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(Hypertension. 2007;49:704.)
© 2007 American Heart Association, Inc.

Original Articles, Part 2

Association of Adrenal Steroids With Hypertension and the Metabolic Syndrome in Blacks

From the Medical College of Wisconsin (S.K., J.M.K., C.E.G., H.R., J.M., T.A.K.), Milwaukee; Aurora St Luke’s Medical Center (H.R.), Milwaukee, Wis; and Mayo Foundation and Clinic (R.J.S.), Rochester, Minn.

Correspondence to Theodore A. Kotchen, MD, Division of Endocrinology (Department of Medicine), 257 Dynacare Building, 9200 West Wisconsin Ave, Milwaukee, WI 53226. E-mail tkotchen{at}mcw.edu

	Abstract

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Blacks have a high prevalence of hypertension and adrenal cortical adenomas/hyperplasia. We evaluated the hypothesis that adrenal steroids are associated with hypertension and the metabolic syndrome in blacks. Ambulatory blood pressures, anthropometric measurements, and measurements of plasma renin activity (PRA), aldosterone, fasting lipids, glucose, and insulin were obtained in 397 subjects (46% hypertensive and 50% female) after discontinuing antihypertensive and lipid-lowering medications. Hypertension was defined as average ambulatory blood pressure >130/85 mm Hg. Late-night and early morning salivary cortisol, 24-hour urine-free cortisol, and cortisone excretion were measured in a consecutive subsample of 97 subjects (40% hypertensive and 52% female). Compared with normotensive subjects, hypertensive subjects had greater waist circumference and unfavorable lipid profiles, were more insulin resistant, and had lower PRA and higher plasma aldosterone and both late-night and early morning salivary cortisol concentrations. Twenty-four–hour urine-free cortisol and cortisone did not differ. Overall, ambulatory blood pressure was positively correlated with plasma aldosterone (r=0.22; P<0.0001) and late-night salivary cortisol (r=0.23; P=0.03) and inversely correlated with PRA (r=–0.21; P<0.001). Plasma aldosterone correlated significantly with waist circumference, total cholesterol, triglycerides, insulin, and the insulin-resistance index. Based on Adult Treatment Panel III criteria, 17% of all of the subjects were classified as having the metabolic syndrome. Plasma aldosterone levels, but not PRA, were elevated in subjects with the metabolic syndrome (P=0.0002). The association of aldosterone with blood pressure, waist circumference, and insulin resistance suggests that aldosterone may contribute to obesity-related hypertension in blacks. In addition, we speculate that relatively high aldosterone and low PRA in these hypertensive individuals may reflect a mild variant of primary aldosteronism.

Key Words: aldosterone • cortisol • hypertension • metabolic syndrome • insulin resistance • plasma renin activity

	Introduction

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The prevalence of hypertension in African-Americans is among the highest in the world. In the United States, compared with whites, hypertension is 50% more frequent in blacks.^1,2 Blacks develop hypertension at a young age and have higher rates of hypertension-related deaths and cardiovascular complications including stroke, heart disease, and end-stage renal disease.² In both black and white populations, hypertension is frequently associated with centripetal obesity, insulin resistance, and dyslipidemia.^3–5 This constellation of risk factors has been termed the metabolic syndrome and is associated with increased cardiovascular disease morbidity and mortality.^6,7

Based on an earlier study of the records of 35 000 consecutive autopsies, an increased prevalence of adrenal cortical adenomas and hyperplasia has been observed in association with essential hypertension, particularly in younger and middle-aged black adults.⁸ Two of the major steroids secreted by the adrenal cortex are aldosterone, a mineralocorticoid that promotes sodium retention, and cortisol, a glucocorticoid that is a functional antagonist of insulin action. Both steroids have been implicated in the pathogenesis of hypertension and the metabolic syndrome.^9,10

We have observed previously that plasma aldosterone is associated with blood pressure levels in blacks with essential hypertension and, to a lesser extent, in whites.¹¹ Other studies, primarily in white subjects, have found little or no association of aldosterone with blood pressure levels or with hypertension.^12–14 However, in a community-based sample, increased serum aldosterone concentrations within the physiological range predisposed persons to the subsequent development of hypertension.¹⁵ Several reports describe an association of aldosterone with body mass index (BMI) and anthropometric measures of centripetal obesity.^16,17 Based on relatively small groups of subjects, both increased plasma renin activity (PRA) and increased plasma aldosterone concentrations have been measured in obese individuals. Renin and aldosterone have been implicated in the pathogenesis of obesity-related hypertension, and weight loss is accompanied by reductions of PRA and plasma aldosterone.^17,18 Inconsistent associations of PRA and plasma aldosterone have been described with several metabolic risk factors, including triglycerides, insulin resistance, hypertension, and low high-density lipoprotein (HDL) cholesterol.^19,20 In a recent study in the Seychelles, populated predominantly by individuals of East African descent, PRA and plasma aldosterone were each associated with different components of the metabolic syndrome.²¹

