Medications Causing Hyperprolactinemia
Antipsychotic medications are the most common pharmacological cause of hyperprolactinemia, with first-generation (typical) antipsychotics and risperidone among the second-generation agents posing the highest risk. 1, 2
Antipsychotic Agents
High-Risk Antipsychotics
- First-generation (typical) antipsychotics universally cause significant prolactin elevation through dopamine D2 receptor antagonism in the tuberoinfundibular pathway 3, 4
- Risperidone is the atypical antipsychotic most likely to cause hyperprolactinemia, with the FDA label confirming that "risperidone elevates prolactin levels and the elevation persists during chronic administration" and is "associated with higher levels of prolactin elevation than other antipsychotic agents" 5
- Paliperidone (the active metabolite of risperidone) also frequently increases prolactin secretion 6
- Amisulpride is classified as a prolactin-raising antipsychotic 7
Low-Risk Antipsychotics
- Clozapine, olanzapine, quetiapine, ziprasidone, and aripiprazole cause minimal or transient effects on prolactin levels, likely due to higher 5-HT2A:D2 binding ratios and less interference with the tuberoinfundibular pathway 4, 8, 7
Antidepressants
- Selective serotonin reuptake inhibitors (SSRIs) can cause hyperprolactinemia through serotoninergic activity 8
- Monoamine oxidase inhibitors (MAO-I) may elevate prolactin levels 8
- Some tricyclic antidepressants with serotoninergic properties can increase prolactin 8
Gastrointestinal Medications
- Prokinetic agents (such as metoclopramide and domperidone) that antagonize dopamine receptors cause hyperprolactinemia 8
- Prochlorperazine (Stemetil) can lead to menstrual disturbances, galactorrhea, subfertility in women, and decreased libido, erectile dysfunction, and gynecomastia in men 1
Antihypertensive Medications
- Various antihypertensive agents have been associated with prolactin elevation, though specific mechanisms vary 3, 8
Other Medications
- Opiates can increase prolactin levels 8
- Estrogens may induce hyperprolactinemia, though the role of synthetic oral contraceptives in causing mild elevation remains controversial 2
- Anti-androgens are associated with prolactin elevation 8
- H2-receptor antagonists (such as cimetidine) can cause hyperprolactinemia 8
- Anticonvulsants (certain agents) may elevate prolactin 8
- Cholinomimetics have been documented to increase prolactin levels 8
Clinical Mechanism
Medications cause hyperprolactinemia through two primary pathways: direct stimulation of prolactin secretion or antagonism of dopamine's inhibitory effect on lactotroph cells in the anterior pituitary 1, 2. The tuberoinfundibular dopaminergic system normally suppresses prolactin release, and drugs that block D2 receptors in this pathway remove this tonic inhibition 4.
Clinical Consequences
In Women
- Amenorrhea or oligomenorrhea (reported in approximately 45% of women on conventional antipsychotics) 7
- Galactorrhea (approximately 19% prevalence) 7
- Anovulation and infertility 1, 2
In Men
Long-Term Effects
Critical Diagnostic Considerations
Before attributing hyperprolactinemia to medication, exclude: 1, 2
- Primary hypothyroidism (causes hyperprolactinemia in 43% of women and 40% of men with frank hypothyroidism) 1
- Chronic kidney disease (associated with hyperprolactinemia in 30-65% of adult patients) 1
- Severe liver disease 1
- Prolactinomas (most common pathological cause, with levels typically >4,000 mU/L) 1
- Pituitary stalk compression from mass lesions 1
- Macroprolactinemia (accounts for 10-40% of hyperprolactinemia cases and represents biologically inactive prolactin) 1, 2
Important Pitfall
Women are more sensitive than men to the hyperprolactinemic effects of antipsychotics, with approximately 60% of women versus 40% of men treated with prolactin-raising antipsychotics having prolactin levels above the upper limit of normal 7.