Adrenal Insufficiency Syndrome Research Articles

History of Adrenal Research: From Ancient Anatomy to Contemporary Molecular Biology.

The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders.

A Founder Mutation in the POMC 5'-UTR Causes Proopiomelanocortin Deficiency Through Splicing-Mediated Decrease of mRNA.

The syndrome of adrenal insufficiency, obesity, and red hair is a rare autosomal recessive disorder. The majority of disease-causing variants associated with the syndrome are located in the coding region of the POMC gene. This work describes 7 unrelated patients who shared a novel homozygous mutation in the 5'-untranslated region (UTR) of the POMC gene and functionally characterize this novel variant. Whole-exome sequencing (WES) with autozygosity mapping, Sanger sequencing, model expression system studies, and RNA sequencing were used for identification of the disease-causing variant and its subsequent functional characterization. Seven unrelated patients of the Perm Tatar ethnic group presented with hypoglycemia and excessive weight gain, low plasma adrenocorticotropin, and cortisol. Five of 7 children had red hair; 6 of 7 patients also showed signs of bronchial obstruction. WES showed shared autozygosity regions overlapping the POMC gene. Sanger sequencing of the POMC 5'-UTR detected a homozygous variant chr2:25391366C > T (hg19) at the splice donor site of intron 1. As demonstrated by the model expression system, the variant led to a significant decrease in the POMC messenger RNA level. Analyses of the patients' haplotypes were suggestive of the founder effect. We estimate that the mutation must have occurred at least 4.27 generations ago (95% CI, 0.86-7.67). This report presents a new molecular mechanism of POMC deficiency and contributes to the information on phenotypic variability in patients with this disorder.

46, XY Disorder of Sexual Development with Ambiguous Female External Genitalia: A Case Report

Disorder of Sexual Development (DSD) is a group of congenital conditions with atypical development of sex at chromosomal, gonadal or anatomic level. Genetic males with DSD (46 XY DSD) can present with female external genital phenotype, ambiguous, or a micropenis. It is caused by incomplete intrauterine masculinization with or without the presence of Müllerian structures. It results either from decreased synthesis of testosterone or DHT or from impairment of androgen action. Herein, we report a case of a 13-year child raised as female with hoarseness of voice and gradual enlargement of clitoris with hormonal assessment not suggestive of either 5 Alfa Reductase deficiency, Congenital Adrenal Insufficiency Syndrome or 17β-Hydroxysteroid Dehydrogenase deficiency

Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.

Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1–/– mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1–/– mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent a distinct multisystemic disorder of sphingolipid metabolism.

Transphenoidal surgery without steroid replacement in patients with morning serum cortisol below 9 μg/dl (250 Nmol/l)

Adrenal insufficiency is a feared complication in patients undergoing transphenoidal surgery (TSS). Using the insulin tolerance test (ITT) for the preoperative assessment of hypothalamic-pituitary-adrenal (HPA) status is less than ideal, and the morning serum cortisol (MSC) is often used as a proxy for ITT. However, neither the ITT nor the MSC level has been validated to indicate HPA sufficiency compared to a physiological gold standard such as patients' ability to withstand transphenoidal surgery. To evaluate the intraoperative and postoperative course of nine patients with non-ACTH-secreting pituitary adenomas who did not receive intraoperative cortisol replacement despite having a preoperative MSC below 9 μg/dl (250 nmol/l) and to compare this with a set of patients with a preoperative MSC greater than 14.5 μg/dl (400 nmol/l) and another set of patients with MSC below 9 μg/dl (250 nmol/l) who received intraoperative cortisol administration. Preoperative and day 1 and day 2 postoperative MSC, intraoperative anesthetic record, vital signs, fluid balance, medications, and complications were recorded. None of the patients experienced the full syndrome of adrenal insufficiency. One patient with a preoperative MSC <9 μg/dl (250 mol/l) had isolated postoperative fatigue and required cortisol replacement. No patient suffered any life-threatening complications. There were no differences among the three groups in their intraoperative or postoperative courses when compared for intraoperative hypotension, acute blood pressure drop, and administration of vasopressors. This study suggests that TSS can be performed safely in patients with preoperative MSC less than 9 μg/dl (250 nmol/l) in closely monitored settings without intraoperative cortisol administration. Further studies are warranted.

