Clinical Characterization of Patients With Primary Aldosteronism Plus Subclinical Cushing’s Syndrome





Primary aldosteronism (PA) plus subclinical Cushing’s syndrome (SCS), PASCS, has occasionally been reported. We aimed to clinically characterize patients with PASCS who are poorly profiled.


A population-based, retrospective, single-center, observational study was conducted in 71 patients (age, 58.2 ± 11.2 years; 24 males and 47 females) who developed PA (n = 45), SCS (n = 12), or PASCS (n = 14). The main outcome measures were the proportion of patients with diabetes mellitus (DM), serum potassium concentration, and maximum tumor diameter (MTD) on the computed tomography (CT) scans.


The proportion of DM patients was significantly greater in the PASCS group than in the PA group (50.0% vs. 13.9%, p <  0.05), without a significant difference between the PASCS and SCS groups. Serum potassium concentration was significantly lower in the PASCS group than in the SCS group (3.2 ± 0.8 mEq/L vs. 4.0 ± 0.5 mEq/L; p <  0.01), without a significant difference between the PASCS and PA groups. Among the 3 study groups of patients who had a unilateral adrenal tumor, MTD was significantly greater in the PASCS group than in the PA group (2.7 ± 0.1 cm vs. 1.4 ± 0.1 cm; p <  0.001), without a significant difference between the PASCS and SCS groups.


Any reference criteria were not obtained that surely distinguish patients with PASCS from those with PA or SCS. However, clinicians should suspect the presence of concurrent SCS in patients with PA when detecting a relatively large adrenal tumor on the CT scans.


Primary aldosteronism (PA), an adrenocortical disorder caused by an adrenal tumor that overproduces aldosterone, accounts for 5 to 15% of patients with hypertension [1]. Cushing’s syndrome (CS), an endocrinopathy resulting from the prolonged, excessive adrenocortical secretion of cortisol, falls roughly into the following 2 categories: adrenocorticotropic hormone (ACTH)-dependent CS and ACTH-independent CS; the former includes Cushing’s disease that is primarily caused by a pituitary ACTH-secreting tumor and ectopic ACTH syndrome resulting from extrapituitary ACTH-secreting tumors (eg, bronchial carcinoid) [2], while the latter is usually caused by unilateral adenomas or carcinomas that provoke the autonomous adrenal cortical secretion [3]. Subclinical Cushing’s syndrome (SCS), an ill-defined endocrine disorder leading to the ACTH-independent secretion of cortisol from an adrenal adenoma that is not fully restrained by pituitary feedback [4], is known to cause hypertension, glucose intolerance, and dyslipidemia [5].

The concurrence of clinically overt hyperaldosteronism and subclinical hypercortisolism is rare in PA patients [6]. To date, a few number of studies have examined the clinicopathological features of patients with PA plus SCS (PASCS), the incidences of which have ranged between about 10 and 20% [78]. Lower plasma ACTH levels and a greater tumor size were found in patients with PASCS than in patients with PA alone [8]. In the clinical settings, we rarely encounter PASCS patients who show a small adrenal tumor on the computed tomography (CT) scans and/or do not have a low plasma ACTH level in blood samples collected in the early morning. To examine the clinical features of PASCS patients in the present study, we compared clinical, laboratory, and imaging characteristics among patients with PA, SCS, or PASCS.



We conducted a population-based, retrospective, single-center, observational study in 187 patients (119 with PA, 54 with SCS, and 14 with PASCS) at Saitama Medical University Hospital, Saitama, Japan, between January 1999 and December 2016. Hypertensive patients with suspected PA or SCS, as well as normotensive or hypertensive patients with an adrenal incidentaloma were referred to our hospital. A total of 116 patients were excluded from the study: 31 who were diagnosed with PA or SCS only because tests required to definitely diagnose these endocrinopathies were not conducted; 61 who failed to meet the new Japanese diagnostic criteria of SCS [9]; 1 who failed to meet the new Korean diagnostic criteria of subclinical hypercortisolism [10]; and 23 who failed to meet the Japanese [11] and United States [12] diagnostic criteria of PA. Therefore, we investigated 71 patients who were definitely diagnosed with PA and/or SCS (45 with PA, 12 with SCS, and 14 with PASCS). This study was approved by the institutional review board of Saitama Medical University. Patients provided written informed consent to the use of their clinical and laboratory data in the study.

Diagnosis of PA and SCS

Hormones required for the diagnosis of PA and SCS were assayed according to the procedures described in the pertinent guidelines [911]. Serum cortisol and plasma ACTH levels were determined by electrochemiluminescence immunoassay, plasma aldosterone concentration (PAC) and plasma renin activity (PRA) by radioimmunoassay, and serum dehydroepiandrosterone sulfate (DHEAS) level by chemiluminescent enzyme immunoassay (SRL Inc., Tokyo, Japan). Blood samples were collected in the early morning (7 a.m. to 9 a.m.). PA was suspected when detecting elevated PAC (≥ 150 pg/mL), low PRA (≤ 1.0 ng/mL/hr), and/or the elevated aldosterone-to-renin ratio (> 200). We conducted the following 3 challenge tests in accordance with the Japanese guidelines of PA [11]: captopril challenge test, furosemide upright posture challenge test, and ACTH challenge test. PA was diagnosed when at least 1 of these 3 challenge tests afforded results compatible with the disease. Furthermore, we also referred to the American guideline of PA [12] for selecting only patients who met the diagnostic criteria for PA. Prior to the confirmatory tests, patients had not received any antihypertensive drugs for at least 2 weeks except for those with severe hypertension treated with calcium-channel blockers and/or α-blockers. Adrenal venous sampling (AVS), whose usefulness was well documented in the Japanese and United States guidelines [11,12,13], was conducted in all of patients who had PA or PASCS to make the differential diagnosis of uni- or bilateral aldosterone hypersecretion.

