Normal Basal Cortisol Levels Research Articles

Adrenal insufficiency with chronic hyponatraemia and normal basal cortisol level: time to review the investigation of hyponatraemia

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

SUN-195 Bilateral Aldosterone-Producing Adenomas: A New Subtype of Bilateral Primary Aldosteronism?

Background: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). PA subtypes include aldosterone-producing adenomas (APA) and bilateral adrenal hyperplasia. To date, few PA patients with bilateral adenomas have been reported, but only one case was well characterized by anatomopathological analysis and clinical outcome after adrenal sparing surgery (1). Clinical case: A 53-year-old woman was referred to investigate resistant HT and hypokalemia. (3.0 mEq/L). PA screening revealed aldosterone (A) of 37.9 ng/dL, renin (R) < 1.6 (4.4-46.1 mUI/L), A/R ratio of 24.8. Confirmatory testing confirmed PA diagnosis: seated saline infusion test (A= 83.3 ng/dL) and intravenous furosemide test (R= 3.1 mUI/L; positive test <13 mUI/L). Hypercortisolism investigation revealed a non-suppressible cortisol after an overnight 1 mg low-dose dexamethasone suppression [cortisol (C)= 2.9 μg/dL and dexamethasone= 701 (˃130 ng/dL)], and normal urinary free cortisol, midnight salivary cortisol, plasma DHEAS and ACTH levels. Computed tomography demonstrated bilateral adrenal nodules without adrenal thickening: 3.5 cm right nodule (pre-contrast density of 7UH density; absolute wash-out of 71%) and 2.5 cm left nodule (pre-contrast density of 8UH density; absolute wash-out of 78%). Sequential adrenal venous (AV) sampling (AVS) under continuous cosyntropin infusion showed a lateralization index of 3.4 (bilateral disease <4). Then, the patient underwent right adrenalectomy and left nodulectomy. In the postoperative period, she presented normalization of K+ levels and complete HT remission. She remained under hydrocortisone replacement for 2 months. After 2 months, biochemical evaluation revealed normal basal cortisol levels (13.3 µg/dL) and biochemical cure of PA (A= 3.1 ng/dL and R= 15.3 mUI/L). Currently, she doesn’t have symptoms of adrenal insufficiency after discontinuation of hydrocortisone. Anatomopathological analysis showed bilateral adenomas (Weiss score of 0) in both sides without adjacent hyperplasia. CYP11B2 immunohistochemistry displayed a strong staining in 50% of cells in the right adenoma and in 30% of cells in the left adenoma. Few aldosterone-producing cell clusters (APCC) were identified in the right zona glomerulosa, which is a frequent finding in normal adrenals. Conclusion: We herein described a very rare case of PA caused by bilateral-producing adenomas, confirmed by AVS and CYP11B2 staining after adrenal sparing surgery.

The Role of Early Life Stress in HPA Axis and Anxiety.

Substantial evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology. The most recent studies reviewed here suggest that early life stressors are associated with an increased risk for anxiety disorders in adulthood. Early life stress predisposes individuals to develop a number of psychiatric syndromes, particularly affective disorders, including anxiety disorders, and is therefore a significant health problem.This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and generalized anxiety disorder (GAD), panic disorder, and phobias and the role of early life stress as an important risk factor for HPA axis dysfunction.The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. In addition to melancholic depression, a spectrum of other conditions may be associated with increased and prolonged activation of the HPA axis, including panic, GAD, phobias and anxiety. Moreover, HPA axis changes appear to be state-dependent, tending to improve upon resolution of the anxiety syndrome. Interestingly, persistent HPA hyperactivity has been associated with higher rates of relapse. These studies suggest that an evaluation of the HPA axis during treatment may help identify patients who are at a higher risk for relapse. These findings suggest that this dysfunction of the HPA axis is partially attributable to an imbalance between glucocorticoid and mineralocorticoid receptors. Evidence has consistently demonstrated that glucocorticoid receptor function is impaired in anxiety disorders. Moreover, normal basal cortisol levels and hyper-responsiveness of the adrenal cortex during a psychosocial stressor are observed in social phobics. Finally, abnormal HPA axis activity has also been observed in generalized anxiety disordered patients. Early stressful life events may provoke alterations of the stress response and thus of the HPA axis that can endure during adulthood, predisposing individuals to develop psychopathology.