A young boy with diffuse hyperpigmentation and delayed puberty

An 18-year-old male patient had presented with diffuse hyperpigmentation after birth and with adrenal insufficiency syndrome since childhood. After puberty, no secondary sexual signs developed. Laboratory examination showed an extremely high concentration of serum triglycerides (9.14 mmol/L) and plasma adrenocorticotropic hormone (>275 pmol/L), however, a low concentration of plasma free cortisone (<25.1-67.6 nmol/L). Abdomen computed tomography detected atrophy of both adrenals glands.

A novel DAX1 gene mutation in a Turkish infant with X-linked adrenal hypoplasia congenita

Adrenal hypoplasia congenita (AHC) is a rare inherited disorder of the adrenal cortex commonly manifested as an early onset adrenal insufficiency syndrome. A novel DAX1 (NR0B1) gene mutation was detected in a Turkish newborn boy presenting with primary adrenal insufficiency. He was from a family with a history of unexplained death of three male siblings in the neonatal period. This report highlights the value of mutational analysis of the DAX1 gene for definitive diagnosis of AHC as well as for genetic counselling because this disorder shows an X-linked genetic pattern of transmission, providing the possibility of finding new cases even in presymptomatic individuals.

Primary Bilateral Adrenal Non-Hodgkin's Burkitt-Like Lymphoma: A Rare Cause of Primary Adrenal Insufficiency. Case Report and Literature Review

Primary bilateral adrenal non-Hodgkin's lymphoma is an extremely rare entity. Only 44 cases have been reported in the literature. The most common presenting symptoms are abdominal pain, fever, asthenia, constipation, weight loss or typical symptoms of adrenal insufficiency, hypertension, darkening of skin, orthostatic hypotension or an addisonian crisis. The case is presented of a 57-year-old man suffering from primary bilateral adrenal lymphoma with symptoms of adrenal insufficiency syndrome associated with bilateral, stabbing lumbar pain and a palpable mass on the left side. Laboratory tests revealed a considerable increase in lactate dehydrogenase levels, adrenal insufficiency, and high corticotropin levels. Abdominal CT scan showed two large adrenal masses. A CT-guided fine needle aspiration biopsy revealed a large B-cell non-Hodgkin's lymphoma. Combination chemotherapy according to the CHOP protocol with cyclophosphamide, doxorubicin, vincristine and prednisolone was initiated, which caused a slight reduction in size of the two adrenal masses. The patient underwent a bilateral adrenalectomy with almost complete excision of the tumors. Replacement therapy with cortisone acetate was initiated postoperatively. Adjuvant combination chemotherapy according to the CHOP protocol was started but renal failure gradually emerged and the treatment could not be completed. The patient died seven months after surgery due to acute bronchial pneumonia and progression of disease. Primary bilateral adrenal non-Hodgkin's lymphoma mainly affects adult men. Diagnosis is based on histological examination. Whether associated or not with radiotherapy, chemotherapy is the most recommended treatment. Surgery, where possible, seems to lead to an increase in survival rates, but it is not possible to draw any definite conclusions on its effectiveness as yet.

Idiopathic achalasia is not allelic to alacrima achalasia adrenal insufficiency syndrome at the ALADIN locus

Background. Evidence indicates that patients with familial achalasia associated with Allgrove or triple-A syndrome (i.e. alacrima, achalasia and adrenocorticotropin-resistant adrenal insufficiency with neurological impairment) have mutations of the alacrima achalasia adrenal insufficiency syndrome ( AAAS) gene. Aim. The present study was aimed at identifying possible AAAS gene mutations in patients with established idiopathic non-familial achalasia. Methods. Genomic DNA of 41 patients was isolated from peripheral blood cells using standard methods. The 16 exons of the AAAS gene (or ALADIN) were screened for mutations using the denaturing high-performance liquid chromatography method. Results. Four heterozygous nucleotidic variations have been identified in patients with idiopathic achalasia, among which three were exonic conservative polymorphisms [i.e. D138D (GAT → GAC), L227L (TTG → CTG) and F285F (TTC → TTT) in exons 5, 7 and 9, respectively]. The fourth nucleotidic variation was located in intron 13 (IVS14−23delT). All variants have been regarded as polymorphisms resulting in a normal ALADIN protein since they are either conservative or lying outside the consensus splice sites. Conclusions. Our data do not support a pathogenetic role for common AAAS gene mutations in patients with idiopathic achalasia as seen in Allgrove syndrome. These findings suggest the participation of different mechanisms in the pathogenesis of idiopathic achalasia.

