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Abstract

Objective:

The objective of this article is to measure serum dehydroepiandrosterone sulfate (DHEA-S) concentration in both genders with primary aldosteronism (PA).

Materials and methods:

The study enrolled 78 subjects with normal controls, 46 subjects with essential hypertension and 85 subjects with PA from October 2007 to June 2011. Subjects with PA were divided into three subtype groups: aldosterone-producing adenoma (APA), bilateral idiopathic hyperplasia (IHA) and PA with negative imaging findings.

Results:

Women with PA (n = 49) had lower serum DHEA-S levels compared with normal controls and subjects with essential hypertension (p < 0.01). In subtype analysis, only female APAs had lower serum DHEA-S levels (p < 0.01 compared with normal controls, p < 0.01 compared with subjects with essential hypertension). In APA, a significant correlation between tumor size and serum DHEA-S was found in women (p < 0.01).

Conclusion:

Our data suggested that serum DHEA-S levels are lower in women with PA. In subtype groups, only women with APA had lower serum DHEA-S. There was no significant difference between subjects with bilateral essential hyperplasia, PA with negative imaging findings, normal controls and subjects with essential hypertension in both genders. The serum DHEA-S level is negatively correlated with the size of APA.

Keywords

Adrenal androgen aldosterone-producing adenoma dehydroepiandrosterone sulfate primary aldosteronism TAIPAI

Introduction

Primary aldosteronism (PA), characterized by autonomous overproduction of aldosterone and suppression of plasma renin activity (PRA), is the most common curable endocrine cause of secondary arterial hypertension.¹ The prevalence of PA is around 4.3%–11.2% in hypertensive patients.^1,2 Patients with PA had higher risk for cardiovascular disease, metabolic dysfunction and renal dysfunction.^3–6

Dehydroepiandrosterone (DHEA) and its sulfated derivative, dehydroepiandrosterone sulfate (DHEA-S), are the most abundant steroids produced by adrenal glands in primates.⁷ Both are stimulated by adrenocorticotropic hormone (ACTH) and are secreted from zona reticularis.⁸ DHEA/DHEA-S are precursors for sex hormones and are implicated to be involved in several aging processes, such as metabolic disease, endothelial dysfunction, atherosclerosis, cognitive dysfunction, decreased muscle strength, and several immune disorders including asthma.^9–14 The serum concentration of DHEA/DHEA-S reaches a peak at age 20 to 30 years, and then gradually decreases.¹⁵ Serum DHEA-S concentrations can reflect the active DHEA pool in most conditions.¹⁶ Clinically, serum DHEA-S concentration is more frequently measured as it has a longer half-life and is more stable than DHEA.¹⁷

In subjects with cortisol-producing adrenal adenomas, serum DHEA-S concentrations are lower, which may result from suppressed ACTH.^18–23 In subjects with adrenal malignancies such as androgen-secreting carcinomas, serum DHEA-S concentrations are higher.²³ However, serum DHEA-S concentration in subjects with PA remains unclear. Recently, cytochrome P-450 carbon 17α-hydroxylase/17,20-lyse (CYP17), an enzyme involved in DHEA/DHEA-S syntheses, has been shown to be down-regulated in subjects with PA.²⁴ The mRNA and protein expression of CYP17 is even lower in subjects with APA than with nodular hyperplasia. It is possible that subjects with PA may have lower serum DHEA-S concentrations.

In the present study, we investigated the serum DHEA-S in subjects with PA including APA and bilateral idiopathic hyperplasia (IHA), as well as in subjects with essential hypertension and normal controls. We explored the determinant of serum DHEA-S concentrations in these subjects and studied whether there were any gender differences.

Materials and methods

Subjects

This study enrolled 85 patients (36 men and 49 women) diagnosed with PA from October 2007 to June 2011. All patients were registered in the Taiwan Primary Aldosteronism Investigation (TAIPAI) database.²⁵ All subjects with PA were confirmed with evidence of autonomous excess of aldosterone production (aldosterone renin ratio > 35) and saline infusion suppression tests (post-saline loading plasma aldosterone concentration (PAC) > 10 ng/dl).^26,27 In addition, another 46 patients (28 and 18 women) with essential hypertension and 78 healthy people (37 men and 41 women) were enrolled as control groups. Essential hypertension was diagnosed by exclusion according to clinical and biochemical investigations. The healthy people were recruited in our health examination center without any major diseases. The study was approved by the institutional review board of National Taiwan University Hospital, Taipei, Taiwan (No. 201103070RC and No. 201110008RB). All subjects gave informed consent.