Relative adrenal insufficiency in adults with sickle cell disease.

Rheological modifications observed in sickle cell anemia are associated with ischemic complications that can cause target organ functional impairment. The objective was to investigate adrenal function of adult patients with sickle cell disease. In this cross-sectional study conducted in a tertiary referral hospital of the capital city of Cameroon, we enrolled ten crisis-free adult patients with sickle cell disease (SCD) and ten age- and sex-matched healthy individuals. We assessed adrenal function by testing basal cortisol levels and 60 min after tetracosactide (Synacthen®) injection using immuno-chemiluminescence method. Post-stimulatory cortisol was defined as primary endpoint and secondary endpoints include basal cortisol levels, post-stimulatory cortisol increments and the fold increase of cortisol one hour after stimulation. Sickle cell patients had an impairment of adrenal function despite no significant difference between patients’ and controls’ for basal or post-stimulatory cortisol levels. In fact, one patient in two failed to achieve a two-fold increase in cortisol levels after stimulation (5/10) as opposed to 1 in 10 in the control population (1/10), P = 0.070. The percent increment of cortisol after stimulation was lower in patients versus controls (133 vs 207, P = 0.047). Relative adrenal insufficiency is frequent in sub-Saharan adult patients with sickle cell disease despite normal basal cortisol levels. Our results suggest that adrenal function require further investigation during SCD crises as these represent an important stress and may worsen the prognosis.

Adrenal insufficiency in the preterm infant

Cortisol production by the human fetal adrenal cortex has been shown to be not adequate at early gestation. This is due to an inefficient expression of 3β-hydroxysteroid dehydrogenase, the enzyme that catalyzes the synthesis of progesterone from pregnenolone, before about 23 weeks of gestation. Whereas, the fetal adrenal cortex it is able to produce dehydroepiandrosterone sulphate for placental estrogen synthesis and to convert placental progesterone to cortisol [1,2]. During the last trimester of pregnancy the fetal adrenal gland undergoes significant anatomical and functional maturation for adaptation to extra-uterine life and cortisol production increases greatly in the last two months of gestation. Cortisol increases synthesis of surfactant, enhances the reabsorption of lung fluid, promotes the conversion of T4 to T3, favors the closure of the ductus arteriosus and maturation of liver and intestinal enzymes [2]. Adrenal insufficiency can be caused by rare conditions such as adrenocortical hypoplasia or congenital enzymatic deficiencies of steroidogenesis, with clinical variables depending on the hormone involved. In preterm infants, the developmental immaturity, combined with increased demands in critical illness, may result in insufficient cortisol production to maintain homeostasis in the face of acute stress or illness, despite apparently normal cortisol levels. This condition is known as “transient or relative adrenal insufficiency” (TAI) [3,4]. TAI usually appears in the first week of life and normalizes in the second week. Infants with TAI can exhibit refractory hypotension (hypotension not responsive to volume expanders and inotropic drugs, but responsive to corticosteroids), respiratory distress, patent ductus arteriosus and bronchopulmonary dysplasia (BPD) [2,3]. Diagnosis of TAI is not easy because many other conditions can cause hypotension in VLBW infants: hypovolemia, myocardial dysfunction, deficient vascular tone, hyaline membrane disease, infection or a combinations of these factors. In addition, normal basal cortisol levels are extremely variable in preterms and to date there is no consensus on the diagnosis of adrenal insufficiency based on tests with adrenocorticotropic hormone (ACTH) [5-8]. Appropriate dose and duration of steroid therapy have not been established yet. On the other hand refractory and persistent hypotension is associated with intraventricular hemorrhage, periventricular leukomalacia, increased mortality and neurological disability [9]. Poor adrenal response has been shown to be associated with later development of BPD and with death [10,11]. For these reasons further studies are needed to evaluate the efficacy and safety of glucocorticoids in the treatment of cardiovascular failure due to TAI in ill preterm and term infants [12,13].

