Adrenal

Hypercortisolism is a state of excess glucocorticoid activity. This section covers the HPA axis that regulates cortisol, the causes and classification of Cushing's syndrome, the diagnostic work-up, and management.

Hypothalamic–Pituitary–Adrenal (HPA) Axis

The axis runs hypothalamus → anterior pituitary → adrenal cortex, with cortisol exerting negative feedback on the top two levels.

• CRH (corticotropin-releasing hormone) — produced by the hypothalamus; acts on the corticotropic cells of the anterior pituitary to make ACTH. Secretion is under tight control of the hypothalamic suprachiasmatic nucleus and follows a circadian rhythm: cortisol is highest in the mornings and reaches its nadir at approximately 11 PM. Even small perturbations of this physiologic rhythm are considered pathologic.
• ACTH — has two functions: it stimulates production of glucocorticoids and androgens by the adrenal cortex, and it plays a critical role in maintaining adrenal cortical vitality. Without ACTH (e.g. when its secretion is suppressed by exogenous steroid intake), all but the mineralocorticoid (aldosterone)-producing cells of the adrenal cortex atrophy. Secretion is stimulated by three factors: CRH (most important), oxytocin, and vasopressin.
• Negative feedback — glucocorticoids act on the hypothalamus and pituitary to inhibit production of CRH and ACTH.

Two clinical notes:

• Patients with hypercortisolism may be at higher risk for post-adrenalectomy adrenal insufficiency than patients with non-cortisol-secreting adrenal pathologies, because function of the contralateral gland may be suppressed.
• Stress, whether physiologic or psychologic, appears to be the most important variable in modulating activity of the HPA axis.

Pathophysiology

Cushing's syndrome is hypercortisolism secondary to excessive production of glucocorticoids by the adrenal cortex. Its causes fall into three main groups — exogenous, ACTH-dependent (endogenous), and ACTH-independent (endogenous):

Group	Share	Mechanism / key points
Exogenous	—	Most common cause of hypercortisolism in the Western world. Can cause virilization, including hirsutism, but should not elevate ketosteroid levels.
ACTH-dependent (endogenous)	85% of endogenous Cushing syndrome	Results from an increased serum ACTH level, caused by pathology extrinsic to the adrenal gland.
ACTH-independent (endogenous)	15% of endogenous Cushing syndrome; relatively rare	Caused by pathology intrinsic to the adrenal gland — unregulated overproduction of glucocorticoids by the adrenal(s), either a unilateral neoplasm or, rarely, bilateral disease.

The ACTH-dependent causes, in turn:

• Primary pituitary pathology (Cushing disease) — the most common cause (80%) of ACTH-dependent hypercortisolism.
• Ectopic ACTH production — nearly always malignant; the most common associated malignancies are bronchial carcinoid, small cell lung cancer, and less often pheochromocytoma.
• Ectopic CRH syndrome — extremely uncommon; bronchial carcinoma is the most common cause.

Subclinical Cushing syndrome is hypercortisolemia in the absence of an overt cushingoid phenotype. Surgical indications remain debated: some argue adrenalectomy should be performed only in patients who are potentially symptomatic and exhibit clinical signs (hypertension, obesity, glucose intolerance, or osteopenia), while others argue surgery should be offered to all patients to prevent the sequelae of hypercortisolism.

Hypercortisolism without Cushing's syndrome — other conditions can stimulate the HPA axis and mimic Cushing's syndrome:

• Some features of Cushing syndrome may be present: morbid obesity, glucocorticoid resistance, poorly controlled diabetes mellitus, pregnancy, depression, alcohol dependence.
• Unlikely to have any clinical features of Cushing syndrome: physical stress (hospitalization, surgery, pain), malnutrition or anorexia nervosa, intense chronic exercise, hypothalamic amenorrhea, corticosteroid-binding globulin excess (raises serum but not urine cortisol).

Diagnosis and Evaluation

History and Physical Exam

(See Campbell's 11th edition, Table 65-2, for the primary effects of glucocorticoids.)

