Autonomous Cortisol Secretion Influences Psychopathological Symptoms in Patients With Primary Aldosteronism

Abstract

Context

Primary aldosteronism (PA) is associated with impaired quality of life (QoL). Autonomous cortisol cosecretion (ACS) is a relevant phenotype of PA, which could contribute to depression and anxiety disorders. This has not been investigated so far.

Objective

To evaluate the prevalence of depression and anxiety in PA patients according to ACS.

Methods

We performed testing for hypercortisolism and evaluated anxiety, depression and QoL by self-rating questionnaires in newly diagnosed PA patients of the German Conn’s Registry; 298 patients were reevaluated at follow-up.

Results

In the overall cohort, scores for anxiety (P < .001), depression (P < .001), and QoL (mental P = .021; physical P = .015) improved significantly at follow-up. This improvement was seen in both subgroups of patients with and without ACS, with the exception of the mental subscore in no-ACS patients. Analysis for sex differences showed that anxiety decreased significantly in females with ACS and no-ACS, whereas males with no-ACS failed to improve. Depression improved significantly in males and females with ACS (P = .004, P = 0.011 respectively), but not in those with no-ACS. Physical subscore of QoL improved significantly (P = .023) in females with ACS and mental subscore (P = .027) in males with ACS, whereas no differences were seen for the no-ACS groups.

Conclusion

Improvement in depression and anxiety scores in response to treatment of PA is more pronounced in patients with ACS in contrast to no-ACS suggesting a role of ACS in the psychopathological symptoms of patients with PA. Furthermore, we observed significant differences in depression and anxiety scores between the sexes.

Hyperaldosteronism, cortisol, SF-12, GAD-7, PHQD

Primary aldosteronism (PA) is the most common cause of secondary hypertension with prevalence up to 10% of all hypertensive patients (1-3). Aldosterone excess in PA leads to several complications, such as higher cardiovascular morbidity and mortality, including atrial fibrillation and cardiac insufficiency, higher cerebrovascular morbidity, and increased rates of renal insufficiency (4-7). Metabolic impairments such as dysregulation of insulin and impaired glucose homeostasis have been found in PA (8, 9) leading to a higher prevalence of diabetes mellitus in PA patients (7, 10).

Patients with PA are physically and mentally impaired. Anxiety and depression were initially described in case reports (11, 12) and later examined in small cohorts with less than 25 PA patients (13-15). It was shown that 52% of PA patients suffered from anxiety disorders compared with 17% of matched patients with essential hypertension and 4% of normotensive controls (14). Murck et al. (16) described in their analysis of a large sample of untreated patients with PA that 56% of male and 61% of female patients suffered from depression.

In the recent years, cortisol cosecretion in PA has been reported and discussed on the basis of several case studies or case series (17-22). Recently, we have investigated a large multicenter cohort of PA patients and revealed that glucocorticoid cosecretion is a phenotype frequently found in PA (23). In a large study of the German Conn’s Registry we showed that over 75% of newly diagnosed PA patients had a pathological response in at least 1 of the Cushing screening tests (24) confirming that autonomous cortisol cosecretion (ACS) is a common feature in large part of PA patients.

Besides effects on somatic parameters, such as impairment of the glucose homeostasis, one could suppose that ACS might also influence psychopathological symptoms. This is because in the pathophysiology of depression a dysregulation of the hypothalamic–pituitary–adrenal system seems to be relevant (25). In patients with cortisol excess, such as Cushing’s disease, quality of life (QoL) is significantly reduced (26) and remains impaired even years after long-time remission (27). Therefore, it is an urgent question to put forward if ACS in PA patients might be a factor influencing the severity of psychopathological symptoms and impairs QoL in PA patients.

In this study, we analyzed ACS and general QoL, anxiety and depression in newly diagnosed PA patients of the German Conn’s Registry. We evaluated patients at diagnosis and 1.9 ± 1.1 years after therapy initiation.

Material and Methods

Study Population

The German Conn’s Registry is a prospective multicenter registry that has investigated diagnosis, therapy, comorbidities, and the longtime outcome in patients with PA throughout Germany since 2008 (4, 28, 29). For inclusion in the registry, patients had to meet the diagnostic criteria for PA, as stated in the guidelines of the Endocrine Society (30). Patients with abnormal aldosterone to renin ratio (ARR) underwent at least 1 confirmatory test (saline infusion, fludrocortisone suppression, captopril challenge test, oral salt loading test with elevated excretion of aldosterone, and metabolites in urine). Before testing, antihypertensive medication was changed whenever possible or indicated (deduction of beta-blockers, central alpha-agonists, angiotensin-converting enzyme blocker, angiotensin receptor blocker for at least 1 week and mineralocorticoid receptor antagonists (MRAs) for at least 4 weeks prior testing), in order to prevent influences on renin–angiotensin–aldosterone system and thus test results. The diagnosis was then made at each center contemplating all clinical and laboratory findings according to the guidelines of the Endocrine Society (30). All patients gave written informed consent. The ethics committees of the University of Munich and of the participating centers approved the protocol. Data protection laws were strictly adhered to. At the time of diagnosis, patients underwent standard procedures including collection of anthropometric data and laboratory testing, which was performed immediately and decentralized.

