Clinical Signs Of Adrenal Insufficiency Research Articles

P-60 Opioid induced secondary adrenal insufficiency: A case report

Abstract Introduction Opioid treatment is common and useful in acute pain management, but long-term opioid treatment is not routinely recommended. Opioids influence the endocrine system by blunting the hypothalamic–pituitary–adrenal (HPA) axis: as ACTH is synthesized from the same precursor protein as beta-endorphins, opioids lower serum cortisol and supress cortisol response through a mechanism of negative feedback. In the same way, naloxone infusion leads to an increase in serum cortisol. Clinical Case A forty-nine-year-old woman was sent to an endocrinology appointment due to altered serum cortisol measurements. She had a past history of Graves’ disease currently in clinical and biochemical remission. Her history was also notable for chronic obstructive pulmonary disease under inhaled corticosteroids and previous toxicophilic habits under methadone replacement treatment. The patient was asymptomatic with a laboratory evaluation of the HPA axis suggestive of adrenal insufficiency –morning serum cortisol measurements persistently under 10μg/dL. Stimulation test with cosyntropin showed an insufficient response with a peak cortisol of 12 μg/dL, confirming adrenal insufficiency. As the patient had no clinical signs of adrenal insufficiency and was maintained under inhaled corticosteroid treatment, she was given an emergency glucocorticoid card and was instructed to take replacement treatment with hydrocortisone in stress situations. Conclusion In this patient, the HPA axis suppression might have been multifactorial resulting from inhaled glucocorticoids and chronic opioid use. Opioids are very common drugs and adrenal insufficiency is probably more frequent than it is accounted for in this population, with unspecific symptoms but possible serious consequences. Therefore, patients under opioid treatment with suggestive symptoms might benefit from adrenal insufficiency exclusion.

Fraction Size, Total Dose and Respiratory Control Impact Local Control in Adrenal SBRT

Stereotactic body radiotherapy (SBRT) is an effective treatment for oligometastatic disease in multiple sites, however, the optimal radiation dose for long term local control of adrenal metastases has not yet been determined. The aim of this study is to evaluate outcomes of adrenal SBRT and to evaluate factors that correlate with local control MATERIALS/METHODS: After IRB approval, a retrospective data review of patients treated with SBRT on adrenal metastases was conducted, at a medical center in Israel between 2015 and 2021. Biologic Equivalent Dose (BED) were calculated using an alpha beta ration of 10. Kaplan Meier and Cox regression were calculated to describe the hazard ratio for local control and survival using statistical software. Fifty-eight cases of adrenal SBRT were identified. The average age was 67 years (ranging 42-92). Forty-three percent of primary tumor was non-small cell lung cancer. The lesions were equally distributed between the right and left adrenal gland. Six patients had bilateral radiation treatment. Fifty-eight percent of the cases were in the setting of oligometastatic disease (less than 5 lesions) with the rest having progression in the adrenal. PET-CT scans were available for follow up in 55% of patients and CT in the rest. The average GTV volume was 42 cm2 respiratory control through 4D and breath hold was performed in 86% of cases. The median follow up time, for local control, was 10 months with a range of 1-54 mos. Univariate analysis local control, during the last follow up, was seen in 74% of cases. Total dosage was equal to or above 72 Gy and dosage per fraction was equal to or above 8 Gy. The use of respiratory motion was found significant for local control. Only a fraction size equal to or above 8 Gy and a total dosage equal to and above 72 Gy were found significant for local failure (HR = 0.26, p = 0.024 and HR = 0.28, p = 0.019). With multivariable analysis the dosage per fraction ≥8 Gy continued to be significant after adjusting for total dose, histology, side, and motion management. Two patients had clinical signs of adrenal insufficiency and both received bilateral adrenal radiation. Bowel toxicity was low: 1 patient had >G3 toxicity. In the largest single institution series reported to date, we found unilateral adrenal SBRT to be safe, however, bilateral treatment harbors a risk of adrenal insufficiency. Dose per fraction ≥8 Gy was the most powerful predictor of local control, and a total dose ≥72gy and motion management were also significant. In conclusion, we propose a treatment regimen with a fraction size of at least 8 Gy and a total dosage of at least 72 Gy for evaluation, in a prospective clinical trial.

