Association Between Aldosterone and Hypertension Among Patients With Overt and Subclinical Hypercortisolism

Kosuke Inoue; Hirofumi Horikoshi; Masao Omura; Yuya Tsurutani; Jun Saito; Tetsuo Nishikawa

J Endo Soc. 2023;7(1)

Abstract and Introduction

Abstract

Introduction: Hypertension is one of the most common clinical features of patients with overt and subclinical hypercortisolism. Although previous studies have shown the coexistence of autonomous cortisol and aldosterone secretion, it is unclear whether aldosterone plays a role in hypertension among patients with hypercortisolism. Therefore, we examined the associations of plasma aldosterone concentrations (PACs) with hypertension among patients with overt and subclinical hypercortisolism.

Methods: This single-center retrospective cohort study included patients with adrenal tumor and serum cortisol levels after 1-mg dexamethasone suppression test >1.8 μg/dL (50 nmol/L). Using multivariable regression models adjusting for baseline characteristics, we investigated the association of PACs with systolic blood pressure and postoperative improvement of hypertension after the adrenalectomy.

Results: Among 89 patients enrolled in this study (median age, 51 years), 21 showed clinical signs of Cushing syndrome (overt hypercortisolism) and 68 did not show clinical presentations (subclinical hypercortisolism). We found that higher PACs were significantly associated with elevated systolic blood pressure among patients with subclinical hypercortisolism (adjusted difference [95% CI] = +0.59 [0.19–0.99], P = 0.008) but not among those with overt hypercortisolism. Among 33 patients with subclinical hypercortisolism and hypertension who underwent adrenalectomy, the postoperative improvement of hypertension was significantly associated with higher PACs at baseline (adjusted risk difference [95% CI] = +1.45% [0.35–2.55], P = 0.01).

Conclusion: These findings indicate that aldosterone may contribute to hypertension among patients with subclinical hypercortisolism. Further multi-institutional and population-based studies are required to validate our findings and examine the clinical effectiveness of the intervention targeting aldosterone for such patients.

Introduction

Cortisol production in the adrenal gland is regulated by the hypothalamus-pituitary-adrenal (HPA) axis. Subclinical hypercortisolism is a status characterized by the alteration of HPA axis secretion without typical signs or symptoms of overt hypercortisolism (eg, moon face, truncal obesity, easy bruising, thin extremities, proximal myopathy, cutaneous purple striae).^[1,2] Although overt hypercortisolism can be detected by its clinical presentations or severe complications, it is sometimes challenging for clinicians to appropriately diagnose subclinical hypercortisolism because of the absence of such clinical presentations.^[2] The 1-mg overnight dexamethasone suppression test (1-mg DST) measures the response of the adrenal glands to ACTH through the HPA axis and therefore has been widely used for screening and diagnosis of subclinical hypercortisolism.^[1,3] The European Society of Endocrinology Guideline has defined a partial suppression of the HPA axis (ie, serum cortisol levels after 1-mg DST [F-DST] > 1.8 μg/dL [50 nmol/L]) without clinical signs of overt cortisol hypersecretion as "possible autonomous cortisol secretion" and recommended screening these patients for metabolic disorders including hypertension and type 2 diabetes mellitus to offer appropriate treatment of these comorbidities.^[4]

Hypertension is one of the most common and distinguishing clinical features in patients with subclinical hypercortisolism^[2] as well as overt hypercortisolism.^[5] Although hypertension can be triggered by excess cortisol levels,^[5,6] it is still unclear whether even slightly elevated cortisol levels among individuals with subclinical hypercortisolism contribute to the occurrence of hypertension. This raises another potential mechanism to cause hypertension such as the coexistence of hyperaldosteronism (ie, excess aldosterone that is an essential steroid hormone for sodium reabsorption, water retention, and blood pressure control).^[7] Previous studies have reported that 10% to 20% of primary aldosteronism is accompanied by cortisol-producing adenoma,^[8–10] and autonomous cortisol secretion was decreased after the resection of the aldosterone-producing adenoma (a subtype of primary aldosteronism).^[11] Furthermore, a previous mass spectrometry-based analysis revealed that cortisol secretion was frequently found in patients with primary aldosteronism.^[12] Although these studies have examined cortisol biosynthesis in primary aldosteronism,^[13] evidence about whether aldosterone plays a role in the occurrence of hypertension among people with subclinical hypercortisolism is limited.

