#519 Mild Autonomous Cortisol Secretion

March 30, 2026 | By Mobeen Ahmad

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Exploring Uncharted Waters!

Become a master of cortisol and learn how to identify and treat a common condition in patients with adrenal tumors! Join us as we learn about mild autonomous cortisol secretion (MACS) with Dr. Irina Bancos (@irinabancos), an internationally renowned adrenal expert!

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Show Segments

• Intro
• Advice for listeners
• Adrenal incidentaloma Definition (Case 1)
• Hormonal workup for adrenal incidentalomas
• Defining mild autonomous cortisol secretion (MACS)
• Significance and prevalence of MACS
• Diagnostic testing for MACS
• Treatment options for MACS (surgery vs. comorbidity management)
• Post surgical management of MACS (Case 2)
• Diagnostic testing for adrenal insufficiency (AI)
• Glucocorticoid withdrawal syndrome management
• Deciding when patients are able to come off of steroids after AI
• Outcomes after adrenalectomy in MACS
• Take home points

Disclosures

Dr. Bancos has the following disclosures:

• Consulting, advisory board or safety monitoring board (all fees to institution): Recordati, Corcept, Esteve, Spruce, Sparrow, Diurnal, Neurocrine, Lufordi, Adaptyx, Crinetics, Xeris, AstraZeneca, NovoNordisc, Camurus.
• Research grant for investigator initiated research (to institution): Esteve, Recordati

Mild Autonomous Cortisol Secretion Pearls

1. Adrenal incidentalomas are common, and incidence increases with age (up to 10% in patients greater than 70 years of age)
2. MACS is the most common hormonal abnormality in patients with adrenal incidentalomas, occurring in 19-50% of adrenal incidentaloma patients
3. MACS adenomas tend to be lipid rich (<10 Hounsfield units)
4. A 1 mg dexamethasone suppression test (DST) is the most sensitive test for MACS, with patients often having a normal 24 hour urine free cortisol and late night salivary cortisol
5. ACTH independence should be ensured after a DST by measuring an ACTH level on a day separate from your 1 mg dexamethasone suppression test (values <10 pg/ml indicate an adrenal source of cortisol secretion)
6.  Patients often have subtle symptoms and do not have the classic appearance we see with Cushing syndrome
7. Treatment involves either surgical removal of the adrenal adenoma or management of MACS related comorbidities
8. After adrenalectomy, these patients are at risk for adrenal insufficiency and should either be put empirically on steroids or have their morning cortisol and a cosyntropin stim test checked to see if their other adrenal gland is making a sufficient amount of cortisol

Show Notes: Mild Autonomous Cortisol Secretion

Adrenal Incidentalomas

Definition

Adrenal incidentalomas are adrenal masses found incidentally on imaging when you are not looking for adrenal disease (Fassnacht et al. 2023). By definition, this excludes adrenal lesions found during the workup of suspected hormonal excess from the adrenal gland (work up for Cushing syndrome, pheochromocytoma, primary aldosteronism etc.) or when searching for metastases from a known cancer during staging (Fassnacht et al. 2023). Per guidelines, workup should be done if lesions are greater than or equal to 1 cm in size, however per Dr. Bancos, her practice is to evaluate any adrenal mass, even if it is less than 1 cm as you may be catching early disease. In the general population, the prevalence of adrenal incidentalomas ranges from 1-7%, with incidence increasing with age (Fassnacht et al. 2023). Studies have shown that in patients >70 years of age, the incidence of adrenal incidentalomas can be as high as 10% (Fassnacht et al. 2023, Prete and Bancos 2024). Due to the increasing use of cross-sectional imaging, there has been a 10 fold increase in the incidence of incidentalomas over the past two decades (Prete and Bancos 2024). Most of these (80-96%) are notably benign (Prete and Bancos 2024). 

Imaging and Biochemical Assessment

When evaluating adrenal incidentalomas, the two major questions that we are faced with are if the lesion is concerning for a malignancy and if the mass is functional (secreting excessive amounts of hormone). In terms of imaging, a CT scan without contrast is considered the first line imaging modality for the workup of adrenal incidentalomas (Fassnacht et al. 2023). 

A CT scan without contrast can help stratify whether a lesion is concerning for a possible adrenal cancer (Fassnacht et al. 2023). When using a CT scan without contrast, Hounsfield units (HU) play a key role in assessing malignancy potential and are a measure of density, with HU of less than 10 being indicative of a lipid-rich lesion and greater than or equal to 10 being lipid poor (Fassnacht et al. 2023). Lipid-poor lesions are more concerning for potential adrenal carcinomas or pheochromocytomas (Fassnacht et al. 2023).  Studies have shown that lesions less than 10 HU are virtually never adrenal carcinoma, with risk of cancer increasing at higher Hounsfield units (Fassnacht et al. 2023). Pheochromocytomas also tend to have higher Hounsfield units, with biochemical testing for pheochromocytoma with plasma metanephrines indicated only when the HU are greater than or equal to 10 (Fassnacht et al. 2023). Previously, using contrast enhanced CT with washout (assessing how long it takes contrast to wash out of the lesion) was utilized to help differentiate between malignant masses vs benign appearing masses, however cutoffs for this strategy have not been validated in larger studies (Fassnacht et al. 2023). In large lesions (greater than 4 cm) that are dense (>20 HU), there is a significant risk for adrenal cancer and they should undergo prompt surgical evaluation (Fassnacht et al. 2023). Regardless of size, lesions less than 10 HU and homogenous are not concerning for cancer and follow up imaging is no longer recommended (Fassnacht et al. 2023). In patients with lesions that are indeterminate, additional imaging can be considered along with discussion with a multidisciplinary team to assess for underlying malignancy or surgical intervention (Fassnacht et al. 2023).

