Secondary Adrenal Insufficiency: Recent Updates and New Directions for Diagnosis and Management

Secondary adrenal insufficiency is the most common subtype of adrenal insufficiency; it is caused by certain medications and pituitary destruction (pituitary masses, inflammation, or infiltration) and is rarely associated with certain germline variants. In this review, we discuss the etiology, epidemiology, and clinical presentation of secondary adrenal insufficiency and focus on the diagnostic and management challenges. We also review the management of selected special populations of patients and discuss patient-important outcomes associated with secondary adrenal insufficiency.     

Biochemical Diagnosis of Adrenal Insufficiency: the Added Value of Dehydroepiandrosterone Sulfate Measurements

ObjectiveTo review biochemical tests used in establishing the challenging diagnosis of adrenal insufficiency.MethodsWe reviewed the relevant literature, including our own data, on various biochemical tests used to determine adrenal function. The advantages and limitations of each approach are discussed.ResultsBaseline measurements of serum cortisol are helpful only when they are very low (≤ 5 μg/dL) or clearly elevated, whereas baseline plasma adrenocorticotropic hormone levels are helpful only when primary adrenal insufficiency is suspected. Measurements of baseline serum dehydroepiandrosterone sulfate (DHEA-S) levels are valuable in patients suspected of having adrenal insufficiency. Although serum DHEA-S levels are low in patients with primary or central adrenal insufficiency, a low level of this steroid is not sufficient by itself for establishing the diagnosis. A normal age- and sex-adjusted serum DHEA-S level, however, practically rules out the diagnosis of adrenal insufficiency. Many patients require dynamic biochemical studies, such as the 1-μg cosyntropin test, to assess adrenal function.ConclusionIn establishing the diagnosis of central adrenal insufficiency, we recommend measurements of baseline serum cortisol and DHEA-S levels. In addition to these, determination of plasma levels of aldosterone, adrenocorticotropic hormone, and renin activity is necessary when primary adrenal insufficiency is suspected. With a random serum cortisol level of ≥ 12 μg/dL in the ambulatory setting or a normal age- and sex-adjusted DHEA-S level (or both), the diagnosis of adrenal insufficiency is extremely unlikely. When serum DHEA-S levels are low or equivocal, however, dynamic testing will be necessary to determine hypothalamic-pituitary-adrenal axis function. (Endocr Pract. 2011;17:261-270)     

Adrenal Insufficiency Attributable to Adrenal Hemorrhage: Long-Term Follow-Up with Reference to Glucocorticoid and Mineralocorticoid Function and Replacement

ObjectiveTo describe the long-term follow-up of acute adrenal insufficiency attributable to bilateral adrenal hemorrhage.MethodsWe performed a retrospective review of medical records of four patients who underwent follow-up for 6½ to 19 years.ResultsDespite published reports of more than 500 patients with bilateral massive adrenal hemorrhage through 2001, no long-term data assessing the continuing requirements for glucocorticoid and mineralocorticoid replacement are available. After follow-up of four patients with acute bilateral adrenal hemorrhage and glucocorticoid insufficiency for 6½ to 19 years, we document the absence of need for long-term mineralocorticoid replacement on the basis of no occurrence of postural hypotension, normal electrolytes, normal baseline or cosyntropin-stimulated serum aldosterone levels, and generally, though not invariably, normal plasma renin activity levels. We further document the improvement in either or both baseline and cosyntropin-stimulated serum cortisol levels in three of the four patients and the ability of one patient to function normally without cortisol replacement for 4 years. Adrenal histologic findings in this last-mentioned patient revealed previously undescribed changes consistent with regeneration and myelolipoma. Finally, we confirm bilateral atrophic adrenal glands by computed tomography 5½ to 11½ years after bilateral adrenal hemorrhage in three of the four patients.ConclusionLong-term follow-up of patients with acute adrenal insufficiency attributable to adrenal hemorrhage demonstrates, for the first time, absence of need for prolonged mineralocorticoid replacement and some improvement in endogenous glucocorticoid function in at least some of these patients. (Endocr Pract. 2004;10: 55-61)     

Autoimmune Hyperthyroidism due to Secondary Adrenal Insufficiency: Resolution with Glucocorticoids

