Effect of adrenocorticotropic hormone stimulation during adrenal vein sampling in primary aldosteronism

Adrenal vein sampling (AVS) is fundamental for subtype diagnosis in patients with primary aldosteronism. AVS protocols vary between centers, especially for diagnostic indices and for use of adrenocorticotropic hormone (ACTH) stimulation. We investigated the role of both continuous ACTH infusion and bolus on the performance and interpretation of AVS in a sample of 76 patients with confirmed primary aldosteronism. In 36 primary aldosteronism patients, AVS was performed both under basal conditions and after continuous ACTH infusion, and in 40 primary aldosteronism patients, AVS was performed both under basal conditions and after ACTH IV bolus. Both ACTH protocols determined an increase in the rate of successful cannulation of the adrenal veins. Both ACTH infusion and bolus determined a significant increase in selectivity index for the right adrenal vein and ACTH bolus for the left adrenal vein. Lateralization index was not significantly different after continuous ACTH infusion and IV bolus. In 88% and 78% of the patients, the diagnosis obtained was the same before and after ACTH infusion and IV bolus, respectively. However, the reproducibility of the diagnosis was reduced using less stringent criteria for successful cannulation of the adrenal veins. This study shows that ACTH use during AVS may be of help for centers with lower success rates, because a successful adrenal cannulation is more easily obtained with this protocol; moreover, this technique performs at least as well as the unstimulated strategy and in some cases may be even better. Stringent criteria for cannulation should be used to have a high consistency of the diagnosis.     

New concepts in adrenal vein sampling for aldosterone in the diagnosis of primary aldosteronism

Improved diagnostic techniques and adoption of a systematic and thorough diagnostic workup can lead to identification of the surgically correctable forms of primary aldosteronism (PA) far more frequently than expected. Adrenalectomy can provide long-term normalization of blood pressure and correction of PA in most patients with an aldosterone-producing adenoma. Forms needing surgical correction are generally held to be less common than forms requiring medical therapy; however, this can be a misconception arising from the lack of systematic use of adrenal vein sampling (AVS). Currently AVS still remains the “gold standard” for identifying unilateral causes of PA that are surgically curable. The criteria for selecting patients to undergo AVS, the technique for performing AVS, and the criteria for analyzing and interpreting its results are summarized here.     

Jugular venous sampling: an alternative to petrosal sinus sampling for the diagnostic evaluation of adrenocorticotropic hormone-dependent Cushing's syndrome

Bilateral sampling of the inferior petrosal sinuses (IPSS) to distinguish Cushing's disease from the ectopic ACTH syndrome is accurate but risky and technically difficult. Bilateral sampling of the internal jugular vein (JVS) is simpler and presumably safer. To compare jugular and petrosal sinus venous sampling for distinguishing Cushing's disease from ectopic ACTH syndrome, we studied 74 patients with surgically proven Cushing's disease, 11 with surgically confirmed, and three with occult ectopic ACTH secretion. Patients underwent JVS and IPSS with administration of CRH on separate days. Ratios of central-to-peripheral ACTH in venous samples were calculated. At 100% specificity, IPSS correctly identified 61 of 65 patients with Cushing's disease [sensitivity, 94%; confidence interval (CI), 84-98%]. When patients with abnormal venous drainage were excluded, sensitivity was 98% (CI, 90-100%). JVS had a sensitivity of 83% (CI, 71-91%) at 100% specificity. Receiver operated characteristics plot areas under the curve were similar (0.968 +/- 0.020 and 0.974 +/- 0.016, area under the curve +/- se, JVS vs. IPSS). Although petrosal sampling had better diagnostic accuracy, CIs overlapped (95% CI, 90-100% vs. 86% CI, 78-94%). Centers with limited sampling experience may choose to use the simpler JVS and refer patients for IPSS when the results are negative.     