The low-dose (1-mg) dexamethasone suppression test (DST) and the corticotropin-releasing hormone (CRH) challenge test were conducted, and the diurnal rhythms of cortisol were also determined—all for the diagnosis of SCS. Moreover, the high-dose (8-mg) DST was also conducted to rule out ACTH-dependent CS. Test results were assessed in accordance with the diagnostic criteria advocated by the Japan Endocrine Society [9] to make the definite diagnosis of SCS. Concretely, patients were required to meet the requisites 1–3)—1) presence of an adrenal incidentaloma; 2) lack of characteristic features of Cushing’s syndrome; and 3) normal basal serum cortisol levels, as well as to have either of the requisites 4–6)—4) the cutoff value of serum cortisol level for the diagnosis of SCS was ≥ 5 μg/dL after the 1-mg DST, 5) the cutoff value of serum cortisol level for the diagnosis of SCS was ≥ 3 μg/dL after the 1-mg DST, and at least 1 of “Low plasma levels of ACTH in the early morning,” “No diurnal changes in serum cortisol levels,” “Unilateral uptake on adrenal scintigraphy,” “Low serum levels of DHEAS,” or the presence of “Transient adrenal insufficiency or atrophy of the attached normal adrenal cortex after removal of the adrenal tumor,” or 6) the cutoff value of serum cortisol level for the diagnosis of SCS was ≥ 1.8 μg/dL after the 1-mg DST, with the presence of “Low plasma levels of ACTH in the early morning” and “No diurnal changes in serum cortisol levels,” or the presence of “Transient adrenal insufficiency or atrophy of the attached normal adrenal cortex after removal of the adrenal tumor.” In the present study, we examined only patients who met the requisites 1–3) and either 1 of the requisites 4–6) as patients with SCS. All patients underwent 128-slice CT of the adrenal glands. 131I-adosterol adrenal scintigraphy was conducted in all of patients who had SCS or PASCS to specify the laterality of the adrenal tumor. Consequently, 7 of 12 patients with SCS and 8 of 14 patients with PASCS underwent adrenalectomy. Postsurgical histopathological examination confirmed cortisol hypersecretion based on the atrophy of the normal area adjacent to the adenoma of the removed adrenal gland [9].

Study outcome measures

At the initial visit, all patients were checked up for their age and sex. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and the outcome measures listed in Table 1 were examined in untreated patients. At the time of admission to the hospital for making the definite diagnosis, height and body weight were measured to calculate body mass index (BMI). In the early morning of the next day of admission to the hospital, blood pressures were measured. Blood samples were collected to determine PAC, PRA, as well as plasma ACTH, serum cortisol, and serum DHEAS levels. The laterality of the adrenal tumor was confirmed based on the results from AVS and/or CT. The Hounsfield number and MTD of adrenal tumors were determined on the CT scans.

Table 1 Clinical, laboratory, and imaging characteristics of untreated patients with PA, SCS, or PASCS

The following terms were defined for PASCS: hypertension, SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg [14]; diabetes mellitus (DM), an fasting plasma glucose (FPG) level ≥ 126 mg/dL, a 2-h plasma glucose level ≥ 200 mg/dL in the 75-g oral glucose tolerance test, and/or a serum hemoglobin A1c (HbA1c) level ≥ 6.5% in national glycohemoglobin standardization program [15]; and dyslipidemia, a serum triglyceride (TG) level ≥ 150 mg/dL, a serum high-density lipoprotein cholesterol (HDL-C) level < 40 mg/dL, or a serum low-density lipoprotein cholesterol (LDL-C) level ≥ 140 mg/dL [16]. To specify the source of aldosterone hypersecretion by AVS, the following diagnostic criteria were used: 1) the laterality ratio (LR) and the contralaterality ratio (CR) calculated before and after the ACTH challenge test in reference to the Japanese guidelines of PA [11]; 2) the absolute PAC value of ≥ 14,000 pg/mL in reference to the articles of Ohmura [17] and Makita [18]; and 3) the aldosterone ratio of the right and left adrenal veins. According to the Japanese guidelines of PA [11], an LR of > 4 and a CR of < 1 after the ACTH challenge test were used as the cutoff values. Tumor laterality was determined based on a CR of < 1 and the absolute PAC value of ≥ 14,000 pg/mL when the ACTH challenge test indicated an LR of 2 to 4 or a discrepancy occurred in tumor laterality before and after the ACTH challenge test. Since serum cortisol levels considerably differed in the adrenal veins of PASCS patients, the adrenal gland secreting cortisol predominantly was determined based on the aldosterone ratio and on the right-to-left ratio of aldosterone and cortisol in the adrenal veins in reference to the article of Hiraishi et al. [8]. Moreover, tumor laterality was determined based on the results from 131I-adosterol adrenal scintigraphy and on the absolute value of PAC in reference to the articles of Funder et al. [12] and Minami et al. [13]. We did not measure plasma metanephrine concentrations, although the measurement thereof is useful for determining the need for AVS [19] in patients with the suspected concurrence of aldosterone and cortisol hypersecretion.