ObjectiveTo describe the course of autoimmune hyperthyroid disease in a patient with corticotropin (ACTH) deficiency treated with glucocorticoids.MethodsWe report the clinical presentation, laboratory data, imaging studies, and management of a patient with weight loss, fatigue, apathy, hallucinations, and arthritis.ResultsAutoimmune hyperthyroidism (positive thyroperoxidase and thyroglobulin antibodies and borderline positive thyrotropin receptor antibody) was diagnosed in a 71-year-old woman. New psychotic symptoms prompted brain magnetic resonance imaging, which revealed a partially empty sella. Undetectable morning cortisol, undetectable ACTH, and failure to stimulate cortisol with synthetic ACTH (cosyntropin 250 mcg) secured the diagnosis of long-standing secondary adrenal insufficiency. Hydrocortisone replacement improved the patient’s symptoms, resolved the thyroid disease, and decreased thyroid antibody titers. In retrospect, the patient recalled severe postpartum hemorrhage requiring blood transfusion at age 38 years. A Sheehan event probably occurred 33 years before the patient presented with corticotropin deficiency. Hyperthyroidism accelerated cortisol metabolism and provoked symptoms of adrenal insufficiency.ConclusionsThe hypocortisolemic state may precipitate hyperimmunity and autoimmune thyroid disease. Rapid resolution of hyperthyroidism and decreased thyroid antibody titers with glucocorticoid treatment support this hypothesis. (Endocr Pract. 2011;17:85-90)     

Catecholamine Phenotyping: Clues to the Diagnosis, Treatment, and Pathophysiology of Neurogenetic Disorders

Abstract: One purpose of clinical neurochemistry has been to indicate "activities" of catecholamine systems, by assaying levels of the effector compounds or their metabolites in body fluids such as plasma, cerebrospinal fluid, urine, or microdialysate. This review discusses a new purpose: relating specific catecholaminergic phenotypes to neurogenetic disorders. Distinctive catecholamine patterns in several neurogenetic conditions reflect enzyme deficiencies as direct or indirect effects of gene mutations. These neurochemical patterns can provide potentially important clues to the diagnosis, treatment, and pathophysiology of neurogenetic disorders. Linking genetic abnormalities with molecular mechanisms and clinical manifestations of disease represents a useful new direction in clinical neurochemistry.     

Overt and Subclinical Adrenal Insufficiency in Pulmonary Tuberculosis

BackgroundTuberculosis of the adrenal glands may cause overt or subclinical adrenal insufficiency. An algorithm-based approach including assessment of paired basal cortisol and plasma adrenocorticotropic hormone (ACTH), short Synacthen, and plasma renin activity assays could be useful to diagnose all forms of adrenal insufficiency.MethodsThis cross-sectional study included consecutive, treatment-naive subjects diagnosed with pulmonary tuberculosis. Tuberculosis severity was classified by radiological criteria. Baseline parameters plus morning (8 am) serum cortisol and paired plasma ACTH were measured in all patients. Synacthen stimulation tests and plasma renin activity assays were performed as required.ResultsEighty-four treatment-naive consecutive cases of pulmonary tuberculosis were evaluated for adrenal insufficiency. Twenty-seven (32.14%) subjects had normal adrenocortical function and 8 (9.5%), 7 (8.3%), 40 (47.6%), and 2 (2.4%) subjects had stage 1, stage 2, stage 3, and stage 4 adrenal insufficiency, respectively. Serum cortisol was negatively correlated with radiological severity (P = .01) and duration of illness (P = .001). Adrenal dysfunction was present in 27.3%, 82.5%, and 80% of those with radiologically minimal, moderately advanced, and far-advanced disease, respectively. Mean cortisol was 19.74 ± 5.52, 17.42 ± 8.53, and 15.71 ± 7.14 (μg/dL) in the 3 groups, respectively (P = .042). Hyponatremia was present in 83.3% of the patients. Serum sodium was negatively correlated with severity but not with the duration of disease.ConclusionThe prevalence of overt and subclinical adrenal dysfunction in pulmonary tuberculosis was high and was correlated with disease severity and duration. An algorithmic approach may be useful to detect the same and may have important clinical implications.     

