Publications

The Primary Aldosteronism Foundation maintains a list of salient publications. Topics range from pathogenesis to the implications of excess aldosterone. We regularly update the list with new topics, and new articles are added as they become public.

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Mutual Effects of Melatonin and Activin on Induction of Aldosterone Production by Human Adrenocortical Cells

Abstract/Summary:

Melatonin has been reported to suppress adrenocorticotropin (ACTH) secretion in the anterior pituitary and cortisol production in the adrenal by different mechanisms. However, the effect of melatonin on aldosterone production has remained unknown. In this study, we investigated the role of melatonin in the regulation of aldosterone production using human adrenocortical H295R cells by focusing on the activin system expressed in the adrenal. Melatonin receptor MT1 mRNA and protein were expressed in H295R cells and the expression levels of MT1 were increased by activin treatment. Activin increased ACTH-induced, but not angiotensin II (Ang II)-induced, aldosterone production. Melatonin alone did not affect basal synthesis of either aldosterone or cortisol. However, melatonin effectively enhanced aldosterone production induced by co-treatment with ACTH and activin, although melatonin had no effect on aldosterone production induced by Ang II in combination with activin. These changes in steroidogenesis became apparent when the steroid production was evaluated by the ratio of aldosterone/cortisol. Melatonin also enhanced dibutyryl-AMP-induced aldosterone/cortisol levels in the presence of activin, suggesting a functional link to the cAMP-PKA pathway for induction of aldosterone production by melatonin and activin. In accordance with the data for steroids, ACTH-induced, but not Ang II-induced, cAMP synthesis was also amplified by co-treatment with melatonin and activin. Furthermore, the ratio of ACTH-induced mRNA level of CYP11B2 compared with that of CYP17 was amplified in the condition of treatment with both melatonin and activin. In addition, melatonin increased expression of the activin type-I receptor ALK-4 but suppressed expression of inhibitory Smads6/7, leading to the enhancement of Smad2 phosphorylation. Collectively, the results showed that melatonin facilitated aldosterone production induced by ACTH and activin via the cAMP-PKA pathway. The results also suggested that mutual enhancement of melatonin and activin receptor signaling is involved in the induction of aldosterone output by adrenocortical cells.

Authors: Takayuki Hara, Fumio Otsuka, Naoko Tsukamoto-Yamauchi, Kenichi Inagaki, Takeshi Hosoya, Eri Nakamura, Tomohiro Terasaka, Motoshi Komatsubara, Hirofumi Makino
Keywords: melatonin, activin
DOI Number: 10.1016/j.jsbmb.2015.04.012
Publication Year: 2015

Follistatin-Like 1 Regulates Hypertrophy in Heart Failure With Preserved Ejection Fraction

Abstract/Summary:

Heart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of all clinical presentations of heart failure, (HF) and its prevalence is expected to increase. However, there are no evidence-based therapies for HFpEF; thus, HFpEF represents a major unmet need. Although hypertension is the single most important risk factor for HFpEF, with a prevalence of 60% to 89% from clinical trials and human HF registries, blood pressure therapy alone is insufficient to prevent and treat HFpEF. Follistatin-like 1 (Fstl1), a divergent member of the follistatin family of extracellular glycoproteins, has previously been shown to be elevated in HF with reduced ejection fraction and associated with increased left ventricular mass. In this study, blood levels of Fstl1 were increased in humans with HFpEF. This increase was also evident in mice with hypertension-induced HFpEF and adult rat ventricular myocytes stimulated with aldosterone. Treatment with recombinant Fstl1 abrogated aldosterone-induced cardiac myocyte hypertrophy, suggesting a role for Fstl1 in the regulation of hypertrophy in HFpEF. There was also a reduction in the E/A ratio, a measure of diastolic dysfunction. Furthermore, HFpEF induced in a mouse model that specifically ablates Fstl1 in cardiac myocytes (cardiac myocyte-specific Fstl1 knockout [cFstl1-KO]) showed exacerbation of HFpEF with worsened diastolic dysfunction. In addition, cFstl1-KO-HFpEF mice demonstrated more marked cardiac myocyte hypertrophy with increased molecular markers of atrial natriuretic peptide and brain natriuretic peptide expression. These findings indicate that Fstl1 exerts therapeutic effects by modulating cardiac hypertrophy in HFpEF.