A High-Dose Cortisol Receptor Antagonist for the Management of Severe Hyperglycemia in a Patient With an Adrenocortical Carcinoma

The management of functional adrenocortical carcinoma (ACC) is challenging as it involves treating the underlying endocrinological abnormalities such as hypercortisolism. Competitive glucocorticoid receptor antagonist such as mifepristone (Korlym®) can be used to treat dysglycemia secondary to hypercortisolism. A 59-year-old male was admitted for dizziness and lightheadedness. Past medical history was significant for hypertension, and obesity. During evaluation, patient was found to have a random blood glucose of 663 mg/dL and a hemoglobin A1c of 14.4% with a previous of 5.8%. After admission, patient required 62.9 units of IV insulin over 9 hours to stabilize blood glucose. Due to the high insulin requirement and clinical presentation, a concern for hypercortisolism was considered and workup revealed an 8am cortisol level of 28.3 mcg/dL, and dexamethasone suppression test with cortisol of 50.4 mcg/dL, dexamethasone level 209 ng/dL and ACTH of <5 pg/mL. Patient was discharged on glargine 40 units SC BID and aspart 10 units SC TID AC. Seventeen days after discharge, patient was admitted with hyperglycemia (233 mg/dL), hypokalemia (2.5 mg/dL), abdominal pain, nausea, and vomiting. CT of abdomen revealed a 9.3 x 10.8 x 9 cm retroperitoneal mass arising from the left adrenal. Patient was started on mifepristone (Korlym®) 600mg PO daily while inpatient as his acute hyperglycemia was insufficiently controlled for consideration to open adrenalectomy. Within 24 hours of starting therapy, patient’s insulin requirement was de-escalated, and euglycemia was maintained for 20 days until surgery. Postoperative pathology demonstrated a 12.1cm resected tumor consistent with adrenocortical carcinoma. No clinical signs of adrenal insufficiency occurred postoperatively despite not stopping mifepristone (Korlym®) prior to surgery. Discussion: Adrenocortical carcinomas (ACC) are rare malignancies with an annual incidence of 0.7–2 cases per million population. They carry a poor prognosis with 5-year survival between 16–47%. The clinical presentation varies on the functional activity of these tumors and approximately 60% of them are cortisol secreting. The management of functioning-ACCs is challenging. Our patient presented with hyperglycemia secondary to hypercortisolism that was recurrent and difficult to control. He was started on mifepristone (Korlym®), a FDA approved potent competitive glucocorticoid receptor antagonist for the treatment of dysglycemia secondary to all forms of Cushing disease. In our patient, mifepristone provided a significant and rapid glycemic control, requiring to decrease the dose of insulin. Conclusion: This case demonstrates a safe and acute use of mifepristone (Korlym®) without initial titration in an inpatient monitored setting making this medication a viable option for management and optimization of hyperglycemia secondary to hypercortisolism.This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the authors and do not necessarily express the official views of the HCA Healthcare or any of its affiliated entities.

Adrenal function following ACTH therapy for infantile spasms: A retrospective study

ObjectiveTo determine if treatment with ACTH for infantile spasms (IS) is associated with secondary adrenal insufficiency. Patients and methodsThis is a retrospective study of patients diagnosed with infantile spasms and treated with ACTH between 2007 and 2018 at Soroka University Medical Center (SUMC). We reviewed the records of patients who had a post-hormonal laboratory assessment of their adrenal function; either a low dose ACTH test or a random morning cortisol level and looked for laboratory or clinical signs of adrenal insufficiency. ResultsBetween the years 2007 and 2018, 45 children were diagnosed with IS at our Pediatric Neurology Unit, 20 patients were treated with ACTH, of them 14 children met the inclusion criteria and had a post-treatment laboratory assessment of adrenal function by low dose ACTH test or morning cortisol level. Five children had a normal low dose ACTH test, two had normal morning cortisol level, five were not conclusive, and two had subnormal levels of cortisol. None of the children showed clinical signs of adrenal insufficiency. ConclusionOur study adds to the limited literature on this topic and in contrast to previous publications suggests that adrenal suppression should not occur after ACTH treatment.

Glucocorticoid Withdrawal – Heterozygous Carriers of Congenital Adrenal Hyperplasia at Risk?

High dose glucorticoid therapy is an integral component of numerous pediatric treatment schemes e. g. for chronic inflammative, neurological or haematooncological disorders. To prevent iatrogenic Addisonian crisis gradual dose reduction is usually conducted. If clinical signs of adrenal insufficiency occur despite tapering, hydrocortisone substitution is frequently initiated following a purely pragmatic approach without further etiological assessment.

