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Steroid profiling in the diagnosis of mild and overt Cushing’s syndrome

https://doi.org/10.1016/j.beem.2021.101488Get rights and content

In this review, we provide a comprehensive overview of the utility of steroid profiling for diagnosis of management of overt Cushing syndrome and mild autonomous cortisol secretion.

A diagnosis of Cushing syndrome is made through a multistep process that includes confirmation of endogenous hypercortisolism, followed by determination of its cause. Steroid metabolomic testing applied to serum or urine steroids and their metabolites can provide additional and novel insights into alterations of steroid biosynthesis and metabolism and its causes. In particular, increased availability and advances in mass spectrometry-based steroid analysis, coupled with machine learning-based algorithms, have facilitated the development of tailored diagnostic and subtyping approaches for autonomous cortisol secretion and might be useful for detecting low grade autonomous glucocorticoid secretion and in predicting and monitoring of disease severity and associated comorbidities.

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.

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