone, aldosterone, and cortisol,
EXAMETHASONE-suppressible hyperaldoI
I steronism is a familial form of hypertension
A . ^ ^ in which features of mineralocorticoid excess
(hypokalemia, low plasma renin concentration) and
elevated blood pressure remit during glucocorticoid
treatment. 13 Basal aldosterone secretion is increased2
and aldosterone response to adrenocorticotropic hormone (ACTH) is exaggerated,4 but the exact cause of
these biochemical abnormalities, and indeed of the
From the MRC Blood Pressure Unit (J.M.C. Connell, C.J. Kenyon, R. Fraser, K. Watt, and A.F. Lever), Western Infirmary,
Glasgow, and the MRC Population and Cytogenetics Unit (J.E.T.
Corrie), Western General Hospital, Edinburgh, Scotland.
Address for reprints: Dr. J.M.C. Connell, MRC Blood Pressure
Unit, Western Infirmary, Glasgow Gil 6NT, Scotland.
Received September 18, 1985; accepted January 28, 1986.
669
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HYPERTENSION
670
plasma levels of 18-hydroxycortisol were measured,
since urinary levels of this steroid are known to be
elevated in this condition.89
Subjects and Methods
Case Histories
Subject 1 presented with a blood pressure of 150/95
mm Hg at 8 years of age (1966). He was referred for
further investigation in 1982; at that time blood pressure was poorly controlled by propranolol, 80 mg
b.i.d. Basal blood pressure (no therapy having been
given for 4 weeks) was 210/128 mm Hg. Adrenal
computed tomographic scan was normal. Data summarized in Tables 1 and 2 led to the diagnosis of
dexamethasone-suppressible hyperaldosteronism.
Subject 2, the brother of Subject 1, was found at 29
years of age (1982) to have hypertension (160/106 mm
Hg). Investigation, the results of which are summarized in Tables 1 and 2, confirmed the diagnosis of
dexamethasone-suppressible hyperaldosteronism.
Since these studies were completed, both subjects
have been receiving dexamethasone, 0.25 mg/day,
and have good control of blood pressure.
Protocol
All studies were performed in hospital while the
subjects were maintained on a diet containing 150
mmol of sodium and 60 mmol of potassium per day.
Hypotensive drugs were withdrawn at least 4 weeks
before admission.
Basal plasma steroid concentrations were measured
in each subject 1) without therapy, 2) after 4 weeks of
dexamethasone treatment (0.5 mg q.i.d.), and 3) after
4 weeks of bromocriptine treatment (2.5 mg t.i.d.).
Total body sodium and potassium were measured before and after 4 weeks of dexamethasone treatment.
Adrenal responses to graded infusions of ACTH (Synacthen; 0.1, 1, and 10 ng/kg/min) or ANG II (Hyper-
VOL. 8, No
8, AUGUST
tensin; 1, 2, and 4 ng/kg/min) were studied on separate
days. Details of the experimental infusion procedures
are as follows:
1. Infusion of ACTH without long-term dexamethasone or bromocriptine treatment.
2. Infusion of ACTH with a concomitant infusion of dopamine
(1 pig/kg/min) without long-term dexamethasone or bromocriptine treatment.
3. Infusion of ACTH after 4 weeks of dexamethasone (0.5 mg
q.i.d.) therapy.
4. Infusion of ACTH after 4 weeks of bromocriptine (Parlodel;
2.5 mg t.i.d.) therapy.
5. Infusion of ANG II without long-term dexamethasone or
bromocriptine treatment.
6. Infusion of ANG II after 4 weeks of dexamethasone treatment.
7. Administration of metoclopramide (10 mg i. v. bolus) before
and after 4 weeks of dexamethasone treatment.
Dexamethasone (1 mg p.o.) was given 10 and 2
hours before the start of all ACTH infusions to suppress endogenous ACTH secretion. Infusions of
ACTH and ANG II without long-term dexamethasone
treatment were given at least 6 months after withdrawal of the steroid. The ANG II infusion studies were
performed following overnight fast while the subjects
were supine. Infused substances were delivered
through an indwelling cannula into a forearm vein;
serial blood samples were drawn from a heparinized
intravenous cannula in the opposite forearm.