Adrenal vein sampling for primary aldosteronism: the assessment of selectivity and lateralization of aldosterone excess baseline and after adrenocorticotropic hormone (ACTH) stimulation

BACKGROUND: Adrenal vein sampling is crucial for identifying the primary aldosteronism subtypes, but the cutoff values for ascertaining selectivity of catheterization and lateralization of aldosterone secretion remain controversial. OBJECTIVES: To investigate the safety of adrenal vein sampling, the cutoff values for the selectivity and lateralization indexes, and the effect of adrenocorticotropic hormone stimulation on selectivity index and lateralization index performance. DESIGN: We assessed the proportion of selective adrenal vein sampling at different selectivity index cutoff values in 151 consecutive patients with primary aldosteronism undergoing bilaterally simultaneous adrenal vein sampling. Aldosterone-producing adenoma was diagnosed on the basis of the evidence of primary aldosteronism and lateralized aldosterone secretion, adenoma at pathological examination, and normokalemia, and correction of primary aldosteronism and cure or improvement of hypertension at follow-up. In 44 patients with bilaterally selective adrenal vein sampling and unequivocal diagnosis of aldosterone-producing adenoma on the basis of all these criteria, we examined the cutoff values of the lateralization index for assessing the lateralization of aldosterone excess and the effect of adrenocorticotropic hormone stimulation on selectivity index and lateralization index. RESULTS: Adrenal vein rupture occurred in one case (0.7%). Bilaterally selective adrenal vein sampling decreased steadily (from 79.9 to 40.2%) with increase in the selectivity index cutoffs from 1.1 to 5.0. Likewise, the proportion of correctly identified aldosterone-producing adenomas decreased (from 95.5 to 43.2%) with increase in lateralization index cutoffs from 1.125 to 5.0. Adrenocorticotropic hormone improved the assessment of selectivity but exerted a confounding effect on lateralization index. CONCLUSION: Adrenal vein sampling is safe; increasing the selectivity index cutoffs lowers the number of usable adrenal vein samplings; higher lateralization index cutoff values lead to missing a proportion of aldosterone-producing adenomas. The improved selectivity rate provided by adrenocorticotropic hormone stimulation should be weighed against the loss of correct lateralization.     

Predicting surgically remedial primary aldosteronism: role of adrenal scanning,posture testing,and adrenal vein sampling

Distinguishing surgically remedial forms from other causes of primary aldosteronism (PA) may be difficult, and it is made more challenging by the earlier detection of milder disease. The technical demands of bilateral adrenal vein sampling (AVS)-increasingly advocated for localizing a unilateral autonomous lesion (UAL)- and lack of agreed criteria for establishing unilateral autonomy, add further to the diagnostic challenge. This retrospective review of 49 hypokalemic patients with unequivocal PA (41 with surgically proven and remedial UAL, eight patients with bilateral adrenal hyperplasia) analyzes the value of computerized tomography adrenal scanning (n = 32), 4 h erect posture testing (n = 42), and AVS (n = 27) in predicting and lateralizing a surgically remedial lesion. A fall in plasma aldosterone during 4 h erect posture (positive test) occurred in 63% of patients with UAL and in none with bilateral adrenal hyperplasia. A positive posture test or computerized tomography adrenal scan (single focal macroadenoma) both had high positive predictive value (100% and 89% respectively), but low sensitivity for diagnosis of UAL. AVS, undertaken during low dose ACTH stimulation, localized the UAL in all cases (positive predictive value 100%) where the aldosterone/cortisol ratio of blood drawn from the uninvolved gland was less than that of peripheral blood (contralateral ratio <1). Biochemical severity, reflected by overnight supine plasma aldosterone, was strongly correlated with the degree of contralateral gland suppression (n = 16, r = 0.79, P < 0.001). Importantly, the AVS findings show that when bilateral access is not possible, UAL can be successfully lateralized when only one adrenal vein (the contralateral) is accessed, or the ipsilateral vein is sampled in subjects whose posture test was positive. In this series of patients with overt (hypokalemic) PA, preoperative testing successfully identified a surgically remedial lesion in 39 of 41 cases. Confirmation of the recommended diagnostic approach must now await larger prospective studies.     

Combined primary aldosteronism and preclinical Cushing's syndrome: an unusual case presentation of adrenal adenoma.