Effects of acute organophosphate poisoning on pituitary target gland hormones at admission, discharge and three months after poisoning: A hospital based pilot study.

Background:Organophosphate compound (OPC) poisoning is common in the developing countries such as India. The acute and later effects of OPC poisoning on pituitary and target gland hormones is largely unknown.Materials and Methods:This prospective study was conducted at Postgraduate Institute of Medical Education and Research between January 2012 and March 2013. Fourteen patients (8 males, age 18-50 years) with acute OPC poisoning were included in the study based on the history and clinical features, documented decreased in plasma cholinesterase activity or presence of the OPC in gastric lavage/blood samples. The hormonal parameters were done at baseline, at the time of discharge and at three months of follow-up.Results:A total of 14 patients out of 46 with the mean age of 30.1 ± 10.3 years were finally eligible for the study. Hormonal alterations at admission were similar to sick euhormonal syndrome. Overall 7 of them had nine hormonal deficits at three months of follow up, 4 having sub normal basal cortisol level and two each had low testosterone and growth hormone and only one had thyroxine deficiency.Conclusion:Acute organophosphate poisoning results in endocrine dysfunction akin to sick euhormonal syndrome. However, in a small subset of patients, varying level of hormonal insufficiency may occur either at admission or later. These observations need re-validation in a larger group of patients with specific OPC.

The Characterization Of Adrenal Insufficiency and Identification Of Its Risk Factors In Patients With Plasma Cell Dyscrasias

BackgroundThe introduction of proteasome inhibitors and immunomodulatory agents to treat patients with multiple myeloma (MM) and AL amyloidosis have greatly improved survival in these patients and allowed for the use of relatively steroid-sparing regimens. However, 40 mg of dexamethasone is still more than 50 times basal glucocorticoid secretion. Therefore, intermittent dosing of dexamethasone, the longest acting oral corticosteroid, while beneficial in terms of reducing side effects from chronic glucocorticoid excess, may still compromise endogenous adrenal gland function.Our hypothesis was that prolonged, intermittent use of high dose steroids can result in adrenal insufficiency in some patients. The aim of this retrospective study was to determine the characteristics of patients who developed AI. MethodsInclusion criteria for this retrospective case series were patients who had plasma cell disorders and who had been diagnosed with AI based on symptoms concordant with a low serum cortisol level (normal 6.7 - 22.6 mcg/dL), an inadequate cortisol response on an ACTH stimulation test, or for those patients with a fulminant clinical presentation - a rapid clinical improvement upon initiation of low dose maintenance corticosteroid replacement therapy.Exclusion criteria were patients who had serum cortisol levels checked in the setting of recent administration of corticosteroids, who had an adequate cortisol response to an ACTH stimulation test in the setting of a normal basal cortisol level, or who did not require replacement therapy to achieve resolution of symptoms. ResultsSixteen patients met the inclusion criteria over a span of approximately 18 months. Two patients had AL amyloidosis, 12 had MM, and 2 had both. 3 patients were excluded. The median age of patients at the time of AI diagnosis was 61.5 (Range: 44-76).The median number of steroid-containing cycles taken before the diagnosis of AI was 10.5 (Range: 4-50) over a median of 27 months (Range: 3-129). The median cumulative steroid consumption was 1000 mg of dexamethasone. Of note, the 2 primary AL amyloid patients only received 4 and 8 cycles of corticosteroids and a lower amount of cumulative corticosteroids, 768 and 800 mg, respectively prior to being diagnosed with AI.The symptoms and signs of AI at the time of diagnosis included fatigue (88% of patients), diarrhea (56%), hypotension (56%), orthostasis (44%) and weight loss (31%). Other symptoms that appeared in multiple patients included nausea, diffuse myalgia, fever, and cardiovascular shock. The median time between the last steroid dose and the serum cortisol assay was 7 days (Range: 1-62), which resulted in a median serum cortisol of 3.7 mcg/dL (Range 0.5-21 mcg/dL).Of the seven patients who had serum ACTH levels checked, only one patient (with primarly AL amyloid) had an elevated ACTH of 68 (normal 12-46 pg/mL), suggesting a possible component of primary AI. Five patients also underwent ACTH stimulation tests, two of which demonstrated an inappropriate response, defined as a lower rise in serum cortisol than expected.To treat AI, patients received about 15-20 mg of hydrocortisone (equivalent to 0.6- 0.8 mg of dexamethasone) on days not receiving steroids for treatment of their malignancy. 2 patients requiring pressors for shock also required stress dose steroids. For patients with AI symptoms, normalization of hypotension and weight required a median of 9 days (Range 2-43 days) and 2 months (Range 0.3-20 months) respectively to return to their pre-AI levels. Orthostasis resolved after a median of 33 days (Range: 22-72 days), however, orthostatics were not checked at each clinic visit. ConclusionsOur study shows that chronic treatment with even intermittent high-dose steroids can lead to AI, typically characterized by such nonspecific symptoms as fatigue, diarrhea, and dizziness occurring 3-4 days after the last exogenous steroid administration. Unfortunately, the debilitating presentation of some patients with orthostasis/hypotension as well as an already demanding schedule for chemotherapy visits makes optimal cortisol and ACTH stimulation testing challenging. A high index of suspicion for AI is required to initiate diagnostic and therapeutic interventions in a timely fashion to minimize the morbidity and mortality of this condition. Disclosures:Chari:Millenium : Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees.