For subtype identification of unilateral aldosterone secretion (UAS) and bilateral aldosterone secretion (BAS) adrenal imaging (magnetic resonance imaging or computed tomography) and adrenal vein sampling were performed (31). Patients who were not suitable candidates for surgery or refused surgery did not undergo adrenal vein sampling. Patients with BAS and patients who were not suitable candidates for surgery or refused surgery received medical therapy with MRAs. Patients with UAS who were eligible for surgery and agreed to the surgical procedure underwent unilateral adrenalectomy (ADX).

By March 1, 2020, 1240 patients with PA were enrolled in the registry in 7 endocrine centers. For the present study, we included all PA patients who underwent a testing for hypercortisolism, including 1 mg dexamethasone suppression test (DST), 24-hour urinary free cortisol (UFC), and/or late-night salivary cortisol (LNSC) at baseline visit. Patients with missing data for aldosterone, renin, potassium, or blood pressure were excluded. The study population consists of 503 patients that were recruited in 2 centers (Munich, Berlin) of the German Conn’s Registry (Fig. 1).

Figure 1.

Flow diagram demonstrating selection of patients with primary aldosteronism from the German Conn’s Registry. Dexamethasone suppression test (DST), 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC).

Definitions and Laboratory Measurements

ACS was assumed as an indicator for hypercortisolism when at least 1 of the 3 screening tests (DST, LNSC, or UFC) was above normal reference values (≥51 nmol/L; >1.45 ng/mL; >83 µg/24 hours, respectively). Reference values were similar to those suggested by the Endocrine Society Practice Guideline “Diagnosis of Cushing’s syndrome” (32). We used a solid-phase antigen-linked technique (cortisol; Liaison/DiaSorin, Saluggia, Italy) for serum cortisol measurement (29); a chemiluminescence immunoassay for urinary cortisol measurement (Siemens ADVIA Centaur) with within- and between-assay coefficients of variation <7%; and a luminescence immunoassay (IBL, Hamburg, Germany) for salivary cortisol determination with within- and between-assay coefficients of variation <9% and 6% (33).

Blood pressure (BP) was measured up to 3 times on each arm after at least 5 minutes of resting with standard sphygmomanometers.

Questionnaires

We assessed QoL with the 12-item Short-Form Health Survey (SF-12) (34), a reliable synopsis of the longer SF-36 questionnaire. This questionnaire scale is able to discriminate between physical and mental impairment of QoL (35) and asks for the subjective perception of health, affection in the everyday life and pain or difficulties with social components. Higher SF-12 scores indicate less physical and mental complaints. The average score of the German population are 53.3 for males, and 51.3 for females for mental subscore; and 50.2 for males and 47.9 for females for the physical subscore (36).

For assessment of depression we employed the Patient Health Questionnaire (PHQD), using the short form, containing 9 questions to discover depression and depressive symptoms (37). Depending on how often specific depressive symptoms are experienced, the more points (0-3) are added up in the analysis of the questionnaire resulting in higher scores. Mood, sleep, eating, moving, or concentration problems as well as thoughts regarding self-harming intentions and suicide are addressed. A score 5-9 points indicates mild, 10-14 points middle, and >15 points severe depression.

For assessing anxiety, we used the well approved 7-item Generalized Anxiety Disorder Scale (GAD-7) (38, 39). The questionnaire asks for anxiety within general behavior and events, issues with coping abilities and other symptoms like restlessness or impaired concentration. A score of 5-9 points indicates mild, 10-14 points middle, and >15 points severe anxiety.

Questionnaires that were incompletely answered or had missing values were excluded from further analysis. Each of the questionnaires was investigated separately with another subdivision into women and men.

We recorded the psychiatric medication in all patients, comprising of agomelatine, alprazolam, amitriptyline, aripiprazole, carbamazepine, citalopram, diazepam, duloxetine, escitalopram, fluoxetine, fluspirilene, lamotrigine, lorazepam, melperone, mirtazapine, modafinil, nortriptyline, opipramol, pregabalin, prothipendyl, quetiapine, sertraline, sulpiride, trimipramine, and venlafaxine.