Mutations in NR5A1 and PIN1 associated with idiopathic hypogonadotropic hypogonadism

We tested the hypothesis that mutations in NR5A1 and PIN1 cause disorders in gonadotropin-gonadal system development and function, throught direct DNA sequencing of the coding sequence and splice-sites of NR5A1 and PIN1 in 50 subjects with sporadic idiopathic hypogonadotropic hypogonadism. These patients were recruited from the Pediatrics section of Tongji Hospital, Tongji Medical College, in Wuhan, China. None of the affected subjects had clinical signs of adrenal insufficiency. The NR5A1 and PIN1 mutations were found in 7 of the 50 cases. These 7 individuals presented severely low serum concentrations of testosterone or of estradiol and gonadotropin. Adrenal insufficiency was not diagnosed in any of these patients. Consequently, NR5A1 and PIN1 mutations should be considered in idiopathic hypogonadotropic hypogonadism patients with normal karyotypes and without adrenal insufficiency.

Merits and pitfalls of mifepristone in Cushing's syndrome

Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness and tolerability of mifepristone in Cushing's syndrome (CS). Retrospective study of patients treated in seven European centers. Twenty patients with malignant (n=15, 12 with adrenocortical carcinoma, three with ectopic ACTH secretion) or benign (n=5, four with Cushing's disease, one with bilateral adrenal hyperplasia) CS were treated with mifepristone. Mifepristone was initiated with a median starting dose of 400 mg/day (200-1000). Median treatment duration was 2 months (0.25-21) for malignant CS, and 6 months (0.5-24) for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of adrenal insufficiency), and biochemical parameters (serum potassium and glucose) were evaluated. Treatment was stopped in one patient after 1 week due to severe uncontrolled hypokalemia. Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5 patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week. Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20 patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure levels in 3/20 patients. Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency. Mifepristone provides a valuable treatment option in patients with severe CS when surgery is unsuccessful or impossible.

Sekundäre Nebennierenrindeninsuffizienz nach lokaler Triamcinolonacetonid-Gabe

Two women, aged 74 and 57 years, were admitted for endocrinological work-up. The 74-year-old women had clinical signs of adrenal insufficiency after she had been given one triamcinolone acetonide intra-articular injection 3 months before. The 57-year-old women who had over several years been repeatedly received local triamcinolone acetonide injections for degenerative changes in her cervical spine for several years and needed reoperative investigation. Physical examination was unremarkable in both patients: they had no signs of Cushing's syndrome. Serum cortisol and plasma adrenocorticotropic hormone (ACTH) were reduced in both patients. Endocrinological tests in the 74-year-old patient showed reduced free cortisol excretion in the urine, normal cortisol response in the ACTH test and subnormal cortisol stimulation during the corticotropin-releasing-hormone test and the insulin tolerance test. Magnetic resonance imaging of the sella was normal. The 57-year-old patient had a reduced cortisol response. The results of endocrinological tests in both patients were consistent with secondary adrenal insufficiency after local injection of triamcinolone acetonide. In the 74-year-old patient substitution treatment with hydrocortisone was started and resulted in rapid improvement of the symptoms. Perioperative intravenous substitution was advised for the 57-year-old patient . Locally administered synthetic glucocorticoids can be associated with systemic adverse effects, such as secondary adrenal insufficiency. Clinically significant secondary adrenal failure can be produced not only by long-term administration of triamcinolone acetonide, but possibly also if it is injected just once.

21-hydroxylase autoantibodies in adult patients with endocrine autoimmune diseases are highly specific for Addison's disease. Belgian Diabetes Registry.