Statistical analyses

Continuous and categorical variables were analyzed according to the one-way analysis of variance and Fisher’s exact test, respectively. Two of the 3 study groups were analyzed according to Student’s t-test. Bonferroni’s correction was applied to the p values from Student’s t-test or Fisher’s exact test in multiple comparisons between 2 among the 3 study groups. Blood steroid profiles were compared between 2 groups according to Student’s t-test or the Mann-Whitney U-test.

In addition, the multiple linear regression analysis adjusted for age, sex, and BMI was performed to examine differences in MTD and serum potassium concentration among the PA, SCS, and PASCS groups. MTD was not measured in 1 of 42 patients in the PA group who had a unilateral adrenal tumor. Therefore, the data from the patient were excluded as the missing data.

A value of p <  0.05 was considered statistically significant. The JMP software version 9.0 (SAS Institute, Cary, NC, USA) was used to make all statistical analyses except multiple linear regression analysis that was performed using the STATA software version 14 (Stata Corp, College Station, TX, USA).


Study population

The clinical, laboratory, and imaging characteristics of 71 patients are shown in Table 1. Mean age was 58.2 ± 11.2 years, females (n = 47, 66.2%) were predominant, and mean BMI was 25.2 ± 4.5 kg/m2. No significant difference was found in age, sex, and BMI among the PA, SCS, and PASCS groups (Table 1). SBP and DBP of patients with untreated hypertension were 165.6 ± 26.1 mmHg and 96.0 ± 13.6 mmHg, respectively, in the PA group in contrast to 145.6 ± 26.9 mmHg and 80.0 ± 12.7 mmHg, respectively, in the SCS groups. DBP was significantly greater (p <  0.01) in the PA group than in the SCS group.

Comorbidities are shown in Table 1. Hypertension occurred in 45 (100%), 9 (75.0%), and 13 (92.9%) patients in the PA, SCS, and PASCS groups, respectively. The proportion of patients with hypertension was significantly greater (p <  0.05) in the PA group than in the SCS group; however, no significant difference was found between the PASCS group and the PA group. Notably, the incidence of hypertension was 100% in patients with PA. DM occurred in 6 (14.0%), 6 (50.0%), and 7 (50.0%) patients in the PA, SCS, and PASCS groups, respectively. The proportion of DM patients was significantly greater (p <  0.05) in the PASCS group than in the PA group. Dyslipidemia occurred in 25 (56.8%), 10 (83.3%), and 9 (64.3%) patients in the PA, SCS, and PASCS groups, respectively; however, no significant difference was found among these study groups.

Results from laboratory tests are shown in Table 1. FPG was greater not statistically but numerically in the PASCS group than in the PA group (131.6 ± 52.1 mg/dL vs. 103.8 ± 28.5 mg/dL; p = 0.09). On the other hand, FPG was statistically greater in the SCS group than in the PA group (150.0 ± 60.7 mg/dL vs. 103.8 ± 28.5 mg/dL; p <  0.01). HbA1c was greater not statistically but numerically in the PASCS group than in the PA group (6.5 ± 2.1% vs. 5.7 ± 0.9%; p = 0.21). On the other hand, HbA1c was significantly greater in the SCS group than in the PA group (7.3 ± 2.2% vs. 5.7 ± 0.9%; p <  0.01). Serum potassium concentration was significantly lower in the PA group than in the SCS group (3.3 ± 0.7 mEq/L vs. 4.0 ± 0.5 mEq/L; p <  0.01) and in the PASCS group than in the SCS group (3.2 ± 0.8 mEq/L vs. 4.0 ± 0.5 mEq/L; p <  0.01). No significant difference was found in serum potassium concentration between the PA group and the PASCS group. Serum alkaline phosphatase (ALP) level was significantly greater in the PASCS group than in the PA group (279.1 ± 105.4 U/L vs. 212.3 ± 46.3 U/L; p <  0.01). No significant difference was found in serum ALP level between the SCS group and the PASCS group.

Subsequently, differences in CT Hounsfield units and MTD of adrenal tumors among the 3 study groups were examined with respect to 65 patients who had a unilateral adrenal tumor (Table 2). MTD on the CT scans was significantly greater in the PASCS group than in the PA group (2.7 ± 0.1 cm vs. 1.3 ± 0.1 cm; p <  0.001) and was also greater in the SCS group than in the PA group (2.7 ± 0.2 cm vs. 1.3 ± 0.1 cm; p <  0.001). No significant difference was found in MTD between the SCS group and the PASCS group. MTD was significantly smaller in the PA group than in the other 2 groups, was second smallest in the SCS group, and was largest in the PASCS group (Table 2). MTD ranged as follows: 0.3–2.2 cm, 1.8–3.5 cm, and 1.1–5.0 cm in the PA, SCS, and PASCS groups, respectively (Fig. 1).

