Athina Markou

High prevalence of autonomous cortisol and aldosterone secretion from adrenal adenomas

Objectives  Previous studies based on standard endocrine testing have shown a variable incidence of autonomous cortisol secretion (ACS) or autonomous aldosterone secretion (AAS) in patients with single adrenal adenomas (SAA). We tested whether the use of appropriate controls and modification of standard testing, aiming at eliminating interference from endogenous ACTH, reveals previously undetected subtle ACS and AAS by SAA.

Patients with apparently nonfunctioning adrenal incidentalomas may be at increased cardiovascular risk due to excessive cortisol secretion.

CONTEXT Although adrenal incidentalomas (AIs) are associated with a high prevalence of cardiovascular risk (CVR) factors, it is not clear whether patients with nonfunctioning AI (NFAI) have increased CVR. OBJECTIVE Our objective was to investigate CVR in patients with NFAI. DESIGN AND SETTING This case-control study was performed in a tertiary general hospital. SUBJECTS SUBJECTS included 60 normotensive euglycemic patients with AI and 32 healthy controls (C) with normal adrenal imaging. MAIN OUTCOME MEASURES All participants underwent adrenal imaging, biochemical and hormonal evaluation, and the following investigations: 1) measurement of carotid intima-media thickness (IMT) and flow-mediated dilatation, 2) 2-hour 75-gram oral glucose tolerance test and calculation of insulin resistance indices (homeostasis model assessment, quantitative insulin sensitivity check, and Matsuda indices), 3) iv ACTH stimulation test, 4) low-dose dexamethasone suppression test, and 5) NaCl (0.9%) post-dexamethasone saline infusion test. RESULTS Based on cutoffs obtained from controls, autonomous cortisol secretion was documented in 26 patients (cortisol-secreting AI [CSAI] group), whereas 34 exhibited adequate cortisol and aldosterone suppression (NFAI group). IMT measurements were higher and flow-mediated vasodilatation was lower in the CSAI group compared with both NFAI and C and in the NFAI group compared with C. The homeostasis model assessment index was higher and quantitative insulin sensitivity check index and Matsuda indices were lower in the CSAI and NFAI groups compared with C as well as in CSAI compared with the NFAI group. The area under the curve for cortisol after ACTH stimulation was higher in the CSAI group compared with the NFAI group and C and in the NFAI group compared with C. In the CSAI group, IMT correlated with cortisol, urinary free cortisol, and cortisol after a low-dose dexamethasone suppression test, whereas in the NFAI group, IMT correlated with area under the curve for cortisol after ACTH stimulation and urinary free cortisol. CONCLUSIONS Patients with CSAI without hypertension, diabetes, and/or dyslipidemia exhibit adverse metabolic and CVR factors. In addition, NFAIs are apparently associated with increased insulin resistance and endothelial dysfunction that correlate with subtle but not autonomous cortisol excess.

High prevalence of autonomous aldosterone secretion among patients with essential hypertension

Eur J Clin Invest 2011; 41 (11): 1227–1236

Stress-induced Aldosterone Hyper-Secretion in a Substantial Subset of Patients With Essential Hypertension