Excess production of cortisol, such as what occurs in Cushing’s syndrome, results in striking similarities to the metabolic syndrome, including hypertension, insulin resistance, and dyslipidemia.²² Subtle increases of cortisol and this cardiovascular disease risk profile have also been observed in patients with "incidental" adrenal adenomas, and these patients have been labeled as having "subclinical" Cushing’s syndrome.²³ Limited and inconsistent evidence suggests that serum cortisol levels are associated with blood pressure and other components of the metabolic syndrome in patients who do not have Cushing’s syndrome, particularly in obese individuals.^24–26 These observations raise the possibility that subtle increases of glucocorticoid production contribute to the pathogenesis of the metabolic syndrome.

The present study evaluated the potential contributions of aldosterone and cortisol to hypertension and to the metabolic syndrome in blacks. Both normotensive and hypertensive individuals were studied under standardized, controlled conditions at an inpatient clinical research center.

	Methods

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Subjects were defined as black (African American) based on self-identification, birth in the continental United States, both parents reported as being black, and English as the native language. Subjects were recruited from a variety of community resources and health providers within the Milwaukee area. Informed consent was obtained from all of the subjects, and the protocols were approved by the Froedtert Memorial Lutheran Hospital/Medical College of Wisconsin Institutional Review Board.

All of the subjects ranged in age from 18 to 55 years. The initial designation of hypertension was based on a screening clinic systolic blood pressure 140 mm Hg and a diastolic blood pressure 90 mm Hg or taking antihypertensive medications. Pregnant subjects and subjects with secondary hypertension, diabetes mellitus, serum creatinine concentrations >2.2 mg/dL, BMI >36 mg/kg,² chronic debilitating illness, and substance abuse were excluded. Before further study, subjects taking antihypertensive and lipid-lowering medications discontinued these agents for 1 week and 4 weeks, respectively. Subjects were then admitted to an inpatient general clinical research center. Blood pressures were measured over a 24-hour period with an Accutracker (Suntech Medical Instruments Inc) every 30 minutes during the day (6:00 AM to 8:00 PM) and every 60 minutes during the night (8:00 PM to 6:00 AM). Subjects were considered to have hypertension if the average daytime systolic blood pressure was 130/85 mm Hg.

Standardized anthropometric measurements included height, weight, and waist and hip circumferences. Waist circumference was taken at the narrowest point between the umbilicus and superior iliac spine. Peripheral venous blood was collected after an overnight fast for measurement of plasma concentrations of sodium, potassium, creatinine, total cholesterol, HDL cholesterol, triglycerides, and serum concentrations of glucose and insulin. PRA and plasma aldosterone were measured in the midmorning after subjects had been supine for 60 minutes and again after standing for 10 minutes. Salivary samples were obtained for measurement of cortisol at 11:00 PM on the day after admission and at 7:00 AM the following morning. A 24-hour urine sample was collected for measurements of sodium, potassium, creatinine, cortisol, and cortisone excretion.

Based on Adult Treatment Panel III guidelines, the metabolic syndrome was defined as the presence of 3 of the following criteria²⁷: (1) abdominal obesity (waist circumference >102 cm in men and >88 cm in women; (2) hypertriglyceridemia (150 mg/dL); (3) low HDL cholesterol (< 40 mg/dL in men and <50 mg/dL in women); (4) high ambulatory blood pressure (130/85 mm Hg); and (5) high fasting glucose (110 mg/dL). Insulin resistance was calculated with the Homeostasis Model Assessment (HOMA) insulin resistance index, a web-based program made available by Oxford University.²⁸ The degree of insulin resistance is related to the height of the index. HOMA insulin resistance has been shown to correlate well with the euglycemic clamp technique in both normotensive and hypertensive individuals.²⁹

Sodium, potassium, and creatinine were measured using an Olympus automated analyzer. Glucose was measured with an automated glucose oxidase enzymatic assay. Insulin was measured by using a commercially available double antibody, equilibrium radioimmunoassay (Linco Corp). Plasma cholesterol was measured by an enzymatic procedure. HDL cholesterol was measured in a same-day assay after selective precipitation of the low-density lipoprotein fraction. Triglycerides were measured by an enzymatic procedure based on the conversion of triglycerides to glycerol and its subsequent conversion to dihydroxyacetone phosphate and hydrogen peroxide. Low-density lipoprotein cholesterol was calculated using Friedwald’s formula.