Authors: Komei Tanaka, María Valero-Muñoz, Richard M. Wilson, Eric E. Essick, Conor T. Fowler, Kazuto Nakamura, Maurice van den Hoff, Noriyuki Ouchi, Flora Sam
Keywords: follistatin
DOI Number: 10.1016/j.jacbts.2016.04.002
Publication Year: 2016

Novel Action of Activin and Bone Morphogenetic Protein in Regulating Aldosterone Production by Human Adrenocortical Cells

Abstract/Summary:

We have uncovered a functional bone morphogenetic protein (BMP) and activin system complete with ligands (BMP-6 and activin βA/βB), receptors (activin receptor-like kinase receptors 2, 3, and 4; activin type-II receptor; and BMP type-II receptor), and the binding protein follistatin in the human adrenocortical cell line H295R. Administration of activin and BMP-6 to cultures of H295R cells caused concentration-responsive increases in aldosterone production. The mRNA levels of steroidogenic acute regulatory protein or P450 steroid side-chain cleavage enzyme, the rate-limiting steps of adrenocortical steroidogenesis, were enhanced by activin and BMP-6. Activin and BMP-6 also activated the transcription of steroidogenic acute regulatory protein as well as the late-step steriodogenic enzyme CYP11B2. Activin enhanced ACTH-, forskolin-, or dibutyryl-cAMP- but not angiotensin II (Ang II)-induced aldosterone production, whereas BMP-6 specifically augmented Ang II-induced aldosterone production. Activin and ACTH but not BMP-6 increased cAMP production. Follistatin, which inhibits activin actions by binding, suppressed basal and ACTH-induced aldosterone secretion but failed to affect the Ang II-induced aldosterone level. Furthermore, MAPK signaling appeared to be involved in aldosterone production induced by Ang II and BMP-6 because an inhibitor of MAPK activation, U0126, reduced the level of aldosterone synthesis stimulated by Ang II and BMP-6 but not activin. In addition, Ang II reduced the expression levels of BMP-6 but increased that of activin βB, whereas ACTH had no effect on these levels. Collectively, the present data suggest that activin acts to regulate adrenal aldosterone synthesis predominantly by modulating the ACTH-cAMP-protein kinase A signaling cascade, whereas BMP-6 works primarily by modulating the Ang II-MAPK cascade in human adrenal cortex in an autocrine/paracrine fashion.

Authors: Jiro Suzuki, Fumio Otsuka, Kenichi Inagaki, Masaya Takeda, Toshio Ogura, Hirofumi Makino
Keywords: activin, follistatin
DOI Number: 10.1210/en.2003-0968
Publication Year: 2004

Primary Aldosteronism and Obstructive Sleep Apnea: the Strong Ties Between Them

Abstract/Summary:

Recently, the relationship between PA/aldosterone and obstructive sleep apnea (OSA) has been intensely examined. As indicated in Fig. 1, aldosterone overproduction induces sodium-water reabsorption and elevates the nocturnal fluid shifting to the neck, which results in pharyngeal edema and the upper airway obstruction to worsen OSA. In contrast, intermittent hypoxia-induced by OSA activates renin-angiotensin system, which also results in aldosterone overproduction. Moreover, in relation to obesity-related hypertension, it has recently been proposed that undetermined adipocyte-derived factor(s) secreted from adipocytes may also induce aldosterone secretion. Interestingly, both ACTH and cortisol levels have been reported to be increased in OSA patients [10], suggesting that OSA also activates hypothalamic–pituitary–adrenal axis. Although the expression level of 11β-hydroxysteroid dehydrogenase type 2, which converts cortisol to cortisone in the distal nephron, in OSA has not been reported, it is possible that the increased cortisol may also induce the sodium-water reabsorption since both cortisol and aldosterone bind to mineralocorticoid receptors with similar affinities. However, the prevalence of PA among OSA remains uncertain, and it is still controversial whether hypertensive patients with OSA should be screened for PA.

