Introduction: Patients with primary adrenal insufficiency receive long - term glucocorticoid replacement therapy, which may cause osteoporosis.

AIM OF THE STUDY: The aim of the study was to assess the effect of glucocorticoid replacement therapy in patients with Addison´s disease on bone mineral density (BMD), parameters of calcium - phosphate (Ca-P) metabolism as well as on bone turneover markers. PATIENTS AND METHODS: The study group consisted of 46 patients with Addison´s disease (12men, 17 pre- and 17 postmenopausal women, the control group consisted of 44 healthy individuals (8 men, 16 prepre- and 16 postmenopausal women). Ca-P metabolism parameters, bone turnover markers and adrenal hormones were examined in all groups. BMD was measured by dual-energy X-ray absorptiometry in the lumbar spine (BMD lumb) and forearm (BMDfore). RESULTS: We did not confirm an increased prevalence of osteoporosis and osteopenia in patients with Addison´s disease. BMD values did not correlate with hydrocortisone (HCT) doses, HCT doses calculated on body weight and body surface area as well as with duration of substitution treatment. Patients with daily HCT doses > 25 mg had significantly lower BMD in lumbar spine compared with patients with daily HCT doses 25 mg. In study group we observed decreased levels of adrenal androgens, in women also estradiol. Decreased level of serum calcium and increased level of osteocalcin, bone alkaline phosphatase, 25- hydroxyvitamin D were present in women with Addison´s disease. RANKL/OPG ratio was higher in patients with Addison´s disease compared with controls. CONCLUSION: Glucocorticoid replacement therapy is not a significant risk factor for development of osteoporosis in patients with Addison disease, because this therapy only physiologically replaces endogenous cortisol deficiency. An increased RANKL / OPG ratio may indicate a relative lack of OPG. It is possible that female patients, despite adequate substitution, have an increased bone turnover and a relatively higher risk of decrease in BMD. Potential risks are higher doses of glucocorticoid replacement therapy (HCT > 25 mg daily) and a typical steroid constellation (decreased adrenocortical androgens DHEA and DHEAS and in women also estradiol).

[Immune checkpoint inhibitors and endocrinological side effects].

Immune checkpoint inhibitors including anti-cytotoxic T-lymphocyte-associated antigen-4 and anti-programmed cell death-1 have revolutionized cancer therapy but have also induced serious immune-related adverse events including hormonal dysfunction. The objective of this review is to characterize the incidence, clinical presentation, management and prognosis of the endocrine-related adverse events including hypophysitis, thyroid dysfunction and diabetes mellitus. Combination therapy is associated with an increased risk of adverse events. We recommend close monitoring of the hormone levels and glycaemic status during and a year after treatment.

Visceral Fat and Novel Biomarkers of Cardiovascular Disease in Patients With Addison's Disease: A Case-Control Study.

Context: Patients with Addison's disease (AD) have increased cardiovascular mortality. Objective: To study visceral fat and conventional and exploratory cardiovascular risk factors in patients with AD. Design: A cross-sectional, single-center, case-control study. Subjects: Patients (n = 76; n = 51 women) with AD and 76 healthy control subjects were matched for sex, age, body mass index (BMI), and smoking habits. Main outcome measures: The primary outcome variable was visceral abdominal adipose tissue (VAT) measured using computed tomography. Secondary outcome variables were prevalence of metabolic syndrome (MetS) and 92 biomarkers of cardiovascular disease. Results: The mean ± standard deviation age of all subjects was 53 ± 14 years; mean BMI, 25 ± 4 kg/m2; and mean duration of AD, 17 ± 12 years. The median (range) daily hydrocortisone dose was 30 mg (10 to 50 mg). Median (interquartile range) 24-hour urinary free cortisol excretion was increased in patients vs controls [359 nmol (193 to 601 nmol) vs 175 nmol (140 to 244 nmol); P < 0.001]. VAT did not differ between groups. After correction for multiple testing, 17 of the 92 studied biomarkers differed significantly between patients and control subjects. Inflammatory, proinflammatory, and proatherogenic risk biomarkers were increased in patients [fold change (FC), >1] and vasodilatory protective marker was decreased (FC, <1). Twenty-six patients (34%) vs 12 control subjects (16%) fulfilled the criteria for MetS (P = 0.01). Conclusion: Despite higher cortisol exposure, VAT was not increased in patients with AD. The prevalence of MetS was increased and several biomarkers of cardiovascular disease were adversely affected in patients with AD.