PRA was measured by a modification of the method of Sealey and Laragh,³⁰ with the use of angiotensin I antisera kindly provided by Dr Jean Sealey (Cornell University Medical Center). Plasma aldosterone was measured by radioimmunoassay with a commercially available assay kit (Coat-a-Count Aldosterone, Diagnostic Products Corp). Salivary cortisol was measured by using a Food and Drug Administration-cleared enzyme immunoassay purchased from Salimetrics LLC.³¹ Urine-free cortisol was measured by high-performance liquid chromatography/tandem mass spectrometry.³²

Differences in continuous variables between hypertensive and normotensive subjects within each group were tested by t test or Wilcoxon rank sum test, depending on the distribution of variables. Multiple linear regression analysis was carried out to test the association of blood pressure with HOMA insulin resistance and other traits of the metabolic syndrome after adjusting for age and gender. Results are presented as mean±SE, and P<0.05 is considered statistically significant.

	Results

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A total of 182 hypertensive and 215 normotensive subjects were studied. As shown in Table 1, compared with normotensive subjects, hypertensive subjects had a higher BMI (P<0.0001), a larger mean waist circumference (P<0.001), and higher waist:height ratio (P<0.0001). There were no group differences in mean concentrations of plasma sodium, potassium, creatinine, 24-hour creatinine clearance, or 24-hour urine sodium or potassium excretion. Plasma concentrations of triglycerides, total cholesterol, and low-density lipoprotein cholesterol were significantly higher (P<0.02 or less), and HDL cholesterol was lower (P<0.01) in the hypertensive subjects. Serum insulin concentrations were higher in the hypertensive subjects (P<0.01), and based on the HOMA index, hypertensive subjects were more insulin resistant than the normotensive subjects (P<0.04). Supine and standing plasma aldosterone concentrations were higher in the hypertensive subjects (P<0.0004), whereas PRA was lower (P<0.001) in the hypertensive subjects (Figure 1). The statistical significance of the above differences persisted after adjustment for the relatively small age difference in the normotensive and hypertensive subjects.

View larger version (14K): [in this window] [in a new window]   Figure 1. Supine and standing PRA and plasma aldosterone in normotensive and hypertensive subjects.

The possibility that some of the hypertensive subjects might have primary aldosteronism was considered. Supine plasma aldosterone was <15 ng/dL in 180 of the 182 hypertensive subjects. However, in each of 2 hypertensive subjects, supine plasma aldosterone concentrations were 16.1 ng/dL. In these 2 subjects, standing PRA was 5.0 and 0.2 ng/mL per hour, and serum K+ was 4.9 and 3.8 mEq/L, respectively. Primary aldosteronism was considered a possible diagnosis in the subject with the lower PRA; however, this subject declined further diagnostic testing. Excluding this 1 subject from the data analysis did not alter any of the mean values or levels of statistical significance.

Salivary cortisol, urine cortisol, and cortisone excretion were measured in a consecutive subsample of 57 normotensive and 39 hypertensive subjects. The anthropometric and metabolic differences between the normotensive and hypertensive subjects in the subsample were similar to those in the total groups. After being in the hospital for >24 hours, late-night salivary cortisol was higher (P<0.01) in the hypertensive subjects; salivary cortisol was also higher (P<0.03) the following morning (Figure 2). Twenty-four–hour urine-free cortisol and cortisone did not differ between hypertensive and normotensive subjects.

View larger version (13K): [in this window] [in a new window]   Figure 2. Late-night and early morning salivary cortisol in normotensive and hypertensive subjects.

Overall, including both normotensive and hypertensive subjects, average 24-hour systolic and diastolic blood pressures were positively correlated with BMI, waist circumference, waist:height ratio, total cholesterol, low-density lipoprotein cholesterol, triglycerides, serum insulin, and the HOMA insulin resistance index (Table 2). Supine and standing plasma aldosterone concentrations were also correlated with BMI, waist circumference, and waist:height ratio. Aldosterone concentrations were also correlated with plasma cholesterol, triglycerides, insulin, and the HOMA insulin resistance index. In contrast, PRA was not correlated with any of these anthropometric or metabolic variables. In the subsample, there were no significant correlations between salivary cortisol and the anthropometric or metabolic variables associated with the metabolic syndrome.