The classic symptoms of hypercortisolism are nonspecific: central obesity, moon facies, buffalo hump, facial plethora, menstrual disturbances, hirsutism, proximal muscle weakness, easy bruisability, and abdominal striae. Cushing syndrome also produces systemic features — dyslipidemia, insulin resistance, and hypertension — similar to the highly prevalent metabolic syndrome.

Urological complications of Cushing's syndrome:

• Erectile dysfunction and decreased libido.
• Hypogonadal hypogonadism — relatively common in men with Cushing syndrome. Consider initiating a hypercortisolism work-up in men with low libido or erectile problems, low testosterone, and low gonadotropin levels.
• Urolithiasis — up to 50% of patients with Cushing syndrome have urolithiasis; stone formers with cushingoid features should also receive a hypercortisolemia evaluation.

Labs

The three most frequently performed tests for confirming hypercortisolism:

Test	Sensitivity	Specificity
Overnight low-dose dexamethasone suppression test (LD-DST)	85–90%	95–99%
Late-night salivary cortisol	92–100%	93–100%
24-hour urinary free cortisol	80–98%	45–98%

The 2011 CUA Guidelines on Incidental Adrenal Mass recommend the LD-DST. Second-line tests include the 2-day low-dose dexamethasone suppression test and midnight plasma cortisol testing.

Low-dose dexamethasone suppression test (LD-DST)

• Recommended in the evaluation of an incidental adrenal mass (2011 CUA Guidelines).
• Determines the presence of endogenous hypercortisolism, not the cause.
• A supraphysiologic 1 mg dose of dexamethasone (3–4× physiologic glucocorticoid levels) is given overnight, followed by measurement of morning serum cortisol, to test the glucocorticoid negative-feedback system.
• Without hypercortisolism: dexamethasone acts on the anterior pituitary corticotropes, suppresses ACTH production, and reduces serum cortisol.
• With endogenous hypercortisolism: dexamethasone fails to suppress cortisol production (pituitary adenomas are relatively insensitive to glucocorticoid inhibition), so serum cortisol remains elevated.
• Exogenous steroid use cannot be ruled out with this test — exogenous steroids, including the test dose, are not detected by the serum cortisol assay.

Drugs that affect the overnight LD-DST:

• Accelerate dexamethasone metabolism (CYP3A4 induction): phenobarbital, phenytoin, carbamazepine, primidone, rifampin, rifapentine, ethosuximide, pioglitazone.
• Impair dexamethasone metabolism (CYP3A4 inhibition): aprepitant/fosaprepitant, itraconazole, ritonavir, fluoxetine, diltiazem, cimetidine.
• Increase cortisol-binding globulin and may falsely elevate cortisol: estrogens, mitotane.

The LD-DST can yield up to a 50% false-positive rate in women using oral contraceptives, which raise cortisol-binding globulin and thereby increase total (but not bioavailable) cortisol.

Late-night salivary cortisol and midnight plasma cortisol demonstrate a perturbation — and in some cases complete disruption — of the diurnal variation in cortisol.

24-hour urinary free cortisol may not be sensitive for subclinical Cushing syndrome, and the Endocrine Society recommends against it for the metabolic evaluation of adrenal incidentalomas. Drugs that increase the result: carbamazepine, fenofibrate (when measured by high-performance liquid chromatography), some synthetic glucocorticoids (immunoassays), and inhibitors of 11β-hydroxysteroid dehydrogenase type 2 (licorice, carbenoxolone).

