Cortisol Excess: Unsafe at Any Level?

A new study finds that even low levels of the “mild cortisol excess” associated with adrenal incidentalomas can increase cardiometabolic risk.  

Benign tumors on adrenal glands may not be so benign when it comes to patients’ overall health, according to the largest study to date on the topic. An international consortium of researchers found that the mild autonomous cortisol secretion (MACS) that commonly results from adrenal incidentalomas is associated with a significantly higher risk of cardiometabolic disease.  

These tumors are very common, discovered incidentally in approximately 5% of abdominal imaging studies performed for reasons unrelated to the adrenal glands. Although some tumors clearly increase cortisol secretion to a level that leads to a diagnosis of Cushing syndrome, the impact of milder cortisol elevations has been unclear.

Previous studies of MACS — sometimes termed subclinical Cushing syndrome — have been small and reported ambiguous and sometimes contradictory findings that have led to inconsistent recommendations on treatment. In an effort to obtain more definitive data, researchers recruited 1,300 patients with benign adrenal tumors from 14 endocrine secondary and tertiary care centers and published their results online on Jan. 4 in the Annals of Internal Medicine.

“Patients who don’t have overt Cushing syndrome are not always followed as closely as they should be. There are conflicting recommendations of whether you should remove these mild autonomous cortisol-secreting adrenal tumors or just watch the patients and not necessarily do something. The study implies that we should be more open to adrenalectomy than we previously have been in these patients. At a minimum, we need close follow-up of developing co-morbidities and other issues to make personalized, individualized decisions on each patient’s care.”

Lauren Fishbein, MD, PhD, associate professor of medicine in endocrinology, metabolism, and diabetes, University of Colorado, Aurora, Colorado

Patients underwent a dexamethasone suppression test and had their net steroid production assessed with a 24-hour urine collection. The researchers categorized the patients into four groups based on their dexamethasone test results according to guidelines from the European Society of Endocrinology for the treatment of adrenal incidentalomas:

  • 50% were rated as having a “nonfunctioning” adrenal tumor (morning serum cortisol of less than 50 nmol/L or 1.8 mcg/dL);
  • 35% were placed in the MACS-1 group (serum cortisol of 50 to 138 nmol/L or 1.8 to 5 mcg/dL);
  • 11% were in the MACS-2 group (serum cortisol over 138 nmol/L but without clinical signs of Cushing syndrome); and
  • 5% had Cushing syndrome based on high levels of cortisol and clinical signs.

The researchers then reviewed the patients’ charts to examine the relationship between their cortisol levels and the presence and severity of hypertension and diabetes. “We found that patients with MACS have a significantly increased risk of both high blood pressure and type 2 diabetes than patients with a nonfunctioning tumor,” says corresponding author Wiebke Arlt, MD, chair of medicine at the University of Birmingham in the U.K. “Patients with MACS who had hypertension were much more likely to be taking more than three hypertensive drugs, and patients with MACS with diabetes were more likely to be on insulin, compared with patients with nonfunctioning tumors.”

The study found that patients with MACS-2 had “an increased cardiometabolic burden similar to that seen in Cushing syndrome, even if they do not display typical features of clinically overt cortisol excess.”

Arlt adds that the study found that MACS “predominantly affects women, so is a major factor potentially defining the metabolic health of women after the menopause. It is a previously overlooked relatively common cause of type 2 diabetes and high blood pressure.”

The study also found a distinct continuum of greater cortisol levels being associated with greater risk.

Confirming Suspicions

“The study confirmed what was reported in other smaller studies,” says Richard Auchus, MD, PhD, professor of internal medicine and pharmacology at the University of Michigan, who was not involved in the study. “The difference is that with the large size there is much higher confidence with the results.”

“We found that patients with MACS have a significantly increased risk of both high blood pressure and type 2 diabetes than patients with a nonfunctioning tumor. Patients with MACS who had hypertension were much more likely to be taking more than three hypertensive drugs, and patients with MACS with diabetes were more likely to be on insulin, compared with patients with nonfunctioning tumors.”

Wiebke Arlt, MD, chair of medicine, University of Birmingham, Birmingham, U.K.

