FAQ: Identifying Undiagnosed Hypercortisolism and Subsequent Treatment

This FAQ was fact-checked by Jennifer Goldman, PharmD, CDCES, BC‑ADM, FCCP​​.​

Hypercortisolism is a disorder characterized by prolonged exposure to elevated cortisol levels. Cortisol is a glucocorticoid hormone produced by the adrenal glands that plays an important role in metabolism, blood pressure regulation, immune function, and the body’s stress response. Excess cortisol may result from exogenous glucocorticoid use or endogenous overproduction caused by pituitary adenomas, adrenal tumors, or ectopic adrenocorticotropic hormone (ACTH) secretion.

For pharmacists, recognizing hypercortisolism is important because many patients initially present with metabolic abnormalities (eg, hyperglycemia, weight gain, hypertension) before receiving a formal diagnosis. In some individuals, worsening diabetes or difficult-to-control blood glucose may be one of the earliest clues. The term Cushing syndrome is often used for endogenous cortisol overproduction, whereas mild autonomous cortisol secretion describes adrenal incidentaloma-related cortisol excess without classic Cushing symptoms.

Q1: Why should pharmacists be concerned about undiagnosed hypercortisolism?

Hypercortisolism is often underrecognized because its symptoms overlap with common chronic conditions such as obesity, type 2 diabetes (T2D), hypertension, depression, and metabolic syndrome. Patients may spend years being treated for individual symptoms without clinicians recognizing an underlying endocrine disorder.

Pharmacists are uniquely positioned to identify patients who may warrant further evaluation because they frequently encounter medication patterns suggestive of uncontrolled disease. A patient receiving multiple antihypertensive agents, escalating diabetes therapy, lipid-lowering medications, and antidepressants despite persistent symptoms may have an underlying endocrine cause contributing to treatment resistance.

Undiagnosed hypercortisolism can lead to significant complications, including poorly controlled diabetes, cardiovascular disease, osteoporosis, infections, psychiatric disturbances, and increased mortality. Early recognition and referral may improve patient outcomes and reduce long-term complications.

Q2: How does hypercortisolism contribute to hyperglycemia?

Excess cortisol has profound metabolic effects that promote insulin resistance and increased glucose production. Cortisol stimulates hepatic gluconeogenesis, decreases peripheral glucose uptake, and impairs pancreatic beta cell function. Together, these mechanisms increase circulating glucose levels and make glycemic control more difficult.

Patients with hypercortisolism may present with:

• new-onset hyperglycemia or diabetes
• rapid worsening of previously controlled diabetes
• persistent hyperglycemia despite intensification of therapy
• significant insulin resistance requiring high insulin doses
• concurrent hypertension, central obesity, and dyslipidemia

Some patients may initially appear to have uncomplicated T2D, but additional physical findings or resistant metabolic abnormalities should prompt consideration of hypercortisolism.

Because Cushing syndrome is rare, routine screening of all patients with T2D is not recommended. Testing is better focused on those with additional characteristic clinical features or resistant cardiometabolic disease.

Q3: Which patients are at greatest risk for hypercortisolism?

Hypercortisolism can occur in a wide range of patients, although certain groups are more likely to be affected. Endogenous Cushing syndrome is relatively rare, but mild or subclinical hypercortisolism may be more common than previously recognized.

Pharmacists should maintain a higher index of suspicion in patients with:

• difficult-to-control diabetes
• resistant hypertension requiring multiple medications
• rapid or unexplained weight gain
• central obesity with relatively thin extremities
• early-onset osteoporosis or unexplained fractures
• recurrent infections
• proximal muscle weakness
• depression, anxiety, or cognitive changes
• easy bruising or poor wound healing
• menstrual irregularities or decreased libido
• history of adrenal incidentalomas (even if previously labeled nonfunctioning, and particularly when new hypertension, diabetes, or fracture develop)

Patients receiving chronic corticosteroid therapy are also at risk for exogenous Cushing syndrome. Pharmacists should carefully review all potential glucocorticoid exposures, including oral, injectable, inhaled, topical, ophthalmic, and intranasal formulations.