Table 2 Maximum tumor diameters and computed tomography Hounsfield units of adrenal tumors in patients who had a unilateral adrenal tumor
Fig. 1

Maximum tumor diameters in patients with PA, SCS, or PASCS who had a unilateral adrenal tumor. PA, primary aldosteronism; SCS, subclinical Cushing’s syndrome, PASCS, primary aldosteronism plus subclinical Cushing’s syndrome

The blood steroid profiles of patients with PA or PASCS are shown in Table 3. PAC was significantly greater in the PASCS group than in the PA group (255.0 [713.3–153.5] vs. 208.0 [273.0–159.8]; p <  0.005). No significant difference was found in PRA in the morning, while the PAC/PRA ratio was significantly greater in the PASCS group than in the PA group (1450.0 [5010.0–529.4] vs. 1258.3 [1956.3–643.1]; p <  0.005). The PAC/PRA ratio in the captopril challenge test was significantly greater in the PASCS group than in the PA group (3028.5 ± 3648.9 vs. 730.7 ± 745.7; p <  0.001) as with PAC in the captopril challenge test (348.6 ± 340.1 vs. 149.0 ± 94.2; p <  0.005). Serum cortisol level was significantly greater in the PASCS group than in the PA group (16.4 ± 6.6 μg/dL vs. 12.4 ± 4.3 μg/dL; p <  0.05). The mean serum cortisol level was 17.8 ± 5.9 μg/dL in the SCS group and was not significantly greater in the SCS group than in the PASCS group (17.8 ± 5.9 μg/dL vs. 16.4 ± 6.6 μg/dL; p = 0.49). No significant difference was found in plasma ACTH and serum DHEAS levels in the early morning; however, these variables were not significantly lower in the PASCS than in the PA group (p = 0.29 for ACTH and p = 0.40 for DHEAS). On the other hand, the peak plasma ACTH levels in the CRH challenge test were significantly lower in the PASCS group than in the PA group (18.9 ± 8.9 vs. 57.1 ± 10.8; p <  0.005) (Table 3) and were not significantly greater in the SCS group than in the PASCS group (15.3 ± 5.6 μg/dL vs. 18.9 ± 8.9 μg/dL; p = 0.64).

Table 3 Blood steroid profiles of patients with PA or PASCS

Multiple linear regression analysis on MTD and serum potassium concentration with respect to patients in the PA, SCS, and PASCS groups who had a unilateral adrenal tumor

MTD was significantly greater in the PASCS and SCS groups than in the PA group with respect to patients who had a unilateral adrenal tumor (Table 2). Therefore, we conducted a multiple linear regression analysis adjusted for age, sex, and BMI to examine differences in MTD among the PA, SCS, and PASCS groups. Consequently, MTD was significantly smaller in the PA group than in the PASCS group (difference, – 1.19 cm; 95% CI, – 1.66 to – 0.72 cm). However, no significant difference was found in MTD between the SCS group and the PASCS group (Table 4). Serum potassium concentration was significantly greater in the SCS group than in the PASCS group (difference, 0.97 mEq/L; 95% CI, 0.38 to 1.54 mEq/L). However, no significant difference was found in serum potassium concentration between the PASCS group and the PA group (Table 4).

Table 4 Multiple regression analysis on maximum tumor diameter and serum potassium concentration with respect to patients in the PA, SCS, and PASCS groups who had a unilateral adrenal tumor (n = 65)

The cutoff value of 2.4 cm for tumor size seemed to produce the largest proportion of classified patients (91.0%). Patients with PA who had a tumor size of > 2.4 cm almost certainly had the elements of PASCS (specificity 100%). Namely, the sensitivity and specificity were calculated to be 58.0 and 100%, respectively, when the cutoff point for tumor diameter was set to 2.4 cm. The odds ratio for tumor diameter when comparing PA with PASCS was 0.06 (95% CI, 0.006–0.261).


We found several clinical and laboratory differences between patients with PASCS and patients with either PA or SCS. Regarding the impact of PA and SCS on glucose metabolism, the risk of developing DM in SCS is enhanced by the overproduction of cortisol that leads to increased gluconeogenesis [20]. Moreover, the risk is also enhanced by PA through 1) a hypokalemia-induced decrease in initial pancreatic insulin release and 2) a reduction in insulin sensitivity [21,22,23]. Hypokalemia is caused by the mineralocorticoid receptor-mediated overexcretion of potassium from the kidneys in both hypercortisolism and hyperaldosteronism [122425]. Serum potassium concentration decreased significantly in the PA group than in the SCS group (p <  0.01). Similarly, the concurrence of PA and SCS significantly decreased serum potassium concentration against the SCS group (p <  0.01), but not the PA group. Of special note was the fact that the PASCS group involving both hyperaldosteronism and hypercortisolism did not show any greater decrease in serum potassium concentration as compared with the PA group. The mineralocorticoid receptors (MRs) bind both mineralocorticoids and glucocorticoids with high affinity (deoxycorticosterone = corticosterone ≥ aldosterone = cortisol) [26]. On the other hand, a cortisol-degrading enzyme—11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)—is expressed in renal epithelial cells and regulates the binding of aldosterone to the MRs by impeding cortisol binding to the MRs through the inactivation of cortisol to cortisone [2627]. Namely, this physiological event explains the MR-mediated renal excretion of potassium that is enhanced by both cortisol and aldosterone. We hypothesize that the renal potassium excretion-enhancing activity is greater for aldosterone than for cortisol due to the 11β-HSD2-induced, extensive inactivation of cortisol and that the hyperaldosteronism-enhanced renal excretion of potassium in patients with PASCS becomes more apparent, with the less effect of hypercortisolism on renal potassium excretion. Zallocchi et al. [28] described that renal 11β-HSD2 activity is regulated by glucocorticoids, is downregulated following adrenalectomy, and is restored by corticosterone replacement. These findings lead us to hypothesize that 11β-HSD2 may suppress the binding of corticosteroids to the MRs almost completely in subclinical hypercortisolism or that the expression/activity of renal 11β-HSD2 may be increased in PA. However, these hypotheses require further research for its demonstration.

