Endogenous pathologic hypercortisolism, or Cushing's syndrome, is associated with poor quality of life, morbidity, and increased mortality. Early diagnosis may mitigate against this natural history of the disorder. The clinical presentation of Cushing's syndrome varies, in part related to the extent and duration of cortisol excess. When hypercortisolism is severe, its signs and symptoms are unmistakable. However, most of the signs and symptoms of Cushing's syndrome are common in the general population (e.g., hypertension and weight gain) and not all are present in every patient. In addition to classical features of glucocorticoid excess, such as proximal muscle weakness and wide purple striae, patients may present with the associated comorbidities that are caused by hypercortisolism. These include cardiovascular disease, thromboembolic disease, psychiatric and cognitive deficits, and infections. As a result, internists and generalists must consider Cushing's syndrome as a cause, and endocrinologists should search for and treat these comorbidities. Recommended tests to screen for Cushing's syndrome include 1 mg dexamethasone suppression, urine free cortisol, and late night salivary cortisol. These may be slightly elevated in patients with physiologic hypercortisolism, which should be excluded, along with exogenous glucocorticoid use. Each screening test has caveats and the choice of tests should be individualized based on each patient's characteristics and lifestyle. The objective of this review is to update the readership on the clinical and biochemical features of Cushing's syndrome that are useful when evaluating patients for this diagnosis.
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Lynnette K Nieman
Smita Baid Abraham, Brent S Abel, Domenica Rubino, Tonja Nansel, Sheila Ramsey, and Lynnette K Nieman
Obese (OB) individuals and patients with Cushing's syndrome (CS) often have similar clinical presentations. While each group has reduced health-related quality of life (HRQL), it is not known whether the degree of impairment is different and might distinguish between them. The objective of this study was to compare HRQL in these two populations.
Three hundred and twenty-seven OB patients (48.1±11.7 years; 72.5% women) with weight gain and at least two features of CS were recruited from an outpatient weight management clinic. Sixty-six untreated patients with CS (41.6±13.2 years; 78.8% women) presented to the NIH Clinical Center for evaluation. Subjects completed the SF-36 survey and a locally created symptom questionnaire.
After adjusting for symptom count, OB patients had a significantly higher (better HRQL) mean physical component summary (PCS) score than CS patients (44.9±0.6 vs 35.4±1.5, P<0.0001). However, the mean mental component summary (MCS) score was lower (worse HRQL) in the OB group (41.6±0.6 vs 50.7±1.6, P<0.0001). Symptom count showed significant correlations with PCS and MCS scores. BMI correlated with PCS (r=−0.29) in OB but not in CS patients. BMI was not associated with MCS in either group.
HRQL is significantly different between OB and CS patients. Surprisingly, after adjusting for symptom count, OB patients showed worse mental health scores than the CS population. Significant differences in HRQL and symptom count may suggest which OB patients should be screened for CS.
John Newell-Price, Lynnette K Nieman, Martin Reincke, and Antoine Tabarin
Clinical evaluation should guide those needing immediate investigation. Strict adherence to COVID-19 protection measures is necessary. Alternative ways of consultations (telephone, video) should be used. Early discussion with regional/national experts about investigation and management of potential and existing patients is strongly encouraged. Patients with moderate or severe clinical features need urgent investigation and management. Patients with active Cushing’s syndrome, especially when severe, are immunocompromised and vigorous adherence to the principles of social isolation is recommended. In patients with mild features or in whom a diagnosis is less likely, clinical re-evaluation should be repeated at 3 and 6 months or deferred until the prevalence of SARS-CoV-2 has significantly decreased; however, those individuals should be encouraged to maintain social distancing. Diagnostic pathways may need to be very different from usual recommendations in order to reduce possible exposure to SARS-CoV-2. When extensive differential diagnostic testing and/or surgery is not feasible, it should be deferred and medical treatment should be initiated. Transsphenoidal pituitary surgery should be delayed during high SARS-CoV-2 viral prevalence. Medical management rather than surgery will be the used for most patients, since the short- to mid-term prognosis depends in most cases on hypercortisolism rather than its cause; it should be initiated promptly to minimize the risk of infection in these immunosuppressed patients. The risk/benefit ratio of these recommendations will need re-evaluation every 2–3 months from April 2020 in each country (and possibly local areas) and will depend on the local health care structure and phase of pandemic.
Barry D Albertson, R Blake Hill, Kellie A Sprague, Karen E Wood, Lynnette K Nieman, and D Lynn Loriaux
Albertson BD, Hill RB, Sprague KA, Wood KE, Nieman LK, Loriaux DL. Effect of the antiglucocorticoid RU486 on adrenal steroidogenic enzyme activity and steroidogenesis. Eur J Endocrinol 1994;130: 195–200. ISSN 0804–4643
RU486, a synthetic steroid receptor antagonist, has strong antiprogesterone and antiglucocorticoid properties. Chronic RU486 administration in two patients with ectopic secretion of adrenocorticotropin (ACTH) has been associated with decreasing plasma cortisol concentrations. One explanation of this finding is that RU486 may directly inhibit adrenal steroidogenesis. To test this hypothesis, we measured the effect of RU486 on specific steroidogenic enzymatic steps using an in vivo rat and an in vitro monkey model. Hypophysectomized–castrated–ACTH-replaced Sprague-Dawley rats were given RU486 i.p. at daily doses of 0, 0.0005, 0.005, 0.05, 0.5 and 5 mg/kg body weight per day for 7 days. The animals were sacrificed, and blood and adrenal glands collected. Adrenal cortical mitochondria and microsomes were purified from the rats and from two untreated Cynomolgus macaque monkeys. Specific steroidogenic enzyme activities were measured in the rat by the incorporation of 14C-labeled steroid substrates into products. A similar protocol was used to assay the steroidogenesis in the monkey adrenal fractions in the presence and absence of added RU486. Although rat adrenal weights decreased significantly at the highest RU486 dose, plasma levels of corticosterone were similar in control and treated rats. Rat adrenal 3β-hydroxysteroid dehydrogenase/isomerase (3-HSD), 21-hydroxylase (21-OH) and 11-hydroxylase (11-OH) activities decreased with increasing RU486 doses, with 21-OH and 11-OH being most severely affected. Monkey adrenal 3-HSD, 21-OH, 11-OH, 1 7-hydroxylase and 17,20-desmolase similarly decreased in the presence of increasing in vitro concentrations of RU486. Taken together, these results suggest that RU486 directly inhibits adrenal steroidogenesis, with a locus of action at several key enzymatic steps in the glucocorticoid pathway. This steroidogenic blockade may account for the observed decreases in glucocorticoids during RU486 treatment.
Lynette K Nieman, Developmental Endocrinology Branch, NICHD, Building 10, Room 10N262, NIH, Bethesda, MD 20892, USA