Lauren Fishbein, MD, PhD, associate professor of medicine in endocrinology, metabolism, and diabetes at the University of Colorado, who was also not involved in the study, says the results are not surprising: “I think the study confirms a lot of what we suspected. But it is the first large study that really proves it.”

Tip of the Iceberg?

In an invited editorial that accompanied the study, Andre Lacroix, MD, professor of medicine at the University of Montreal teaching hospital, wrote: “The data clearly support the European Society of Endocrinology guideline [on management of adrenal incidentalomas] that clinicians should determine precisely the cardiometabolic consequences of mild cortisol secretion in patients with adrenal lesions.”

One limitation of the study that the authors acknowledge was that there was no matched control group of patients who had had scans with no adrenal incidentaloma found. Lacroix tells Endocrine News that this lack of a control group could “mask the fact that even lower amounts of cortisol production may also have some deleterious effects because even the patients who have so-called non-functional tumors have a very high prevalence of hypertension or diabetes. If you look at the group that has very low cortisol production, 64% of those individuals have hypertension. In the general population, hypertension prevalence in adults is about 30%. The study may be showing only the tip of the iceberg of problems caused by excess cortisol.”

Auchus echoes this sentiment: “One aspect that was shocking to me was the very high prevalence of co-morbidities in the non-functioning adrenal tumor group: 80% were overweight or obese, 64% had hypertension, and 26% had diabetes (with 17% taking insulin). Yet the authors still saw differences graded to cortisol production. There is no escaping that even a little too much cortisol is not healthy in the long run, but the quandary remains regarding how to best assess the patients and what to do about it.”

Lacroix says that one confounding factor is that a cortisol level is a crude measure: “We currently lack a good marker of the real biological effect of cortisol.”

What to Do About It

“I think this study does push for the importance of not ignoring this group of mild adrenal cortisol-secreting tumors,” Fishbein says. “Patients who don’t have overt Cushing syndrome are not always followed as closely as they should be. There are conflicting recommendations of whether you should remove these mild autonomous cortisol-secreting adrenal tumors or just watch the patients and not necessarily do something. The study implies that we should be more open to adrenalectomy than we previously have been in these patients. At a minimum, we need close follow-up of developing co-morbidities and other issues to make personalized, individualized decisions on each patient’s care.”

“One aspect that was shocking to me was the very high prevalence of co-morbidities in the non-functioning adrenal tumor group … Yet the authors still saw differences graded to cortisol production. There is no escaping that even a little too much cortisol is not healthy in the long run, but the quandary remains regarding how to best assess the patients and what to do about it.”

Richard Auchus, MD, PhD, professor of internal medicine and pharmacology, University of Michigan, Ann Arbor, Michigan

Arlt notes that the study underscores the importance of investigating “incidentally discovered nodules on their adrenal, which are often ignored. It is important that these patients are assessed with a dexamethasone suppression test. If they have MACS, then they should be regularly assessed for their metabolic health. If their metabolic health is impaired, it should be considered whether the adrenal nodule be removed or the patient should receive medication to better control the metabolic risk.”

Seaborg is a freelance writer based in Charlottesville, Va. In the February issue, he wrote about race and gender disparities in treating pediatric patients with growth hormone therapy.

You may also like

  • New Cushing’s Syndrome Research Presented at ENDO 2022

    The pharmacology data focus on the human body’s homeostatic response to potent HSD-1 inhibition by SPI-62. Results highlight that urinary free cortisol is distinct from intracellular cortisol that causes symptoms in patients with Cushing’s syndrome or autonomous cortisol secretion. Sparrow Pharmaceuticals, a clinical-stage biopharmaceutical company developing novel, targeted therapies to address unmet needs in both endocrinology…

  • All About Adrenal: Analyzing Two Years of Research

    When the ENDO 2022 session “Clinical Year in Review: All Things Adrenal” gets underway, Gary Hammer, MD, PhD, will treat attendees to the series of advances that have been made in adrenal science and clinical practice over the last two years, from adrenal homeostasis, glucocorticoid biology, and adrenal insufficiency to Cushing’s, tumors, pheochromocytoma, and more….

Find more in