In terms of biochemical evaluation of adrenal incidentalomas, it is suggested that all adrenal adenomas be screened for mild autonomous cortisol secretion (MACS), regardless of imaging characteristics (Fassnacht et al. 2023). This is done by performing a 1 mg dexamethasone suppression test, which involves administering a dose of 1 mg of dexamethasone at 11 PM and obtaining a morning cortisol level at 8 AM with a dexamethasone level (Fassnacht et al. 2023). Workup for primary aldosteronism should be performed if patients have hypertension or hypokalemia in the presence of an adrenal mass (Fassnacht et al. 2023). This can be performed using a plasma aldosterone level, aldosterone renin ratio, and a plasma renin activity or direct renin concentration with a potassium level (Fassnacht et al. 2023). In lesions that are not typical of a benign mass (HU greater than or equal to 10), plasma metanephrines should be obtained to assess for a pheochromocytoma (Fassnacht et al. 2023).

Mild Autonomous Cortisol Secretion

Definition

Mild autonomous cortisol secretion is the most common hormonal abnormality observed in patients with adrenal adenomas (Fassnacht et al. 2023, Prete and Bancos 2024). MACS is characterized by hypercortisolism which does not present with the clinical signs and symptoms we associate with Cushing syndrome (Fassnacht et al. 2023, Prete and Bancos 2024). This condition was previously termed as subclinical or preclinical Cushing syndrome, however this terminology is no longer used as these patients rarely progress to Cushing syndrome (Fassnacht et al. 2023). MACS is referred to as autonomous as cortisol production is independent of ACTH secretion by the pituitary (Fassnacht et al. 2023).

Incidence 

MACS is present in 19-50% of adrenal incidentalomas, with Cushing syndrome only being present in 1-2% (Prete and Bancos 2024). Studies have demonstrated that women tend to present more frequently with MACS, and patients with MACS are more likely to have bilateral adrenal disease as compared to those with nonfunctional adrenal tumors (Prete and Bancos 2024).

Diagnosis

In terms of adrenal imaging characteristics of patients with MACS, patients tend to present with lipid rich (less than 10 HU), homogenous, well-circumscribed nodules (Prete and Bancos 2024). Patients can have unilateral or bilateral adrenal nodules and may also present with primary bilateral macronodular adrenal hyperplasia (PBMAH) (Prete and Bancos 2024). PBMAH is characterized by multiple, bilateral adrenal nodules measuring >1cm in size (Prete and Bancos 2024). It can be difficult to differentiate the difference between PBMAH and bilateral adrenal nodules as some patients with MACS do not undergo surgery and the diagnosis of PBMAH is not made histologically and routine genetic testing for PBMAH is often not performed (Prete and Bancos 2024).

Biochemically, the diagnosis of mild autonomous cortisol secretion is made using a 1 mg dexamethasone suppression test (DST) (Prete and Bancos 2024). If a patient has a morning cortisol level above 1.8 mcg/dL after DST in the setting of one or more adrenal tumors without clinical signs of Cushing syndrome, this is characteristic of MACS  (Fassnacht et al. 2023, Prete and Bancos 2024). Oftentimes these patients do not have a positive 24-hour urine cortisol test or late-night salivary cortisol test (Prete and Bancos 2024). The morning cortisol level after DST should be viewed as a spectrum, with higher cortisol levels being associated with higher morbidity rates (Prete and Bancos 2024). 

When interpreting the results of a DST, one must be aware of errors that can occur with testing. One must ensure that dexamethasone was taken at night (11 PM) and cortisol is tested in the morning (8 AM). Ideally, a dexamethasone level is checked with the cortisol to ensure that the patient received an adequate amount of dexamethasone to truly suppress their hypothalamic-pituitary-adrenal axis (Prete and Bancos 2024, Reincke and Fleseriu 2023). If not, this can lead to false positive results. Additionally, in patients taking oral contraceptive pills or selective estrogen receptor modulators, cortisol binding globulin can be increased leading to a falsely elevated cortisol level after DST (Prete and Bancos 2024, Reincke and Fleseriu 2023). In frail individuals with limited life expectancy, DST may not be beneficial as treatment of MACS related comorbidities may not improve patient outcomes  (Fassnacht et al. 2023, Prete and Bancos 2024).