In addition, supine and standing plasma aldosterone concentrations were significantly correlated with daytime and nighttime systolic and diastolic blood pressures, both before and after statistical adjustment for waist circumference (Table 3). Conversely, supine and standing PRA were inversely correlated with blood pressure. In the subsample, late-night salivary cortisol concentrations were also correlated with blood pressure. The difference between early morning and late-night cortisol was not correlated with the nighttime blood pressure dip.

Overall, waist circumference was significantly correlated with fasting serum insulin (r=0.37; P<0.0001) and with insulin resistance (r=0.25; P<0.0001). Based on Adult Treatment Panel III criteria, 17% of all of the subjects were classified as having the metabolic syndrome. The prevalence of hypertension in subjects with the metabolic syndrome was 94%; hypertension prevalence in subjects without the metabolic syndrome was 37% (P<0.0001). Supine and standing plasma aldosterone concentrations were higher in subjects with the metabolic syndrome (Table 4 and Figure 3). Aldosterone concentrations tended to be higher in hypertensive subjects with the metabolic syndrome than in hypertensive subjects who did not have the metabolic syndrome, although these differences were not statistically significant. PRA did not differ in those with or without the metabolic syndrome, and the plasma aldosterone:PRA ratio was higher in subjects with the metabolic syndrome (P<0.01).

View larger version (13K): [in this window] [in a new window]   Figure 3. Supine and standing PRA and plasma aldosterone in subjects with the metabolic syndrome and in subjects without the metabolic syndrome.

	Discussion

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Despite low PRA, plasma aldosterone was higher in the hypertensive than in the normotensive subjects, and overall aldosterone was correlated with blood pressure. In addition, both aldosterone and blood pressure were correlated with the anthropometric and metabolic components of the metabolic syndrome, including serum insulin and insulin resistance. In contrast, PRA was inversely related to blood pressure and was not associated with any other components of the metabolic syndrome. Individuals with the metabolic syndrome had higher plasma aldosterone concentrations and a higher aldosterone:PRA ratio than those without the syndrome. Salivary cortisol concentrations were also modestly higher in hypertensive individuals, and overall blood pressures were correlated with nighttime salivary cortisol concentrations.

These observations raise a question about the stimulus for elevated plasma aldosterone and salivary cortisol concentrations in the hypertensive subjects and about the potential physiological relationship of these steroids to hypertension and the metabolic syndrome. Plasma and urine potassium did not differ in normotensive and hypertensive subjects. Although adrenocorticotropic hormone (corticotropin [ACTH]) may acutely stimulate aldosterone secretion, long-term sustained elevations of ACTH do not.^33,34 In the present study, there was no correlation between plasma aldosterone and salivary cortisol, albeit measured at different times. However, we cannot exclude the possibility that elevations of aldosterone and cortisol in the hypertensive subjects may be related to small variations of ACTH. Alternatively, genetic variation in the 2 closely related genes encoding for the 2 late pathway steroidogenic enzymes, 11 ß hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2), may result in an increase in cortisol and aldosterone production, respectively, independent of external regulators, such as angiotensin II, potassium, and ACTH.³⁵

It is also possible that the higher plasma aldosterone concentrations in hypertensive subjects and in subjects with the metabolic syndrome are in some way related to the association of aldosterone with waist circumference. Free fatty acids released from visceral adipose tissue have been shown to stimulate aldosterone production,³⁶ perhaps to a greater extent in blacks than in whites.³⁷ Alternatively, insulin has been reported to stimulate aldosterone secretion in vitro and in experimental animals.^38,39 Consistent with previous reports, we observed that centripetal obesity is associated with insulin resistance and hyperinsulinemia. Overall, plasma aldosterone was correlated with plasma insulin and insulin resistance. Taken together, these data are consistent with the hypothesis that the elevated insulin levels or other adipokines in individuals with centripetal obesity function as a secretagogue for aldosterone.

Salivary cortisol reflects the unbound, biologically active form of serum cortisol, and late-night salivary cortisol measurements have been introduced recently as a promising screening test for the evaluation of Cushing’s syndrome.⁴⁰ There is less within-individual variation of late-night versus early morning cortisol. In patients with Cushing’s syndrome, the circadian decline in cortisol is attenuated, and late-night cortisol measurements are more discriminating as a screening test than measurements obtained early in the day.⁴¹ Small increases in salivary cortisol have been reported to correlate with decreased bone mineral density in elderly subjects, suggesting that these modest elevations have a physiological impact.⁴² However, in the present study, salivary cortisol was not associated with BMI, waist circumference, plasma lipids, plasma insulin, or insulin resistance. Nevertheless, based on the well-known actions of glucocorticoids, it seems reasonable to hypothesize that cortisol plays a pathophysiological role in the metabolic syndrome.