The proportion of DM patients increased significantly in the PASCS group than in the PA group (p <  0.05), which is in line with a previous study that described abnormal glucose metabolism in PA patients with cortisol hypersecretion [29]. Hyperaldosteronism found in patients with PA also induces abnormal glucose metabolism [21,22,23], although being less intense as compared with hypercortisolism found in patients with SCS. The proportions of DM patients in the PA and SCS groups increased, which resulted to nullify a statistically significant difference in the proportion of DM patients between the 2 study groups. The fact that the risk for DM is increased in PA patients with mild glucocorticoid excess has been reported [30,31,32]; the finding was also described in Japanese patients with PA and patients with PASCS [33].

Interestingly, patients with PASCS involving hypercortisolism- and hyperaldosteronism-induced hypokalemia showed neither additive or synergic impact on abnormal glucose metabolism contrary to our prediction. The proportion of DM patients was comparable between the PASCS group and the SCS group. However, the reason for these findings is unknown, awaiting the further accumulation of clinical evidence.

MTD was significantly smaller (p <  0.001) in the PA group than in the PASCS or SCS group, and multiple regression analysis on MTD revealed that MTD was significantly larger by 1.2 cm in the PASCS group than in the PA group (p <  0.001). Previous studies [834] examined the clinical characteristics of patients with PA or PASCS and described significant differences in MTD between the 2 study groups. Their results were concordant with and support our results that indicated no significant difference in MTD between the PASCS group and the SCS group.

Most of previous clinical studies in patients with SCS have described adrenal tumors of ≥ 2 cm in diameter [3536]. In addition, an adrenal adenoma causing the overproduction of both cortisol and aldosterone is considered to have a ≥ 2.5 cm diameter [34]. In the present study, however, the adrenal tumor was smaller in both patients with SCS and patients with PASCS. Concretely, the smallest MTD was 1.1 cm in patients with PASCS (Fig. 1). None of patients, who had PA and an adrenal tumor < 1 cm in diameter, developed SCS. Therefore, the dexamethasone suppression test may not be required for them.

Regarding bone metabolism impairment in SCS, the risk of developing osteoporosis is enhanced by the overproduction of cortisol in SCS [3738]. On the other hand, hyperaldosteronism is also known to increase the risk for osteoporosis [39]. SCS and PA are the risk factors for a reduction in BMD and an increase in vertebral fracture [37,38,39]. In the present study, serum ALP level was significantly greater in the PASCS group than in the PA group (p <  0.01). No significant difference was found in serum ALP level between the SCS group and the PASCS group. If this ALP represents bone alkaline phosphatase (BAP), the deleterious effects of hyperaldosteronism on bone metabolism might be masked by the severe abnormalities of bone metabolism caused by hypercortisolism in patients with PASCS. However, the relevant effects are difficult to assess by means of bone metabolism markers [eg, BAP] in patients with hypercortisolism as found in SCS [37]. Unfortunately, we neither used bone metabolism markers, nor measured BMD. Therefore, we will intend to investigate these variables in the future.


The present study has several limitations. First, the study was retrospective in design and had a relatively small number of patients. Therefore, selection bias and sampling bias cannot be discarded. Second, not all patients underwent AVS or had a histopathological diagnosis. Patients, to whom challenge tests for either PA or SCS were conducted, were not included in the present study. Hence, the number of patients resulted to be relatively small. Third, the lack of data in the present study impeded the analysis of BMD and bone metabolism markers. Fourth, 131I-adosterol adrenal scintigraphy is not only useful for the diagnosis of SCS, but also is a very important imaging modality to predict postsurgical hypoadrenalism [40]. However, we could not investigate the latter.


We could not obtain any reference criteria to surely distinguish patients with concurrent endocrinopathies from those with a single endocrinopathy. However, clinicians should suspect the presence of concurrent SCS in patients with PA when detecting an adrenal tumor (≥ 1 cm in diameter) on the CT scans.

Availability of data and materials

The datasets analyzed during the current study are available from the corresponding author on a reasonable request.