The effect of types I and III interferons on adrenocortical cells and its possible implications for autoimmune Addison's disease.

Autoimmune Addison's disease (AAD) is caused by selective destruction of the hormone-producing cells of the adrenal cortex. As yet, little is known about the potential role played by environmental factors in this process. Type I and/or type III interferons (IFNs) are signature responses to virus infections, and have also been implicated in the pathogenesis of autoimmune endocrine disorders such as type 1 diabetes and autoimmune thyroiditis. Transient development of AAD and exacerbation of established or subclinical disease, as well as the induction of autoantibodies associated with AAD, have been reported following therapeutic administration of type I IFNs. We therefore hypothesize that exposure to such IFNs could render the adrenal cortex susceptible to autoimmune attack in genetically predisposed individuals. In this study, we investigated possible immunopathological effects of type I and type III IFNs on adrenocortical cells in relation to AAD. Both types I and III IFNs exerted significant cytotoxicity on NCI-H295R adrenocortical carcinoma cells and potentiated IFN-γ- and polyinosine-polycytidylic acid [poly (I : C)]-induced chemokine secretion. Furthermore, we observed increased expression of human leucocyte antigen (HLA) class I molecules and up-regulation of 21-hydroxylase, the primary antigenic target in AAD. We propose that these combined effects could serve to initiate or aggravate an ongoing autoimmune response against the adrenal cortex in AAD.

Induction of CXCL10 chemokine in adrenocortical cells by stimulation through toll-like receptor 3.

Addison's disease is a prototypic organ-specific autoimmune disease affecting the adrenal cortex. The CXC chemokine ligand 10 (CXCL10) is expressed early in viral infections, and is produced by primary adrenocortical cells stimulated by certain cytokines. CXCL10 is also elevated in the serum of Addison's disease patients. We therefore investigated if the viral RNA substitute polyinosine-polycytidylic acid (poly (I:C)) could influence the cytokine induced production of CXCL10 by adrenocortical cells. We found that poly (I:C) could induce CXCL10 in NCI-H295R adrenocortical carcinoma cells, either alone or synergistically along with cytokines interferon-γ and tumor necrosis factor-α. This effect was found to be mediated by toll-like receptor 3 and both nuclear factor κB (NFκB) and signal transducer and activator of transcription-1 (STAT1), but not type I interferons, seemed to be involved. We propose that the combination of environmental and endogenous factors presented here, could contribute to the multifactorial pathogenesis of autoimmune Addison's disease.

Assessment of salivary free cortisol levels by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in patients treated with mitotane.

OBJECTIVE: Mitotane is an adrenocytolytic agent used in adrenocortical carcinoma, inducing adrenal insufficiency, requiring replacement treatment. Such therapy is not easy to monitor because of mitotane interference. Salivary cortisol reflects a free fraction of plasma cortisol and may be useful in such patients. DESIGN: The aim of our study was to evaluate salivary cortisol by HPLC coupled to tandem-mass spectrometry (LC-MS/MS) and by an electrochemiluminescence immunoassay (ECLIA) in patients treated with mitotane. We enrolled 6 patients receiving mitotane and 2 Addison disease patients as negative controls and determined salivary cortisol rhythm. We also determined the salivary cortisol rhythm in 8 healthy subjects. Salivary samples (n=112) were assayed by ECLIA, using Roche Modular E170, and by LC-MS/MS. RESULTS: The mean values obtained by ECLIA were significantly higher than those obtained by LC-MS/MS in the mitotane group (p<0.001). In fact, in the group measured by LC-MS/MS, we observed several peaks eluting at a retention time different from the cortisol group, presumably due to cortisol-like analogues. In Addison disease, since steroidogenesis is absent, salivary cortisol values measured by the two methods did not show any significant difference (p=0.61). CONCLUSIONS: Salivary cortisol measured by LC-MS/MS is a selective method, excluding cortisol analogues accumulating in treated patients. Therefore, LC-MS/MS offers an effective system to monitor replacement therapy in mitotane treated patients.

Metabolic and cardiovascular profile in patients with Addison's disease under conventional glucocorticoid replacement.

