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Ursula Kuhnle, Ariel Rösler, Judith A. Pareira, Peter Gunzcler, Lenore S. Levine and Maria I. New

Abstract.

The effect of normalization of sodium balance was evaluated in children with aldosterone deficiency of several etiologies. In salt-losing congenital adrenal hyperplasia (CAH), treatment with a mineralocorticoid in doses that normalized plasma renin activity (PRA) induced a marked increase in linear growth. Serum 17-hydroxyprogesterone (17-OHP) and androgens fell further when adequate sodium balance was achieved, allowing in some cases a reduction in glucocorticoid replacement dose. Together with PRA measurement they were the most sensitive indicators of adequate mineralocorticoid and glucocorticoid replacement therapy. In 2 teenage children with aldosterone deficiency due to Addison's and autoimmune polyglandular disease similar improvement in growth as well as onset of puberty occurred when sodium balance was normalized by increased mineralocorticoid therapy. These studies show that adequate sodium balance is essential for normal growth and pubertal development.

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D. Armanini, S. Endres, U. Kuhnle and P. C. Weber

Abstract. The binding characteristics of glucocorticoid and mineralocorticoid receptors were determined in T-and B-lymphocytes from the spleen of four deceased kidney donors. The number of glucocorticoid and mineralocorticoid receptors was equivalent in T- and B-cells (respectively, 1308 ± 364 and 1335 ± 520 glucocorticoid receptors per cell, and 174 ± 29 and 164 ± 24 mineralocorticoid receptors per cell). The number of binding sites per cell was 5- to 10-fold higher for dexamethasone than for aldosterone. The apparent dissociation constant of dexamethasone for glucocorticoid receptors was 2-fold higher than that of aldosterone for mineralocorticoid receptors. In conclusion, subpopulations of human lymphocytes have an equal number of glucocorticoid and mineralocorticoid receptors.

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K Hagenfeldt, E Martin Ritzen, H Ringertz, J Helleday and K Carlstrom

AIM: To study bone mass, body composition and androgenic/anabolic activity in adult women with virilizing congenital adrenal hyperplasia (CAH) treated with glucocorticoids since infancy and to relate this to the postmenarcheal glucocorticoid impact. PATIENTS AND METHODS: Thirteen adult women with virilizing CAH treated with gluco- and mineralocorticoids but otherwise medicine-free were investigated with respect to bone mineral content, body composition by dual energy X-ray absorptiometry and endocrine status. In addition an index of accumulated postmenarcheal exogenous glucocorticoid impact was calculated. Seven of the patients had regular menstrual periods, and six were oligomenorrheic but responded with withdrawal bleedings on cyclic progestagens. The data for the patients were compared with those of age-matched healthy reference subjects. RESULTS: In spite of their shorter stature, CAH patients were significantly heavier and had a significantly higher body mass index and fat/lean body mass ratio than the controls. Their bone mineral area density (BMD) was significantly lower than that of the controls. Serum concentrations of androgens were subnormal in all except two of the patients. Strong negative associations were found between BMD and the calculated index of accumulated postmenarcheal glucocorticoid dose but not between BMD and circulating androgen levels. CONCLUSION: The results indicate that glucocorticoids were administered in excess in most of the patients, resulting in subnormal levels of adrenocortical androgens, increased body fat and bone demineralization. Increased catabolic activity due to hypercortisolism rather than decreased androgenic/anabolic steroids is probably the major cause of the subnormal BMD in the treated CAH patients.

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E Charmandari, CG Brook and PC Hindmarsh

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders resulting from deficiency of one of the five enzymes required for synthesis of cortisol in the adrenal cortex. The most common form of the disease is classic 21-hydroxylase deficiency, which is characterized by decreased synthesis of glucocorticoids and often mineralocorticoids, adrenal hyperandrogenism and impaired development and function of the adrenal medulla. The clinical management of classic 21-hydroxylase deficiency is often suboptimal, and patients are at risk of developing in tandem iatrogenic hypercortisolism and/or hyperandogenism. Limitations of current medical therapy include the inability to control hyperandrogenism without employing supraphysiologic doses of glucocorticoid, hyperresponsiveness of the hypertrophied adrenal glands to adrenocorticotropic hormone (ACTH) and difficulty in suppressing ACTH secretion from the anterior pituitary. Puberty imposes increased difficulty in attaining adrenocortical suppression despite optimal substitution therapy and adherence to medical treatment. Alterations in the endocrine milieu at puberty may influence cortisol pharmacokinetics and, consequently, the handling of hydrocortisone used as replacement therapy. Recent studies have demonstrated a significant increase in cortisol clearance at puberty and a shorter half-life of free cortisol in pubertal females compared with males. Furthermore, children with classic CAH have elevated fasting serum insulin concentrations and insulin resistance. The latter may further enhance adrenal and/or ovarian androgen secretion, decrease the therapeutic efficacy of glucocorticoids and contribute to later development of the metabolic syndrome and its complications.