Of the 503 patients who had a test for ACS, 346 patients answered at least 1 of the 3 questionnaires at baseline (Fig. 1). A follow-up visit was performed in 86% of these patients (n = 298) (Fig. 1).

Statistical Analysis

IBM SPSS Statistics 26 was used for statistical analysis. Values are expressed as mean ± SD if results were distributed normally, otherwise numbers are displayed as median and 25th to 75th percentile. Categorical data is presented in percentage and absolute numbers. Normal distribution was assessed by using Shapiro-Wilk-Test.

P < .05 was considered to be statistically significant. We performed paired t-test or Wilcoxon signed rank test for comparison between baseline and follow-up of continuous data and McNemar test for categorical data. For subtyping ACS and Non-ACS groups, differences were determined by unpaired t-test, Mann–Whitney U test or χ  ² for categorical numbers. When a t-test was used for analyzing, numbers were distributed normally in both groups.

Results

Cohort of PA Patients (n = 298) With at Least 1 Test for Hypercortisolism and at Least 1 Questionnaire Filled Out at Baseline and With a Follow-up Visit

Baseline and follow-up data (after 1.9 ± 1.1 years) were analyzed in the consecutive cohort of 298 PA patients (Table 1). The QoL assessed by SF-12 questionnaire was lower in PA patients at baseline compared to the German reference population (physical subscore 45.9 ± 10.1 vs 49.6 ± 8.7; mental subscore 47.7 ± 11.3 vs 52.3 ± 8.0) (40). The patients demonstrated the typical clinical and biochemical improvements with therapy (Table 1). QoL showed significant improvement in mental and physical scores at follow-up (mental P = .021; physical P = .015) (Table 1). Also, anxiety scores assessed by GAD-7 and depression scores assessed by PHQ-D decreased significantly (P < .001, P < .001, respectively) (Table 1). Analysis regarding the type of PA therapy revealed significant higher GAD-7 scores in patients with MRA than ADX therapy at follow-up (4.9 ± 4.4 vs 3.7 ± 4.4; P = .017), whereas no differences were present in PHQ-D scores (P = .08). PA patients with MRA therapy scored worse at follow-up in the mental subscore of the SF-12 questionnaire compared with PA patients with ADX (48.2 ± 10.6 vs. 53.3 ± 8.3; P = .001), whereas no differences could be found for the physical subscore.

Table 1.

Characteristics of patients with primary aldosteronism (PA) patients at baseline and at follow-up after 1.9 + 1.1 years, and who filled out at least 1 of 3 questionnaires (SF-12, GAD-7, PHQD)

Variable	Baseline (n = 298)	Follow-Up (n = 298)	P Value
male n (N%)	174 (58.4%)	174 (58.4%)	—
Age (years)	52.0 ± 10.9	53.9 ± 11.1	—
BMI (kg/m2)	27.6 ± 4.8 (26.8; 6.58)	28.1 ± 4.8 (27.1; 6.3)	.336
Systolic BP (mmHg)	152 ± 20 (150; 26) n = 276	135 ± 17 (133; 20) n = 290	.000
Diastolic BP (mmHg)	98 ± 12 (94; 16) n = 276	88 ± 11 (87; 13) n = 290	.000
WHR female	0.9 ± 0.1 (0.9; 0.1) n = 112	0.9 ± 0.1 (0.9; 0.1) n = 88	.254
WHR male	1.0 ± 0.1 (1.0; 0.1) n = 155	1.0 ± 0.1 (1.0; 0.1) n = 123	.723
Potassium (mmol/L	3.6 ± 0.5	4.4 ± 0.4 (4.4; 0.5) n = 294	.000
HbA1c (%)	5.4 ± 0.6 (5.3; 0.6) n = 293	5.6 ± 0.7 (5.5; 0.6) n = 291	.000
HDL-cholesterol (mg/dl)	59 ± 17 (58; 24) n = 297	55 ± 16 (53; 23) n = 291	.000
LDL-cholesterol (mg/dl)	117 ± 33 n = 296	113 ± 33 n = 287	.018
Triglycerides (mg/dl)	111 ± 75 (95; 67) n = 297	136 ± 101 (113; 80) n = 292	.000
Cholesterol (mg/dl)	194 ± 35 n = 297	189 ± 39 (188; 49) n = 292	.111
GFR (mL/min)	87 ± 63 (81; 24) n = 297	70 ± 17 (69; 21) n = 294	.000
PAC (ng/L)	225 ± 235 (165; 132) n = 297	224 ± 214 (176; 192) n = 291	.127
PRC (ng/L)	6.9 ± 12.6 (3.4; 5.5) n = 297	38.7 ± 79.3 (14.9; 28.2) n = 291	.000
ARR	67.8 ± 92.4 (43.3; 58) n = 297	21.7 ± 39.3 (12.4; 16) n = 291	.000
Depression (%)	75 (25.2%)	82 (27.5%)	.065
Anxiety (%)	32 (10.7%)	37 (12.4%)	.227
On psychiatric medication (%)	23 (7.7%)	28 (9.4%)	.332
physical subscore (SF-12)	45.9 ± 10.1 (49; 15)	47.5 ± 9.6 (51; 13.5)	.021
mental subscore (SF-12)	47.7 ± 11.3 (52; 19) n = 279	50.0 ± 10.2 (54; 13) n = 213	.015
Anxiety score (GAD-7)	5.4 ± 4.4 (4; 6) n = 274	4.5 ± 4.5 (3.5; 5) n = 214	.000
Depression score (PHQD)	6.9 ± 6.0 (5; 8.3) n = 270	5.6 ± 5.6 (4; 6) n = 213	.000
Major depression	21 (7.0%)	17 (5.7%)	1.0
other depression	30 (10.1%)	7 (2.3%)	.004
Panic syndrome (PHQD)	7 (2.3)	2 (0.7%)	.219
Lateralization (UAS/BAS/unknown)	128 (40.6%)/121 (43%)/49 (16.4%)	—	—
Therapy (ADX/MRA/other)	—	93 (31.2%)/183 (61.4%)/22 (7.4%)	—