After the DST is confirmed to have been performed correctly, we must ensure that the excess cortisol is ACTH independent (Reincke and Fleseriu 2023). An ACTH level should be obtained with levels that are low or low normal consistent with ACTH independent hypercortisolism and greater than 20 being consistent with either a Cushing disease or ectopic ACTH production (Reincke and Fleseriu 2023). Additionally, physicians can use dehydroepiandrostendione sulfate (DHEA-S) levels to further support a diagnosis of MACS, with levels of less than 60-70 mcg/dL having a sensitivity and specificity of 82 percent (Saini et al. 2025). Dr. Bancos thinks of DHEA-S levels as the HbA1c of ACTH, with lower levels representing chronic ACTH suppression in the setting of hypercortisolism due to MACS. This is because DHEA-S is normally mediated by ACTH levels and therefore given in MACS ACTH is suppressed, the DHEAS levels also are generally suppressed.

Clinical Manifestations

MACS by definition typically does not have clinical manifestations of Cushing syndrome. In clinical practice however, patients with MACS may exhibit clinical symptoms of Cushing syndrome (Prete and Bancos 2024). In a study of clinicians using a standardized checklist for hypercortisolism (obesity, supraclavicular or dorsoclavicular fat pads, and rounded facies), signs were found in 78-90% of patients with Cushing syndrome, however they were also found in 21-38% of those with MACS (Prete and Bancos 2024). Therefore, at times it can be difficult to differentiate between Cushing syndrome and MACS.

Why is recognizing MACS important?

Multiple studies have demonstrated that MACS is associated with numerous comorbidities including hypertension, type 2 diabetes, obesity, and vertebral fractures (Prete and Bancos 2024). Interestingly, some of the cardiovascular manifestations of MACS are also seen in patients with nonfunctional adrenal tumors, particularly those that demonstrate a cortisol level slightly below the 1.8 ug/dL cutoff used for diagnosing MACS (Prete and Bancos 2024). Multiple studies have also shown that MACS is associated with higher mortality rates as compared to individuals with nonfunctional adrenal tumors and the general population (Prete and Bancos 2024).

Treatment of MACS

According to the latest adrenal incidentaloma guidelines, patients diagnosed with MACS should be considered for adrenalectomy after consideration of the patient’s age, comorbidities, and surgical risk (Prete and Bancos 2024). Previous studies have generally shown improvements in cardiovascular risk factors such as hypertension, diabetes, and potentially dyslipidemia with adrenalectomy, however, many of these studies are retrospective and may use different definitions for MACS (Prete and Bancos 2024). A recent prospective study by Dr. Bancos’ group demonstrated improvements in hypertension, glycemic control, and obesity in individuals who underwent adrenalectomy and were followed for 12 months (Chacko et al. 2025). Further long term studies are needed to elucidate if adrenalectomy affects rates of MACE. Additionally, research is also needed to assess whether early intervention with adrenalectomy in patients without comorbidities is beneficial in preventing comorbidities from developing (Prete and Bancos 2024).

After adrenalectomy, patients are at risk for adrenal insufficiency (AI) with approximately 50% of them developing AI (Prete and Bancos 2024). In general, there are two approaches to assessing the risk of AI. The first is to discharge the patient on steroids from the hospital and taper them as an outpatient while assessing the HPA axis for recovery using a morning cortisol level (Prete and Bancos 2024). A morning cortisol of greater than 10 ug/dL drawn before the patient has taken steroids for the day is indicative of an adequate HPA axis (Beushlein et al. 2024). Another way to assess the HPA axis prior to the patient being discharged is to obtain a basal morning cortisol after adrenalectomy and a cosyntropin stimulation test (Prete and Bancos 2024). A morning cortisol level of <10 ug/dL and a cortisol of  <18 ug/dL after cosyntropin stimulation would be indicative of potential AI (Hamidi et al. 2025). Of note, a recent study by Hamidi et al. did note that the basal cortisol and the cosyntropin stimulation test were 78% concordant, with more discordance seen in patients with bilateral adrenal nodules (Hamidi et al. 2025).  

When bilateral adrenal nodules are present, some centers have developed adrenal venous sampling protocols to differentiate which nodule is producing excess amounts of cortisol, however these have not been standardized to this point (Prete and Bancos 2024). In patients with PBMAH, it is recommended that the adrenal gland that is larger be removed and that patients are monitored for recurrence of MACS in the future (Prete and Bancos 2024).

Links

1. Endocrine Society

Goal

Listeners will recognize mild autonomous cortisol secretion as an entity associated with numerous metabolic comorbidities and develop a framework to the diagnosis of MACS.

Learning objectives

1. Recognize mild autonomous cortisol secretion as a risk factor for numerous comorbidities and view it as a distinct entity from Cushing syndrome
2. Develop a framework to the diagnosis of MACS and conceptualize why certain testing is more accurate than others
3. Recognize post surgical implications of adrenalectomy in MACS patients and the importance of long term follow up and monitoring

Citation

Ahmad M, Bancos I,Williams PN, Watto MF. “#519 Mild Autonomous Cortisol Secretion”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast March 30, 2026