Childhood stressful events, HPA axis and anxiety disorders

Anxiety disorders are among the most common of all mental disorders and their pathogenesis is a major topic in psychiatry, both for prevention and treatment. Early stressful life events and alterations of hypothalamic pituitary adrenal (HPA) axis function seem to have a significant role in the onset of anxiety. Existing data appear to support the mediating effect of the HPA axis between childhood traumata and posttraumatic stress disorder. Findings on the HPA axis activity at baseline and after stimuli in panic disordered patients are inconclusive, even if stressful life events may have a triggering function in the development of this disorder. Data on the relationship between stress, HPA axis functioning and obsessive-compulsive disorder (OCD) are scarce and discordant, but an increased activity of the HPA axis is reported in OCD patients. Moreover, normal basal cortisol levels and hyper-responsiveness of the adrenal cortex during a psychosocial stressor are observed in social phobics. Finally, abnormal HPA axis activity has also been observed in generalized anxiety disordered patients. While several hypothesis have attempted to explain these findings over time, currently the most widely accepted theory is that early stressful life events may provoke alterations of the stress response and thus of the HPA axis, that can endure during adulthood, predisposing individuals to develop psychopathology. All theories are reviewed and the authors conclude that childhood life events and HPA abnormalities may be specifically and transnosographically related to all anxiety disorders, as well as, more broadly, to all psychiatric disorders.

An unique exonic splicing mutation in the CYPI7AI gene as the cause of steroid 17α-hydroxylase deficiency