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Clifford I. Chappel, George Rona and Roger Gaudry

ABSTRACT

The influence of mineralocorticoids and glucocorticoids on cardiac necrosis produced by isoproterenol was studied in intact and adrenalectomized rats. Mineralocorticoid therapy, deoxycorticosterone acetate or 9α-fluorocortisol caused an increased mortality and aggravated the heart lesions while pretreatment with glucocorticoids, cortisone or 9α-fluoro-16-hydro-cortisol (triamcinolone) had no appreciable effect. The actions of these steroids were substantially the same in intact animals or adrenalectomized animals maintained on saline. The significance of these results and their possible relationship to electrolyte balance are discussed.

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Benjamin Lechner, Katharina Lechner, Daniel Heinrich, Christian Adolf, Finn Holler, Holger Schneider, Felix Beuschlein and Martin Reincke

In patients with primary aldosteronism, specific treatment provides prognostic benefit over optimal antihypertensive therapy and is therefore crucial to reduce mortality and morbidity in this subgroup of patients with hypertension. Prognostic relevance has been shown for adrenalectomy in unilateral disease and for medical treatment with mineralocorticoid receptor antagonists in bilateral adrenal hyperplasia. Collectively, evidence points to the superiority of surgical treatment compared to medical treatment. The causal approach of removing the mineralocorticoid excess, as well as the often-accompanying glucocorticoid excess, might provide one biologically plausible explanation for the observation of slightly better outcomes with surgical therapy. However, in patients living with primary aldosteronism, medical treatment is often insufficient for three major reasons. First and foremost, no marker of sufficient aldosterone blockade has yet been established and therefore adequate treatment of the aldosterone excess is often dismissed as a treatment goal. Second, side effects often limit patient compliance. Third, as recommendations differ from other indications like heart failure, drug dosing is often inadequate. The aim of this review is first to provide an overview over medical treatment options and second to review potential markers for treatment surveillance in patients with primary aldosteronism.

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Isabelle Benoit, Delphine Drui, Lucy Chaillous, Benoît Dupas, Jean-François Mosnier, Bernard Charbonnel and Bertrand Cariou

Context

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive ACTH-resistance syndrome characterized by glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Here, we report the case of a young woman with a corticotroph pituitary adenoma as the initial presentation of FGD.

Case report

A 15-year-old girl was referred to our institution for a 16 mm pituitary adenoma associated with glucocorticoid deficiency. Clinical and biological features were evocative of FGD. DNA sequencing did not identify mutations in either the melanocortin 2 receptor (MC2R) or the MC2R accessory protein genes, indicating type 3 FGD. Despite adequate glucocorticoid replacement, plasma ACTH levels remained increased and pituitary magnetic resonance imaging (MRI) showed a progression of the tumour size resulting in optic chiasm compression with intra-tumoural haemorrhaging. When the patient was 26 years old, it was decided that she would undergo transsphenoidal surgery. The histomorphological analysis identified a well-individualized pituitary adenoma immunoreactive for ACTH. The proband's sister also exhibited type 3 FGD associated with pituitary hyperplasia upon MRI.

Conclusion

This case highlights the relationship between FGD and hyperplasia of ACTH-producing cells, potentially leading to histologically proven pituitary corticotroph adenomas. This observation raises the question of the pituitary MRI's significance in the follow-up of FGD.