To address this knowledge gap, we performed a cohort study examining the association between aldosterone and hypertension among patients with adrenal tumor and F-DST >1.8 μg/dL, stratified by whether patients had clinical signs of Cushing syndrome or not. We first analyzed the cross-sectional association between aldosterone and blood pressure at baseline. Then, we analyzed the longitudinal association between aldosterone at baseline and the improvement rate of hypertension after the adrenalectomy. Last, to further clarify the role of aldosterone in the regulation of blood pressure in subclinical hypercortisolism, we described the difference in aldosterone response to ACTH after the adrenalectomy according to the postoperative improvement of hypertension.

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Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Demographic characteristics and endocrine parameters of patients with overt and subclinical hypercortisolism
Patients' characteristics^a	Patients with overt hypercortisolism (N = 21)	Patients with subclinical hypercortisolism (N = 68)	P
Age, y	46 [38–52]	54 [47–63]	0.002
Female, n (%)	18 (85.7)	46 (67.7)	0.11
Body mass index, kg/m²	23.4 [20.6–26.2]	23.1 [21.7–25.1]	0.94
Systolic blood pressure, mm Hg	156 [140–182]	162 [151–191]	0.29
Diastolic blood pressure, mm Hg	98 [92–110]	100 [90–110]	0.73
Serum potassium, mEq/L^b	3.9 [3.5–4.0]	3.8 [3.6–4.0]	0.98
eGFR, mL/min/1.73 m²	86.7 [77.3–123.0]	82.1 [69.8–87.7]	0.02
Tumor size by CT scan, mm	28 [25–30]	22 [17–26]	0.001
ACTH, 8:00 AM	−^c	6.6 [2.4–11.8]	—
F, 8:00 AM	16.6 [12.5–18.8]	9.5 [7.7–12.0]	<0.001
PRA, 8:00 AM	0.7 [0.4–1.3]	0.5 [0.2–1.0]	0.10
PAC, 8:00 AM	8.3 [7.2–9.8]	9.2 [7.2–16.2]	0.09
ARR, 8:00 AM	10.0 [6.4–16.7]	21.0 [9.8–46.5]	0.02
F after DST	16.5 [14.4–18.7]	5.1 [3.2–7.5]	<0.001
Urine cortisol	220.0 [105.0–368.0]	49.5 [37.4–78.5]	<0.001
Urine aldosterone	5.7 [3.9–10.1]	7.2 [4.8–13.1]	0.16

Conversion to SI units: ACTH, pg/mL × 0.220 for pmol; F, μg/dL × 27.6 for nmol/L; PAC, ng/dL × 27.7 for pmol/L; urine aldosterone, μg/day × 2.77 for nmol/d; Urine cortisol, μg/day × 2.76 for nmol/d.
Abbreviations: ARR, aldosterone-to-renin ratio; CRH, corticotropin-releasing hormone; CT, thin-section computed tomography; DST, 1-mg dexamethasone suppression test; eGFR, estimated glomerular filtration rate; F, serum cortisol; PRA, plasma renin activity; PAC, plasma aldosterone concentration.
^aData are presented as median (interquartile range) or count (proportions) unless otherwise indicated.
^bSerum potassium levels were controlled using potassium supplement/tablets at enrollment.
^cUndetected in all cases.