Background :1 7a-Hydroxylase/17,20-lyase deficiency (17OHD) caused by a mutation in the CYP17A1 gene is characterized by hypertension, hypokalemia, and abnormal development of the genitalia. The majority of CYP17A1 mutations are located in the coding sequence, and several intronic splicing site mutations have been reported. Objective: A 2.5-year-old girl with 46,XY disordered sex development exhibited a nearly normal basal cortisol level and reduced sexual steroids. This study is aimed to explore the molecular basis and analyze its possible influence on the phenotype of the patient. Methods and results: Mutation analysis revealed compound heterozygous CYP17A1 mutations, with c.985_987delinsAA in one allele and a synonymous substitution (c.1263GOA) in another allele. In vitro expression analysis of the allelic minigene showed that the novel nucleotide variation located in exon 8 induces a splicing signal, which results in an aberrant splicing of CYP17A1 mRNA and a missing portion of exon 8. The translation product includes the deletion of six or seven amino acids from residue position 415 without causing a frameshift. Consistent with the result of molecular modeling, functional studies in transiently transfected HEK-293T cells with the aberrantly spliced enzyme proteins showed that the deleted proteins completely abolished the enzyme activity. However, RT-PCR indicated the existence of a small fraction of normal, functionally intact enzyme, which may explain the partial masculinization of this patient. Conclusion: This is the first description of an exonic splicing mutation in CYP17A1 relevant to the 17OHD phenotype. It also demonstrates the importance of studying synonymous change in such patients with less severe phenotype.

A unique exonic splicing mutation in the CYP17A1 gene as the cause for steroid 17α-hydroxylase deficiency

17α-Hydroxylase/17,20-lyase deficiency (17OHD) caused by a mutation in the CYP17A1 gene is characterized by hypertension, hypokalemia, and abnormal development of the genitalia. The majority of CYP17A1 mutations are located in the coding sequence, and several intronic splicing site mutations have been reported. A 2.5-year-old girl with 46,XY disordered sex development exhibited a nearly normal basal cortisol level and reduced sexual steroids. This study is aimed to explore the molecular basis and analyze its possible influence on the phenotype of the patient. Mutation analysis revealed compound heterozygous CYP17A1 mutations, with c.985_987delinsAA in one allele and a synonymous substitution (c.1263G>A) in another allele. In vitro expression analysis of the allelic minigene showed that the novel nucleotide variation located in exon 8 induces a splicing signal, which results in an aberrant splicing of CYP17A1 mRNA and a missing portion of exon 8. The translation product includes the deletion of six or seven amino acids from residue position 415 without causing a frameshift. Consistent with the result of molecular modeling, functional studies in transiently transfected HEK-293T cells with the aberrantly spliced enzyme proteins showed that the deleted proteins completely abolished the enzyme activity. However, RT-PCR indicated the existence of a small fraction of normal, functionally intact enzyme, which may explain the partial masculinization of this patient. This is the first description of an exonic splicing mutation in CYP17A1 relevant to the 17OHD phenotype. It also demonstrates the importance of studying synonymous change in such patients with less severe phenotype.

Pituitary volume and third ventricle width in euthymic patients with bipolar disorder

Many of the clinical and neuroendocrine features of bipolar disorder involve hypothalamic structures. Although current neuroimaging techniques inadequately resolve the structural components of the hypothalamus, evidence of derangement can be sought by examining the adjacent third ventricle and the functionally related pituitary. To investigate the structure and function of the hypothalamic-pituitary-adrenal axis in euthymic patients with bipolar disorder. Euthymic adult patients with bipolar disorder (n=49) were compared with matched normal control subjects (n=47). Pituitary volume and third ventricle width were assessed on MRI scans. Basal salivary cortisol levels were measured. The width of the third ventricle in patients with bipolar disorder exceeded that of controls (mean +/- SD (in mm): 3.87 +/- 1.96 versus 2.56 +/- 1.34; d=0.76, ANOVA F=12.7, p=0.001), with the greatest differences found in males. Third ventricle width increased with age across the groups (F=16.97, p<0.001). Pituitary volumes did not differ between patients and controls (mean +/- SD (in mm(3)): 632 +/- 176 versus 679 +/- 159). Overall, females had larger pituitaries than males (703 +/- 160 versus 595 +/- 161; d=0.67, F=9.65, p=0.003; all subjects), but female patients had smaller pituitaries compared to female controls (637 +/- 178 versus 756 +/- 126; d=0.65, F=5.04, p=0.03). No difference was found in a comparable analysis of males. Pituitary volume did not differ between patients prescribed and not prescribed antipsychotic drugs. Basal salivary cortisol levels did not differ between patients and controls. In euthymic patients with normal basal cortisol levels, pituitary volume and third ventricle width were found to differ from normal controls. These differences were related to gender, may be important in the pathogenesis of bipolar disorder and could link the vegetative and endocrine abnormalities seen in this condition. Such findings may reflect a trait abnormality or be a consequence of previous episodes.