The diagnostic specificity of recombinant 21-hydroxylase autoantibodies (21OH-Ab) for Addison's disease was tested in adult patients with either Graves' disease (GD), insulin-dependent diabetes mellitus (IDDM), or polyendocrinopathy, as well as in healthy controls. Using a radiobinding assay with in vitro translated recombinant human 21-hydroxylase, we found 21OH-Ab in 24/28 (86%) idiopathic Addison patients, and using an immunofluorescence assay we found adrenal cortex autoantibodies (ACA) in 12/28 (43%) patients (P = 0.002). All the 12 ACA-positive sera were also positive for 21OH-Ab and ACA were found in 11/15 (73%) patients with less than 15 years and in 1/13 (8%) patients with 15-38 years of disease duration (P = 0.002). 21OH-Ab were present in 3/92 (3%) patients with GD, in 1/180 (0.6%) with IDDM and in 0/106 healthy subjects. The 21OH-Ab-positive GD and IDDM patients were also positive for ACA. None of 17 patients with polyendocrinopathy, but without Addison's disease, had 21OH-Ab. None of the 180 Belgian IDDM patients had Addison' s disease or developed an adrenal insufficiency at follow up. In two out of three Graves patients, the presence of 21OH-Ab was associated with clinical and biochemical signs of adrenal insufficiency. Of the 89 21OH-Ab-negative patients with GD none had Addison's disease at the time of blood sampling, and 79 were followed up for 5.6-7.5 years and none developed clinical signs of adrenal insufficiency. We conclude that the presence of 21OH-Ab in patients with endocrine autoimmune diseases is highly specific for Addison's disease.

Dehydroepiandrosterone, 17alpha-hydroxyprogesterone and aldosterone responses to the low-dose (1 micro g) ACTH test in subjects with preclinical adrenal autoimmunity.

The appearance of 21-hydroxylase autoantibodies (21OHAbs) identifies subjects with preclinical adrenal insufficiency. In 21OHAb-positive subjects, the adrenocortical function is best evaluated by peak cortisol (F) levels after the low-dose (1 micro g) ACTH stimulation test (LDT). No information is currently available on the correlation between F and other adrenocortical hormone responses to the LDT in subjects with an ongoing autoimmune adrenal process. In this study, we tested the hypothesis that the dehydroepiandrosterone (DHEA), 17alpha-hydroxyprogesterone (17OHP) and aldosterone (A) responses to the LDT are consensual to that of F during the preclinical phase of autoimmune adrenal insufficiency. We studied 12 subjects positive for 21OHAb, in the absence of clinical signs of adrenal insufficiency. On the basis of peak F levels after the LDT, and according to the lower level of normal observed in 15 healthy volunteers (510.4 nmol/l), patients were subdivided into two groups: group A, n = 6 subjects with normal F response; and group B, n = 6 subjects with impaired F response. Results were expressed as absolute delta increase (Delta) between peak and basal levels. DeltaF was significantly higher in group A (314.5 +/- 115.8 nmol/l) than in group B (151.7 +/- 88.2 nmol/l) (P = 0.041). DeltaDHEA and Delta17OHP were also significantly higher in group A (17.0 +/- 13.5 nmol/l and 6.1 +/- 4.4 nmol/l, respectively) than in group B (0.69 +/- 2.25 nmol/l and 1.9 +/- 1.7 nmol/l, respectively) (P = 0.002 and P = 0.041). The difference in DeltaA between the two groups did not reach statistical significance (group A 321.8 +/- 272.0 pmol/l vs. group B 157.0 +/- 154.0 pmol/l). DeltaDHEA, Delta17OHP and DeltaA tended to correlate positively with DeltaF (P = 0.039, P = 0.039 and P = 0.044, respectively), but the correlations did not reach significance after correction of the P-value. Our study demonstrates a high concordance between F and DHEA, 17OHP and A responses to the LDT in subjects with preclinical adrenal autoimmunity, thus strengthening the concept that the LDT is an accurate test to identify early adrenal dysfunction.

Serum cortisol concentrations in ill preterm infants less than 30 weeks gestational age

Adrenal insufficiency is suspected in some ill preterm infants. The aim of this prospective study was to compare serum cortisol concentrations during the first 2 wk of life of well preterm infants (group A) less than 30 wk of gestational age with the cortisol concentrations of ill preterm infants whose arterial hypotension—a potential sign of adrenal insufficiency—had been treated with catecholamine (group B), and the cortisol concentrations of ill preterm infants who had not been so treated (group C). Cortisol concentrations did not differ significantly between group A (240 nmol/l, 58–659; n= 46) (median, minimum‐maximum) and group C (268 nmo/l, 58–1007; n= 25). Group B had a double‐peaked distribution of cortisol. Two subgroups were formed by taking the highest cortisol level of group A as a threshold: group B1 (110 nmol/1, 41–378; n= 20) and group B2 (1200 nmol/l, 764–1482; n = 8). The cortisol concentrations of group B1 were significantly lower (p= 0.00097) compared to the cortisol concentrations of the well preterm infants (group A). The seventy of illness, which was quantified by two scoring systems, differed significantly among the groups (p &lt; 0.003 for all comparisons) with the following sequence: A &lt; C &lt; B, but not between B1 and B2, as clinical variables were not different between the subgroups.In conclusion, when clinical signs of adrenal insufficiency, such as severe arterial hypotension, were not found in ill preterm infants, serum cortisol concentrations were not different from those of well preterm infants. Seventy‐one percent of preterm infants with catecholamine‐treated arterial hypotension had significantly lower cortisol concentrations, which may reflect adrenal insufficiency, but no differences in the seventy of illness were found between infants with high and low cortisol levels.