A 55-year-old woman was referred to our institution for evaluation of elevated plasma creatine phosphokinase, hypokalemia and hypertension. Her chief complaints were muscle weakness and polyuria. A left adrenal mass, 4 cm in diameter, was noted on computed tomography. Hormonal assessment demonstrated markedly elevated plasma aldosterone concentration, markedly low plasma renin activity, an abnormal diurnal variation in serum cortisol levels, suppressed baseline plasma adrenocorticotrophic hormone, and non-suppression of serum cortisol by dexamethasone suppression test. She showed no symptoms or signs suggestive of Cushing's syndrome. Adrenal scintigraphy with 131I-6-beta-iodomethyl-norcholesterol showed uptake on the left adrenal and inhibition of the contralateral adrenal gland. She was diagnosed with combined primary aldosteronism and preclinical Cushing's syndrome. Cases of combined primary aldosteronism and preclinical Cushing's syndrome are extremely rare. In patients with large aldosterone-producing adenoma, contralateral adrenal insufficiency should be anticipated after the removal of the tumor.     

Regulation of adrenal angiotensin receptor subtypes: a possible mechanism for sympathectomy-induced adrenal hypertrophy.

OBJECTIVE: Previous studies indicate that the adrenal gland plays a compensatory role in the maintenance of blood pressure in chemically sympathectomized rats. However, the mechanisms responsible for compensatory adrenal responses are poorly understood. This study examined the regulation of adrenal growth and type 1 A, 1 B, and type 2 angiotensin II (Ang II) receptor (AT1A, AT1B and AT2) expression in the adrenal gland induced by sympathectomy. METHODS: Five-week-old male Sprague-Dawley rats were treated with either guanethidine (50 mg/kg per day, intraperitoneally) or vehicle for 5 weeks. Norepinephrine and epinephrine levels in the atrium of the heart were measured by high-pressure liquid chromatography. Plasma renin activity was determined by radioimmunoassay. Adrenal AT1 and AT2 receptor density was determined by radioligand binding assay. Adrenal AT1A, AT1B and AT2 mRNA levels were determined by Northern blot analysis. RESULTS: Norepinephrine and epinephrine levels in the atrium of the heart were decreased 86% (P < 0.0001) and 58% (P < 0.05) by guanethidine treatment, respectively. Plasma renin activity was decreased 71% (P< 0.001) in guanethidine-treated rats compared with vehicle. In contrast, the ratio of adrenal to body weight was increased 38% in guanethidine-treated rats compared with vehicle (P< 0.001). Adrenal AT1 and AT2 receptor density was increased by guanethidine treatment (P< 0.05). Adrenal mRNA levels for AT2 (P< 0.001) and AT1A (P< 0.01), but not AT1B (P>0.05), were increased in guanethidine-treated rats compared with vehicle (P< 0.01). There were positive correlations between adrenal weight and AT2 (r = 0.9, P< 0.001) and AT1A (r = 0.6, P< 0.05) but not AT1B (r = - 0.01, P > 0.05) expression. CONCLUSIONS: Impairment of the sympathetic nervous system with guanethidine withdraws the normal stimulation of this system on the circulating renin-angiotensin system, but upregulates the expression of adrenal Ang II receptors. Increased expression of adrenal AT2 and AT1A receptors may play an important role in adaptive adrenal hypertrophy and hormonal responses to sympathectomy.     

In vitro studies in primary aldosteronism: baseline steroid production and aldosterone responses to ACTH and angiotensin II

The spontaneous glucocorticoid production in control adrenal cells (N = 10) and in the adenoma cells (N = 15) exhibited comparable geometric mean values: 1.896 nmol/ml/4-5 x 10(5) cells per 2 h (confidence limits: 0.428-8.391) and 1.852 nmol/ml (0.326-12.241), respectively. The same results were obtained for the three samples of nodular hyperplasia cells. When cortisol and corticosterone were measured separately, there was no significant difference between the outputs for control cells and those for pathological cells. Baseline aldosterone production in control cells showed a geometric mean of 2.525 pmol/ml (0.236-27.192). In the 15 adenomas, spontaneous production was extremely important: 57.297 pmol/ml (3.357-976.692). The difference was highly significant (P less than 0.0005). Aldosterone levels in the 3 samples of nodular hyperplasia cells were not different from the control values. In 9 out of the 15 adenomas, aldosterone responses to 10(-10) mol/l ACTH, expressed as stimulated/basal production, were above normal: 3.58 +/- 0.86 (SEM) against 1.48 +/- 0.08 (P less than 0.025). In the remaining 6 and in the 3 samples of nodular hyperplasia cells, there was a slight or no response. Angiotensin II (AII) stimulated both adenoma and nodular hyperplasia cells to varying degrees, without any obvious difference between these two categories. A combination of ACTH (10(-12) mol/l) and AII (10(-12) mol/l) had a synergistic action on aldosterone production in cells classed in the adenoma group. These findings demonstrate that despite the abnormal rate of aldosterone formation in adenoma cells, the production rate of corticosterone and cortisol remains normal. They unmask two functional categories with regard to ACTH in the adenoma group. Finally, they underline the relative insensitivity of nodular hyperplasia cells to ACTH.     

