What causes low prolactin levels?

Causes of Low Prolactin (Hypoprolactinemia)

Primary Causes

Low prolactin levels result from either pituitary damage causing lactotroph destruction or excessive dopaminergic suppression from medications, with pituitary damage being the most clinically significant cause. 1, 2

Pituitary Gland Damage

• Extensive pituitary damage from any cause (surgery, radiation, trauma, infarction, infiltrative disease) can destroy lactotroph cells and result in hypoprolactinemia 1, 2
• Hypoprolactinemia serves as a marker for extensive pituitary gland damage and dysfunction, often indicating more severe pituitary compromise 2
• When hypoprolactinemia occurs with other pituitary hormone deficiencies, it represents panhypopituitarism with low prolactin, a distinct entity from panhypopituitarism with normal or elevated prolactin 1
• Isolated prolactin deficiency (without other pituitary hormone deficits) is rare 2

Medication-Induced Hypoprolactinemia

• Dopamine agonists (cabergoline, bromocriptine) used to treat hyperprolactinemia can suppress prolactin to very low or undetectable levels 1, 3
• Direct-acting dopamine receptor agonists, particularly ergot derivatives, are potent suppressors of prolactin secretion 3
• Other dopaminergic medications including amphetamine, methylphenidate, and nomifensine can lower prolactin levels 3

Other Pharmacologic Causes

• GABA-mimetic drugs (muscimol, sodium valproate) can suppress prolactin secretion 3
• Histamine H2-receptor agonists lower prolactin levels 3
• Cholinergic receptor agonists (both muscarinic and nicotinic) can reduce prolactin 3
• Drugs that impair serotonergic neurotransmission (methysergide, metergoline) suppress prolactin 3

Clinical Significance

Manifestations Beyond Lactation Failure

• Metabolic dysfunction: Hypoprolactinemia is associated with insulin resistance, abnormal lipid profiles, obesity, type 2 diabetes mellitus, and fatty liver 1, 2
• Cardiovascular risk: Increased risk for cardiovascular disease has been reported 2
• Sexual dysfunction: Both reproductive problems and sexual dysfunction can occur 1, 2
• Lactation failure: The most well-established clinical manifestation, particularly important in postpartum women 1

Diagnostic Considerations

• Very low prolactin levels should be avoided in patients receiving dopamine agonist treatment to prevent unwanted metabolic and sexual effects 1
• Hypoprolactinemia is not traditionally included in the classification of hypopituitarism, leading to underrecognition 1

Diagnostic Approach

Laboratory Confirmation

• Basal prolactin levels below 5 ng/mL for males and below 7 ng/mL for females suggest hypoprolactinemia 2
• TRH stimulation test: Peak prolactin responses below 18 ng/mL for males and below 41 ng/mL for females confirm hypoprolactinemia 2
• Low or undetectable serum prolactin levels with absent prolactin peak on TRH stimulation are diagnostic 2

Important Pitfall

• Do not confuse with the "hook effect": In patients with large pituitary tumors and seemingly low prolactin, the high-dose hook effect can cause falsely low measurements due to assay saturation 4, 5, 6
• Serial dilutions must be performed when large pituitary lesions are present with unexpectedly normal or low prolactin to exclude macroprolactinoma 4, 5, 6