Authors: Akira Sugawara, Hiroki Shimada, Yuri Otsubo, Takumi Kouketsu, Atsushi Yokoyama
Keywords: obstructive sleep apnea
DOI Number: 10.1038/s41440-023-01303-0
Publication Year: 2023

Clinical Course of Patients With Adrenal Incidentalomas and Cortisol Autonomy: a German Retrospective Single Center Cohort Study

Abstract/Summary:

Adrenal incidentalomas with cortisol autonomy are associated with increased cardiovascular morbidity and mortality. Specific data on the clinical and biochemical course of affected patients are lacking. A retrospective study was conducted from a tertiary referral centre in Germany. After exclusion of overt hormone excess, malignancy and glucocorticoid medication, patients with adrenal incidentalomas were stratified according to serum cortisol after 1 mg dexamethasone: autonomous cortisol secretion (ACS), >5.0; possible ACS (PACS), 1.9-5.0; non-functioning adenomas (NFA), ≤1.8 µg/dl. A total of 260 patients were enrolled (147 women (56.5%), median follow-up 8.8 (2.0-20.8) years). At initial diagnosis, median age was 59.5 (20-82) years, and median tumour size was 27 (10-116) mm. Bilateral tumours were more prevalent in ACS (30.0%) and PACS (21.9%) than in NFA (8.1%). Over time, 40/124 (32.3%) patients had a shift of their hormonal secretion pattern (NFA to PACS/ACS, n=15/53; PACS to ACS, n=6/47; ACS to PACS, n=11/24; PACS to NFA, n=8/47). However, none of the patients developed overt Cushing’s syndrome. Sixty-one patients underwent adrenalectomy (NFA, 17.9%; PACS, 24.0%; ACS, 39.0%). When non-operated patients with NFA were compared to PACS and ACS at last follow-up, arterial hypertension (65.3% vs. 81.9% and 92.0%; p<0.05), diabetes (23.8% vs. 35.6% and 40.0%; p<0.01), and thromboembolic events (PACS: HR 3.43, 95%-CI 0.89-13.29; ACS: HR 5.96, 95%-CI 1.33-26.63; p<0.05) were significantly less frequent, along with a trend towards a higher rate of cardiovascular events in case of cortisol autonomy (PACS: HR 2.23, 95%-CI 0.94-5.32; ACS: HR 2.60, 95%-CI 0.87-7.79; p=0.1). Twenty-five (12.6%) of the non-operated patients died, with higher overall mortality in PACS (HR 2.6, 95%-CI 1.0-4.7; p=0.083) and ACS (HR 4.7, 95%-CI 1.6-13.3; p<0.005) compared to NFA. In operated patients, prevalence of arterial hypertension decreased significantly (77.0% at diagnosis to 61.7% at last follow-up; p<0.05). The prevalence of cardiovascular events and mortality did not differ significantly between operated and non-operated patients, whereas thromboembolic events were significantly less frequent in the surgical treatment group. Our study confirms relevant cardiovascular morbidity in patients with adrenal incidentalomas (especially those with cortisol autonomy). These patients should therefore be monitored carefully, including adequate treatment of typical cardiovascular risk factors. Adrenalectomy was associated with a significantly decreased prevalence of hypertension. However, more than 30% of patients required reclassification according to repeated dexamethasone suppression tests. Thus, cortisol autonomy should ideally be confirmed before making any relevant treatment decision (e.g. adrenalectomy).

Authors: Hanna Remde, Stefanie Kranz, Sarah Maria Morell, Barbara Altieri, Matthias Kroiss, Mario Detomas, Martin Fassnacht, Timo Deutschbein
Keywords: cortisol secretion, incidentaloma
DOI Number: 10.3389/fendo.2023.1123132
Publication Year: 2023

Adrenal Incidentaloma: Cardiovascular and Metabolic Effects of Mild Cortisol Excess

Abstract/Summary:

In the vast majority of cases adrenal incidentalomas (AI) are benign adrenocortical adenomas. They are present in up to 10% of the population over 70 years, with incidence increasing with age. Mild cortisol excess (MCE) in the context of AI is defined as autonomous cortisol secretion (ACS) in the absence of the classical clinical features of Cushing’s syndrome. MCE has been reported in up to at least one third of patients with AI. Numerous studies have shown that MCE in AI is associated with increased cardiovascular events and mortality, likely to be consequent upon both hemodynamic changes and inflammatory pathways, and a worse metabolic phenotype characterized by: pancreatic β-cell dysfunction, insulin resistance, visceral obesity and dyslipidemia. There is currently no level 3 evidence from large intervention randomized controlled trials to guide management of MCE in AI, and there is a lack of predictive tools to allow stratification to intervention of only those patients who would benefit in terms of improved metabolic and cardiovascular end-points. Here, we describe the mal-effects of cortisol on cardiovascular and metabolic tissues and discuss management strategies based on current largely observational data.

Authors: Alan Kelsall, Ahmed Iqbal, John Newell-Price
Keywords: autonomous cortisol secretion, incidentaloma
DOI Number: 10.21037/gs.2019.11.19
Publication Year: 2020