Q4: What does hypercortisolism look like clinically?

The clinical presentation of hypercortisolism can vary considerably depending on the severity and duration of cortisol excess. Some patients develop classic physical features, whereas others present with more subtle metabolic abnormalities.

Common signs and symptoms include the following:

• central weight gain, particularly around the abdomen and upper back
• facial rounding or “moon facies”
• dorsocervical fat pad (“buffalo hump”)
• purple abdominal striae
• thin skin and easy bruising
• facial plethora
• acne or hirsutism
• muscle weakness, especially when climbing stairs or standing from a seated position
• fatigue
• hypertension
• hyperglycemia or diabetes
• osteoporosis
• mood changes, depression, irritability, or insomnia

Many patients report frustration with inability to lose weight despite lifestyle changes. Others may describe worsening blood pressure or blood glucose control despite medication adherence.

Q5: When should pharmacists suspect hypercortisolism in patients with hyperglycemia?

Pharmacists should consider hypercortisolism when hyperglycemia occurs alongside other suspicious clinical features or when conventional treatment approaches appear ineffective.

Potential red flags include the following:

• escalating diabetes therapy without adequate glycemic control
• requirement for unusually high insulin doses
• concurrent resistant hypertension
• weight gain despite reported dietary changes
• multiple metabolic comorbidities occurring together at a relatively young age
• characteristic physical findings such as purple striae or proximal muscle weakness
• recurrent hospitalizations for metabolic complications
• osteoporosis
• emotional or psychiatric symptoms accompanied by metabolic dysfunction

Pharmacists practicing in ambulatory care, endocrinology, primary care, or community settings may be especially likely to identify these patterns over time. It is important to note that one symptom alone is not sufficient; however, a cluster of multiple and progressive features is a cause for concern. The likelihood of hypercortisolism increases as more characteristic features accumulate, especially when they develop or worsen over time, despite appropriate therapy.

Q6: How is hypercortisolism diagnosed?

The diagnosis of hypercortisolism typically begins with screening tests that assess cortisol excess. Because cortisol secretion fluctuates throughout the day, testing usually involves evaluating whether normal cortisol regulation has been disrupted.

Recommended first-line screening options may include the following:

• Late-night salivary cortisol: measures cortisol levels late at night, when cortisol should normally be low. Elevated late-night cortisol may suggest loss of normal circadian rhythm.
• 24-hour urinary free cortisol: measures the amount of cortisol excreted in the urine over a full day. Elevated levels may indicate cortisol excess.
• Overnight dexamethasone suppression test: patients take 1-mg dose of dexamethasone at night, followed by simultaneous dexamethasone and cortisol measurements the next morning. In healthy individuals, dexamethasone suppresses cortisol production. Failure to suppress cortisol may indicate hypercortisolism.
• Other factors to consider: poor sleep, acute illness, significant alcohol use, and depression may all elevate late-night cortisol or urinary free cortisol.

No single test is perfect, and false-positive results can occur. If screening results are abnormal, patients are generally referred to endocrinology for confirmatory testing and evaluation of the underlying cause.

Q7: What role do pharmacists play in the diagnostic process?

Pharmacists can support the diagnostic process in several ways. First, they may identify concerning symptom patterns or medication histories that warrant referral. Second, they can help ensure appropriate test preparation and medication review.

Important pharmacist responsibilities include the following:

• reviewing glucocorticoid exposure from all dosage forms
• identifying medications that may interfere with testing
• counseling patients on proper collection procedures for salivary or urinary testing
• reinforcing adherence to diagnostic instructions
• encouraging follow-up with endocrinology or primary care

Pharmacists may also help differentiate medication-induced metabolic complications from endogenous endocrine disease.

Q8: How is hypercortisolism treated?

Treatment depends on the underlying cause of cortisol excess.