Diagnosis of APA, IHA and PA with negative imaging findings

Among the 85 patients with PA, 44 patients received unilateral adrenalectomy. APA was defined by evidence of adenoma at computed tomography (CT) scan and pathology-proved adenoma. IHA was defined on the basis of: 1) bilateral adrenal hyperplasia shown in CT scan or magnetic resonance imaging (MRI), 2) bilateral adrenal lesions on ¹³¹I NP-59 scan, 3) no lateralization after bilateral adrenal venous sampling (lateralization was defined by a greater than four-fold difference in the aldosterone/cortisol ratio between bilateral adrenal veins) or 4) pathology reports if the patient received an operation. Nine of the PA patients who had no imaging abnormality and did not receive adrenal venous sampling and operation were defined as PA with negative imaging findings.

Measurements of serum total cholesterol, high-density lipoprotein (HDL) cholesterol, potassium, creatinine, PAC, PRA, DHEA-S concentrations and tumor sizes of adenomas

Serum total cholesterol, HDL cholesterol, potassium, and creatinine were measured by an immunochemistry analyzer (Beckman AU 2700, Beckman Coulter, CA, USA). PAC was measured by commercial radioimmunoassay kits (Aldosterone Maia Kit; Adaltis Italia, Bologna, Italy). PRA was measured as the generation of angiotensin-I in vitro by commercial radioimmunoassay kits (Cisbio, Bedford, MA). Serum DHEA-S was measured by competitive chemiluminescent enzyme immunoassay (Immulite/Immulite 1000, Siemens, Berlin, Germany). For DHEA-S, intra-assay coefficients of variation ranged from 6.8 to 9.5%, and inter-assay coefficients of variation ranged from 8.1% to 15%. For subjects with APA, we measured the tumor sizes in CT or MRI.

Statistical analysis

Data were expressed as mean ± standard deviation (SD) in metric and S.I. units except aldosterone-renin ratio (ARR). ARR was summarized as median and interquartile ranges. Serum DHEA-S, total cholesterol, HDL cholesterol, PRA, PAC, ARR, potassium, creatinine and tumor size were logarithmically transformed to approximate normal distribution in the analyses. Analysis of variance (ANOVA) tests, Student’s t tests, and Pearson’s chi square tests were used to identify the differences in various demographic and metabolic characteristics among different groups. Bonferroni’s correction was applied for post-hoc comparison. Age-adjusted DHEA-S concentrations were based on statistic models composed of age and group. Linear predictions in each group were calculated using mean value of age. Pearson’s correlation coefficients and linear regression models were applied to analyze the relationship between serum DHEA-S and adenoma size. A two-tailed p value below 0.05 was considered significant. Stata/SE 11.0 for Windows (StataCorp LP, Texas) was used for statistical analyses.

Results

A total of 209 subjects, including 101 men and 108 women, were included with a mean age of 45.3 ± 8.7 years (range 21–75 years). As shown in Table 1, subjects were divided into groups of normal controls, essential hypertension and PA. Each group included 78, 46 and 85 subjects, respectively. Subjects with PA were older than those with essential hypertension, more obese than normal controls, had higher blood pressure, higher PAC, lower PRA, higher ARR, lower serum potassium and lower estimated glomerular filtration rate (eGFR) than the other two groups. Subjects with PA showed a lower serum DHEA-S than the other two groups (p <0.001). If we adjusted for age, subjects with PA had lower serum DHEA-S than subjects with essential hypertension (p = 0.013) and had borderline lower serum DHEA-S than normal controls (p = 0.076). For further analysis, we divided the subjects by gender. As shown in Figure 1, after adjusting for age, women with PA (n = 49) had lower serum DHEA-S compared with normal controls and subjects with essential hypertension (p = 0.04 compared with normal control, p = 0.0296 compared with essential hypertension). However, serum DHEA-S levels in men with PA (n = 36) were no different from subjects with normal control or essential hypertension, after adjusting for age (p = 0.74).

Table 1.

Clinical characteristics in normal subjects, subjects with essential hypertension, and subjects with primary aldosteronism.