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PM Stewart

Two isoforms of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) interconvert the active glucocorticoid, cortisol, and inactive cortisone. 11beta-HSD1 acts predominantly as an oxo-reductase in vivo using NADP(H) as a cofactor to generate cortisol. In contrast, 11beta-HSD2 is a NAD-dependent dehydrogenase inactivating cortisol to cortisone, thereby protecting the mineralocorticoid receptor from occupation by cortisol. In peripheral tIssues, both enzymes serve to control the availability of cortisol to bind to corticosteroid receptors. 11beta-HSD2 protects the mineralocorticoid receptor from cortisol excess; mutations in the HSD11B2 gene explain an inherited form of hypertension, the syndrome of 'apparent mineralocorticoid excess', in which 'Cushing's disease of the kidney' results in cortisol-mediated mineralocorticoid excess. Inhibition of 11beta-HSD2 explains the mineralocorticoid excess state seen following liquorice ingestion and more subtle defects in enzyme expression might be involved in the pathogenesis of 'essential' hypertension. 11beta-HSD1 by generating cortisol in an autocrine fashion facilitates glucocorticoid receptor-mediated action in key peripheral tIssues including liver, adipose tissue, bone and the eye. 'Cushing's disease of the omentum' has been proposed as an underlying mechanism in the pathogenesis of central obesity and raises the exciting possibility of selective 11beta-HSD1 inhibition as a novel therapy for patients with the metabolic syndrome. 'Pre-receptor' metabolism of cortisol via 11beta-HSD isozymes is an important facet of corticosteroid hormone action. Aberrant expression of these isozymes is involved in the pathogenesis of diverse human diseases including hypertension, insulin resistance and obesity. Modulation of enzyme activity may offer a future therapeutic approach to treating these diseases whilst circumventing the endocrine consequences of glucocorticoid excess or deficiency.

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Lee S Nguyen, Nathalie Rouas-Freiss, Christian Funck-Brentano, Monique Leban, Edgardo D Carosella, Philippe Touraine, Shaida Varnous, Anne Bachelot and Joe-Elie Salem

Background

HLA-G is an immune checkpoint molecule, naturally expressed during pregnancy, playing a critical role in the tolerance of the fetal semi-allograft from the maternal immune system. While HLA-G expression levels are associated with progesterone, the influence of other hormones is still unclear. Congenital adrenal hyperplasia (CAH) represents an adequate model to study the hormonal influence on biomarkers as it leads to impaired cortisol biosynthesis and increased progesterone and androgens production due to 21-hydroxylase enzyme deficiency.

Methods

In a cross-sectional study of CAH patients matched on sex and age with healthy control, the association between circulating levels of soluble HLA-G and hormones was assessed by use of non-parametric analyses tests. Multivariable linear regressions were performed on normalized data.

Results

Overall, 83 CAH patients and 69 healthy controls were included. Among CAH patients, all were under glucocorticoid and 52 (62.6%) were under mineralocorticoid supplementation. Compared to controls, CAH patients had increased HLA-G levels (15 vs 8 ng/mL, P = 0.02). In controls, HLA-G level was independently associated with progesterone and estradiol (β = 0.44 (0.35–1.27) and −0.44 (−0.94, −0.26) respectively, both P values = 0.001). In CAH patients, HLA-G level was independently associated with mineralocorticoid supplementation dosage (β = 0.25 (0.04–0.41), P = 0.001) and estradiol (β = −0.22 (−0.57, −0.02), P < 0.001).

Conclusion

CAH patients had higher HLA-G levels than healthy controls. HLA-G level was positively associated with progesterone and corticosteroid supplementation, and negatively with estradiol. The association between mineralocorticoid, renin and HLA-G levels may suggest a role of the renin-angiotensin system in the expression of soluble HLA-G.

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Brian R Walker

Abstract

Chronic excessive activation of glucocorticoid receptors induces obesity, insulin resistance, glucose intolerance, dyslipidaemia and hypertension. Subtle abnormalities of the hypothalamic–pituitary–adrenal axis and/or of tissue sensitivity to glucocorticoids are also associated with these cardiovascular risk factors in patients with the metabolic syndrome. Furthermore, glucocorticoids have direct effects on the heart and blood vessels, mediated by both glucocorticoid and mineralocorticoid receptors and modified by local metabolism of glucocorticoids by the 11β-hydroxysteroid dehydrogenase enzymes. These effects influence vascular function, atherogenesis and vascular remodelling following intra-vascular injury or ischaemia. This article reviews the systemic and cardiovascular effects of glucocorticoids, and the evidence that glucocorticoids not only promote the incidence and progression of atherogenesis but also modify the recovery from occlusive vascular events and intravascular injury. The conclusion is that manipulation of glucocorticoid action within metabolic and cardiovascular tissues may provide novel therapeutic avenues to combat cardiovascular disease.