Table 2. Cross-sectional association of demographic characteristics and endocrine parameters with systolic blood pressure among patients with overt and subclinical hypercortisolism
Outcome	Systolic blood pressure at baseline
Groups	Patients with overt hypercortisolism		Patients with subclinical hypercortisolism
Parameters	Adjusted coefficient (95% CI)	P	Adjusted coefficient (95% CI)	P
Age, y	+1.73 (0.17–3.30)	0.03	+0.49 (−0.13 to 1.10)	0.12
Female	−7.48 (−76.75 to 61.79)	0.81	+15.38 (−0.83 to 31.59)	0.06
Body mass index	+5.47 (−2.4 to 13.33)	0.15	+1.07 (−0.49 to 2.63)	0.17
Serum potassium	+11.29 (−23.42 to 45.99)	0.48	−9.61 (−26.38 to 7.15)	0.26
eGFR	−0.12 (−1.00 to 0.77)	0.77	−0.44 (−0.89 to 0.01)	0.06
Tumor size	−2.39 (−6.92 to 2.14)	0.26	+0.40 (−0.46 to 1.26)	0.35
F, 8:00 AM^a,b	+1.96 (−1.27 to 5.18)	0.20	+1.26 (−1.00 to 3.52)	0.27
PAC, 8:00 AM^a	−2.86 (−7.38 to 1.66)	0.18	+0.59 (0.19–0.99)	0.008

Abbreviations: DST, 1-mg dexamethasone suppression test; eGFR, estimated glomerular filtration rate; F, serum cortisol; PRA, plasma renin activity; PAC, plasma aldosterone concentration.
^aACTH and PRA were not included in the main model because they have strong correlation with F and PAC, respectively (ie, multicollinearity). The results did not change when additionally adjusting for ACTH and PRA.
^bThe results did not change when we replaced F at 8:00 AM with F after DST (Supplementary Table S2).

Table 3. Longitudinal association of demographic characteristics and endocrine parameters with hypertension improvement after the adrenalectomy among patients with subclinical hypercortisolism ^a
Outcome	Hypertension improvement after the adrenalectomy
Parameters	Adjusted risk difference (95% CI)	P
Age	+2.36% (1.08–3.64)	0.001
Sex (female)	−11.32% (−61.37 to 38.73)	0.64
Body mass index	−5.08% (−10.29 to 0.13)	0.06
Systolic blood pressure	−0.67% (−1.77 to 0.43)	0.22
Serum potassium	−0.06% (−31.84 to 31.71)	1.00
eGFR	+0.53% (−0.36 to 1.42)	0.23
Tumor size	+0.79% (−1.35 to 2.93)	0.45
F, 8:00 AM^b,c	−2.81% (−7.43 to 1.81)	0.22
PAC, 8:00 AM^b	+1.45% (0.35–2.55)	0.01

Abbreviations: eGFR, estimated glomerular filtration rate; F, serum cortisol; PRA, plasma renin activity; PAC, plasma aldosterone concentration.
^aAnalysis was not performed for patients with overt hypercortisolism because only 2/18 cases failed to show improved hypertension after the adrenalectomy.
^bACTH and PRA were not included in the main model because they have strong correlation with F and PAC, respectively (ie, multicollinearity). The results did not change when additionally adjusting for ACTH and PRA.
^cThe results did not change when we replaced F at 8:00 AM with F after DST (Supplementary Table S3).

Table 4. Aldosterone and cortisol response to ACTH a year after the adrenalectomy according to hypertension improvement status among patients with subclinical hypercortisolism ^a
Outcome: hypertension improvement status after the adrenalectomy	Improvement (+) (N = 23)	Improvement (−) (N = 10)
Parameters	Median [IQR]	Median [IQR]	P
PAC 60 min after ACTH stimulation	13.6 [10.0–16.7]	15.5 [13.7–43.1]	0.05^b
F 60 min after ACTH stimulation	16.9 [13.7–20.6]	18.5 [13.5–24.7]	0.61
PAC/F ratio 60 min after ACTH stimulation	0.70 [0.52–1.39]	1.27 [0.50–5.44]	0.26

Conversion to SI units: F, μg/dL × 27.6 for nmol/L; PAC, ng/dL × 27.7 for pmol/L.
Abbreviations: F, serum cortisol; PAC, plasma aldosterone concentration.
^aAnalysis was not performed for patients with overt hypercortisolism because only 2/18 cases failed to show improved hypertension after the adrenalectomy.
^bThe association was also observed after adjusting for baseline characteristics (eg, age, sex, body mass index, systolic blood pressure, serum potassium, estimated glomerular filtration rate, tumor size) and F 60 min after ACTH stimulation a year after the adrenalectomy (Supplementary Table S4).