Best Practice & Research Clinical Endocrinology & Metabolism
6Steroid profiling in the diagnosis of mild and overt Cushing’s syndrome
Introduction
Overt Cushing syndrome (CS) is mostly caused by increased stimulation of the adrenals by adrenocorticotropin (ACTH), due to a pituitary tumor (Cushing disease; 70–75%) or ectopic ACTH secretion (10–15%). In the remaining 10–15% cases, autonomous cortisol secretion from an adrenocortical adenoma, or, less frequently, adrenocortical carcinoma, are the most common causes [1]. Rarely, autonomous adrenal cortisol excess is caused by primary bilateral macronodular adrenal hyperplasia [2], or primary pigmented nodular adrenocortical disease [1].
The incidence rate of adrenal tumors has increased 10-fold over the last 20 years [3]. Adrenal incidentalomas occur in 5–7% of adults undergoing cross-sectional abdominal imaging, and the majority of these are benign adrenocortical adenomas [3,4]. When evaluated with an overnight dexamethasone suppression test, 30–50% of patients with adrenal adenomas demonstrate mild autonomous cortisol secretion (MACS) [3,4]. Patients with MACS lack clinical signs of overt CS, but suffer a higher rates of cardiovascular comorbidities, abnormal bone health, increased frailty, and mortality [[5], [6], [7], [8], [9], [10]].
Diagnosis of both CS and MACS can be challenging. The diagnosis of CS is based on clinical evaluation and measurement of a combination of biochemical parameters [11], while the diagnosis of MACS has more recently been based on dexamethasone suppression testing [12,13]. In this review, we will discuss the role of steroid profiling in making a diagnosis of CS or MACS.
Section snippets
Diagnostic challenges of Cushing syndrome
CS presents with a wide range of clinical features that include obesity, abdominal fat redistribution, dorsocervical and supraclavicular fat pads, striae, thinning of the skin, easy bruising, and proximal myopathy. Patients may present with recent onset, or worsening of hypertension, diabetes mellitus type 2, dyslipidemia, osteoporosis, depression, or anxiety [11]. However, no single clinical feature is 100% predictive of CS and the clinical diagnosis might be difficult in mild CS cases.
The
Challenges in diagnosis of mild autonomous cortisol secretion
MACS is diagnosed in up to 50% of patients with incidentally discovered adrenal adenomas [4]. MACS is more common in postmenopausal women, patients with large, or bilateral tumors [6,41]. Unlike patients with CS, patients with MACS do not present with typical physical features, such as striae, supraclavicular pads, dorsocervical pads, or proximal myopathy. Moreover, most patients with MACS do not progress towards overt CS [42]. The diagnosis is based on biochemical parameters only [12,13].
Over
Principles of steroid metabolomics
The adrenal cortex is the major site of steroidogenesis. Circulating steroids are available for action through binding to the cellular steroid receptors and can be measured in serum or plasma (serum/plasma steroid profiling), Table 1, Fig. 1. Notably, steroid production follows a diurnal rhythm, with most measurements performed in the morning. Steroids can undergo metabolism in the liver, or can be directly excreted in the urine [47,48]. Measurements of steroids in a 24 h urine sample represent
Steroid measurements
Steroid measurements have historically been performed with competitive immunoassays since steroids and their metabolites are of insufficient size to allow binding by two separate antibodies, as is done in immunometric assays (also known as “sandwich assays”). Unfortunately, this reduces the analyte specificity of steroid immune assays. The problem is exacerbated by the fact that different steroids are very similar to each other and their respective metabolites. Moreover, steroid hormone
Steroid metabolome in overt Cushing syndrome and MACS
Steroid profiling in CS depends on the etiology (ACTH-dependent vs ACTH independent), and the severity of CS. In all patients with CS, excessive amounts of glucocorticoids are observed in either blood or urine measurements. Androgen production/excretion is very low in ACTH-independent CS, while elevated in the ACTH-dependent CS. In patients with MACS, steroid profiling results are is similar to ACTH-independent CS, though milder abnormalities are seen.
Clinical implications
Steroid profiling is a promising tool and has the potential to aid clinicians to make a more definitive diagnosis of overt CS or MACS. Though most studies discussed above had a small sample size, their results have been concordant in distinguishing ACTH dependent and ACTH independent causes of endogenous cortisol excess. These preliminary results need further validation in a prospective study of patients with CS.