Adrenocorticotropic hormone
Alkaline phosphatase
Body mass index;
corticotropin-releasing hormone
computed tomography
Diastolic blood pressure
Dehydroepiandrosterone sulfate
Fasting plasma glucose
Hemoglobin A1c
High-density lipoprotein cholesterol
Hounsfield unit
Low-density lipoprotein cholesterol
Maximum tumor diameter
National glycohemoglobin standardization program
Primary aldosteronism
Plasma aldosterone concentration
Primary aldosteronism plus subclinical Cushing’s syndrome
Plasma renin activity
Systolic blood pressure
Subclinical Cushing’s syndrome
Uric acid


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The authors would like to express their gratitude Kazuyuki Inoue, MD and Takujiro Iuchi, MD for their role in the data collection. The authors also thank Satoshi Sakima, MD, for valuable discussions about the manuscript.


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SY analyzed and interpreted the data, drafted, and finalized the manuscript. YK performed statistical analyses, YH, YK, SI, YO, MI, II, AS, and MN contributed to the discussion and critically revised the manuscript, AS and MN are taking full responsibility for the work as a whole. All authors read and approved the final manuscript.

Correspondence to Shigemitsu Yasuda.

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Yasuda, S., Hikima, Y., Kabeya, Y. et al. Clinical characterization of patients with primary aldosteronism plus subclinical Cushing’s syndrome. BMC Endocr Disord 20, 9 (2020).

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  • Primary aldosteronism
  • Subclinical Cushing’s syndrome
  • Adrenal tumor
  • Maximum tumor diameter
  • Diabetes mellitus
  • Serum potassium

Cyclic Cortisol Production May Lead to Misdiagnosis in Cushing’s

Increased cortisol secretion may follow a cyclic pattern in patients with adrenal incidentalomas, a phenomenon that may lead to misdiagnosis, a study reports.

Since cyclic subclinical hypercortisolism may increase the risk for heart problems, researchers recommend extended follow-up with repeated tests to measure cortisol levels in these patients.

The study, “Cyclic Subclinical Hypercortisolism: A Previously Unidentified Hypersecretory Form of Adrenal Incidentalomas,” was published in the Journal of Endocrine Society.

Adrenal incidentalomas (AI) are asymptomatic masses in the adrenal glands discovered on an imaging test ordered for a problem unrelated to adrenal disease. While most of these benign tumors are considered non-functioning, meaning they do not produce steroid hormones like cortisol, up to 30% do produce and secrete steroids.

Subclinical Cushing’s syndrome is an asymptomatic condition characterized by mild cortisol excess without the specific signs of Cushing’s syndrome. The long-term exposure to excess cortisol may lead to cardiovascular problems in these patients.

While non-functioning adenomas have been linked with metabolic problems, guidelines say that if excess cortisol is ruled out after the first evaluation, patients no longer need additional follow-up.

However, cortisol secretion can be cyclic in Cushing’s syndrome, meaning that clinicians might not detect excess amounts of cortisol at first and misdiagnose patients.

In an attempt to determine whether cyclic cortisol production is also seen in patients with subclinical Cushing’s syndrome and whether these patients have a higher risk for metabolic complications, researchers in Brazil reviewed the medical records of 251 patients with AI — 186 women, median 60 years old — followed from 2006 to 2017 in a single reference center.

Cortisol levels were measured after a dexamethasone suppression test (DST). Dexamethasone is used to stop the adrenal glands from producing cortisol. In healthy patients, this treatment is expected to reduce cortisol levels, but in patients whose tumors also produce cortisol, the levels often remain elevated.

Patients were diagnosed with cyclic subclinical Cushing’s syndrome if they had at least two normal and two abnormal DST tests.

From the 251 patients, only 44 performed the test at least three times and were included in the analysis. The results showed that 20.4% of patients had a negative DST test and were considered non-functioning adenomas.

An additional 20.4% had elevated cortisol levels in all DST tests and received a diagnosis of sustained subclinical Cushing’s syndrome.

The remaining 59.2% had discordant results in their tests, with 18.3% having at least two positive and two negative test results, matching the criteria for cyclic cortisol production, and 40.9% having only one discordant test, being diagnosed as possibly cyclic subclinical Cushing’s syndrome.

Interestingly, 20 of the 44 patients had a normal cortisol response at their first evaluation. However, 11 of these patients failed to maintain normal responses in subsequent tests, with four receiving a diagnosis of cyclic subclinical Cushing’s syndrome and seven as possibly cyclic subclinical Cushing’s.

Overall, the findings suggest that patients with adrenal incidentalomas should receive extended follow-up with repeated DST tests, helping identify those with cyclic cortisol secretion.

“Lack of recognition of this phenomenon makes follow-up of patients with AI misleading because even cyclic SCH may result in potential cardiovascular risk,” the study concluded.


Most Subclinical Cushing’s Patients Don’t Require Glucocorticoids After Adrenalectomy

Patients with subclinical hypercortisolism, i.e., without symptoms of cortisol overproduction, and adrenal incidentalomas recover their hypothalamic-pituitary-adrenal (HPA) axis function after surgery faster than those with Cushing’s syndrome (CS), according to a study.

Moreover, the researchers found that an HPA function analysis conducted immediately after the surgical removal of adrenal incidentalomas — adrenal tumors discovered by chance in imaging tests — could identify patients in need of glucocorticoid replacement before discharge.

