What is the appropriate diagnostic and treatment approach for a patient with elevated prolactin and adrenocorticotropic hormone (ACTH) levels?

Diagnostic and Treatment Approach for Elevated Prolactin and ACTH

When a patient presents with both elevated prolactin and ACTH, you must first determine whether these represent two separate pituitary adenomas (a rare "double adenoma"), a single plurihormonal adenoma, or if the prolactin elevation is secondary to stalk compression from an ACTH-secreting tumor.

Initial Diagnostic Evaluation

Confirm True Hypersecretion of Both Hormones

Prolactin Assessment:

• Measure serum prolactin in a single blood sample at any time of day 1
• If modestly elevated (up to 5 times upper limit of normal), repeat with 2-3 samples at 20-60 minute intervals using an indwelling cannula to exclude stress-related elevation 1
• Use age-specific and sex-specific reference ranges, as prolactin varies significantly with age and sex 1
• Exclude secondary causes: hypothyroidism, renal/hepatic impairment, and medications causing hyperprolactinaemia 1
• Prolactin >150-200 ng/mL strongly suggests a macroprolactinoma 1

ACTH and Cortisol Assessment:

• First confirm hypercortisolism using at least two of three tests: 24-hour urinary free cortisol (2-3 collections), late-night salivary cortisol (2-3 measurements), or overnight 1 mg dexamethasone suppression test 1, 2
• Measure morning (08:00-09:00h) plasma ACTH once hypercortisolism is confirmed 2
• ACTH >5 ng/L indicates ACTH-dependent disease; ACTH >29 ng/L has 70% sensitivity and 100% specificity for Cushing disease 2
• Eliminate exogenous glucocorticoid use before testing 1

Imaging to Characterize the Lesion(s)

Obtain high-quality pituitary MRI with thin slices (3T preferred over 1.5T):

• Look for a single adenoma that could be plurihormonal 1
• Assess for two distinct adenomas (extremely rare) 1
• Evaluate for macroadenoma causing stalk compression (which can cause mild prolactin elevation up to 100-150 ng/mL) 1
• In children/adolescents, microadenomas ≤2 mm are common in Cushing disease and may be difficult to visualize 1

Key imaging interpretation:

• Adenoma ≥10 mm on MRI strongly suggests the diagnosis without need for additional localization studies 1
• Adenoma 6-9 mm requires additional testing such as CRH stimulation 1
• No adenoma or <6 mm lesion necessitates bilateral inferior petrosal sinus sampling (BIPSS) to confirm pituitary source 1

Determining the Clinical Scenario

Scenario 1: Macroprolactinoma with Stalk Compression

If prolactin is markedly elevated (>200 ng/mL) and a large pituitary mass is present, the ACTH elevation may be secondary to loss of normal hypothalamic dopaminergic inhibition rather than true Cushing disease 1. In this case, treat the prolactinoma first and reassess ACTH/cortisol after tumor shrinkage.

Scenario 2: True Cushing Disease with Mild Prolactin Elevation

If ACTH is clearly elevated with confirmed hypercortisolism and prolactin is only mildly elevated (<100 ng/mL), this likely represents stalk compression from the corticotroph adenoma 1. Treat as Cushing disease.

Scenario 3: Plurihormonal Adenoma

If both hormones are significantly elevated with a single adenoma on imaging, this represents a plurihormonal tumor 1. Surgical resection is first-line treatment.

Scenario 4: Two Distinct Adenomas (Extremely Rare)

If imaging clearly shows two separate lesions, this represents double adenomas 1. Surgical approach must address both lesions.

Treatment Algorithm

For Predominant Cushing Disease (ACTH-Driven)

First-Line: Transsphenoidal Surgery

• Surgery by an experienced pituitary neurosurgeon is the primary treatment for Cushing disease 1
• Success rates are approximately 50% in pediatric series and higher in adults with microadenomas 1
• Postoperative hypoadrenalism indicates successful resection 1
• Assess for growth hormone deficiency 3-6 months postoperatively in children 1

If Surgery Fails or is Contraindicated:

• Medical therapy options include ketoconazole, metyrapone, or osilodrostat as steroidogenesis inhibitors 1
• Pasireotide (somatostatin analogue) is an option but not recommended in children 1
• Monitor ACTH levels during medical therapy, as significant elevations may indicate tumor growth requiring MRI 1
• Combination therapy can be considered if monotherapy inadequate 1

Radiotherapy:

• Reserved for uncontrolled tumor growth with incomplete surgical and medical response 1
• Not used in patients with skull base fibrous dysplasia 1

For Predominant Prolactinoma

First-Line: Dopamine Agonist Therapy

• Cabergoline is the preferred dopamine agonist 1, 3
• Starting dose: 0.25 mg twice weekly 3
• Titrate by 0.25 mg twice weekly every 4 weeks up to maximum 1 mg twice weekly based on prolactin levels 3
• Before initiating treatment, perform cardiovascular evaluation including echocardiography to assess for valvular disease 3

Monitoring on Cabergoline:

• Assess prolactin levels at 3-6 month intervals initially 1
• Repeat MRI 3-6 months after starting treatment for macroprolactinomas 1
• Echocardiography every 6-12 months or as clinically indicated (watch for edema, new murmur, dyspnea, heart failure) 3
• Assess for bone mineral density 2 years after diagnosis in children/adolescents 1
• After 6 months of normal prolactin, consider discontinuing with periodic monitoring 3

Surgery for Prolactinoma:

• Reserved for dopamine agonist resistance, intolerance, or patient preference 1
• Consider in patients with contraindications to cabergoline (valvular disease, fibrotic complications) 3

For Plurihormonal Adenomas

Surgical resection is first-line treatment 1

• Address both hormone hypersecretion surgically
• Post-operative medical therapy may be needed for residual disease
• If prolactin remains elevated post-surgery, add cabergoline 1
• If cortisol remains elevated post-surgery, use steroidogenesis inhibitors 1

Critical Monitoring and Follow-Up

Immediate Post-Treatment:

• Assess for hypopituitarism and provide hormone replacement as needed 1
• In children, ensure growth hormone replacement if deficient to achieve adequate final height 1
• Monitor for adrenal insufficiency after successful Cushing disease treatment (typically recovers within 12 months) 1

Long-Term Surveillance:

• MRI every 6-12 months initially, then frequency based on clinical scenario and tumor proximity to optic chiasm 1
• Biochemical monitoring: prolactin every 3-6 months, cortisol/ACTH as clinically indicated 1
• In children, monitor growth, puberty, and bone health longitudinally 1

Common Pitfalls to Avoid

• Do not assume mild prolactin elevation (<100 ng/mL) with a pituitary mass represents a prolactinoma—this is often stalk compression from another adenoma type 1
• Do not start medical therapy for Cushing disease without confirming hypercortisolism with multiple tests—false positives occur with obesity, depression, and alcoholism 1, 2
• Do not use cabergoline without baseline and serial echocardiography—cardiac valvulopathy is a serious complication, especially at higher doses 3
• Do not perform BIPSS while patient is on steroidogenesis inhibitors—these must be stopped for accurate interpretation 2
• In children, do not miss the combination of weight gain with growth deceleration—this is the hallmark presentation of pediatric Cushing syndrome 1