Increased Saliva Cortisol Awakening Response in Patients with Mild Cognitive Impairment

Background: It is unknown whether HPA-axis dysfunction is present in patients with mild cognitive impairment (MCI). The aim of the present study was to investigate whether cortisol levels are elevated among patients with MCI and/or whether the individuals have adequate feedback control of their HPA axis. Material and Methods: 27 patients with MCI and 15 healthy controls were included in the study. Saliva samplings were performed 5 times a day before intake of 0.5 mg dexamethasone, and 5 times a day after intake of dexamethasone, respectively. Results: Significantly higher cortisol levels were found 15 min after awakening among patients with MCI in comparison with the controls, both before and after dexamethasone administration (p < 0.05). Also, the ratio between cortisol at awakening time and 15 min after awakening was lower in the patient group after dexamethasone administration (p < 0.05). There were no significant differences in basal cortisol levels before or after dexamethasone between groups. Conclusion: The results indicate that there is an HPA-axis disturbance, with normal basal cortisol levels and increased awakening response among patients with MCI. The dissociation between basal values and the awakening response may be of pathophysiological importance for the cognitive impairment.

Computed tomographic correlation with pituitary function in Sheehan's syndrome.

Twenty six patients with Sheehan’s syndrome were studied with high-resolution computed tomography (CT) and the sequential pituitary stimulation test in order to correlate the CT findings of the sella turcica with the pituitary reserve functions. CT revealed 21 completely empty sella (CES), 4 partially empty sella (PES) and 1 normal sella. Panhypopituitarism occurred in 1 of 4 patients with PES and 20 of 21 with CES. One patient showing normal sella had a normal preservation of prolactin (PRL), thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH) and lutenizing hormone (LH). In all patients with PES and CES, growth hormone (GH) responses to hypoglycemia and PRL responses to thyrotropin releasing hormone (TRH) were blunted. Three (75.0%) with PES had normal basal cortisol levels, which were more frequent than two (9.6%) with CES; however, most of the PES (3 of 4) and CES (20 of 21) demonstrated blunted cortisol responses to hypoglycemia. Three (75.0%) with PES and only one (4.8%) with CES had normal thyroxine levels and TSH responses to TRH. None with PES showed decreased basal and stimulated levels of FSH and LH, whereas 15 of 21 with CES did. The pituitary functions of the patients having considerable amounts of pituitary remnants visualized by CT were relatively preserved for TSH, cortisol, FSH and LH. Considering the above results, changes in the amounts of pituitary remnants detected by CT might correlate with hormonal secretory capacity.

132 Different ACTH response to i.v. metyrapon and hCRF in hypothalamic-pituitary hypofunction

Previously we have demonstrated subnormal ACTH response with low basal ACTH level and normal basal cortisol level to i.v. metyrapon in hypothalamicpituitary hypofunction (21st Ann.Meet.of ESPE, Helsinki, 1982). The purpose of our present study was to asses the ACTH-cortisol responsiveness to CRF in the same patients. Human CRF (1-41) - hCRF (Bissendorf) - was given i.v. in the dose of 1 μg/kgbw at 8.00 a.m. after an overnight fast. Basal levels of ACTH (pg/ml) and cortisol (μg/100 ml) were measured before and 30, 60 and 90 minutes after hCRF application. In 5 patients with “ACTH-deficiency” (according to the i.v. metyrapon test) hCRF induced a detectable rise of ACTH, followed by an increase of cortisol secretion (Tabl.I). In 2 patients there were no significant changes of ACTH and cortisol levels.