What medications can cause hyperprolactinemia?

Medications That Cause Elevated Prolactin

Medications are one of the most common causes of hyperprolactinemia, acting either through direct stimulation of prolactin secretion or by blocking dopamine's inhibitory effect on lactotroph cells. 1

Primary Offending Medication Classes

Antipsychotic Agents (Most Common)

Typical (conventional) antipsychotics are the most frequent and significant offenders for causing hyperprolactinemia. 2

• Risperidone is particularly notable among atypical antipsychotics for causing significant prolactin elevation, comparable to typical antipsychotics, especially at doses >6 mg/day 3, 4
• Risperidone elevates prolactin levels persistently during chronic administration, with 82-87% of adolescents and 49% of children showing elevated prolactin levels in clinical trials 3
• Other atypical antipsychotics causing minimal prolactin elevation include clozapine, olanzapine, quetiapine, and ziprasidone 5, 4

Antidepressants

• Antidepressants with serotonergic activity can cause hyperprolactinemia, including: 6
  • Selective serotonin reuptake inhibitors (SSRIs)
  • Monoamine oxidase inhibitors (MAOIs)
  • Some tricyclic antidepressants (TCAs)

Gastrointestinal Medications

• Prokinetic agents (medications that increase bowel motility) are well-documented causes 7, 6
• Prochlorperazine (Stemetil) can cause hyperprolactinemia leading to menstrual disturbances, galactorrhea, and sexual dysfunction 1

Antihypertensive Medications

• Various antihypertensive agents can elevate prolactin levels 7, 6

Other Medication Classes

• Opiates/opioids are known to increase prolactin secretion 6, 4
• Estrogens may induce hyperprolactinemia, though the role of synthetic oral contraceptives in causing mild elevation remains controversial 8
• Anti-androgens 6
• H2-receptor antagonists 6
• Anticonvulsants 6
• Cholinomimetics 6

Mechanism of Action

The primary mechanism is antagonism of dopamine D2 receptors in the tuberoinfundibular pathway, which normally provides tonic inhibition of prolactin secretion. 1, 4

• Dopamine acts as the prolactin release-inhibiting factor from the hypothalamus 4
• Any disruption of the hypothalamic-pituitary connection results in loss of this inhibitory tone and subsequent hyperprolactinemia 4
• Typical antipsychotics and risperidone cause more significant dopamine blockade in this pathway compared to other atypical agents 4

Clinical Consequences

Women are more sensitive than men to the hyperprolactinemic effects of antipsychotics. 6

In Women:

• Amenorrhea/oligomenorrhea 1, 8
• Anovulation and infertility 1, 8
• Galactorrhea 1, 8
• Loss of libido 4

In Men:

• Decreased libido 1, 8
• Erectile dysfunction 1, 8
• Gynecomastia 1, 8
• Hypospermatogenesis 4

Critical Diagnostic Pitfalls

Before attributing hyperprolactinemia to medication, you must exclude other causes including hypothyroidism, renal or hepatic disease, prolactinomas, and pituitary stalk compression. 8

• Hypothyroidism causes hyperprolactinemia in 43% of women and 40% of men with primary hypothyroidism 1
• Chronic kidney disease is associated with hyperprolactinemia in 30-65% of adult patients 1, 8
• Severe liver disease is also associated with hyperprolactinemia 1, 8
• Macroprolactinemia accounts for 10-40% of all hyperprolactinemia cases and represents biologically inactive prolactin complexes that should be measured when prolactin is mildly or incidentally elevated 1, 8

Diagnostic Approach

Review of medications, particularly dopamine antagonists, is crucial in the initial evaluation of any patient with hyperprolactinemia. 1

• Measure baseline macroprolactin levels when prolactin is mildly or incidentally elevated 8
• Consider temporarily stopping the suspected medication to determine if prolactin levels normalize 7
• Perform MRI or CT scan if structural lesion cannot be excluded 7
• In patients with large pituitary masses but paradoxically normal or mildly elevated prolactin, request manual serial dilutions to rule out the "hook effect" (occurs in ~5% of macroprolactinomas) 1

Management Strategies

If hyperprolactinemia is symptomatic, management options include: 7

• Switching to an alternative medication that does not cause hyperprolactinemia (in consultation with prescribing physician/psychiatrist)
• For antipsychotic-induced hyperprolactinemia: gradual discontinuation combined with initiation of olanzapine or clozapine 6
• Using estrogen/testosterone replacement therapy for hypogonadal symptoms 7
• Cautiously adding a dopamine agonist or aripiprazole 7, 2