Porcine adrenal adrenocorticotropic hormone receptors: characterization, changes during neonatal development, and response to a stressor.

ACTH receptors were characterized in the porcine adrenal cortex using a biologically active [125I] Tyr23,Phe2,Nle4ACTH(1-38) analog, and a 149,000 X g(av) total particulate tissue preparation. Binding of this labeled ACTH analog to adrenocortical ACTH receptors was demonstrated to be time and temperature dependent, tissue and hormone specific, saturable, reversible, have a binding optimum at pH 7.5, and be dependent on the presence of Ca++. Scatchard analyses of saturation data using the computer program LIGAND indicated a single class of high affinity binding sites [association constant (Ka) = 2.00 +/- 0.25 10(9) M-1)]. Hill plots of saturation data had slopes (b = 0.83 +/- 0.09) that did not differ from 1, and hence also indicated a single class of binding sites. The rate constant of association (k1 = 3.72 +/- 1.19 X 10(8) min-1M-1) was compatible with the known rapidly occurring action of ACTH in pigs in vivo. Kinetic experiments also indicated the ACTH receptors to be of high affinity (4.18 +/- 0.54 X 10(10) M-1; n = 4). Receptor-associated degradation occurring to analog during incubations involved cleavage of the peptide into fragments rather than deiodination and could be partially prevented by use of 0.01% bacitracin. Subsequently, a study was conducted to determine changes in the ability of piglets to respond, in terms of plasma cortisol, to the physiological and psychological stressor of overnight maternal deprivation (MD) at various neonatal ages (days 3-31 of age); to measure age-related and stressor-associated changes in adrenal ACTH receptors; and to associate any changes in adrenal response with changes in ACTH receptors. Plasma cortisol obtained by venipuncture did not vary with age in either control or MD piglets but was elevated by MD (16.98 +/- 2.5 vs. 68.3 +/- 8.2 ng/ml). There was no effect of MD and associated hormonal perturbations on adrenal ACTH receptors. However, there were significant age-related differences in these receptors, with a 1.6-fold increase in concentrations (55.6 +/- 12.0 fmol/mg protein), and a 63% decrease (P less than 0.05) in affinity (4.19 +/- 0.86 x 10(8) M-1) evident at 17 days of age compared with 10 and 24 days of age. The significance of these age-related changes in ACTH receptors for adrenal function remains to be determined; however, it is evident that in neonatal pigs, there is no stress nonresponsive period.     

Studies on abnormalities of adrenal steroidogenesis in essential hypertension, primary aldosteronism and renovascular hypertension: responses of plasma steroids to angiotensin III