OBJECTIVE: Although two studies have shown that Addison's disease (AD) is still a potentially lethal condition for cardiovascular, malignant, and infectious diseases, a recent retrospective study showed a normal overall mortality rate. Differently from secondary hypoadrenalism, scanty data exist on the role of conventional glucocorticoid replacement on metabolic and cardiovascular outcome in AD. SUBJECTS AND METHODS: In 38 AD under conventional glucocorticoid replacement (hydrocortisone 30 mg/day or cortisone 37.5 mg/day) ACTH, plasma renin activity (PRA), DHEAS, fasting glucose and insulin, 2-h glucose after oral glucose tolerance test, serum lipids, 24-h blood pressure and intima-media thickness (IMT) were evaluated and compared with 38 age-, sex- and body mass index (BMI)-matched controls (CS). RESULTS: AD had ACTH and PRA higher and DHEAS lower (p<0.0005) than CS. Mean waist was higher (p<0.05) in AD than in CS. Although no differences were found for mean gluco-lipids levels, a higher percentage of AD compared to CS were IGT (8 vs 0%), hypercholesterolemic (18 vs 8%), and hypertriglyceridemic (18 vs 8%); none of the AD and CS showed either HDL<40 mg/dl or LDL>190 mg/dl. At the multiple regression analysis, in both AD and CS, BMI was the best predictor of 2-h glucose and age of total and LDL cholesterol; in AD, no significant correlation was found between the above mentioned metabolic parameters and either hormone levels or disease duration. In both AD and CS 24-h blood pressure and IMT were normal. CONCLUSIONS: Our study shows a higher prevalence of central adiposity, impaired glucose tolerance and dyslipidemia in AD patients.

[Neurological and psychiatric aspects of some endocrine diseases. The role of neurosteroids and neuroactive steroids]. / Néhány endokrin betegség neurológiai és pszichiátriai vonatkozása. neuroaktív szteroidok és neuroszteroidok.

Regardless of their origin, neuroactive steroids are capable of modifying neural activities by modulating different types of membrane receptors. Neurosteroids are synthesized de novo in neurones and glia. Steroidogenic enzymes are found in the central nervous system. Classical steroid receptors are localized in the cytoplasm, they exert regulatory actions on the genome, and their activation causes medium- and long-term effects. Non-classical receptors are located within the membrane and act as mediators of short-term effects. Other important players are co-repressors and co-activators that can interfere with or enhance the activity of steroid receptors. Beyond their function in stress, corticosteroids play a very important role in fear, anxiety, and memory functions. Patients with Cushing's syndrome frequently develop mood disorder, reversible brain atrophy with transient memory loss, rarely delirium or psychosis. Well-known peripheral symptom is steroidal myopathy. In patients with Addison's disease the main signs are weakness of muscles, lack of energy, decreased mental functions and reduced quality of life. Estrogen and progesterone have their own respective hormone receptors, whereas allopregnanolone acts via the GABA receptors. These hormones have significant role in the development of brain, the architecture of neural circuits and dendrites, density of axonal connections, and the number of neurons. They influence maturation, neuroprotection, seizures, cognitive functions, mood, anxiety, pain, and restitution of peripheral nerves. Androgens also affect cognitive functions, pain, anxiety, mood, and additionally aggression.

Glucocorticoid replacement therapy in patients with Addison's disease.

One hundred and fifty years ago, Thomas Addison published his classic paper on the 'Constitutional and Local Effects of Disease of the Supra-renal Capsules', in which he described 11 patients with the disorder that would come to bear his name. Adrenal insufficiency is a rare disease, but its prevalence is increasing. The most frequent causes of adrenal insufficiency in western countries are autoimmune adrenalitis, but other causes include, tuberculosis systemic fungal infections, AIDS, metastatic carcinoma and isolated glucocorticoid deficiency. It is clear that autoimmunity precedes overt Addison's disease by years, as in many autoimmune endocrine disorders. Adrenocortical function is lost over a period of years as it progresses to overt Addison's disease. This editorial discusses the controversial glucocorticoid replacement therapy in patients with Addison's disease, and aims to provide a good review of literature and suggested guidelines for appropriate treatment of this disease.

11 beta-Hydroxysteroid dehydrogenase activity in hypothalamic obesity.