Clinical Presentation and Outcomes of Opioid-Induced Adrenal Insufficiency

Objective: Opioid-induced adrenal insufficiency (OIAI) may develop in patients treated with chronic opioids due to suppression of the hypothalamic-pituitary-adrenal axis. Our objective was to describe the clinical manifestations, biochemical presentation, and clinical course of OIAI.Methods: A retrospective study of adults diagnosed with OIAI between 2006 and 2018 at an academic center. Opioid daily dose was converted into morphine milligram equivalents (MMEs).Results: Forty patients (women, n = 29 [73%]) taking chronic opioids at a daily median MME dose of 105 (60 to 200) mg and median duration of 60 (3 to 360) months were diagnosed with OIAI. Patients reported fatigue (n = 29, 73%), musculoskeletal pain (n = 21, 53%), and weight loss (n = 17, 53%) for a median of 12 (range, 1 to 132) months prior to diagnosis, and only 7.5% (n = 3) of patients were identified with OIAI through case detection. Biochemical diagnosis of OIAI was based on (1) low morning cortisol, baseline adrenocorticotropic hormone and/or dehydroepiandrosterone sulfate in 59% (n = 26) of patients or (2) abnormal cosyntropin stimulation test in 41% (n = 14) of patients. With glucocorticoid replacement, 16/23 (70%) patients with available follow-up experienced improvement in symptoms. Opioids were tapered or discontinued in 15 patients, of whom 10 were followed for adrenal function and of which 7 (70%) recovered from OIAI.Conclusion: Minimum daily MME in patients diagnosed with OIAI was 60 mg. OIAI causes significant morbidity, and recognition requires a high level of clinical suspicion. Appropriate glucocorticoid treatment led to improvement of symptoms in 70%. Resolution of OIAI occurred following opioid cessation or reduction.     

Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells

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Immune Checkpoint Inhibitor-Induced Adrenalitis and Primary Adrenal Insufficiency: Systematic Review and Optimal Management

ObjectiveImmune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4 or programmed death 1 and its ligand (programmed death ligand 1) have been approved for the treatment of a variety of cancers. However, ICI therapy is associated with a risk of immune-related adverse events. In this study, we reviewed reported cases of adrenalitis and primary adrenal insufficiency (PAI)—rare but lethal endocrine immune-related adverse events—in patients who underwent ICI therapy.MethodsWe searched multiple databases (PubMed, Web of Science, Cochrane, and Scopus) up to February 2020 for case reports on adrenalitis and PAI caused by ICIs.ResultsWe identified 15 case reports on ICI-induced adrenalitis and PAI and reviewed their clinical presentation, characteristics, immunologic and imaging features, and treatment. We also developed a screening strategy for PAI in patients treated with ICIs.ConclusionGiven the morbidity and mortality associated with acute adrenal crisis, physicians—especially endocrinologists and oncologists—should be aware of this particular risk. PAI caused by autoimmune adrenalitis predominantly occurs in patients treated with programmed death 1 inhibitor monotherapy. PAI often coexists with other endocrinopathies and requires mineralocorticoid as well as glucocorticoid replacement. Even after withdrawal of ICIs, PAI can persist and requires lifelong replacement therapy.     

Current Knowledge and Practices of Heath Care Professionals on Opioid-Induced Adrenal Insufficiency

Objective: Opioid-induced adrenal insufficiency (OIAI) is reported in up to 29% of chronic opioid users through suppression of the hypothalamus-pituitary-adrenal axis. Unrecognized adrenal insufficiency leads to increased morbidity and potentially death; thus, healthcare provider (HCP) awareness of OIAI is crucial. The aim of the present study was to assess the knowledge and current practices of HCPs regarding OIAI and to identify factors associated with decreased awareness.Methods: We carried out a cross-sectional, anonymous survey of HCPs in internal medicine specialties that prescribe or care for patients taking chronic opioids.Results: Of 91 (30%) participants who completed the survey, 51 (56%) were men and 52 (57%) were in training. Most responders were general internal medicine providers (n = 33, 36%), followed by endocrinologists (n = 13, 14%) and various other specialties (n = 45, 49%). While 61 (67%) of respondents prescribed opioids, only 17 (19%) were comfortable in their knowledge of opioid side effects. Among nonendocrine providers, 53 (68%) identified adrenal insufficiency as a known opioid-induced endocrinopathy. Compared to other providers, endocrinologists were more likely to recognize opioid-related endocrinopathies (69% versus 24%, P = .01) and to identify the correct symptoms for OIAI (38% versus 9%, P <.001). One in four nonendocrine providers reported discomfort in managing glucocorticoid replacement therapy. The majority (60%) of providers indicated that online resources and continuing medical education lectures would improve knowledge of OIAI.Conclusion: Our study identified several deficiencies in HCP knowledge of opioid-induced endocrine effects, especially in nonendocrine providers. As many symptoms of OIAI overlap with those of underlying conditions, OIAI could be potentially missed, highlighting the need to further educate providers about opioid-induced endocrinopathies.Abbreviations: ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; CME = continuing medical education; HCP = healthcare professional; OIAI = opioid-induced adrenal insufficiency     