The relative adrenal insufficiency syndrome in the intensive care unit: incidence and relationship to outcome

The aim of the current study was to investigate the incidence of relative adrenal insufficiency in a large cohort of critically ill patients. Furthermore, we wished to assess the relationship of adrenal function tests to outcome of patients admitted to an adult medical and surgical ICU. To this end, 151 (119 men) critically ill patients having various principal diagnoses were studied. The median age was 52 years (range 17–84 years). The median APACHE II score was 11. Blood was sampled within 48 hours of admission for measurement of serum concentrations of baseline cortisol and corticotropin (ACTH). Immediately after, a low-dose (1 μg) ACTH stimulation test was performed. Patients having stimulated cortisol levels below 18 μg/dl were defined as non-responders to the test. Median values for baseline cortisol and ACTH were 16.0 μg/dl (range 0.3–61.3 μg/dl) and 16.8 pg/ml (range 0.9–166.4 pg/ml) respectively. The median stimulated cortisol value was 22.4 μg/dl (range 4.7–70.0 μg/dl) and the median increment in cortisol was 7.1 μg/dl (range 0.2–25.6 μg/dl). There was a positive correlation between ACTH and baseline cortisol (r = 0.42, P < 0.001). Thirty-nine (26%) patients were non-responders to the low-dose ACTH stimulation test. Overall mortality was 26%. Non-survivors were older (64 vs 24 years, P = 0.002), and had a higher APACHE II score (13 vs 11, P = 0.007) compared with survivors. There were no differences between the two groups with regard to baseline or stimulated cortisol levels. Similarly, ACTH and the increment in cortisol was comparable in the two groups. In conclusion, this study involving a large number of severely ill patients showed that the relative adrenal insufficiency syndrome is quite common in the ICU; however, baseline or stimulated cortisol concentrations do not differ between survivors and non-survivors on admission to the ICU.

The relative adrenal insufficiency syndrome revisited: which patients will benefit from low-dose steroids?

Several clinical studies have given rise to optimism about low-dose steroid treatment in patients with sepsis. It reduces time to shock reversal and may even have a positive effect on mortality. The pathophysiology of the relative adrenal insufficiency syndrome has not yet been determined, and the usefulness of basal and stimulated cortisol levels in diagnosing this syndrome is still uncertain. This review will examine recent evidence to elucidate these questions. Studies performed in more than 1000 patients in intensive care show convincingly that in general serum cortisol levels are increased. Basal or stimulated cortisol levels are at best useful to predict mortality in patients in intensive care, not to decide which patients to treat or when to discontinue treatment. Measuring free cortisol concentrations rather than total cortisol concentrations in critically ill patients may lead to new research strategies to identify the mode of action of low-dose steroid treatment. It has been shown that low-dose corticosteroid administration to catecholamine-dependent patients in septic shock results in shock reversal. There seems to be a relative shortage of cortisol, because low-dose hydrocortisone administration resulting in cortisol levels as much as four times the already increased levels results in shock reversal. Strong evidence for a positive effect on mortality is still lacking, perhaps because of the relatively low number of patients investigated. A very important topic in interpreting studies is that total (free plus protein-bound) cortisol has been measured. Future studies should also measure free cortisol concentrations, which could add to our knowledge of the pathophysiology and treatment of the relative adrenal insufficiency syndrome. On the basis of current knowledge, there is no evidence to support a treatment strategy based on a random or stimulated cortisol level. At the moment, rapid hemodynamic improvement of catecholamine-dependent patients after the administration of low-dose corticosteroids still seems the best available clue to diagnosis.

