Mineralocorticoids

BackgroundConventional glucocorticoid (GC) replacement for patients with adrenal insufficiency (AI) is inadequate. Patients with AI continue to have increased mortality and morbidity and compromised quality of life despite treatment and monitoring.Objectivesi) To review current management of AI and the unmet medical need based on literature and treatment experience and ii) to offer practical advice for managing AI in specific clinical situations.MethodsThe review considers the most urgent questions endocrinologists face in managing AI and presents generalised patient cases with suggested strategies for treatment.ResultsOptimisation and individualisation of GC replacement remain a challenge because available therapies do not mimic physiological cortisol patterns. While increased mortality and morbidity appear related to inadequate GC replacement, there are no objective measures to guide dose selection and optimisation. Physicians must rely on experience to recognise the clinical signs, which are not unique to AI, of inadequate treatment. The increased demand for corticosteroids during periods of stress can result in a life-threatening adrenal crisis (AC) in a patient with AI. Education is paramount for patients and their caregivers to anticipate, recognise and provide proper early treatment to prevent or reduce the occurrence of ACs.ConclusionsThis review highlights and offers suggestions to address the challenges endocrinologists encounter in treating patients with AI. New preparations are being developed to better mimic normal physiological cortisol levels with convenient, once-daily dosing which may improve treatment outcomes.

Stress hormones, such as corticosteroids, modulate the transmission of hippocampal glutamatergic synapses and NMDA receptor (NMDAR)-dependent synaptic plasticity, favouring salient behavioural responses to the environment. The corticosterone-induced synaptic adaptations partly rely on changes in NMDAR signalling, although the cellular pathway underlying this effect remains elusive. Here, we demonstrate, using single molecule imaging and electrophysiological approaches in hippocampal neurons, that corticosterone specifically controls GluN2B-NMDAR surface dynamics and synaptic content through mineralocorticoid signalling. Strikingly, extracellular corticosterone was sufficient to increase the trapping of GluN2B-NMDAR within synapses. Functionally, corticosterone-induced potentiation of AMPA receptor content in synapses required the changes in NMDAR surface dynamics. These high-resolution imaging data unveiled that, in hippocampal networks, corticosterone is a natural, potent, fast and specific regulator of GluN2B-NMDAR membrane trafficking, tuning NMDAR-dependent synaptic adaptations.

Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of the 11β-hydroxysteroid dehydrogenase type 2, a GR regulated gene. We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism, incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid-independent hypertension.

PurposePatients with primary adrenal insufficiency (PAI) require mineralocorticoid replacement therapy in addition to glucocorticoids. These therapies should be considered in combination because most glucocorticoids also possess mineralocorticoid activity. We aimed to investigate the relationship between fludrocortisone and hydrocortisone-equivalent dosing in patients with PAI.MethodsData were obtained from the European Adrenal Insufficiency Registry (EU-AIR), a multinational, multicenter, observational study conducted between August 7, 2012, and October 31, 2020, in endocrinology centers in Germany, Italy, the Netherlands, Sweden, and the UK. Patients with PAI (excluding congenital adrenal hyperplasia or known hypertension) and treated with immediate-release hydrocortisone (IRHC), modified-release hydrocortisone (MRHC), or cortisone acetate were included. The relationship between hydrocortisone-equivalent and fludrocortisone doses and mineralocorticoid potency corrected for body surface area (BSA) was examined.ResultsOverall, 670 (mean age: 46.2 years; 453 [67.6%] women) of 924 patients with PAI in EU-AIR were analyzed. Of those who received at least one dose of fludrocortisone (n = 350), 45 patients (12.9%) were receiving hydrocortisone-equivalent doses/BSA of ≤ 10 mg/day/m2, 170 patients (48.6%) > 10-15 mg/day/m2, and 133 patients (38.0%) > 15 mg/day/m2. No clear associations were found between total daily fludrocortisone dose/BSA and hydrocortisone-equivalent dose/BSA, or between combined mineralocorticoid potency/BSA and systolic or diastolic blood pressure and sodium or potassium levels. Higher systolic blood pressure was found in IRHC than MRHC groups.ConclusionsFludrocortisone prescription in PAI appears to be independent of glucocorticoid replacement therapy. IRHC and MRHC might differ in mineralocorticoid effect owing to different pharmacokinetic profiles.Clinical trial registrationNCT01661387.