Some Clues and Pitfalls in the Diagnosis of Acromegaly

ObjectiveTo describe a case of acromegaly in a young woman using oral contraceptives who had nonspecific symptoms and persistent hyperphosphatemia and to analyze the reasons for delay in diagnosis.MethodsA 31-year-old woman underwent evaluation for failure of menstrual flow to resume after discontinued use of oral contraceptives. Clinical and laboratory findings are summarized, and atypical manifestations of acromegaly are discussed.ResultsThe patient complained of weight gain, acne, and increased facial hair growth, and laboratory tests showed a low estradiol level and hyperinsulinemia. “Postpill amenorrhea” and polycystic ovary syndrome were considered possible diagnoses. During subsequent endocrinology consultation, hyperphosphatemia was present on three occasions during a 7-month period. Hormonal studies for evaluation of pituitary function revealed increased insulin-like growth factor-I and growth hormone (GH) levels. Acromegaly was suspected, and the increased GH level failed to suppress after a glucose load. Magnetic resonance imaging revealed a pituitary macroadenoma with suprasellar extension. Visual field testing showed bitemporal abnormalities. Transsphenoidal resection successfully removed the GH-producing tumor, and hormone replacement therapy was initiated postoperatively.ConclusionThe textbook presentation of GH excess is a late feature of acromegaly. The diagnosis in a young woman can be easily missed when clinicopathologic findings are not classic and the picture is further clouded by factors such as oral contraceptive use. Features may also resemble polycystic ovary syndrome, a more common condition in women of childbearing age. This case also illustrates that hyperphosphatemia, overlooked in this patient, can precede the full-blown clinical manifestations of acromegaly and serve as a subtle clue to the underlying disease. Awareness of these situations and screening for high GH levels in patients with unexplained, persistent hyperphosphatemia are advisable for making an early correct diagnosis and providing appropriate therapy. (Endocr Pract. 2004;10:348-352)     

Glucocorticoid-Induced Adrenal Insufficiency: A Study of the Incidence in Hospital Patients and A Review of Peri-Operative Management

Objective: Glucocorticoid (GC) pharmacotherapy is an effective treatment for a range of diseases, but exposure can suppress the hypothalamic-pituitary-adrenal axis, leading to glucocorticoid-induced adrenal insufficiency (GC-AI) in some patients. However, the incidence of diagnosed GC-AI and the associated health burden, including the incidence of adrenal crises (ACs), are unknown. Although GC-AI treatment is based on well-established principles, there are no agreed protocols regarding the peri-operative management of exposed patients. The aims of this study were to assess the incidence of diagnosed GC-AI in hospital patients and review current approaches to peri-operative management of surgical patients with GC exposure.Methods: An analysis of hospital admission data concerning adult patients diagnosed with GC-AI and a review of published recommendations for peri-operative GC cover.Results: Between 2001 and 2013, admission with a diagnosis of GC-AI in New South Wales, Australia was rare (annual average of 22.5 admissions/year) and ACs were even more rare (n = 3). Almost two-thirds (64.4%, n = 188) of the patients with diagnosed GC-AI were aged between 50 and 79 years and 45.2% (n = 132) had a comorbid infection. The current approach to peri-operative management of patients with GC exposure appears to be influenced by both the absence of clear guidelines and historic practices. This results in the exposure of some patients to supraphysiologic doses of GCs during the peri-operative period.Conclusion: Hospital admission with a diagnosis of GC-AI (with or without an AC) is very rare. Clear guidelines on peri-operative GC cover are necessary to avoid overreplacement with supraphysiologic doses in susceptible patients.Abbreviations: AC = adrenal crisis; ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; CI = confidence interval; GC = glucocorticoid; GC-AI = glucocorticoid-induced adrenal insufficiency; HPA = hypothalamic-pituitary-adrenal; OR = odds ratio