The conquest of Addison's disease

Background A review of the understanding and treatment of adrenal insufficiency was undertaken to emphasize common themes in the history of endocrine disorders. Methods Literature survey. Results: The presence of the adrenal glands, initially ignored by anatomists, was first described by Eustachius and later confirmed by Casserius. Bartholin identified the glands as ductless. In 1855, Thomas Addison described the clinical syndrome of adrenal insufficiency. Medullary hormonal effects were described by Oliver and Shäfer in 1895; epinephrine was isolated by Takamini, and the secretory patterns were characterized by Cannon. Cortical function was elucidated by Biedl and Stewart and Rogoff, and the first cortical hormones were synthesized by Reichenstein. Hormonal replacement therapy paved the way for the first bilateral adrenalectomy, which was performed in 1950. Conclusions This review underscores the historical themes in endocrine diseases: discovery of the glands, identification of their hormonal products, use of the hormones for therapy, and biosynthesis for pharmacologic applications.

ACTH INSENSITIVITY, AUTONOMIC NERVOUS SYSTEM DISORDERS AND SENSORY POLYNEUROPATHY

A 10 year old boy is described with a syndrome of adrenal insufficiency due to selective ACTH insensitivity associated with autonomic nervous system disorders and sensory polyneuropathy. Production of glucocorticoids and adrenal androgens were insufficient, but there were no signs of even latent mineralocorticoid insufficiency (after 4 days of low sodium dlet-9mEq/L NaCl/day). In addition to achalasia, defective lacrimation, anisocoria and hyperkeratosis of palmes and soles, we also found defective sweating, permanent cutis anserina (impaired function of smooth hair muscles) and electromyographically proved sensory polyneuropathy, which were not previously reported in this rare syndrome.

Selective ACTH insensitivity associated with autonomic nervous system disorders and sensory polyneuropathy

A 10-year-old boy is described with a syndrome of adrenal insufficiency due to selective ACTH insensitivity associated with autonomic nervous system disorders. In addition to insufficient production of glucocorticoids and adrenal androgens, achalasia, defective lacrimation, anisocoria and hyperkeratosis of palms and soles we also found defective sweating, permanent cutis anserina and sensory polyneuropathy, which have not been reported previously in this rare syndrome.

Addison's Disease in a Seven-Year-Old Boy1

CASE REPORTS of classical Addison's disease in children are infrequent. Atkinson (1), reviewing the literature up to 1937, found 40 cases which he believed could be interpreted as adrenal insufficiency. Only 5 of these occurred in children under 10 years of age. Since that time, there have been 5 additional cases noted in the literature. Three of these have been classified in the syndrome of adrenal insufficiency associated with macrogenitosomia (Butler et. al., 2; Thelander and Cholffin, 3; Wilkins et. al., 4). Anderson (5) in 1942 reported the case of an 11-year-old boy with primary Addison's disease which he believed was the result of primary atrophy of the adrenals. Renshaw and Manning (6) observed a 12-year-old boy who, at autopsy, proved to have tuberculosis of the adrenals. Recently we have had under observation a 7-year-old boy with adreno-cortical insufficiency, whose case report should perhaps be added to the growing literature on this subject.

Blood Sugar and Chloride Changes in Adrenalectomized Rats During Adaptation to Various Stimuli

Summary and ConclusionsExperiments in the rat show that continuous exposure to non-specific damaging agents elicits a characteristic 3-stage general adaptation syndrome which is of considerably shorter duration in the adrenalectomized animal than in the normal. During the first stage, the blood chlorides and blood sugar are decreased; during the second stage, both these values return to normal in spite of continued treatment and the general condition of the animals is considerably improved. During the final third stage of exhaustion, hypoglycemia and hypochloremia reappear and general resistance decreases again. These experiments are in agreement with the conception that the primary cause of the adrenal insufficiency syndrome is a disturbance in the mechanism of adaptation and more particularly a decrease in the ability to maintain adaptation once it is acquired. The decrease in blood sugar, blood chlorides, blood volume, thermoregulating ability, muscular efficiency, etc., as well as the increase in bloo...