CONTEXT Aldosterone (ALD) secretion is regulated mainly by angiotensin II, K(+), and adrenocorticotropic hormone (ACTH). Mineralocorticoid receptor antagonists (MRAs) have effectively been used for the treatment of patients with hypertension who do not have primary aldosteronism (PA). OBJECTIVE We tested whether chronic stress-related ACTH-mediated ALD hypersecretion and/or zona glomerulosa hypersensitivity could be implicated in the pathogenesis of essential hypertension (ESHT). PATIENTS AND METHODS One hundred thirteen hypertensives without PA and 61 normotensive controls underwent an ultralow-dose (0.03-μg) ACTH stimulation and a treadmill test. Patients with ALD hyper-response according to the cutoffs obtained from controls received treatment with MRAs and underwent genomic DNA testing for the presence of the CYP11B1/CYP11B2 chimeric gene and KCNJ5 gene mutations. A control group of 22 patients with simple ESHT received treatment with MRAs. RESULTS Based on the cutoffs of ALD and aldosterone-to-renin ratio (ARR) post-ACTH stimulation obtained from controls, 30 patients (27%) exhibited an ALD but not cortisol (F) hyper-response (HYPER group). This group had no difference in basal ACTH/renin (REN) concentrations compared with controls and the 83 patients with hypertension (73%) without an ALD hyper-response to ACTH stimulation. Patients in the HYPER group demonstrated significantly higher ALD concentrations, ARR, and ALD/ACTH ratio (AAR) in the treadmill test. Treatment with MRAs alone produced normalization of blood pressure in these patients whereas patients with hypertension with neither PA nor ALD hyper-response to ACTH stimulation who served as a control group failed to lower blood pressure. Also, two novel germline heterozygous KCNJ5 mutations were detected in the HYPER group. CONCLUSIONS A number of patients with hypertension without PA show ACTH-dependent ALD hyper-secretion and benefit from treatment with MRAs. This could be related to chronic stress via ACTH hyper secretion and/or gene-mutations increasing the zona glomerulosa responsiveness to excitatory stimuli.

Evidence of Primary Aldosteronism in a Predominantly Female Cohort of Normotensive Individuals: A Very High Odds Ratio for Progression into Arterial Hypertension

CONTEXT Primary aldosteronism (PA) is an established cause of hypertension, whereas high-normal serum aldosterone levels have been linked to an increased risk for hypertension. OBJECTIVE We aimed to define the post-fludrocortisone-dexamethasone suppression test (FDST) normal cutoff values of aldosterone and the aldosterone to renin ratio and evaluate the presence of PA in normotensive individuals. DESIGN This study was designed as a case-control study. SETTING The study was performed in a tertiary general hospital. PATIENTS One hundred normotensive participants (80 females), mean age 53 years, were studied. MAIN OUTCOME MEASURES All participants underwent baseline biochemical and hormonal evaluation, FDST, and adrenal computerized tomography. Blood pressure was assessed at baseline and after 5 years. RESULTS Sixty-nine participants with normal adrenal computerized tomography who remained normotensive after 5 years were used as a control population to calculate the cutoff values of adequate aldosterone suppression. PA was defined as a combination of post-FDST aldosterone to renin ratio of 0.93 ng/dL · μU/mL or greater (100% sensitivity and 96% specificity) and post-FDST aldosterone of 2.96 ng/dL or greater (100% sensitivity and 61% specificity on receiver-operating characteristic analysis). Thirteen of 100 participants had PA at baseline and 11 (85%) developed hypertension, whereas only 20 of 87 without PA (23%) developed hypertension at 5 years [odds ratio (OR) 18.42, 95% confidence intervals (CI) 3.76-90.10, P < .0001]. Logistic regression analysis showed a positive relation of PA [odds ratio (OR) 16.30, confidence interval (CI) 1.78-150.30, P = .01] and a negative relation of serum potassium (OR 0.39, CI 0.19-0.79, P = .01) with the development of hypertension. CONCLUSIONS Normotensive PA represents a clinical entity referring to normotensive individuals with PA who are at increased risk for hypertension.

The effect of tibolone on bone mineral density in postmenopausal women with osteopenia or osteoporosis--8 years follow-up.

OBJECTIVES This longitudinal observational study evaluated the effect of 8 years of uninterrupted treatment of tibolone on bone mineral density (BMD) in postmenopausal women with significant osteopenia or osteoporosis. MATERIAL AND METHODS Subjects were 66 postmenopausal women (29 with moderate or severe osteopenia and 37 with osteoporosis) who took tibolone (2.5 mg nocte) uninterruptedly for over 8 years and who attended for annual BMD assessments. Their mean age was 66.7 (0.86) years (range 50-86 years). BMD measurements at the lumbar spine and proximal femur were performed annually by dual-energy X-ray absorptiometry (DEXA). RESULTS During the 8 years of treatment with tibolone there was a significant increase in BMD at the spine (P < 0.001) and at the hip (P < 0.001). Women who did not have previous oestrogen therapy had significantly greater response to tibolone than those who had previous treatment with conventional hormone replacement therapy (HRT). CONCLUSION This long-term observational study provides evidence of the effectiveness of tibolone in postmenopausal women with moderate/severe osteopenia and osteoporosis in terms of a significant increase in BMD.