In the present study, effects of angiotensin on the adrenal steroidogenesis were studied in essential hypertension, primary aldosteronism and renovascular hypertension (RVH). Angiotensin III(A III), an analogue of angiotensin II, was administered to 17 normal volunteers (9 male and 8 female), 44 patients with essential hypertension (EH) (15 with high renin; HREH, 15 with normal renin; NREH and 14 with low renin; LREH), 8 patients with primary aldosteronism (5 with adrenal adenoma; APA and 3 with bilateral adrenocortical hyperplasia; IHA) and 5 patients with renovascular hypertension. In all the patients with hypertension and normal subjects, blood pressure (BP) and plasma concentrations of progesterone (P), corticosterone (B), aldosterone (Aldo), 17 alpha-hydroxyprogesterone(17-OHP) and cortisol(F) were measured before and after intravenous administration of A III (0.1, 0.5, 1.0, 10, 20 and 40 ng/kg/min, for 15 min, respectively). 1) BP rose from 164 +/- 19/88 +/- 8 to 180 +/- 19/112 +/- 10 mmHg [systolic BP(SBP); P less than 0.01, diastolic BP(DBP); P less than 0.01] in HREH, from 162 +/- 12/96 +/- 7 to 186 +/- 11/118 +/- 8 mmHg in NREH(SBP; P less than 0.01, DBP; P less than 0.01), 165 +/- 12/94 +/- 8 to 202 +/- 12/126 +/- 9 mmHg in LREH(SBP; P less than 0.001, P less than 0.001) and 118 +/- 8/72 +/- 7 mmHg to 136 +/- 11/88 +/- 8 mmHg in controls (SBP; P less than 0.01, DBP; P less than 0.01). The elevation in NREH and LREH was greater than that in HREH and controls. The elevations of BP both in APA and IHA were remarkably greater than that in controls and as similar as LREH(APA; 174 +/- 21/103 +/- 12 to 204 +/- 18/136 +/- 8 mmHg, IHA; 176 +/- 10/104 +/- 4 to 206 +/- 17/138 +/- 10 mmHg). The elevation in RVH was similar to that in NREH(173 +/- 9/108 +/- 8 to 194 +/- 13/132 +/- 10 mmHg). 2) Plasma P increased from 25.5 +/- 7.5 to 39.5 +/- 13.8 ng/100 ml(P less than 0.001) in HREH, from 28.0 +/- 7.7 to 45.3 +/- 12.7 ng/100 ml(P less than 0.001) in NREH, from 23.8 +/- 8.2 to 47.2 +/- 19.4 ng/100 ml(P less than 0.001) in LREH and 26.6 +/- 11.0 to 43.4 +/- 14.6 ng/100 ml in controls. The increment in HREH or NREH was similar to that in controls(P less than 0.1, respectively), whereas greater than controls in LREH(P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

Control of aldosterone secretion during sodium restriction: Adrenal receptor regulation and increased adrenal sensitivity to angiotensin II

The mechanism of increased adrenal sensitivity to angiotensin II during the aldosterone response to sodium restriction was investigated in the rat. Sodium restriction for 36 hr markedly increased the aldosterone-stimulating effect of low-dose (1 ng/min) infusion of angiotensin II and caused enhanced binding of (125)I-labeled angiotensin II to the zona glomerulosa in vivo. Conversely, in vivo binding of (125)I-labeled angiotensin II was significantly decreased after 36 hr of high-sodium intake. In isolated glomerulosa cells, the increased binding of angiotensin II after sodium restriction was shown to result from a significant increase in receptor affinity (+80%) and a smaller increase in receptor concentration (+25%). The corresponding aldosterone responses in dispersed cells showed an increase in sensitivity to angiotensin II, commensurate with the increased receptor affinity. More prolonged sodium restriction (4 days) caused a further increase in angiotensin receptor concentration (+70%) and maximal aldosterone response (+50%), whereas the binding affinity of adrenal receptors and the sensitivity of the in vitro aldosterone response had returned to normal. During sodium loading for 36 hr and 4 days, the converse effects on adrenal angiotensin II receptors and aldosterone production were observed. Also, in contrast to the consistent increase in angiotensin II receptors in the adrenal glands of sodium-restricted animals, the angiotensin II binding capacity of uterine smooth muscle was decreased by 40% after 7 days of sodium restriction.The rapid regulation of receptor affinity and concentration during changes in sodium intake provides a basis for the dynamic modulation of aldosterone responses by dietary sodium content. During sodium restriction, the sequential changes in receptor affinity and concentration account for the enhanced binding and steroidogenic actions of angiotensin II in vivo and in vitro. These receptor changes, and the converse effects of sodium loading, serve as a local regulatory mechanism in the physiological control of adrenal sensitivity and aldosterone secretion. The opposite finding in smooth muscle-that sodium restriction decreases the concentration of angiotensin II receptors-is consistent with the divergent effects of changing sodium balance upon vascular and adrenal responses to angiotensin II.