• Exogenous hypercortisolism. If chronic corticosteroid therapy is responsible, gradual tapering may be appropriate when clinically feasible. Abrupt discontinuation should be avoided because it may precipitate adrenal insufficiency.
• Pituitary tumors causing excess ACTH production are commonly treated with transsphenoidal surgery.
• Adrenal tumors or carcinomas may require surgical removal.
• Ectopic ACTH production. Treatment focuses on identifying and managing the underlying tumor source.
• Medical therapy. Some patients may require medications that reduce cortisol production or block cortisol activity, particularly when surgery is not possible or while awaiting definitive treatment. Medical options include adrenal steroidogenesis inhibitors, glucocorticoid receptor antagonists, and pituitary-directed agents.
  • Pharmacists should be wary that oral estrogens can result in false positives, and CYP3A4 inducers lower dexamethasone levels and blunt suppression.

Even after treatment begins, metabolic complications such as diabetes and hypertension may persist for some time and require ongoing management.

Q9: What is the pharmacist’s role after diagnosis?

Pharmacists remain essential members of the care team following diagnosis and treatment. Patients with hypercortisolism often require complex medication management and close monitoring.

After diagnosis, pharmacists can:

• optimize diabetes therapy during changes in cortisol levels
• monitor for hypoglycemia as cortisol excess resolves
• help manage antihypertensive and lipid-lowering therapy
• counsel patients on adherence and adverse effects
• monitor for adrenal insufficiency after surgery or steroid tapering
• support osteoporosis prevention and treatment
• identify possible drug-drug interactions between endocrine therapies

As cortisol levels normalize, insulin resistance may improve substantially. Patients previously requiring intensive diabetes regimens may need dose reductions to avoid hypoglycemia.

Q10: Why is early recognition important?

Many patients initially present with common conditions such as obesity, hypertension, or T2D, but untreated cortisol excess may progressively worsen cardiovascular and metabolic health over time. Excess cortisol promotes insulin resistance, increased hepatic glucose production, visceral fat accumulation, and dyslipidemia, all of which can contribute to persistent hyperglycemia, escalating insulin requirements, and difficult-to-control hypertension. Delayed diagnosis has also been associated with increased risks of myocardial infarction, stroke, heart failure, thromboembolic events, osteoporosis, fragility fractures, proximal muscle weakness, infections, impaired wound healing, and psychiatric symptoms such as depression, anxiety, irritability, and cognitive impairment. Importantly, many complications of hypercortisolism may improve once cortisol levels are controlled, particularly when the condition is identified early.

Patients may experience improvements in glycemic control, blood pressure, muscle strength, mood, and overall quality of life, and some individuals may require fewer diabetes or antihypertensive medications after treatment; however, long-standing cardiovascular disease, skeletal complications, and metabolic dysfunction may not fully resolve after prolonged cortisol exposure, underscoring the importance of timely recognition and referral.

Even after remission, patients carry an increased risk of cardiometabolic events compared with the general population, particularly when diagnosis is delayed. Long-term follow-up is important to monitor for recurrence, manage residual comorbidities, and continue cardiovascular risk reduction.

Summary for Clinical Practice

For clinical practice, pharmacists should recognize hypercortisolism as a potentially underdiagnosed endocrine disorder that may contribute to resistant hyperglycemia, uncontrolled hypertension, unexplained weight gain, and worsening metabolic dysfunction. Because symptoms often overlap with common chronic conditions such as obesity, T2D, depression, and metabolic syndrome, patients may remain undiagnosed for years despite escalating therapy.

Pharmacists are well positioned to identify concerning patterns, including increasing insulin requirements, multiple antihypertensive medications without adequate control, central obesity, proximal muscle weakness, osteoporosis, easy bruising, recurrent infections, and characteristic physical findings such as purple striae or “moon facies.” Screening typically involves late-night salivary cortisol, 24-hour urinary free cortisol, or overnight dexamethasone suppression testing, followed by endocrinology referral for confirmatory evaluation.

Early recognition is important because untreated cortisol excess increases the risk of cardiovascular disease, fractures, psychiatric complications, and impaired quality of life; however, many metabolic and clinical abnormalities may improve after appropriate treatment. Pharmacists are vital in identifying at-risk patients, reviewing glucocorticoid exposure, supporting diagnostic testing, optimizing cardiometabolic therapy, and monitoring medication adjustments as cortisol levels normalize.