Serum Steroid Precursors May Aid in Adrenal Disease Diagnoses

Miriam E. Tucker

May 07, 2019

LOS ANGELES — Measuring serum steroid precursors can aid in the diagnosis of adrenal disorders, new research suggests. 

The findings were presented April 26 here at the American Association of Clinical Endocrinologists (AACE) 2019 Annual Scientific & Clinical Congress by Shobana Athimulam, MD, a clinical endocrinology fellow at the Mayo Clinic, Rochester, Minnesota.

Athimulam explained that patients with adrenal disorders "present with a wide spectrum of symptoms. As endocrinologists, we acknowledge that sometimes history, initial lab work — measurements of cortisol in the 24-hour urine collection, in the morning serum sample at baseline or after dexamethasone suppression, or in saliva, which are standard-of-care tests — and not always give a clear-cut diagnosis when managing adrenal disorders."

But tests to aid in several diagnostic challenges in the workup of adrenal tumors and subtypes of Cushing syndrome are already available, she told Medscape Medical News.

"What is unique about our study is that these serum steroid precursor measurements using liquid chromatography-mass spectrometry (LC-MS) exist. [They are] widely available in most reference labs and not exclusive to tertiary centers and research use only."

But they are "underutilized and reserved for unique situations, such as workup for congenital adrenal hyperplasia. Hence, our findings are applicable to a clinical endocrinologist practicing anywhere and translation into practice is possible immediately, after validation in larger cohort studies," she emphasized.

Asked to comment, session moderator Lance Sloan, MD, medical director of the Texas Institute for Kidney and Endocrine Disorders, Lufkin, told Medscape Medical News, "I think it's very impressive. We certainly would like easier tests to do in clinical endocrinology on an outpatient basis to be able to differentiate whether someone has cancer of the adrenal gland or not."

"Or [to indicate] whether or not it's an adrenocorticotropic hormone (ACTH) dependent or independent type of tumor, without having to hospitalize [patients] or do other tests that take longer or are more difficult…I think it's very exciting for the clinical community."

Transform the Adrenal Practice

The specific clinical management dilemmas addressed in the study were (1) differentiating malignant adrenal mass (adrenocortical carcinoma from benign adrenal mass); (2) differentiating mild autonomous cortisol secretion (MACS) from nonfunctioning adrenal tumors; (3) differentiating ACTH-dependent versus -independent Cushing syndrome; and (4) differentiating pituitary versus ectopic tumor in ACTH-dependent Cushing syndrome.

A total of 370 patients (62% women) were prospectively enrolled over 3 years. Inclusion criteria were any type of Cushing syndrome or adrenal mass and available biomaterial. Those on exogenous steroids were excluded.

The precursors 11-deoxycortisol (DCORT), 17-hydroxypregnenolone (17OHPreg), 17-hydroxyprogesterone (17OHProg), pregnenolone, and androstenedione were all measured by LC-MS.

Dehydroepiandrostenedione sulfate (DHEAS) and cortisol were measured by automated chemiluminescent competitive immunoassay. For analysis, the steroids were converted into percentages of upper age- and sex-adjusted normal range.

The patients' final diagnoses included 128 nonfunctioning adrenal tumors (NFAT), 63 mild autonomous cortisol secretion (MACS) (formerly known as subclinical Cushing), 34 aldosteronoma, 33 pituitary Cushing disease, 26 pheochromocytoma, 22 other benign adrenal mass, 21 adrenal Cushing syndrome, 19 adrenocortical carcinoma (ACC), 17 other adrenal malignancy, and seven ectopic Cushing syndrome.

The 19 patients with ACC had between two to 12 times statistically significant elevations in several of the precursors. Multivariable analysis of just the three precursors 17OHPreg, 17OHProg, and DCORT accurately predicted ACC (area under the curve, 0.99; P < .0001).  

With ACC, "sometimes patients can have masses as big as 8 to 10 cm but the cortisol itself might not be that high. But these precursors are typically elevated despite a normal cortisol value," Athimulam explained.   

"This is due to inefficient enzymatic activity within the tumor cells that affect conversion. Hence, measuring these steroid precursors will add value when working up a patient with suspected ACC."

Diagnoses Not Always Dependent on Severity of Hypercortisolism

For the benign adrenal adenomas, DCORT was highest in patients with adrenal cortisol excess (P < .0001), while 17OHPreg (P = .03) and DHEAS (P = .0003) were lowest compared to patients with MACS and NFAT.

"DCORT is also produced by the adrenal tumor mass itself, and hence, it is elevated. But 17OHPreg and DHEAS are produced by the normal adrenal cortex and these are suppressed when cortisol production occurs in excess," she noted.

Patients with ACTH-independent Cushing syndrome demonstrated lower 17OHPreg and DHEAS (P < .0001 for both) compared with ACTH-dependent Cushing but no differences in DCORT or 17OHProg.

And among those with ACTH-dependent Cushing syndrome, those with ectopic Cushing had higher DCORT (P = .005) and 17OHProg (P = .04), with DCORT being a significant predictor of ectopic Cushing syndrome even after correcting for cortisol concentrations (P = .02).

Another major dilemma, Athimulam said, is "when you have a patient with ACTH-dependent Cushing but a negative MRI. Is it coming from a pituitary or ectopic source?"

"We found that 17OHProg and DCORT were several-fold significantly higher in patients with ectopic Cushing. We do acknowledge that the number of patients with ectopic Cushing was only seven, but we still saw a significant difference between the two groups, even after adjusting for cortisol values, suggesting that it's not dependent on the severity of hypercortisolism."

She added, "We suspect these precursors are much more elevated in ectopic versus pituitary because the degree of hypercortisolemia in ectopic Cushing is so severe that there may be a relative enzyme deficiency to keep up with the production and these precursors tend to build up. But of course we need to expand our cohort and validate it in larger studies."

Sloan commented, "They'll be doing more studies and increasing the database, which of course will increase the likelihood of the community adapting some of these things into usual clinical practice."

"But it is certainly something I'm going to start to consider using in my practice," he concluded.

The work was funded by the Transform the Adrenal Practice initiative of the Mayo Clinic. Athimulam had no further disclosures. Sloane has reported serving as a consultant and/or speaker for AstraZeneca, Janssen, Merck, Pfizer, Boehringer Ingelheim, Lilly, and Novo Nordisk. 

AACE 2019. Presented April 26, 2019.

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