	Normal	Essential hypertension	Primary aldosteronism	p
N	78	46	85
Age	44.9 (7.0)	43.2 (10.1)	46.9 (9.0)^b	0.052
Gender (M/F)	37/41	28/18	36/49^b	0.13
BMI, kg/m²	22.9 (2.8)	25.5 (4.0)	25.8 (4.1)^a	<0.001
SBP, mmHg	116.3 (11)	140.1 (19.3)	153.6 (21.3)^a,b	<0.001
DBP, mmHg	70.5 (8.7)	85.1 (14.0)	91.8 (15.5)^a,b	<0.001
Medication for hypertension, n (%)	0	41 (89.1)	77 (90.6)^a	<0.001
Hypertension, n (%)	0	46 (100)	79 (93.0)^a	<0.001
Total cholesterol, mg/dl^c	194.2 (38.2)	197.5 (35.6)	203.2 (32.0)	0.2
HDL cholesterol, mg/dl^c	49.5 (13.0)	43.9 (11.6)	47.5 (13.9)	0.076
PRA, ng/ml/hr^c	NA	3.9 (5.4)	1.6 (3.9)^b	<0.001
PAC, ng/dl^c	NA	35.6 (26.7)	56.2 (35.3)^b	<0.001
ARR, ng/dl per ng/ml/hr^c	NA	17.4 (7.9–29.3)	115.9 (45.6–387.3)^b	<0.001
Potassium, mEq/l^c	4.14 (0.2)	4.2 (0.3)	3.5 (0.7)^a,b	<0.001
Creatinine, mg/dl^c	0.84 (0.2)	0.96(0.3)	1.0 (0.4)^a	0.002
eGFR, ml/min	97.3 (13.5)	89.7 (16.0)	82.6 (21.2)^a,b	<0.001
DHEA-S, μmol/l^c	4.55 (2.2)	5.77 (3.6)	4.04 (2.9)^{a, b}	<0.001

Mean (SD) or median (interquartile ranges) are shown; M: male; F: female; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; HDL: high-density lipoprotein; PRA: plasma renin activity; PAC: plasma aldosterone concentration; ARR: aldosterone renin ratio; eGFR: estimated glomerular filtration rate; DHEA-S: dehydroepiandrosterone sulfate; NA: not available; ^ap < 0.05 vs. normal; ^bp < 0.05 vs. essential hypertension; ^clogarithmically transformed for statistical analyses.

Figure 1.

Age-adjusted ln serum DHEA-S in normal subjects, subjects with essential hypertension (EH), and subjects with primary aldosteronism (PA) by gender. Means (95% CI) are shown. * p < 0.05 vs. subjects with PA.

According to pathology reports, imaging findings and bilateral adrenal venous sampling results, we further divided the subjects with PA into three groups: APA, IHA and PA with negative imaging findings. Clinical records of these three groups are shown in Table 2. Subjects with APA had lower potassium than subjects with IHA. There was no difference in serum DHEA-S level among these three groups (p = 0.59, p = 0.44 if adjusted for age). For further analysis, we divided the subjects by gender. However, there was no difference in serum DHEA-S level among these three groups in both genders after adjusting for age (p = 0.65 in men, p = 0.45 in women). We then further compared serum DHEA-S concentrations of these three groups with normal controls and those with essential hypertension in both genders. We found that only women with APA had significantly lower serum DHEA-S concentrations than normal control subjects and those with essential hypertension (p = 0.006 compared with normal controls, p = 0.029 compared with those with essential hypertension). As shown in Figure 2, after adjusting for age, women with APA had lower serum DHEA-S concentrations than normal controls and those with essential hypertension (p = 0.01 compared with normal control subjects, p = 0.007 compared with subjects with essential hypertension). In both genders, there were no significant differences of serum DHEA-S concentrations in normal control subjects, those with essential hypertension, IHA, and PA with negative imaging findings.

Table 2.

Serum DHEA-S concentration in subjects with aldosterone-producing adenoma (APA), bilateral idiopathic hyperplasia (IHA) and primary aldosteronism with negative imaging findings (PA with NIF).