After extensive suprasellar operations for hypothalamic tumor removal, some patients develop Cushing-like morbid obesity while they receive replacement doses of glucocorticoids. In this study, we examined the hypothesis that target tissue conversion of inactive 11-ketosteroids to active 11 beta-OH glucocorticoids might explain the obesity of some patients with hypothalamic lesions. Toward this aim, we studied 10 patients with hypothalamic obesity and secondary adrenal insufficiency and 6 control Addisonian patients while they were on glucocorticoid replacement therapy. Pituitary hormone deficiencies were replaced when medically indicated. Twenty-four-hour urine was collected after a single oral dose of 12 mg/m(2) hydrocortisone acetate. The ratios of free and conjugated cortisol (F) to cortisone (E) and their metabolites, [tetrahydrocortisol (THF)+5 alpha THF]/tetrahyrdocortisone (THE), dihydrocortisols/dihydrocortisones, cortols/cortolones, and (F+E)/(THF+THE+5 alpha THF), were considered to represent 11 beta-hydroxysteroid dehydrogenase (HSD) activity. The 11-OH/11-oxo ratios were significantly higher in the urine of patients with hypothalamic obesity. The 11-OH/11-oxo ratios, however, did not correlate with the degree of obesity, yet a significant correlation was found between conjugated F/E and the ratio of visceral fat to sc fat measured by computerized tomography at the umbilical level. The consequence of increased 11 beta-HSD1 activity and the shift of the interconversion toward cortisol may contribute to the effects of the latter in adipose tissue. We propose that deficiency of hypothalamic messengers after surgical injury induces a paracrine/autocrine effect of enhanced glucocorticoid activity due to up-regulated 11 beta-HSD1 activity.

TNF mediates a murine model of Addison's crisis.

Addison's crisis is the most serious complication of adrenal insufficiency. To elucidate the mechanism of this disorder following infection, the role of TNF in adrenalectomized murine models of Addison's crisis and Addison's disease (chronic hypoglucocorticoidism) were examined. Adrenalectomy conferred a 40-fold increased sensitivity to the lethal effects of lipopolysacharride (LPS) (P < .001). Enhanced sensitivity to LPS was found to increase with duration of adrenal insufficiency (P < .02). Enhanced lethality to heat-killed Streptococcus pneumonia was also demonstrated (P < 0.02). Necropsy of endotoxin-killed adrenalectomized mice demonstrated similar pathologic findings to those found by others when the control mice were administered a lethal dose of either LPS or TNF. Adrenalectomized TNF receptor Ia and Ib double null mice were demonstrated to be resistant to the lethal effects of LPS (P < 0.02). Pretreatment with anti-TNF, but not control antisera, was found to prevent death in LPS-treated wild-type adrenalectomized mice as well (P < 0.02). Studies into the mechanism by which TNF was precipitating Addison's crisis demonstrated enhanced sensitivity to TNF (3-fold; P < 0.02), and a marked increase in serum TNF concentration (approximately 5-fold; P < 0.001) following LPS challenge. The effect of TNF upon long-term survival in adrenalectomized mice was examined in TNF-receptor Ia- and Ib-deficient mice. Deficiencies in either the TNF-receptor Ia or Ib was noted to confer a survival advantage relative to colony controls following adrenalectomy (P < 0.02). In summary, both LPS-induced Addison's crisis and chronic adrenal insufficiency are disorders of TNF disregulation. Based upon these data, therapeutic strategies targeted at controlling TNF in adrenal insufficiency are suggested.

Pulsatile luteinizing hormone secretion in patients with Addison's disease. Impact of glucocorticoid substitution.