Analyses
Plasma samples from each experiment were frozen
at - 20°C and subsequently analyzed as a batch. Total
body electrolyte composition was measured by neutron activation analysis, performance characteristics of
which have been defined previously.l0 Plasma electrolytes were measured by autoanalyzer. Plasma renin,
ANG II, cortisol, aldosterone, and 18-hydroxycortisol
were measured by radioimmunoassay methods that
have been described elsewhere.""14 Plasma 11-deoxy-
TABLE 1. Basal (0800) Blood Pressure, Plasma Renin and Electrolyte Concentrations and Total Body Electrolyte
Content Before and After Treatment with Dexamethasone and Bromocriptine
Variable
Blood pressure
(mm Hg)
Plasma active renin
concentration (/iU/ml)
Serum potassium (mM)
Serum sodium (mM)
Total body sodium (mM)
Total body potassium
(mM)
Untreated
210/112
<3
3.3
142
4029 (108)
Subject 1
Dexamethasone*
134/84
68
4.2
139
3656 (99)
1986
Bromocriptinet
Untreated
120/76
160/106
<3
3.4
141
—
<3
3.5
141
3817 (101)
Subject 2
BromoDexamethasone* criptinet
132/86
49
4.2
139
3494 (94)
132/78
<3
3:4
141
—
—
—
4355 (104)
3995 (99)
4384 (109)
4655 (112)
Values in parentheses represent percentage of predicted values based on data from normal subjects of comparable age
and morphometry.
•Dexamethasone: 0.5 mg q.i.d. for 4 weeks.
tBromocriptine: 2.5 mg t.i.d. for 4 weeks.
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DEXAMETHASONE-SUPPRESSIBLE HYPERALDOSTERONISM/Conne// et al.
671
TABLE 2. Plasma Concentrations of Corticosteroids Before (0800) and After Treatment with Dexamethasone and
Bromocriptine
Subject 1
Subject 2
Normal
DexaBromorange
BromoDexaUntreated methasone* criptinet
at 0800
Untreated methasone* criptinet
Variable
Plasma
14-25
15
Cortisol Qxg/dl)
27
Aldosterone (ng/dl)
4-16
1 l-Deoxycorticosterone
19
4-16
(ng/dl)
138
Corticosterone (ng/dl)
80-800
18-Hydroxycortisol
1000
34-150
(ng/dl)
Urine
18-Hydroxycoitisol
2732
28-220
(Mg/24hr)
•Dexamethasone: 0.5 mg q.i.d. for 4 weeks.
tBromocriptine: 2.5 mg t.i.d. for 4 weeks.
corticosterone and corticosterone also were measured
by radioimmunoassay after paper chromatography of
neutral extracts in Bush-type solvent systems. Antisera
to these compounds were raised in rabbits using bovine
serum albumin conjugated to the third position. Within-batch coefficients of variation for 11-deoxycorticosterone and corticosterone were 6.2% and 8.2%, respectively. Between-batch coefficients of variation
were 9.7% and 12.0%, respectively. Plasma prolactin
concentrations were measured by radioimmunoassay
using a double-antibody method calibrated with international reference standards. The interassay and intraassay coefficients of variation for this assay are between 8 and 12%.
<1
4
18
23
13
20
<1
2
16
17
1
41
40
—
21
309
1
61
83
—
133
1155
950
87.4
927
225
1946
2800
270
1500-t
20
750-
-10
Aldosterooe
£ ID
o *->
1500-, Subject 2
p
/
v
11-deoxy-20 h J.
•—
s % corticosterone
/
Results
Blood pressure was high and plasma renin and potassium concentrations low in both subjects (see Table
1). Dexamethasone (0.5 mg q.i.d. for 4 weeks) therapy lowered blood pressure and increased potassium
and renin concentrations. Associated with these
changes were substantial reductions in total body sodium (373 and 323 mmol in Subjects 1 and 2, respectively) and equivalent increases in total body potassium.
Bromocriptine treatment caused a reduction in blood
pressure without affecting plasma potassium or renin
concentrations, thus indicating that no major changes
in body sodium content or plasma volume had
occurred.
Plasma concentrations of all steroids (cortisol,
aldosterone, corticosterone, 11-deoxycorticosterone,
and 18-hydroxycortisol) varied synchronously during
a 24-hour period; peak levels occurred at 0800 (Figure
1). Aldosterone and 11-deoxycorticosterone concentrations were above the normal range at 0800, but not
during the evening or night. Levels of 18-hydroxycortisol were high throughout the 24-hour period.