	APA	IHA	PA with NIF	p
N	41	20	9
Age (years)	46.7 (9.9)	49 (8.0)	47.8 (7.9)	0.6
Gender (M/F)	16/25	8/12	5/4	0.7
SBP, mmHg	155.8 (21.5)	153.1 (23.1)	153.8 (17.0)	0.9
DBP, mmHg	90.0 (13.6)	93.9 (16.5)	100.5 (14.3)	0.2
Drug for hypertension, n (%)	38 (92.7)	19 (95.0)	7 (77.8)	0.3
Hypertension, n (%)	39 (95.1)	19 (95.0)	8 (88.9)	0.7
Total cholesterol, mg/dl^c	198.7 (28.9)	215.5 (35.6)	197.2 (32.4)	0.2
HDL cholesterol, mg/dl^c	48.2 (15.9)	43.5 (13.0)	48.4 (10.3)	0.5
PRA, ng/ml/hr^c	1.0 (2.9)	1.6 (4.4)	1.7 (2.9)	0.2
PAC, ng/dl^c	60.0 (37.3)	39.5 (17.0)	52.4 (20.9)	0.13
ARR, ng/dl per ng/ml/hr^c	249.9 (50.1–1680)	84.5 (41.7–331.8)	86.9 (53.5–173.3)	0.15
Potassium, mEq/l^c	3.2(0.7)^a	3.8 (0.6)	3.7 (0.5)	0.012
Operation, n (%)	41 (100)^a,b	3 (15.0)	0 (0)	< 0.001
Bilateral adrenal venous sampling, n (%)	5 (12.2)	7 (35.0)	0 (0)	0.029
Creatinine, mg/dl^c	1.0 (0.3)	1.11 (0.68)	1.0 (0.3)	0.9
eGFR, ml/min	82.2 (21.5)	79.7 (24.2)	82.3 (15.4)	0.9
DHEA-S, μmol/l^c	3.7 (2.6)	3.9 (2.5)	5.3 (4.7)	0.6

Mean (SD) or median (interquartile ranges) are shown. M: male; F: female; SBP: systolic blood pressure; DBP: diastolic blood pressure; HDL: high-density lipoprotein; PRA: plasma renin activity; PAC: plasma aldosterone concentration; ARR: aldosterone renin ratio; eGFR: estimated glomerular filtration rate; DHEA-S: dehydroepiandrosterone sulfate; NA: not available. ^ap < 0.05 vs. bilateral idiopathic hyperplasia; ^bp < 0.05 vs. primary aldosteronism with negative imaging finding; ^clogarithmically transformed for statistical analyses.

Figure 2.

Age-adjusted ln serum DHEA-S in normal subjects, subjects with essential hypertension (EH), aldosterone-producing adenoma (APA), bilateral idiopathic hyperplasia (IHA) and primary aldosteronism with negative imaging findings (PA with NIF) by gender. Means (95% CI) are shown. * p < 0.05 vs. normal subjects. † p < 0.05 vs. essential hypertension.

As serum DHEA-S was lower in women with APA, we analyzed the relationship among serum DHEA-S level and tumor size, serum potassium, serum ARR and PAC for both genders. We found a significant inverse correlation between tumor size and serum DHEA-S level in women but not in men (p = 0.009 vs. p = 0.86), as shown in Figure 3. Adjusting for age, tumor size and serum DHEA-S level still showed a borderline inverse relationship in women (p = 0.051) but not in men (p = 0.82).

Figure 3.

The relationship between tumor size and in serum DHEA-S concentration in aldosterone-producing adenoma by gender.

Discussion

In the present study, we demonstrated for the first time that subjects with PA had lower serum DHEA-S concentrations than subjects with essential hypertension or normal control women. In subtype analysis, only female APAs had lower serum DHEA-S concentrations. In both genders, there were no differences in serum DHEA-S concentrations among normal control subjects and those with essential hypertension, IHA, and PA with NIF. In women with APA, serum DHEA-S concentration was negatively correlated with size of the adrenal tumor.

In 1996, Zsuzsa et al. reported low DHEA-S in two pathology-confirmed adrenal adenomas with low plasma renin activity.²⁸ In 1997, Tóth et al. demonstrated that 17 out of 59 subjects with APA had low DHEA-S, but lacked data for adrenal hyperplasia and different genders.²⁹

Four enzymes are involved in the synthesis and regulation of DHEA-S. CYP17, cytochrome b5 (CYB5) and steroid sulfotransferase (SULT2A1) are enzymes for synthesis. Three-β-hydroxysteroid dehydrogenase (HSD3B2) is an enzyme that can convert DHEA to androstenedion, and its activity is inversely related to DHEA-S concentration.³⁰ In a previous study, CYP17 has been shown to be down-regulated in subjects with APA and nodular hyperplasia.²⁴ However, the expression of HSD3B2, CYB5 and SULT2A1 in PA remains unknown. The low CYP17 level in PA may explain our findings.

