What causes elevated serum prolactin levels?

Causes of Elevated Serum Prolactin Levels

Elevated serum prolactin levels (hyperprolactinemia) are most commonly caused by medications, particularly antipsychotics, followed by pituitary adenomas, physiological conditions, and various pathological states affecting the hypothalamic-pituitary axis. 1, 2

Common Causes of Hyperprolactinemia

Physiological Causes

• Pregnancy (levels can reach 10.0-209.0 ng/mL) 1, 3
• Lactation/breastfeeding
• Sleep
• Stress
• Exercise

Pathological Causes

Medication-Induced (Pharmacological)

• Antipsychotic medications:

  • Typical antipsychotics (e.g., haloperidol) 4
  • Some atypical antipsychotics (e.g., risperidone) 5, 2
  • Mechanism: Blockade of dopamine D2 receptors in the tuberoinfundibular pathway 2

• Other medications:

  • Antidepressants (particularly some SSRIs)
  • Antihypertensive agents (particularly verapamil, methyldopa)
  • Gastrointestinal prokinetics (metoclopramide, domperidone)
  • Opiates 2

Pituitary Disorders

• Prolactinomas (prolactin-secreting pituitary adenomas) - responsible for approximately 50% of pathological hyperprolactinemia cases 6
• Other pituitary tumors causing stalk compression
• Empty sella syndrome

Hypothalamic Disorders

• Tumors (craniopharyngiomas, meningiomas)
• Infiltrative diseases (sarcoidosis, histiocytosis)
• Radiation to the hypothalamus
• Trauma affecting the pituitary stalk

Other Endocrine Disorders

• Primary hypothyroidism (via increased TRH)
• Adrenal insufficiency
• Polycystic ovary syndrome

Systemic Conditions

• Chronic renal failure
• Cirrhosis
• Chest wall lesions/trauma (via neural pathways)

Laboratory Artifacts

• Macroprolactinemia (biologically inactive high molecular weight prolactin complexes) 7, 8
  • Found in up to 25% of cases of apparent hyperprolactinemia
  • Patients typically lack symptoms of true hyperprolactinemia
  • Caused by anti-prolactin autoantibodies forming large complexes with prolactin

Reference Ranges for Serum Prolactin

• Non-pregnant females: 3.0-30.0 ng/mL
• Pregnant females: 10.0-209.0 ng/mL
• Postmenopausal females: 2.0-20.0 ng/mL 1

Clinical Implications

Hyperprolactinemia can lead to:

• Hypogonadotropic hypogonadism
• Menstrual irregularities and infertility in women
• Galactorrhea (occurs in <50% of cases) 6
• Sexual dysfunction and decreased libido
• Osteoporosis (due to estrogen deficiency) 6

Diagnostic Approach

When elevated prolactin is detected:

1. Rule out physiological causes (pregnancy, stress)
2. Review medication history thoroughly
3. Consider macroprolactinemia, especially in asymptomatic patients
4. If no obvious cause is found, imaging of the hypothalamic-pituitary region is warranted

Common Pitfalls

• Failure to recognize medication-induced hyperprolactinemia, leading to unnecessary imaging and interventions 2
• Not identifying macroprolactinemia, which requires specific laboratory testing (PEG precipitation) 7, 8
• Missing mild hyperprolactinemia due to pulsatile secretion (multiple samples may be needed)
• Overlooking physiological causes like stress during blood collection

Understanding these various causes is essential for appropriate management of hyperprolactinemia, with treatment directed at the underlying etiology rather than the laboratory finding itself.