2436
/
750-
<
C_>
\
V4V^'8OH cortisol
~
/ /r-^
\
•10
f\^k
/ J
J^Z
Aldosterone CL
•"^.Cortisol
*•
2100 0100 0800 1200 1600 2000
Tine
FIGURE 1. Diurnal rhythm of corticosteroids in two subjects
with dexamethasone-suppressible hyperaldosteronism before
treatment (for normal values see Table 2). Subjects were recumbent from 2400 to 0800 and ambulant thereafter. 11-DOC =
11-deoxycorticosterone.
Dexamethasone transiently reduced aldosterone
concentrations to subnormal values (0 and 1 ng/dl)
within 24 hours, but after 4 weeks of treatment all
values throughout the 24-hour period had risen to within the normal range (Figure 2). There was evidence of
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672
HYPERTENSION
20-,
Subject 2
10-
2400
8, AUGUST
0400 0800 1200 1600 2000
Time
FIGURE 2. Diurnal rhythm of aldosterone concentrations in
two subjects after treatment with dexamethasone, 0.5 mgq. i. d.,
for 4 weeks. Subjects were recumbent from 2400 to 0800 and
ambulant thereafter. Cortisol concentrations were undetectable
throughout.
Subject 1
Subject 1
Aldosterone
/\
« ;
r-0.70
A M\
/
-20
20-
/ *
An
fr*S
10-
Jf
M
Corusoi
•10
'
Aldosterone
SuOJect 2
20-
Subject 2
Aldosterone
\
10-
A /
2100
fW00
M A
-20
r-0.91
r-0.72
-10
A Nr r
Cortisol
0800
1200
1600
1986
an abnormal diurnal pattern of secretion, in that values
were highest at midnight and lowest at 0800. Concentrations of cortisol, corticosterone, 11-deoxycorticosterone, and 18-hydroxycortisol were all reduced during dexamethasone treatment, as was urinary excretion
of 18-hydroxycortisol (see Table 2).
Aldosterone and cortisol were measured in plasma
removed at 30-minute intervals between 0400 and
1600 both in the untreated state and after bromocriptine therapy (Figure 3). The relationship between the
two steroids was close (r = 0.9 and 0.7, respectively);
peak concentrations of aldosterone coincided with
those of cortisol, and levels of both steroids were highest in the morning. In both subjects a rise in cortisol
and aldosterone concentrations was noted around
lunchtime. Bromocriptine treatment had no effect on
therelationshipbetween aldosterone and cortisol concentrations (see Figure 3).
Without long-term dexamethasone treatment,
ACTH infusion caused large increases in aldosterone,
11-deoxycorticosterone, and 18-hydroxycortisol concentrations. For comparison, data derived from eight
normal male subjects studied using an identical protocol are also shown in Figure 4. The sensitivity (slope of
the response) and capacity (maximum response) of
aldosterone and 11 -deoxycorticosterone responses to
ACTH were greater in two subjects with dexamethasone-suppressible hyperaldosteronism than in controls. Following long-term dexamethasone treatment,
the aldosterone responseremainedgreater than normal
in both subjects. The cortisol and corticosterone responses to ACTH were normal without treatment, and
Subject 1
10-
20-,
VOL 8, No
2000
2100
0100
0800
1200
1600
Tine
FIGURE 3. Relationship between plasma aldosterone and cortisol concentrations in two subjects before treatment (left-hand panels) and after 4 weeks of treatment with bromocriptine, 2.5 mg t.i.d. (right-hand panels).
Subjects were recumbent from 2400 to 0800 and ambulant thereafter. Samples were obtained every 30 minutes.
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DEXAMETHASONE-SUPPRESSIBLE HYPERALDOSTERONISM/Conne/Z et al.
Aldosterone
FIGURE 4. Corticosteroid responses to
ACTH (0.1, 1, and 10 ng/kg/min) in Subjects 1 (—) and 2 (—) before treatment (A),
after 4 weeks of dexamethasone, 0.5 mg
q.i.d., treatment (B), after 4 weeks ofbromocriptine, 2.5 mg t.i.d., treatment (C),
and during concurrent dopamine (1.0
Hg/kg/min) infusion (D). Shaded areas in A
andD represent corticosteroid responses to
ACTH in eight normal subjects studied
using identical protocols. Values are means
± SD.