Another interesting result of our study is that only women with APA have significantly lower serum DHEA-S concentrations compared with normal controls and essential hypertension subjects. We failed to detect any differences in the serum DHEA-S levels among IHA, PA with negative imaging findings, normal control, and essential hypertension subjects in both genders. The result is partially consistent with the finding that CYP17 expression is lower in APA than in nodular hyperplasia reported by Cui et al.²⁴ However, in that study, the CYP17 expression in nodular hyperplasia is still lower than in normal adrenal glands. In our study, we could not find differences between the subjects with IHA, normal controls, and those with essential hypertension. There are three possible reasons. First, the clinical definition of IHA is different from pathology-proved nodular hyperplasia. Most of the patients with IHA did not receive an operation.²⁵ Second, the activities of other enzymes such as CYB5, HSD3B2 and SULT2A1 are unknown in IHA, which may diminish the effect of suppressed CYP17 expression in IHA.³⁰ Third, the case numbers of IHA by different genders are relative small. The concentration of serum DHEA-S in different genders with IHA should be further explored with larger sample sizes.

Tumor size of the APA is the only factor associated with the level of serum DHEA-S in the present study. There is no significant correlation between serum DHEA-S and PAC or ARR. If we adjust for age, there still exists a borderline significant relationship between serum DHEA-S level and tumor size. The role of tumor size in APA is still controversial.^31,32 Karashima et al. have reported that CYP17 is lower in the adjacent tissue of PA with adenomas larger than 0.6 cm.³³ Whether the activities of CYP17, CYB5, HSD3B2 and SULT2A1 are in proportion to tumor size in APA should be further studied.

Only in women, we found a significant correlation between DHEA-S and tumor size of APA. The serum DHEA-S level is higher in men after adulthood. In women, adrenal glands are the only site for serum DHEA-S synthesis.¹⁷ In contrast, both testes and adrenal glands can secrete it in men.^34,35 As a consequence, serum DHEA-S may not precisely reflect the production of DHEA/DHEA-S in adrenal glands in men, especially in adrenal diseases. Besides, whether the CYP17 expression differs in genders is still unknown.

In subjects with PA, the treatments of APA and IHA are different. However, differential diagnosis between APA and IHA are still controversial. In a recent study, CYP17, an enzyme involved in DHEA/DHEA-S, has been shown to be down-regulated in subjects with PA. In our study, we found that serum DHEA-S level is lower especially in females with APA but not IHA. This finding may help in the differential diagnosis between APA and IHA in the female population.

The strength of this study is that we analyzed our data in both genders, which was not conducted in previous reports. Since DHEA-S is an androgen, this analytic approach is important. Indeed, we did find different relationships of serum DHEA-S concentrations to APA and tumor size. However, this study is limited in its relatively small sample size. As a result, we cannot confirm that serum DHEA-S concentrations do not decrease in subtypes of PA such as IHA.

Conclusions

In conclusion, we demonstrated that women with PA had lower serum DHEA-S concentrations than subjects with essential hypertension or normal controls. In subtype analysis, only women with APA had lower serum DHEA-S concentrations. There were no differences in serum DHEA-S concentrations among subjects with IHA, PA with NIF, normal controls, and those with essential hypertension. In women with APA, size of the adrenal tumor was negatively correlated with serum DHEA-S concentrations. Our findings demonstrated the relationship between the two important steroid hormones in the adrenal glands. Further studies are needed to evaluate the role of low DHEA-S production in women with PA and to explore whether low DHEA-S concentrations in these patients are associated with aging problems or other metabolic disorders.

Footnotes

Conflict of interest

None declared.

Funding

This work is supported in part by grants from the Hormone Research Fund of National Taiwan University Hospital, Taiwan (IRB numbers: 201103070RC and 201110008RB).

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Serum dehydroepiandrosterone sulfate concentration is lower in women with primary aldosteronism

Abstract

Objective:

Materials and methods:

Results:

Conclusion:

Keywords

Introduction

Materials and methods

Subjects

Diagnosis of APA, IHA and PA with negative imaging findings

Measurements of serum total cholesterol, high-density lipoprotein (HDL) cholesterol, potassium, creatinine, PAC, PRA, DHEA-S concentrations and tumor sizes of adenomas

Statistical analysis

Results

Discussion

Conclusions

Footnotes

Conflict of interest

Funding

References