Although salivary cortisol was elevated, there were no differences in urine-free cortisol or cortisone between hypertensive and normotensive subjects. Salivary cortisol levels provide a more sensitive approach for assessing subtle activation of the hypothalamic–pituitary–adrenal axis than urine-free corticosteroids.^41,43,44 When salivary and urinary cortisol are not greatly elevated, there is essentially no correlation between the two, and salivary cortisol is a better index of hypothalamic–pituitary–adrenal activity than urine-free cortisol.^40,41 Furthermore, many studies have shown an excellent correlation of total and free-plasma cortisol with salivary cortisol in a variety of physiological situations.^45–47 It is possible, however, that the small increase in salivary cortisol in hypertensive subjects was attributable, at least in part, to a decreased conversion of cortisol to cortisone by salivary 11-ß-hydroxysteroid dehydrogenase 2.⁴⁸ Nevertheless, the small increases in salivary cortisol reflect exposure of target tissue to increased glucocorticoid activity.

Elevated, normal, or low circulating cortisol concentrations have been measured in obese individuals.^24,26 However, circulating cortisol may not reflect its activity in target tissues. 11 ß-Hydroxysteroid dehydrogenase type 1 activates functionally inert glucocorticoid precursors (cortisone) to active glucocorticoids (cortisol) within insulin target tissues, such as adipose tissue, thereby resulting in local glucocorticoid action.^49,50 This conversion is more pronounced in visceral than in subcutaneous adipose tissue.⁵¹ Muscle is the major target of insulin action, and 11 ß-hydroxysteroid dehydrogenase type 1 is also expressed in myoblasts. The expression of this cortisol activating enzyme in myoblasts has been shown to correlate with components of the metabolic syndrome, and inhibition of 11 ß-hydroxysteroid dehydrogenase type 1, either pharmacologically or by in vitro downregulation of 11 ß-hydroxysteroid dehydrogenase type 1 expression, decreases insulin resistance.⁵² Furthermore, in visceral adipose tissue, cortisol promotes adipogenesis and adipose tissue hypertrophy.^51,53 Thus, among individuals with centripetal obesity, a vicious cycle may be established whereby there is increased conversion of cortisone into its active metabolite, cortisol, within visceral adipose tissue, and cortisol promotes adipose tissue hypertrophy.

Perspectives
We speculate that both aldosterone and cortisol contribute to the pathogenesis of the metabolic syndrome and low renin hypertension in blacks. Conceivably, increased levels of these hormones in hypertensive subjects may be related to ACTH. Alternatively, in individuals with centripetal obesity, increased conversion of cortisone to cortisol in visceral adipose tissue may result in insulin resistance and subsequent hyperinsulinemia (Figure 4). Increased aldosterone production may be a consequence of hyperinsulinemia or other adipokines released from visceral adipose tissue. Elevated arterial pressure and renin suppression may be related to aldosterone-mediated sodium retention. Since the original description of primary aldosteronism by Jerome Conn in 1955,⁵⁴ there continues to be controversy about the prevalence of this disorder, with estimates ranging from 0.5%–2% to 20%– 30% of hypertensive patients, depending on the study population and the criteria for establishing the diagnosis.⁵⁵ The present finding of relatively high aldosterone and low PRA in these hypertensive patients may reflect a forme fruste or mild variant in the spectrum of disorders considered to represent primary aldosteronism. Furthermore, in addition to lifestyle interventions designed to ameliorate centripetal obesity, the current observations suggest a potential role for mineralocorticoid and glucocorticoid antagonists in the treatment of hypertension and associated cardiovascular disease risk factors. Indeed, increasing evidence suggests an important role for spironolactone in the treatment of "resistant" hypertension.

View larger version (22K): [in this window] [in a new window]   Figure 4. Proposed mechanism for obesity-induced hypertension. FFA indicates free fatty acids.

	Acknowledgments

 
Sources of Funding

This study was supported by National Institutes of Health grants HL 07011 and 5-M01-RR-00058 (General Clinical Research Center). S.K. is supported by National Institutes of Health training grant T32 HL07792.

Disclosures

None.

Received October 3, 2006; first decision October 17, 2006; accepted November 10, 2006.

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