Using this approach, they found that most subclinical patients did not require treatment with hydrocortisone, a glucocorticoid taken to compensate for low levels of cortisol in the body, after surgery.

The study, “Alterations in hypothalamic-pituitary-adrenal function immediately after resection of adrenal adenomas in patients with Cushing’s syndrome and others with incidentalomas and subclinical hypercortisolism,” was published in Endocrine.

The HPA axis is the body’s central stress response system. The hypothalamus releases corticotropin-releasing hormone (CRH) that acts on the pituitary gland to release adrenocorticotropic hormone (ACTH), leading the adrenal gland to produce cortisol.

As the body’s defense mechanism to avoid excessive cortisol secretion, high cortisol levels alert the hypothalamus to stop producing CRH and the pituitary gland to stop making ACTH.

Therefore, in diseases associated with chronically elevated cortisol levels, such as Cushing’s syndrome and adrenal incidentalomas, there’s suppression of the HPA axis.

After an adrenalectomy, which is the surgical removal of one or both adrenal glands, patients often have low cortisol levels (hypocortisolism) and require glucocorticoid replacement therapy.

“Most studies addressing the peri-operative management of patients with adrenal hypercortisolism have reported that irrespective of how mild the hypercortisolism was, such patients were given glucocorticoids before, during and after adrenalectomy,” the researchers wrote.

Evidence also shows that, after surgery, glucocorticoid therapy is administered for months before attempting to test for recovery of HPA function.

For the past 30 years, researchers at the University Hospitals Cleveland Medical Center have withheld glucocorticoid therapy in the postoperative management of patients with ACTH-secreting pituitary adenomas until there’s proof of hypocortisolism.

“The approach offered us the opportunity to examine peri-operative hormonal alterations and demonstrate their importance in predicting need for replacement therapy, as well as future recurrences,” they said.

In this prospective observational study, the investigators extended their approach to patients with subclinical hypercortisolism.

“The primary goal of the study was to examine rapid alteration in HPA function in patients with presumably suppressed axis and appreciate the modulating impact of surgical stress in that setting,” they wrote. Collected data was used to decide whether to start glucocorticoid therapy.

The analysis included 14 patients with Cushing’s syndrome and 19 individuals with subclinical hypercortisolism and an adrenal incidentaloma. All participants had undergone surgical removal of a cortisol-secreting adrenal tumor.

“None of the patients received exogenous glucocorticoids during the year preceding their evaluation nor were they taking medications or had other illnesses that could influence HPA function or serum cortisol measurements,” the researchers noted.

Glucocorticoid therapy was not administered before or during surgery.

To evaluate HPA function, the clinical team took blood samples before and at one, two, four, six, and eight hours after the adrenalectomy to determine levels of plasma ACTH, serum cortisol, and dehydroepiandrosterone sulfate (DHEA-S) — a hormone produced by the adrenal glands.

Pre-surgery assessment of both groups showed that patients with an incidentaloma plus subclinical hypercortisolism had larger adrenal masses, higher ACTH, and DHEA-S levels, but less serum cortisol after adrenal function suppression testing with dexamethasone.

Dexamethasone is a man-made version of cortisol that, in a normal setting, makes the body produce less cortisol. But in patients with a suppressed HPA axis, cortisol levels remain high.

After the adrenalectomy, the ACTH concentrations in both groups of patients increased. This was found to be negatively correlated with pre-operative dexamethasone-suppressed cortisol levels.

Investigators reported that “serum DHEA-S levels in patients with Cushing’s syndrome declined further after adrenalectomy and were undetectable by the 8th postoperative hour,” while incidentaloma patients’ DHEA-S concentrations remained unchanged for the eight-hour postoperative period.

Eight hours after surgery, all Cushing’s syndrome patients had serum cortisol levels of less than 2 ug/dL, indicating suppressed HPA function. As a result, all of these patients required glucocorticoid therapy for several months to make up for HPA axis suppression.

“The decline in serum cortisol levels was slower and less steep [in the incidentaloma group] when compared to that observed in patients with Cushing’s syndrome. At the 6th–8th postoperative hours only 5/19 patients [26%] with subclinical hypercortisolism had serum cortisol levels at ≤3ug/dL and these 5 were started on hydrocortisone therapy,” the researchers wrote.

Replacement therapy in the subclinical hypercortisolism group was continued for up to four weeks.

Results suggest that patients with an incidentaloma plus subclinical hypercortisolism did not have an entirely suppressed HPA axis, as they were able to recover its function much faster than the CS group after surgical stress.


Blood Sample from Tributary Adrenal Gland Veins May Help to Diagnose Subclinical Cushing’s Syndrome

Researchers report a new technique for collecting blood samples from tiny veins of the adrenal glands, called super-selective adrenal venous sampling (ssAVS). The technique can be used to help diagnose diseases marked by excessive release of adrenal hormones, such as subclinical Cushing’s syndrome (SCS) or primary aldesteronism (PA).

The study, titled “A Novel Method: Super-selective Adrenal Venous Sampling,” was published in JOVE, the Journal of Visualized Experiments. JOVE has also made a video that demonstrates the procedure.