Anxiety and depression as pre-existing diagnosis; GAD-7 score: a higher score implies more anxiety symptoms, cut-off ≥ 5; PHQD score: a higher score implies more depression symptoms, cut-off ≥ 5; SF-12 score: a higher score means less physical and mental complaints. Data are displayed as mean ± SD. Additionally, for continuous variables without normal distribution the median and the interquartile range are given in brackets.

Abbreviations: ADX, adrenalectomy; ARR, aldosterone—renin ratio; BAS, bilateral aldosterone secretion; BMI, body mass index; BP, blood pressure; GFR, glomerular filtration rate; MRA, mineralocorticoid receptor antagonist; PAC, plasma aldosterone concentration; PRC, plasma renin concentration; UAS, unilateral aldosterone secretion; WHR, waist to hip ratio (analyzed separately for men and women due to different optimal values in males and females).

Cohort of PA Patients (n = 205) with Dexamethasone Suppression Test and at Least 1 Questionnaire Filled Out at Baseline and With a Follow-up Visit

Because the DST shows the highest sensitivity for detecting an ACS (41), further analysis was performed using only the DST data resulting in 46 PA patients with ACS (22.4%) and 159 with no-ACS (77.6%). Comparison between baseline and follow up visit is presented in Table 2. Patients with ACS who underwent medical therapy received no additional medications aimed at correcting glucocorticoid excess. Variance analysis indicated significant improvement in systolic and diastolic BP, renin levels, ARR and potassium in both groups (ACS and no-ACS), together with worsening of HbA1c levels, triglycerides and the glomerular filtration rate in both groups (Table 2).

Table 2.

Characteristics of patients with primary aldosteronism (PA) patients with autonomous cortisol secretion (ACS = pathologic dexamethasone suppression test [DST]) and without ACS (no ACS = normal DST) at baseline and at follow-up after 1.9 + 1.1 years