60M20-
2000
Cortlcosterooe
ng/100«l
1000
500
11-deoxycortlcosterooe
ng/IOOel
Cortlsol
120
90
§8
502010-
18 Hydroxycortlsol
ng/100al
600100200-
Aldosterone
ng/IOOal
60
10
20
673
2000-
Cortlcosterone
ng/100«l
500-
120
11-deoxy90
cortlcosterone 60
50
ng/IOOnl
Cortlsol
pg/IOOnl
18 Hydroxycortlsol
ng/IOOm
502010-
600-
too200Basal Basal 0.1
1.0
10
Basal Basal
1.0
10
ACTH ng/kg/nln
the cortisol response was attentuated by dexamethasone treatment.
In the untreated state, plasma ANG II concentrations during infusion of the octapeptide ( 1 , 2 , and 4
ng/kg/min) did not correlate with plasma aldosterone
concentrations (Figure 5). In contrast, after dexamethasone treatment, the correlation between plasma ANG
II and aldosterone concentrations was highly significant (r = 0 . 8 , p < 0 . 0 0 1 ) .
Long-term treatment with the dopamine agonist bromocriptine did not affect the aldosterone response to
ACTH. Similarly, no effect on basal steroid concentrations was noted (see Table 2). The acute effects of the
dopamine antagonist metoclopramide (10 mg i.y.)
were assessed in each subject both with and without
dexamethasone treatment (Table 3). In the first subject, 30 minutes after injection of metoclopramide,
plasma aldosterone concentrations increased from 4 to
24 ng/dl without dexamethasone treatment, and from 4
to 19 ng/dl with dexamethasone treatment. The larger
increase noted without dexamethasone therapy was associated with a subjective sensation of unease, and
plasma cortisol also rose from 6 to 19 /Ag/dl. An in-
crease in aldosterone in the second subject following
metoclopramide injection was noted before (from 10 to
20 ng/dl) and after (from 5 to 8 ng/dl) 4 weeks of
dexamethasone treatment; neither response was associated with a rise in plasma cortisol concentrations.
Infusions of dopamine (1 /xg/kg/min) did not affect
aldosterone, corticosterone, 18-hydroxycortisol, or
cortisol responses to ACTH but markedly enhanced
those of 11-deoxycorticosterone (see Figure 4). A
similar effect has been described in normal subjects.13
Plasma prolactin concentrations were below the limit of reliable estimation ( < 6 0 mU/L) during bromocriptine therapy and during dopamine infusions. Basal
prolactin concentrations at other times were normal, as
were prolactin responses to metoclopramide (data not
shown).
Discussion
Both subjects had hyperaldosteronism with hypertension, hypokalemia, and suppression of plasma active renin concentration. Dexamethasone treatment
caused a sustained reduction in aldosterone, normalized blood pressure, and was associated with a pro-
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HYPERTENSION
674
10-
o
o
r-0.01
200
(
Subject 1
Subject 2
0D O
10-
V
r-0.8
10
No
8,
AUGUST
100
Plasaa anglotensln I I (psol/I)
FIGURE 5. Relationship between plasma concentrations of
angiotensin II (note log scale) and aldosterone during angiotensin II infusion in two subjects before treatment (top panel) and
after 4 weeks of dexamethasone, 0.5 mg q.i.d., treatment (bottom panel).
found fall in total body sodium and a rise in total body
potassium. These electrolyte changes over a 4-week
period are greater than those reported in subjects with
tumerous hyperaldosteronism following surgical removal of the tumor." Thus, increased body sodium as
a consequence of renal mineralocorticoid action may
be sufficient to explain the hypertension of dexamethasone-suppressible hyperaldosteronism. However, administration of exogenous aldosterone together with
dexamethasone treatment in patients with this disorder
caused sodium retention without raising blood pressure,17 suggesting that other "hypertensinogenic" ste-
Further evidence of the abnormal pattern of steroids
secreted in response to ACTH was provided by infusion studies. The finding that aldosterone responses to
ACTH were much greater than normal confirmed observations by Ganguly et al.22 In addition, we have
shown that responses of 11-deoxycorticosterone and
18-hydroxycortisol were increased, whereas those
of cortisol and corticosterone were normal. Again,
TABLE 3. Changes in Plasma Cortisol and Aldosterone Concentrations After Metoclopramide (10 mg i.v.)