The adrenal glands are a pair of glands found above the kidneys that produce a variety of hormones, including adrenaline and the steroids aldosterone and cortisol. Excessive production of cortisol in the adrenal glands is the cause SCS, and aldosterone of PA.

These glands have central veins running through them, and three tributary veins (veins that empty into a larger vein). Conventional AVS collects blood from the central veins, but these veins have blood from the adrenal glands as well as blood in wider circulation flowing through them.

ssAVS uses tiny catheters — very long, narrow tubes inserted into blood vessels, called microcatheters — to collect blood from the tributary veins in both adrenal glands. Only blood from the adrenal glands flows through the tributary veins, making analysis of hormone levels easier, and pinpointing the region, or segment, of the gland that is not working properly.

A medical imaging technique, known as angiography, is used to track the positions of the microcatheters. Angiography is a procedure widely used to visualize the inside of blood vessels and organs, and takes roughly 90 minutes.

The paper reported on the use of ssAVS in three patients with adrenal gland disorders, and one (case #2) was diagnosed with SCS and PA. “Overall, in Cases #1 and #2, the ssAVS method clearly indicated segmental adrenal hormone production, not only for aldosterone, but for cortisol, and enabled these patients to be treated by surgery,”  the researchers reported.

Conventional AVS measures hormone levels in whole glands. It is useful for identifying which of the two glands is diseased, and the type of hormone that is overproduced. But sometimes both glands are affected, and only removal of the diseased parts in both glands is safe and effective.

That’s one of the reasons why ssAVS is so useful. By sampling the smaller, tributary veins in three different regions of each gland, the diseased parts can be identified. The diseased parts can then be removed from both glands, if medically advisable, leaving the healthy parts of the glands intact and functional.

ssAVS is also useful because it collects samples of blood coming directly from the adrenal glands, making analysis of hormone levels more reliable.

Researchers concluded that ssAVS is useful in both the diagnosis of adrenal gland disorders and for research that might lead to new therapies.

“Between October 2014 and September 2015, two angiographers … performed ssAVS on 125 cases … with a 100 % success rate and within a reasonable time (58 – 130 min) without adrenal rupture or thrombosis that required surgery,” they wrote. “The ssAVS method is not difficult for expert angiographers, and, thus, is recommended worldwide to treat PA cases for which cAVS does not represent a viable surgical treatment option.”


Basal Cortisol Elevated in Patients with ACTH-Staining Pituitary Macroadenoma

Preoperative identification of patients with silent adrenocorticotrophic hormone-secreting tumors could potentially change the approach to management. A new study aimed to determine whether a preoperative adrenocorticotrophic hormone stimulation test for evaluation of nonfunctional pituitary macroadenoma could aid in identifying adrenocorticotrophic hormone-staining pathology yielded large variability and did not allow clinical utility.

Thus, researchers concluded that larger, multicenter research is needed to determine whether this test can be useful.

“As ACTH stimulation tests are performed routinely when evaluating macroadenoma when there is no suspicion for a state of endogenous hypercortisolism, we sought to determine if the test could reliably identify these pathologies during the preoperative evaluation. We hypothesized that patients with subclinical Cushing’s disease or silent ACTH-secreting tumors would have a higher delta cortisol on the ACTH stimulation tests vs. other types of macroadenoma pathologies,” Kevin Pantalone, DO, ECNU, FACE, staff endocrinologist and director of clinical research in the department of endocrinology at Cleveland Clinic, told Endocrine Today.

Pantalone and colleagues performed a retrospective chart review of 148 patients with pituitary macroadenoma who underwent preoperative ACTH stimulation tests, with the goal of determining whether the test can aid in the identification of ACTH-staining pathology.

Overall, 9.5% of patients showed diffuse staining, 50.6% showed other-staining (diffuse staining for anterior pituitary hormones other than ACTH) and 39.9% showed no staining (no staining for any anterior pituitary hormones).

The researchers calculated delta total cortisol at 30 and 60 minutes from baseline and reviewed preoperative ACTH stimulation tests. Additionally, Pantalone and colleagues compared the basal and maximal delta cortisol between the ACTH-staining pituitary macroadenoma and the non-ACTH staining (n = 134), other staining (n = 75) and non-staining (n = 59) tumors.

According to data reported at the American Association of Clinical Endocrinologists Annual Scientific and Clinical Congress, the ACTH-staining group had higher mean basal cortisol levels compared with the non-ACTH-staining (P = .012), other staining (P = .018) and the non-staining (P = .012) tumors. The researchers found no significant differences in maximal delta cortisol between the groups.

“While we found basal cortisol levels were higher in patients with ACTH-staining pituitary microadenoma vs. non-ACTH-staining macroadenoma, the large variability in cortisol values did not allow for clinical utility,” Pantalone told Endocrine Today.

“Unfortunately, in the end, our study was limited by the number of cases with ACTH-staining pathology. Thus, we were unable to determine if the ACTH stimulation test could reliably assist clinicians in potentially identifying ACTH-staining pathology in the preoperative setting,” he said. “A multicenter study, affording a large number of ACTH-staining tumors, is needed. This may allow for us to determine if the ACTH-stimulation test can really be clinically useful in preoperatively identifying ACTH-staining pathology.” – by Amber Cox

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