Variable	ACS baseline (n = 46)	ACS follow-up (n = 46)	P value	No-ACS baseline (n = 159)	No-ACS Follow-Up (n = 159)	P value	P value (ACS vs no-ACS at follow-up
Age (years)	55.6 ± 10.4	57.5 ± 10.7	.000	51.9 ± 9.9	53.9 ± 10.0	.000	.056
BMI (kg/m2)	27.4 ± 4.9 (26.5; 5.8)	28.1 ± 4.4	.544	27.7 ± 5.0 (26.9; 6.7)	28.1 ± 4.7 (27.1; 6.0)	.505	.803
Systolic BP (mmHg)	156 ± 21 (154; 22) n = 45	137 ± 14 n = 45	.000	150 ± 19 n = 146	134 ± 14 n = 156	.000	.179
Diastolic BP (mmHg)	95 ± 13 n = 45	88 ± 11 n = 45	.001	94 ± 11 n = 146	88 ± 10 n = 156	.000	.581
WHR female (n = 85/205)	0.93 ± 0.27 (0.88; 0.07) n = 16	O.88 ± 0.07 n = 10	.799	0.85 ± 0.08 n = 63	0.85 ± 0.10 (0.86; 0.11) n = 48	.467	.387
WHR male (n = 120/205)	0.99 ± 0.07 n = 29	1.00 ± 0.07 n = 22	.446	0.98 ± 0.08 n = 78	0.98 ± 0.07 n = 62	.357	.548
Potassium (mmol/L	3.5 ± 0.5	4.4 ± 0.4 n = 45	.000	3.7 ± 0.4	4.4 ± 0.4 (4.4; 0.4) n = 158	.000	.842
HbA1c (%)	5.4 ± 0.6 (5.30; 0.63)	5.6 ± 0.5 n = 45	.000	5.4 ± 0.5 (5.3; 0.5) n = 156	5.7 ± 0.8 (5.5; 0.6) n = 155	.000	.756
HDL-cholesterol (mg/dL)	58 ± 17 (58; 23) n = 45	56 ± 15 (53; 27) n = 44	.127	60 ± 17 (59; 25)	56 ± 16 (53; 3) n = 156	.000	.840
LDL-cholesterol (mg/dL)	121 ± 33 n = 45	119 ± 35 n = 44	.625	114 ± 33 n = 158	109 ± 32 n = 153	.068	.031
Triglycerides (mg/dL)	101 ± 50 (87; 74) n = 45	130 ± 71 (119; 85) n = 44	.002	110 ± 84 (94; 64)	132 ± 105 (111. 72) n = 157	.000	.835
Cholesterol (mg/dL)	196 ± 36 n = 45	192 ± 48 (196; 45) n = 44	.828	192 ± 34	187 ± 35 n = 157	.121	.431
GFR (mL/min	78 ± 18	66 ± 17n = 45	.000	87 ± 68 (79; 22) n = 158	72 ± 17 (70; 18) n = 158	.000	.075
PAC (ng/L)	203 ± 118 (165; 125)	273 ± 223 (227; 170 n = 45	.070	234 ± 266 (168; 139) n = 158	209 ± 204 (158; 189) n = 155	.624	.024
PRC (ng/L)	6.0 ± 5.4 (4.2; 5.1)	57 ± 145 (13; 34) n = 45	.000	6.4 ± 10.4 (3.2; 5.2) n = 158	33 ± 57 (15; 29) n = 155	.000	.354
ARR	55.3 ± 55.4 (38.9; 43.0)	28.3 ± 35.8 (17.1; 23.8) n = 45	.001	75.6 ± 110 (47.1; 59.9) n = 158	19.1 ± 34.6 (12.1; 14.1) n = 155	.000	.016
Cortisol after DST (µg/dL)	3.9 ± 2.6 (3.0; 1.9)	—	—	1.2 ± 0.3 (1.2; 0.5)	—	—	—
Depression (%)	12 (26.1%)	12 (28.3%)	1.000	37 (23.3%)	42 (26.4%)	.125	.618
Anxiety (%)	6 (13.0%)	6 (13.0%)	1.000	8 (5.0%)	13 (8.2%)	.063	.248
On psychiatric medication (%)	7 (15.2%)	6 (13.0%)	1.000	8 (5.0%)	10 (6.3%)	.754	.114
SF-12 (physical/mental subscore)	45.4 ± 11.6 (50.0; 17.0)/46.4 ± 11.9 (52.0; 20.5) n = 45	48.1 ± 10.0 (52.0; 12.0)/51.8 ± 8.4 (55.0; 9.3) n = 38	.050/.012	45.6 ± 9.5 (47.0; 14.0)/48.5 ± 11.4 (53.0; 16.0) n = 151	47.0 ± 9.9 (51.0; 16.0)/ 49.3 ± 10.7 (54.0; 13.0) n = 111	.056/.796	.411/.368
Anxiety (GAD-7) score	5.5 ± 4.3 (5.0; 6.0) n = 43	3.9 ± 2.9 (3.0; 4.5) n = 37	.001	5.2 ± 4.2 (4.0; 6.0) n = 147	4.4 ± 4.3 (4.0; 5.0) n = 116	.021	.976
Depression score (PHQD)	7.4 ± 6.6 (6.0; 9.3) n = 42	5.0 ± 5.0 (4.0; 5.0) n = 37	.001	6.8 ± 5.9 (5.0; 9.0) n = 144	5.5 ± 5.4 (4.0; 6.0) n = 116	.018	.821
Major depression/Other depression/Panic syndrome (PHQD)	3 (7.0%)/4 (9.3%)/2 (4.7%) n = 43	2 (5.3%)/1 (2.6%)/0 n = 38	1.000/.375/.500	9 (6.2%)/17 (11.6%)/3 (2.1%) n = 146	7 (6.0%)/4 (3.4%)/1 (0.9%) n = 116	1.000/.065/.500	1.000/1.000/1.000
Lateralization (UAS/BAS/ unknown)	18 (39.1%)/19 (41.3%)/ 9 (19.6%)	—	—	73 (45.9%)/69 (43.4%)/17 (10.7%)	—	—	—
Therapy (ADX/MRA/other)	—	10 (21.7%)/31 (67.4%)/5 (10.9%)	—	—	56 (35.2%) /92 (57.9%) /11 (6.9%)	—	—