Diagnosis and management of Cushing's syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis.

The past 45 yr' experience with Cushing's syndrome (CS) has led to the awareness of its complex nature and, by the same token, brought about an increase in the diagnostic and therapeutic dilemmas. We carried out a retrospective multicentre study on the diagnostic work-up and treatment in 426 patients with CS, subdivided as follows: 288 with Cushing's disease (CD), 80 with an adrenal adenoma, 24 with an adrenal carcinoma, 25 with ectopic ACTH and/or CRH secretion, and 9 with ACTH-independent nodular adrenal hyperplasia. Normal urinary free cortisol (UFC) values among multiple collections were recorded in about 10% of patients with CS. In 28% of patients with ACTH-independent CS, basal ACTH concentrations were within the normal range but did not respond to CRH stimulation. Measurement of ACTH levels by immunoradiometric assay, rather than by RIA, offered a greater chance of recognizing patients with ACTH-independent CS or ectopic secretion. A 50% increase in ACTH or cortisol levels after CRH yielded a diagnostic accuracy of 86% and 61%, respectively, in the differential diagnosis of ACTH-dependent CS. An 80% decrease in cortisol levels after 8 mg dexamethasone overnight, or in UFC values after the classical 2-day administration, excluded an ectopic secretion but carried a low negative predictive value given the high number of nonsuppressors among patients with CD. Pituitary imaging identified an adenoma in 61% of patients with CD. At inferior petrosal sinus sampling, an ACTH centre: periphery gradient after CRH less than 3, correctly classified all patients with ectopic secretion but misdiagnosed 15% of 76 patients with CD. Transsphenoidal pituitary surgery, the standard therapy for CD, resulted in complete remission (appearance of clinical signs of adrenal insufficiency associated with low/normal UFC excretion and, when available, low/normal morning plasma ACTH and cortisol levels) in 69% of patients. The overall relapse rate after pituitary surgery was 17%. The probability of relapse-free survival, as assessed by Kaplan-Meier analysis, was 95% at 12 months, 84% at 2 yr, and 80% at 3 yr. Risk of relapse was significantly correlated with postoperative baseline plasma ACTH and cortisol peak after CRH. No relapses were observed among patients who did not respond to CRH. Other therapeutic approaches for CD, such as pituitary irradiation and medical therapy, resulted in normalization of cortisol secretion in about half of treated cases. In summary, an accurate selection of the available diagnostic tools leads to the correct diagnosis in the majority of patients with CS. The therapeutic options for CD, adrenal carcinoma, and ectopic secretion are, as yet, not fully satisfactory. The high incidence of relapse after pituitary surgery calls for a prolonged follow-up.

Adrenoleukodystrophy and adrenomyeloneuropathy associated with partial adrenal insufficiency in three generations of a kindred

Four cases of adrenoleukodystrophy (ALD) and one case of adrenomyeloneuropathy (AMN) have developed in a kindred over three generations demonstrating that AMN is a clinical variant of ALD. Pituitary-adrenal function studies were performed in 10 family members, including two affected males and four females identified as carriers of ALD/AMN. No pituitary-adrenal abnormality was found in the carriers. However, basal morning plasma adrenocorticotropic hormone (ACTH) levels were markedly elevated in the two males with ALD and AMN, despite the fact that they had no clinical signs of adrenal insufficiency and that morning plasma cortisol levels and their response to maximal exogenous ACTH stimulation appeared to be normal. In addition, the integrated 24-hour response to the administration of ACTH, as reflected by the increase in urinary 17-hydroxycorticosteroid (17-OHCS) excretion, and the response to metyrapone administration were also subnormal in these two cases. Thus, people with ALD and AMN may have subclinical partial adrenocortical insufficiency. No other endocrinologic dysfunction was identified.