The physiological and pathophysiological role of cortisol in pulsatile LH release was investigated in 14 patients (5 men, 6 premenopausal women, and 3 postmenopausal women) with Addison's disease. The explicit effect of cortisol in relation to the effect of corticotropin-releasing factor (CRF), ACTH, and opioids was ensured by hypo-, normo-, and hypercortisolism. Hypocortisolism was obtained by 24-h discontinuation of hydrocortisone (HC) followed by 23-h saline infusion. Eucortisolism was secured by infusion of HC (0.5 mg/kg) over 23 h. Stress-appropriate hypercortisolism was obtained by infusion of HC (2.0 mg/kg) over 23 h, preceded by treatment for 5 days with dexamethasone (1.5 mg/day). To imitate the normal diurnal rhythm for serum cortisol, HC was infused in graduated doses. Blood sampling was performed every 10 min during the last 10 h of the study period, followed by a LH-releasing hormone test (5 microg, i.v.) and a TRH test (10 microg, i.v.). In pre- and postmenopausal women, the mean LH level and the LH pulsatility pattern were similar on the 3 occasions. In contrast, the mean LH level in men was significantly reduced during hypocortisolism compared to that during eucortisolism (3.26 +/- 0.68 vs. 4.49 +/- 0.83 U/L; P < 0.05) and was associated with a clear decrease in LH pulse amplitude (1.09 +/- 0.33 vs. 1.96 +/- 0.53 U/L; P < 0.05). During high doses of glucocorticoids, the mean LH level in men was significantly lower than that during eucortisolism (3.81 +/- 0.88 vs. 4.49 +/- 0.83 U/L; P < 0.05). In both men and women, the mean PRL levels increased significantly (P < 0.05) during hypocortisolism, whereas high glucocorticoid doses suppressed the mean PRL level (P < 0.05). The LH and PRL responses to LH-releasing hormone and TRH were, however, similar during low, medium, and high cortisol levels in both men and women. In conclusion, our data suggest that the attenuation of pulsatile LH secretion in men during hypo- and hypercortisolism is due to variations in the hypothalamic opioid activity secondary to alterations in serum cortisol levels. A higher level of opioid receptor activity in men than in low estrogen women may explain the gender differences.

Inappropriate secretion of adrenocorticotropin from corticotroph hyperplasia in a case of Addison's disease.

A patient with Addison's disease, treated with conventional hydrocortisone replacement, developed deep hyperpigmentation, headache and vomiting. Plasma adrenocorticotropin (ACTH) level was extremely high, showing abnormal diurnal rhythm. Suppression of ACTH with glucocorticoids was attenuated and the responses to ovine corticotropin-releasing hormone (oCRF) and lysine vasopressin (LVP) were absent. Magnetic resonance imaging (MRI) suggested an enlargement of the pituitary gland, while immunohistological examination of pituitary fragments obtained by transsphenoidal surgery revealed corticotroph hyperplasia without microadenoma. Postoperatively, plasma ACTH returned to normal and adequately responded to oCRF and LVP. Over the year since surgery, the symptoms have gradually improved and the patient has resumed normal activities.

Cosecretion of peptides derived from gamma-human atrial natriuretic polypeptide in normal volunteers and patients with essential hypertension and adrenal disorders.

Using two radio-immunoassays for N-terminal and C-terminal fragments of human atrial natriuretic polypeptide (ANP) precursor, gamma-hANP [human atrial natriuretic factor-(1-126)], that is gamma-hANP(1-25) [human atrial natriuretic factor-(1-25)] and alpha-hANP [human atrial natriuretic factor-(99-126)], we studied the secretion of gamma-hANP-derived peptides into circulation from the heart in normal subjects and patients with essential hypertension and adrenal disorders. Volume expansion with 2 litres physiological saline increased plasma gamma-hANP(1-25)-like immunoreactivity concomitantly with plasma alpha-hANP-like immunoreactivity in normal subjects. Infusion of angiotensin II (20 ng/kg per min) or noradrenaline (200 ng/kg per min) also caused a parallel increase in plasma gamma-hANP(1-25)-like and alpha-hANP-like immunoreactivity. Plasma gamma-hANP(1-25)-like immunoreactivity levels were changed together with alpha-hANP-like immunoreactivity in patients with essential hypertension and adrenal disorders. These results indicate that gamma-hANP-derived peptides, alpha-hANP and the 10-k N-terminal fragment of gamma-hANP (N-peptide) are cosecreted from the heart and that the simultaneous measurement of N-peptide and alpha-hANP serves as an indicator of the cardiac endocrine function. The significance of N-peptide as a hormone must await further clarification.

Increased production of alpha-melanocyte-stimulating hormone in the pituitary gland of patients with untreated Addison's disease.

There is evidence that peptides related to alpha-melanocyte-stimulating hormone (alpha-MSH) are involved in regulating the zona glomerulosa of the adrenal cortex in certain species. We have investigated the amount of immunoreactive (IR)-alpha-MSH in the human pituitary gland of patients suffering from Addison's disease. We show increased numbers of cells containing demonstrable IR-alpha-MSH in the anterior lobe in these patients. Using an antiserum with specificity for the acetylated N-terminus of alpha-MSH we suggest that the major form present is desacetyl-alpha-MSH. These findings are in keeping with a role for anterior lobe derived desacetyl-alpha-MSH in the regulation of the human adrenal cortex.