Anxiety and depression as pre-existing diagnosis; GAD-7 score: a higher score implies more anxiety symptoms, cut-off ≥ 5; PHQD score: a higher score implies more depression symptoms, cut-off ≥ 5; SF-12 score: a higher score means less physical and mental complaints. Data are displayed as mean ± SD. Additionally, for continuous variables without normal distribution the median and the interquartile range are given in brackets.

Abbreviations: ADX, adrenalectomy; ARR, aldosterone renin ratio; BMI, body mass index; BP, blood pressure; BAS, bilateral aldosterone secretion; GFR, glomerular filtration rate; PAC, plasma aldosterone concentration; PRC, plasma renin concentration; MRA, mineralocorticoid receptor antagonist; UAS, unilateral aldosterone secretion; WHR, waist to hip ratio (analyzed separately for men and women due to different optimal values in males and females).

The QoL improved significantly for both subscores (physical and mental) in ACS patients, whereas only the physical subscore improved in no-ACS patients at follow-up (Table 2). Anxiety scores and depression scores improved significantly in both ACS and no-ACS patients after therapy initiation (Table 2).

Gender Differences

Because gender differences are known in depression and anxiety (42), the cohort of 205 patients with a DST (Table 2) was further analyzed separately for women and men.

PHQ-D scores improved significantly (P = .011) in women with ACS at follow-up, but not in those of no-ACS (Fig. 2A). However, the improved depression scores in ACS women at follow-up reached similar levels to those in no-ACS women at baseline and at follow-up. Nevertheless, psychiatric medication increased more than 2-fold in no-ACS women from baseline to follow-up (Fig. 2A). A similar pattern was found in men, with significant (P = .004) improvement of depression symptoms in men with ACS at follow-up, but not in men with no-ACS (Fig. 2B).

Figure 2.

Depression symptoms analyzed with the PHQD questionnaire in female (A) and male (B) patients with primary aldosteronism at baseline and after therapy initiation (follow-up) depending on autonomous cortisol co-secretion (ACS) or no-ACS at baseline. A higher score implies more depression symptoms. The cut-off for diagnosis of a depression disorder is ≥5. Data are displayed as mean ± SD. On the right side of the each figure the percentage of patients on psychiatric medication is shown.

Significant improvements regarding anxiety symptoms evaluated by GAD-7 were found in women both with ACS (P = .033) and with no-ACS (P = .006) at follow-up (Fig. 3A). However, in the latter group, the use of psychiatric medication increased nearly 3-fold compared with baseline (Fig. 3A). In men, only those with ACS showed a significant (P = .02) improvement of anxiety symptoms at follow-up, whereas those with no-ACS showed no improvement (Fig. 3B). Interestingly, despite no change in anxiety at follow-up, men with no-ACS had a nearly 3-fold increase in psychiatric medication (Fig. 3B).

Figure 3.

Anxiety symptoms analyzed with the GAD-7 questionnaire in female (A) and male (B) patients with primary aldosteronism at baseline and after therapy initiation (follow-up) depending on autonomous cortisol co-secretion (ACS) or no-ACS at baseline. A higher score implies more anxiety symptoms. The cut-off for diagnosis of an anxiety disorder is ≥5. Data are displayed as mean ± SD. On the right side of the each figure the percentage of patients on psychiatric medication is shown.

Analysis of QoL data from SF-12 questionnaires showed significant (P = .023) improved scores for the physical values in ACS women at follow-up (Fig. 4A) and for mental values in ACS men at follow-up (P = .027) (Fig. 4B). Neither no-ACS women nor men showed significant improvements in SF-12 scores at follow-up.

Figure 4.

Quality of life analyzed with the SF-12 questionnaire with physical and mental subscores in female (A) and male (B) patients with primary aldosteronism at baseline and after therapy initiation (follow-up) depending on autonomous cortisol co-secretion (ACS) or no-ACS at baseline. A higher score means less physical and mental complaints. The average score of the German population is shown as a dotted line (dependent on sex and subscores). Data are displayed as mean ± SD.

