How do functional and non‑functioning pituitary adenomas affect hormone secretion and what are the first‑ and second‑line treatment options?

Pituitary Adenomas and Hormonal Effects

Hormonal Impact by Adenoma Type

Pituitary adenomas affect hormone secretion through two distinct mechanisms: functioning adenomas cause hormone hypersecretion, while non-functioning adenomas cause hormone deficiency through mass effect and compression of normal pituitary tissue. 1

Functioning Adenomas: Hormone Hypersecretion

Functioning adenomas produce excess hormones with specific clinical syndromes:

• Prolactinomas (53% of all adenomas) secrete excess prolactin, causing amenorrhea, galactorrhea, infertility in women, and decreased libido with erectile dysfunction in men 1, 2

  • Even microadenomas as small as 3mm can cause significant prolactin elevation 3
  • Prolactin levels directly correlate with tumor size 3

• Growth hormone-secreting adenomas (12% of tumors) cause acromegaly in adults and gigantism in children, characterized by enlargement of hands, feet, lips, tongue, and facial coarsening 1, 2

  • Children present with increased growth velocity >2 standard deviations above normal, acral enlargement, prognathism, and often delayed puberty 4
  • Associated comorbidities include glucose intolerance, hypertension, carpal tunnel syndrome, left ventricular hypertrophy, and sleep apnea 4

• ACTH-secreting adenomas (4% of tumors) cause Cushing disease with hypercortisolemia, resulting in obesity, hypertension, diabetes, and significant morbidity 1, 2

  • Microadenomas account for 98% of Cushing disease cases in children 3
  • Tumor size does not correlate with degree of hypercortisolism—even very small adenomas cause significant disease 3

• TSH-secreting adenomas (1% of tumors) cause hyperthyroidism 2

Non-Functioning Adenomas: Hormone Deficiency

Non-functioning adenomas (30-54% of all adenomas) do not produce hormones but cause hypopituitarism through compression and destruction of normal pituitary tissue. 5, 1

The prevalence of hormone deficiencies in non-functioning adenomas is substantial:

• Growth hormone deficiency: 61-100% of patients 5
• Hypogonadism: 36-95% of patients 5
• Adrenal insufficiency: 17-62% of patients 5
• Hypothyroidism: 8-81% of patients 5
• Overall hypopituitarism: 37-85% of patients 5
• Panhypopituitarism: 6-29% of patients 5

Additionally, 25-65% of non-functioning adenoma patients develop hyperprolactinemia (mean level 39 ng/mL) due to stalk compression disrupting dopamine inhibition, though levels rarely exceed 200 ng/mL 5

First-Line Treatment Options

Prolactinomas

Dopamine agonists are the definitive first-line treatment for prolactinomas, not surgery. 3

• Cabergoline is preferred over bromocriptine due to superior efficacy and better tolerability 3
• After 2+ years of normalized prolactin levels and no visible tumor on MRI, consider gradual dose reduction and possible discontinuation 3
• Regular serum prolactin measurements and MRI follow-up are required during treatment 3
• Echocardiogram should be performed at treatment initiation, with annual echocardiography for patients on high-dose cabergoline 3

Growth Hormone-Secreting Adenomas

Transsphenoidal surgery is the first-line treatment for GH-secreting adenomas, even when surgical cure is unlikely. 3, 1, 2

• Surgery should be performed by experienced pituitary surgeons in centers performing at least 50 pituitary operations per year 3
• Pre-operative medical therapy with somatostatin analogues may be considered to rapidly control symptoms or support perioperative airway management 3
• Surgical success rates achieve approximately 50% remission in experienced centers 6

ACTH-Secreting Adenomas (Cushing Disease)

Transsphenoidal surgery is the primary treatment for ACTH-secreting adenomas. 3, 7, 2

• Surgery is performed whether or not a microadenoma is visible on MRI 7
• Late-night salivary cortisol is the best screening test 2
• Petrosal sinus sampling for ACTH may be necessary to distinguish pituitary from ectopic sources 2

Non-Functioning Adenomas

Observation with regular MRI surveillance is appropriate for asymptomatic non-functioning microadenomas. 3

Transsphenoidal surgery is indicated for non-functioning adenomas causing mass effects (visual field defects, headaches, or symptomatic hypopituitarism). 5, 7, 2

• Tumor progression occurs in 40-50% of patients under observation alone 3
• Complete hormonal assessment should be performed to identify any hormonal deficiencies 3
• The first radiologic study to evaluate extent of resection should be performed 3 months after surgical intervention 5

Second-Line Treatment Options

For Prolactinomas

Transsphenoidal surgery should be considered for dopamine agonist-resistant prolactinomas if medical therapy fails. 3

For Growth Hormone-Secreting Adenomas

For post-operative residual disease, offer monotherapy or combination medical therapy with somatostatin receptor ligands, GH receptor antagonist (pegvisomant), or dopamine agonists. 3, 6

• Somatostatin analogs (now available in slow-release form) are used when surgery has failed to normalize GH levels or while waiting for delayed effects of radiation therapy 7
• Pegvisomant, the GH-receptor antagonist, is indicated in cases of resistance to somatostatin analogs 7
• Radiotherapy (fractionated or gamma-knife) is offered to patients with uncontrolled tumor growth despite incomplete surgical and medical response 6

For ACTH-Secreting Adenomas

Radiotherapy is reserved for patients who are subtotally resected or remain hypersecretory after surgery. 7

• While waiting for radiotherapy effects, adrenal steroidogenesis inhibitors (ketoconazole, mifepristone, pasireotide) may be indicated 7, 2
• If drugs are not available or not tolerated, bilateral adrenalectomy may be proposed 7

For Non-Functioning Adenomas

Long-term radiologic, endocrinologic, and ophthalmologic surveillance monitoring after surgical and/or radiation therapy is recommended to evaluate for tumor recurrence or regrowth. 5

• MRI with T2 and T1 weighted images with fat suppression sequences is recommended for radiologic follow-up 5
• Post-operative MRI at 3 months assesses extent of residual tumor, with further scan at 6 months to assess for recurrence 3

Critical Clinical Pitfalls

Hook Effect in Prolactin Measurement

For any pituitary lesion with normal or mildly elevated prolactin, request serial dilutions to avoid the "high-dose hook effect" that can falsely lower prolactin measurements. 3

This is particularly important as it can lead to misdiagnosis of a prolactinoma as a non-functioning adenoma, resulting in inappropriate surgical intervention instead of medical management.

Macroprolactin Assessment

Macroprolactin assessment should be performed if prolactin is mildly or incidentally elevated, as 10-40% of hyperprolactinemia cases are due to biologically inactive macroprolactin. 3

Pediatric Considerations

• Genetic testing should be considered in children and adolescents, as certain genetic conditions are associated with pituitary adenomas in this population 5, 3
• Psychiatric side effects of dopamine agonists may be more common in children and adolescents than adults 3
• Treatment should involve a pituitary-specific multidisciplinary team with experts from both pediatric and adult practice 3