Subject 1
Variable
-15
No treatment
Aldosterone (ng/dl)
5
Cortisol Oig/dl)
7
Dexamethasone, 0.5 mg q.i.d. for 4 wk
2
Aldosterone (ng/dl)
<1
Cortisol Oig/dl)
Time (min)
15
30
0
45
-15
15
6
4
6
15
14
24
19
12
14
4
14
<1
19
«= 1
14
<1
<1
1986
roids may also be involved in the pathogenesis of the
hypertension. It is perhaps important that plasma 11deoxycorticosterone levels also were elevated in the
two subjectsreportedherein, and intermittently elevated concentrations of aldosterone and 11-deoxycorticosterone, along with normal levels of cortisol, may be
sufficient to explain all metabolic and hemodynamic
abnormalities in the condition. However, Gomez-Sanchez18 has suggested that the mineralocorticoid activity
of 18-oxocortisol, which is elevated in patients with
this condition, may also contribute to the development
of hypertension.
Apart from the finding of hyperaldosteronism, the
present study also found that plasma 18-hydroxycortisol concentrations are increased, which is in accordance with reports of high urinary levels of the steroid
in this condition.89 Elevated plasma 11-deoxycorticosterone levels also were noted, as in a proportion of
the patients studied by Oberfield et al." The marked
diurnal variation of aldosterone and 11-deoxycorticosterone probably accounts for the finding that plasma
concentrations of these steroids may be normal in subjects with dexamethasone-suppressible hyperaldosteronism." Changes in aldosterone concentration correlated closely with those of cortisol. Interestingly,
levels of both steroids were increased simultaneously
at around lunchtime. Recent careful studies of the periodicity of ACTH secretion have demonstrated arisein
ACTH around mealtimes that is superimposed on the
well-established diurnal pattern of hormone secretion.20 Synchronous changes of aldosterone and cortisol strongly support the suggestion that ACTH is the
principalregulatorof aldosterone secretion in this condition.4-21 Since plasma aldosterone, but not cortisol
or corticosterone, levels are elevated in these patients,
the abnormality appears to concern an aspect of adrenocortical function other than the pituitary- (ACTH)
adrenal (cortisol) axis.
20-
:°
VOL 8,
Subject 2
Time (min)
15
30
0
45
10
6
20
5
11
4
19
3
7
5
<1
<1
5
<1
8
«Cl
<1
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5
DEXAMETHASONE-SUPPRESSIBLE HYPERALDOSTERONISM/Conne// et al.
675
these data suggest that the abnormal aldosterone, 11deoxycorticosterone, and 18-hydroxycortisol synthesis is distinct from the normal zona fasciculata response to ACTH, as assessed by changes in cortisol
concentrations.
As has been observed previously, aldosterone did
not respond to ANG II infusion in untreated subjects.23
With dexamethasone treatment, however, plasma
aldosterone did rise as a function of plasma ANG II
levels. The lack of response without dexamethasone
treatment is compatible with indirect evidence that
aldosterone does not rise during ambulation in subjects
with dexamethasone-suppressible hyperaldosteronism24 and is explained by down-regulation of adrenal
ANG II receptor number as a consequence of suppression of renin and angiotensin due to sodium retention.25 After dexamethasone treatment, when total
body sodium is decreased and renin no longer
suppressed, adoption of upright posture or infusion
of ANG n 19 causes a normal increase in aldosterone levels. Thus, the mechanisms regulating zona
glomerulosa cell function appear to be intact in this
condition.