Separate analysis regarding the type of PA therapy in women and men revealed no significant differences between MRA and ADX in mental subscore of SF-12, in GAD-7 and in PHQ-D. Men with ADX scored worse than men on MRA therapy in the physical subscore of SF-12 (42.4 ± 12.1 vs 52.1 ± 5.5, P = .03).

Discussion

Our study showed that improvement of anxiety, depression and QoL after therapy was more pronounced in PA patients with ACS than with no-ACS. This supports the view that ACS is an important subtype in PA, not only leading to a higher risk of diabetes mellitus (33) and an additional impact on cardiac remodeling (43), but also affecting mental aspects of PA patients. Furthermore, our study reveals significant differences in depression and anxiety between the sexes.

Quality of Life

Somatic as well as mental symptoms confluence in the general wellbeing of an individual and its expectations for a QoL. Using the SF-36 as tool for investigating QoL, Sukor et al. (15), studied 22 PA patients at baseline and 3 and 6 months after ADX. At baseline PA patients showed lower scores than the Australian reference population, and the scores improved after therapy initiation. In a German cohort, PA patients revealed also significantly reduced QoL scores compared with the normal population (36). A larger study (n = 184) confirmed that QoL (assessed by SF-36 and EQ-5D) was lower in patients with PA than the general population in The Netherlands and Poland, especially in women. The authors showed that treatment of PA resulted in significant improvement of QoL and that the improvement after 1 year was higher after ADX than with MRA treatment (44). In PA patients who underwent ADX QoL was restored to the level of the general population (44). Our study confirms those previous findings in PA patients that QoL is reduced at diagnosis and improves with therapy. However, we discovered that QoL improved significantly with both subscores (physical and mental) of QoL in PA patients with ACS, whereas only the physical subscore improved in PA patients with no-ACS at follow-up. This suggests that ACS is an important risk subtype of PA but bears the potential of enhanced improvement through PA therapy initiation.

Possible mechanisms for reduced QoL in PA patients might be hypokalemia (associated with muscle weakness, cramps, paresthesia, palpitations, constipation, polyuria, and nocturia), poorly controlled hypertension, and side effects from antihypertensive medications (15). Furthermore, an incomplete blockade of the mineralocorticoid receptor (MR) might explain differences in QoL between the ADX and MRA groups (44). In addition, side effects of the used antihypertensive medication might cause a worse scoring under MRA therapy than after ADX. In particular, spironolactone is associated with numerous side effects such as gynecomastia, changes in libido, and erectile dysfunction in men, and menstrual irregularities, changes in libido, and breast tenderness and enlargement in women. Furthermore, MR blockade seems to impair some cognitive domains such as selective attention and memory; however, it is possible that in conditions with mineralocorticoid excess blocking MR rather than stimulation of MR exerts beneficial effects on cognition (45). In contrast to patients with PA including those with ACS, patients with Cushing’s disease present with a massive impairment of QoL (26), which remains impaired even after long-term biochemical cure in patients with Cushing’s disease (27). This indicates that the amount of cortisol excess as well as the duration of cortisol excess might be a further relevant factor influencing QoL.

Anxiety

The only study investigating anxiety in PA patients so far is a cross-sectional analysis by Apostolopoulou et al. (46), which demonstrated that patients with treated PA still show higher mean scores for depression and anxiety than the normal population. The authors did not find significant differences in anxiety levels depending on the type of PA therapy (ADX or MRA) (46). In the present study we showed that PA patients had more anxiety symptoms than the normal population, however, importantly patients improved significantly at follow-up. GAD-7 scores were worse in patients with MRA therapy compared with ADX in our cohort supporting the hypothesis of a possible negative effect of spironolactone. Interestingly, the overall improvement at follow-up was even more pronounced in PA patients with ACS than with no-ACS.

One might only speculate about the underlying possible mechanisms for these observations. It was shown that administration of aldosterone in rats caused anxiety-like behavior (47), whereas administration of eplerenone, a MRA, resulted in anxiolytic effects (48). This supports the idea that the brain MR, which is not protected by the 11β-hydroxysteroid dehydrogenase type 2 in most brain areas and therefore occupied by cortisol (49), seems to play an important role in cognitive and emotional function in health and disease (45). The finding in our study is therefore interesting that ACS is an additional factor that influences anxiety in PA patients.

Depression

Up to now, the study by Apostolopoulou et al. (46) was the only study investigating depression in PA patients. It showed significant more depression symptoms in PA patients than the German reference population indicating overall a mild form of depression. In the present study we confirm that PA patients present with more depression symptoms than the normal population; however, patients improved significantly at follow-up. Interestingly, the improvement at follow-up was even more pronounced in PA patients with ACS than with no-ACS. Especially, men with PA and no-ACS remained on an unchanged high level of depression. The type of PA therapy (MRA or ADX) did not play a role in depression, confirming results from the study by Apostolopoulou et al. (46).