The functional status of incidentally discovered bilateral adrenal lesions

Objective  To investigate autonomous cortisol and aldosterone secretion and insulin resistance (IR) indices, in patients with incidentally discovered bilateral adrenal lesions (BA).

Primary aldosteronism in hypertensive patients: clinical implications and target therapy

The prevalence of primary aldosteronism (PA) in hypertensive patients varies according to diagnostic testing and ascertained normal cut‐offs. The aim of this case–control study was to confirm the high prevalence of PA in a large hypertensive population and evaluate the antihypertensive effect of mineralocorticoid receptor antagonists (MRA) treatment.

Primary pigmented nodular adrenocortical disease presenting with a unilateral adrenocortical nodule treated with bilateral laparoscopic adrenalectomy: a case report

IntroductionPrimary pigmented nodular adrenocortical disease is a rare cause of adrenocorticotropic hormone-independent Cushings syndrome. We report an uncommon primary pigmented nodular adrenocortical disease case presenting with a unilateral adrenocortical nodule and provide a brief overview of the existing literature.Case presentationA 27-year-old Caucasian woman was admitted to our Department with adrenocorticotropic hormone-independent Cushings syndrome. Its cause was initially considered a left adrenocortical adenoma based on computer tomography imaging. The patient underwent left laparoscopic adrenalectomy and histological examination revealed pigmented micronodular adrenal hyperplasia. Evaluation for the presence of Carney complex was negative. Six months later recurrence of hypercortisolism was documented and a right laparoscopic adrenalectomy was performed further establishing the diagnosis of primary pigmented nodular adrenocortical disease. After a nine-year follow-up there is no evidence of residual disease.ConclusionsEven though primary pigmented nodular adrenocortical disease is a rare cause of Cushings syndrome, it should be included in the differential diagnosis of adrenocorticotropic hormone-independent Cushings syndrome, especially because adrenal imaging can be misleading mimicking other adrenocortical diseases. Bilateral laparoscopic adrenalectomy is the preferred treatment in these subjects.

Pattern of Adrenal Hormonal Secretion in Patients with Adrenal Adenomas: The Relevance of Aldosterone in Arterial Hypertension

CONTEXT Approximately 10% of hypertensives are considered to exhibit autonomous aldosterone secretion (AAS). Although adrenal incidentalomas (AI) can be found in up to 19% of hypertensive individuals, data on the incidence of AAS in hypertensive patients with AI remain scarce. OBJECTIVE The aim was to study adrenal aldosterone (ALD) secretory pattern in patients with adrenal adenomas with and without arterial hypertension. DESIGN AND SETTING We conducted a case-control study in a tertiary general hospital. PATIENTS AND MAIN OUTCOME MEASURES We investigated 72 normotensive subjects with normal adrenal morphology and 191 subjects divided in three groups: 46 normotensive individuals with an AI (NAI), 89 hypertensive patients with an AI (HAI), and 56 hypertensive patients with an adrenal adenoma identified after investigation for arterial hypertension (HAA). Evaluation of autonomous cortisol secretion was based on a low-dose dexamethasone suppression test. Autonomous ALD secretion was based on a modified saline infusion test (MSI). Normal cutoff levels were obtained from the control matched population. RESULTS Post-MSI ALD levels and the ALD/renin (REN) ratios were significantly elevated in HAI and HAA patients compared to NAI subjects. To evaluate the prevalence of AAS, we applied the combination of post-MSI ALD level and the ALD/REN ratio simultaneously (post-MSI cutoffs, ALD levels, 2.41 ng/dl; ALD/REN ratio, 0.35 ng/dl/μU/ml). Based on these cutoffs, 12% of NAI, 36.4% of HAI, and 54.2% of HAA patients had AAS. The prevalence of autonomous cortisol secretion did not differ among the three groups. CONCLUSIONS Using a MSI test, we found a remarkably increased prevalence of AAS in hypertensive patients with adrenal adenomas, even when the latter represented an incidental finding.