Recent studies have indicated that dopamine might
normally control adrenocortical function by tonically
inhibiting aldosterone secretion. 726 Ganguly et al.27
have suggested that dopaminergic control of mineralocorticoid synthesis is impaired in patients with dexamethasone-suppressible hyperaldosteronism, since administration of the dopamine (D2) receptor antagonist
metoclopramide failed to cause an increase in aldosterone levels in untreated subjects during short-term suppression of ACTH with dexamethasone. In the present
study, in the untreated state, the effects of metoclopramide were equivocal; one subject showed a marked
increase in aldosterone associated with a rise in plasma
cortisol. Similar stress-related changes have been described by Ganguly et al.27 in patients with this disorder and by others28 in normal subjects. After 4 weeks of
dexamethasone treatment, however, metoclopramide
caused an increase in aldosterone in both subjects without changing plasma cortisol concentrations. Since the
aldosterone response to metoclopramide is directly
proportional to the degree of activation of the reninangiotensin system,29 the failure of aldosterone to rise
in untreated dexamethasone-suppressible hyperaldosteronism may reflect the effects of sodium excess
on renin secretion rather than an intrinsic adrenal
abnormality.
The origin of this genetic abnormality is unclear. In
the current study, dexamethasone treatment reduced
basal aldosterone concentration but had no effect on
the aldosterone response to acutely administered
ACTH. This finding may imply that the underlying
adrenal abnormality is not dependent on ACTH stimulation but that expression of the abnormality in terms
of increased aldosterone levels is. Since changes in
adrenocortical cell function during migration may be
due to high intra-adrenal glucocorticoid levels33 or to
changes in the redox state,31 with increasing depth
within the gland, one possible cause of this condition
might be minor abnormalities in adrenocortical vascularization.
Intravenous infusion of dopamine in the current
study did not correct the exaggerated aldosterone response to ACTH, nor did long-term treatment with the
dopamine (D2) antagonist bromocriptine affect basal or
stimulated aldosterone levels. The marked effects of
dopamine on 11-deoxycorticosterone responses to
ACTH are also seen in normal subjects and may reflect
an extra-adrenal effect of dopamine on 11 -deoxycorticosterone synthesis." It seems unlikely that deficiency
of dopaminergic control could account for the abnormalities of mineralocorticoid secretion in these
subjects.
1. Sutherland DJA, Ruse JL, Laidlaw JC. Hypertension, increased aldosterone secretion and low plasma renin activity
relieved by dexamethasone. Can Med Assoc J 1966;95:
1109-1119
2. New MI, Seigal EJ, Peterson RE. Dexamethasone suppressible
hyperaldosteronism. J Clin Endocrinol Metab 1973;37:93-100
3. Ganguly A, Grim CE, Bergstein J, Brown RD, Weinberger
MH. Genetic and pathophysiological studies of a new kindred
with glucocorticoid suppressible hyperaldosteronism manifest
in three generations. J Clin Endocrinol Metab 1981;53:
1040-1046
4. Lee SM, Lightner G, Witte M, Oberfield S, Levine L, New
The cortisol-producing zona fasciculata cells of the
human adrenal cortex are characterized by an ability to
hydroxylate steroids in the 17 position, an inability to
convert corticosterone to aldosterone, and physiological regulation by ACTH rather than ANG II or plasma
potassium.30 Hydroxylation of corticosterone at the 18
position, a putative intermediate step in aldosterone
biosynthesis, does not normally occur in the zona
fasciculata.30
In contrast to zona fasciculata function, aldosteroneproducing zona glomerulosa tissue rapidly converts
corticosterone to aldosterone, is unable to carry out 17hydroxylation reactions, and is primarily regulated by
ANG II rather than ACTH. 30 It is unlikely, however,
that functional separation of the two zones is complete,
since zona fasciculata morphology and function are
thought to arise from centripetal migration of zona
glomerulosa cells. 31 ' 32 A transitional intermediate zone
may exist in which cells display biochemical features
of both zones. Such cells might be capable of 1) 18hydroxylating a 17-hydroxy steroid such as cortisol to
produce 18-hydroxycortisol and, more importantly,
18-oxocortisol, 2) synthesizing aldosterone in response to ACTH rather than ANG II, and 3) secreting
11-deoxycorticosterone. Although this transitional
zone would contribute little to overall adrenocortical
output in normal subjects, we suggest that dexamethasone-suppressible hyperaldosteronism may arise as a
result of its hypertrophy or hyperplasia. A similar
hypothesis based on measurement of 18-oxocortisol in
this condition has been proposed by Gomez-Sanchez. l8
Thus, it may be of importance that the initial work by
Sutherland et al.' described nodules of abnormal tissue
within the zona fasciculata of the adrenal in a patient
with dexamethasone-suppressible hyperaldosteronism.
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