In psychiatric studies dysregulation of the hypothalamus–pituitary–adrenocortical system leading to hypercortisolism and a decreased feedback mechanism have been identified to play a major role in the pathogenesis of major depression (50). They showed that aldosterone and MR activation were worsening factors in regard to severity and outcome of depression (51, 52). On the other hand, it was shown that the MR agonist fludrocortisone as an add-on to escitalopram accelerated treatment response in depressed patients (53). Therefore, one might speculate that ACS in PA patients, as shown in this study, might alter the occupancy of brain MR and GR in a sex-specific way and thus leading to more depressive and anxiety symptoms especially in women, but also to a more favorable response after initiation of specific treatment.

Gender Differences

Our study reveals significant differences in depression, anxiety and QoL between the sexes. The sex differences were also seen within the ACS phenotype (as shown in the physical subscale in women and the mental subscore in men). There are hints of a sexually different activation of MR in fear memory of mice (54). Therefore, data from this study might point to a sexually dimorphic influence of cortisol and aldosterone in patients with PA.

In addition, it is interesting that women and men with ACS had a higher rate of psychiatric medication than their no-ACS counterparts. One possible factor could be that especially in women high scores for anxiety and depression may lead to a specific treatment. Also, the male ACS phenotype seems to show noticeable psychopathological symptoms that induced an antidepressive treatment in those patients. We cannot rule out that these patients would score even worse without medication. The percentage of psychiatric medication from baseline to follow-up did not change in ACS women, but the percentage of women with no-ACS taking psychiatric medication nearly tripled from baseline to follow-up. It might be that the improvement in no-ACS women seen at follow-up might not be solely due to PA therapy, but also by increased prescribed psychiatric medication. The latter might be caused by a closer medical check-up during study participation.

A limitation of the present study is that only a fraction of patients in the registry had sufficient data available and could be included in the study. Furthermore, we did not re-evaluate autonomous cortisol cosecretion after therapy initiation at the time of the follow-up visit. Therefore, we cannot rule out a persistent ACS in our patients.

We observed an increase in HbA1c levels after therapy initiation at the time of follow-up visit. We do not have a pathophysiological explanation for this finding and, therefore, could only speculate on the underlying influences such as increased age, unhealthy diet, physical inactivity or stress.

The strengths of our study are that the German Conn’s Registry, collects data in a prospective and standardized manner. We can present a large-sized and well-characterized cohort with follow-up investigations.

In conclusion, we showed that ACS is an important and common subtype in PA affecting mental aspects of PA patients. Improvement of depression and anxiety after treatment of PA was more pronounced in patients with ACS than with no-ACS suggesting a role of ACS in the psychopathological symptoms of patients with PA. Furthermore, our study reveals significant differences in depression and anxiety between the sexes in PA patients.

Abbreviations

 
• ACS

  autonomous cortisol cosecretion

 
• ADX

  unilateral adrenalectomy

 
• ARR

  aldosterone to renin ratio

 
• BAS

  bilateral aldosterone secretion

 
• BP

  blood pressure

 
• DST

  dexamethasone suppression test

 
• GAD-7

  7-item Generalized Anxiety Disorder Scale

 
• LNSC

  late-night salivary cortisol

 
• MR

  mineralocorticoid receptor

 
• MRA

  mineralocorticoid receptor antagonist

 
• PA

  primary aldosteronism

 
• PHQD

  Patient Health Questionnaire

 
• QoL

  quality of life

 
• SF-12

  12-item Short-Form Health Survey

 
• UAS

  unilateral aldosterone secretion

 
• UFC

  urinary free cortisol

Acknowledgments

We are indebted to Judith Gerards for the help with the patients’ files. The German Conn’s Registry is supported by the Section “Nebenniere, Steroide, Hypertonie” of the German Endocrine Society (DGE, Deutsche Gesellschaft für Endokrinologie).

Financial Support: This work was supported by the Else Kröner-Fresenius Stiftung in support of the German Conn’s Registry-Else-Kröner Hyperaldosteronism Registry (2013_A182, 2015_A171 and 2019_A104 to M.R.), the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No 694913 to M.R.), by the Deutsche Forschungsgemeinschaft (DFG) (within the CRC/Transregio 205/1 “The Adrenal: Central Relay in Health and Disease” to C.A., D.H., and M.R.).

Additional Information

Disclosures: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Data Availability

Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.