Hyperprolactinemia

Hyperprolactinemia is the increased production of prolactin by the anterior pituitary. Physiological hyperprolactinemia can be caused by pregnancy, lactation, and stress. Nonphysiological hyperprolactinemia is most often due to pituitary adenomas (e.g., prolactinomas, corticotroph adenomas) or medications. Other causes are diverse and include primary hypothyroidism and systemic conditions such as chronic kidney disease (CKD) and cirrhosis. Hyperprolactinemia commonly manifests with galactorrhea and/or features of hypogonadotropic hypogonadism, e.g., menstrual cycle abnormalities, infertility, or erectile dysfunction. Patients may also present with features of the underlying cause, e.g., headaches and visual disturbance in prolactinomas. Elevated serum prolactin levels confirm the diagnosis. Assess for non-hypothalamic-pituitary causes; if no diagnosis emerges, a pituitary MRI should be performed to assess for a pituitary adenoma. Prolactinomas are typically managed with dopamine agonists. Discontinuation of the causative agent should be considered for medication-induced hyperprolactinemia.

• Sex: ♀ > ♂
• Prevalence
  • ∼ 0.4% of the general population
  • Hyperprolactinemia is the most common form of hyperpituitarism.

Epidemiological data refers to the US, unless otherwise specified.

Hypothalamic-pituitary ^[1][2][3]

• Pituitary adenomas
  • Prolactinomas: most common cause of nonphysiological hyperprolactinemia ^[2]
  • Other pituitary adenomas, e.g., somatotropinomas and corticotroph adenomas, can also secrete prolactin.
• Hypothalamic-pituitary stalk damage (stalk effect): : Damage to the pituitary stalk and/or portal vessels due to tumors, trauma, or surgery reduces dopaminergic inhibition on pituitary lactotrophs.
• Primary hypothyroidism: : Hypothyroidism leads to increased thyrotropin-releasing hormone (TRH), which stimulates prolactin release.

Hypothalamic dopamine inhibits prolactin secretion, whereas TRH stimulates it.

Pharmacological ^[2][3]

• Dopamine antagonists
  • Typical antipsychotics and atypical antipsychotics: e.g., chlorpromazine, haloperidol, risperidone, amisulpride
  • Antiemetics: e.g., metoclopramide, domperidone
• Tricyclic antidepressants: e.g., clomipramine, amitriptyline
• Antihypertensives: verapamil, reserpine, methyldopa
• Other: H2 receptor antagonists (e.g., cimetidine), opioid analgesics, oral contraceptive pills , cocaine

Other ^[2][3]

• Physiological: sexual intercourse, exercise, lactation, nipple stimulation or hearing a crying infant in lactating individuals, pregnancy, sleep, stress
• Systemic diseases: CKD, cirrhosis, PCOS ^[1]
• Chest wall pathology: e.g., due to surgery or herpes zoster, potentially through activation of the suckling stimulus pathway ^[1]
• Epileptic seizures: In generalized tonic-clonic seizures, hyperprolactinemia is due to epileptic activity in the hypothalamus. ^[3][4]

• ↑ Prolactin → galactorrhea
• ↑ Prolactin → suppression of GnRH → ↓ LH, ↓ FSH → ↓ estrogen, ↓ testosterone → hypogonadotropic hypogonadism
• For more details, see “Hypothalamus and pituitary gland.”

Patients may also present with clinical features of the underlying cause, e.g., bitemporal hemianopsia and headache in pituitary adenomas.

Increased serum prolactin levels confirm the diagnosis. Additional studies are performed to establish the cause.

Serum prolactin

• ↑ Serum prolactin
  • > 20 ng/mL in men ^[3]
  • > 25 ng/mL in women ^[3]
  • > 200 ng/mL: suggestive of prolactinoma ^[1][2]
• Consider potential analytical issues (e.g., the hook effect) if levels do not correlate with the clinical picture. ^[1][2][3]

Additional studies ^[1][2][3]

• If no pharmacological cause has been identified, consider the following:
  • Thyroid function tests: to exclude primary hypothyroidism
  • Serum beta-hCG: to exclude pregnancy
  • BMP and liver chemistries: if CKD or cirrhosis is suspected
  • MRI pituitary gland with IV contrast: as part of pituitary adenoma diagnostics ^[1][5]
• Other studies (e.g., visual field testing, osteoporosis screening) may be requested to assess for complications. ^[2]

Serum prolactin levels < 200 ng/mL suggest a cause other than a prolactinoma, e.g., pharmacological or primary hypothyroidism. ^[2][3]

Always review the patient's medication history for potential causes of hyperprolactinemia.

Approach

• Refer all patients to endocrinology.
• Treatment depends on the severity of symptoms and the underlying cause.
• Assess for and treat complications, e.g., osteoporosis, bitemporal hemianopia.

Nonpharmacological hyperprolactinemia

• Prolactinomas: Dopamine agonists are the treatment of choice for macroprolactinomas and symptomatic microprolactinomas. ^[2];
  • Cabergoline (preferred) or bromocriptine ^[1][6]
  • See “Management of pituitary adenomas” for more information.
• Hypothyroidism: See “Management of hypothyroidism.”
• CKD: See “Management of CKD.” ^[3]
• Stalk effect: surgery (preferred), or radiation therapy if surgery is contraindicated ^[3][5]

Pharmacological hyperprolactinemia ^[1][3]

• Asymptomatic patients
  • Observation
  • Hormone replacement therapy may be considered to reduce osteoporosis risk. ^[1]
• Symptomatic patients
  • Consider discontinuation, dose reduction, or switching causative medications in consultation with specialists (e.g., a psychiatrist). ^[1]
  • A pituitary MRI may be considered if there is no improvement after medication adjustment. ^[3]