Distinguishing the cause — after confirming hypercortisolism, serum ACTH is measured to separate ACTH-independent from ACTH-dependent causes:

• Low serum ACTH → ACTH-independent pathology. Abdominal imaging is indicated to identify the adrenal source. If the adrenals are unremarkable, suspect exogenous steroids or, much less commonly, primary pigmented nodular adrenocortical disease (PPNAD) — in which the adrenal glands are normal in size and show black or brown cortical nodules.
• High serum ACTH → pituitary source (Cushing disease) or ectopic ACTH syndrome. These can be difficult to distinguish, as both pituitary and ACTH-producing tumours are often hard to localize on imaging. Direct measurement of ACTH in the inferior petrosal sinus (the downstream venous plexus draining the pituitary) after CRH stimulation is the gold-standard approach. High-dose dexamethasone suppression testing was used in the past to differentiate the two — its value is limited — on the principle that high enough doses suppress ACTH production by pituitary adenomas, whereas ectopic ACTH production continues despite the high-dose glucocorticoid.

Management

• ACTH-independent disease: ipsilateral adrenalectomy. Medications that block steroid-synthesis enzymes (mitotane, metyrapone, aminoglutethimide, trilostane, ketoconazole, etomidate) are used to bridge a patient to surgery or when surgical intervention is not possible.
• Cushing disease (ACTH-secreting pituitary adenoma): trans-sphenoidal surgical resection. Bilateral adrenalectomy is most often recommended when at least one attempt to treat the primary tumour has failed, and is also necessary in rare instances when hypercortisolism is life-threatening and swift definitive treatment is mandatory; lifelong mineralocorticoid and glucocorticoid replacement is then required in all patients. Patients undergoing bilateral adrenalectomy are at risk (8–29%) of progressive growth of their pituitary adenoma, producing Nelson–Salassa (Nelson) syndrome — ocular chiasm compression, oculomotor deficiencies, and rarely a rise in intracranial pressure. When counselling patients, the urologist must also warn of the rare possibility of residual functioning adrenal tissue remaining after the procedure.
• Ectopic ACTH production: resection of the ACTH-producing tumour, though primary tumour resection is possible in only 10% of patients. For patients with unresectable primary tumours or whose ACTH-producing tissue cannot be identified, bilateral adrenalectomy with lifelong replacement therapy is an excellent therapeutic option.

Self-Test

1. What is the role of ACTH, where is it secreted, and what stimulates its release? Stimulates production of glucocorticoids and sex hormones; secreted from the anterior pituitary; release is stimulated by CRH from the hypothalamus.

2. How are the causes of hypercortisolism/Cushing's syndrome categorized? Which is the most common cause in the Western world? Which category does Cushing's disease fall under? Exogenous vs endogenous; endogenous is further classified as ACTH-dependent vs ACTH-independent. Exogenous is the most common cause in the Western world. Cushing's disease is an ACTH-dependent cause.

3. What are the clinical manifestations of hypercortisolism? Central obesity, moon facies, buffalo hump, facial plethora, erectile dysfunction, decreased libido, menstrual disturbances, hirsutism, proximal muscle weakness, easy bruisability, and abdominal striae.

4. What are the non-adrenal urologic manifestations of hypercortisolism? Hypogonadal hypogonadism (negative feedback from glucocorticoids on the pituitary and hypothalamus) and urolithiasis.

5. What is subclinical Cushing's syndrome? Hypercortisolemia without overt clinical manifestations.

6. Which non-radiographic tests can be used to detect Cushing's syndrome? The low-dose dexamethasone suppression test, late-night salivary cortisol, and 24-hour urinary cortisol.

7. Which form of hypercortisolism cannot be evaluated with the low-dose dexamethasone suppression test? Exogenous (steroid-induced) hypercortisolism — exogenous steroids, including the test dose, are not detected by the serum cortisol assay.

8. After confirming hypercortisolism, how do you distinguish ACTH-dependent from ACTH-independent causes? By measuring serum ACTH.

9. List causes of hypercortisolism other than Cushing's syndrome. Morbid obesity, glucocorticoid resistance, poorly controlled diabetes mellitus, pregnancy, depression, alcohol dependence, physical stress (hospitalization, surgery, pain), malnutrition or anorexia nervosa, intense chronic exercise, hypothalamic amenorrhea, and corticosteroid-binding globulin excess.