There are limitations that prevent the wide use of steroid profiling in clinical
Summary
The diagnostic potential of steroid profiling in disorders of endogenous cortisol excess is promising. Multianalyte assays by LC-MS/MS are facilitating measurements of large panel of steroids overcoming traditional interpretation based on a single hormone value. In the future, steroid profiling combined with customized computational approaches and machine-based learning may provide improvement in diagnosis of steroidogenic disorders, in particular – simplifying the hormonal workup and disease
Role of funding source
This work was partially supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) USA under award K23DK121888 (to IB). The views expressed are those of the author(s) and not necessarily those of the National Institutes of Health USA.
Declaration of competing interest
IB reports consulting with Corcept, Strongbridge, HRA Pharma, and Sparrow Pharmaceutics outside the submitted work.
References (62)
- et al.
Cushing’s syndrome
Lancet
(2015) - et al.
Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study
Lancet Diabetes Endocrinol
(2020) - et al.
Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing’s syndrome: a 15-year retrospective study
Lancet Diabetes Endocrinol
(2014) - et al.
The evaluation of incidentally discovered adrenal masses
Endocr Pract
(2019) - et al.
Pituitary-adrenal function in severe depressive illness
Lancet
(1968) - et al.
Transformation techniques for cross-sectional and longitudinal endocrine data: application to salivary cortisol concentrations
Psychoneuroendocrinology
(2013) - et al.
Determination of cortisol in serum, saliva and urine
Best Pract Res Clin Endocrinol Metabol
(2013) - et al.
Serum steroid profiling in Cushing’s syndrome patients
J Steroid Biochem Mol Biol
(2019) Intracrinology. Mol Cell Endocrinol.
(1991)- et al.
Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: a prospective test validation study
Lancet Diabetes Endocrinol
(2020)
Advancement in steroid hormone analysis by LC-MS/MS in clinical routine diagnostics - a three year recap from serum cortisol to dried blood 17alpha-hydroxyprogesterone
J Steroid Biochem Mol Biol
Interlaboratory comparison study of serum total testosterone [corrected] measurements performed by mass spectrometry methods
Steroids
Clinical peptide and protein quantification by mass spectrometry (MS)
Trac Trends Anal Chem
ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome
N Engl J Med
Adrenal incidentalomas are tied to increased risk of diabetes: findings from a prospective study
J Clin Endocrinol Metab
Evaluation of bone health in patients with adrenal tumors
Curr Opin Endocrinol Diabetes Obes
The impact of mild autonomous cortisol secretion on bone turnover markers
J Clin Endocrinol Metab
Modern management of mild autonomous cortisol secretion
Clin Pharmacol Ther
Frailty in patients with mild autonomous cortisol secretion is higher than in patients with nonfunctioning adrenal tumors
J Clin Endocrinol Metab
Cortisol as a marker for increased mortality in patients with incidental adrenocortical adenomas
J Clin Endocrinol Metab
The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline
J Clin Endocrinol Metab
Management of adrenal incidentalomas: European society of Endocrinology clinical practice guideline in collaboration with the European network for the study of adrenal tumors
Eur J Endocrinol
The optimal cut-off of BIPSS in differential diagnosis of ACTH-dependent Cushing’s syndrome: is stimulation necessary?
J Clin Endocrinol Metab
Elevated late-night salivary cortisol levels in elderly male type 2 diabetic veterans
Clin Endocrinol (Oxf)
Late-night salivary cortisol has a better performance than urinary free cortisol in the diagnosis of Cushing’s syndrome
J Clin Endocrinol Metab
Utility of salivary cortisol measurements in Cushing’s syndrome and adrenal insufficiency
J Clin Endocrinol Metab
Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome
Eur J Endocrinol
High fluid intake increases urine free cortisol excretion in normal subjects
J Clin Endocrinol Metab
Accuracy in 24-hour urine collection at a tertiary center
Rev Urol
The 24-hour urine collection: gold standard or historical practice?
Am J Obstet Gynecol
Accuracy and usefulness of select methods for assessing complete collection of 24-hour urine: a systematic review
J Clin Hypertens (Greenwich).
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