Prolactin inhibitors are a class of drugs that act primarily by suppressing the secretion of prolactin, a peptide hormone synthesized by the anterior pituitary gland. Prolactin plays an essential role in lactation, reproductive function, and immune modulation. Elevated prolactin levels—termed hyperprolactinemia—can result in galactorrhea, amenorrhea, infertility, decreased libido, erectile dysfunction, and hypogonadism.
Pharmacological inhibition of prolactin secretion is primarily achieved through dopamine receptor agonism, specifically targeting dopamine D2 receptors in the pituitary, which suppress prolactin release.
1. Mechanism of Action
The hypothalamic-pituitary axis regulates prolactin secretion primarily through tonic inhibition by dopamine, which is secreted by tuberoinfundibular neurons. Dopamine reaches the anterior pituitary via the hypophyseal portal system and binds to D2 receptors on lactotroph cells, suppressing prolactin release.
Prolactin inhibitors (dopamine agonists) mimic dopamine’s action by:
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Activating D2 receptors on lactotrophs
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Reducing cyclic AMP (cAMP) and intracellular calcium
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Ultimately inhibiting prolactin gene expression and exocytosis
These agents do not affect growth hormone (GH), TSH, or other anterior pituitary hormones unless used in high doses.
2. Primary Drugs in Class
| Generic Name | Brand Name(s) | Classification |
|---|---|---|
| Cabergoline | Dostinex, Cabaser | Long-acting D2 agonist |
| Bromocriptine | Parlodel, Cycloset | Short-acting D2 agonist |
| Quinagolide | Norprolac (EU) | Selective D2 agonist |
| Pergolide | Withdrawn | Ergot derivative |
3. Therapeutic Indications
Prolactin inhibitors are used in the treatment of:
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Hyperprolactinemia (idiopathic or due to prolactinomas)
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Prolactin-secreting pituitary adenomas (micro and macroprolactinomas)
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Hypogonadism due to hyperprolactinemia
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Amenorrhea-galactorrhea syndrome
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Parkinson’s disease (as dopaminergic agents, though rarely used now)
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Type 2 Diabetes Mellitus (bromocriptine quick-release formulation: Cycloset)
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Suppression of physiological lactation (rarely recommended in modern practice)
4. Pharmacokinetic Profiles
| Parameter | Cabergoline | Bromocriptine |
|---|---|---|
| Half-life | ~65 hours | ~6-15 hours |
| Onset of action | Within 3 hours | 1–2 hours |
| Duration | Prolonged (1–2 weeks) | Shorter (daily dosing) |
| Bioavailability | ~60% (oral) | Variable (~28%) |
| Protein binding | ~40% | ~90% |
| Metabolism | Hepatic (CYP3A4 minor) | Hepatic (CYP3A4 major) |
| Excretion | Feces and urine | Bile and feces |
5. Dosage and Administration
Cabergoline
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Hyperprolactinemia:
Initial dose: 0.25 mg twice weekly
Maintenance: 0.25–1.5 mg twice weekly, adjusted based on prolactin levels -
Dosing notes:
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Max dose: 3 mg/week (some cases up to 4.5 mg/week)
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Given with food to reduce nausea
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Long-acting, fewer side effects due to twice-weekly dosing
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Bromocriptine
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Hyperprolactinemia:
Initial dose: 1.25–2.5 mg daily, with titration up to 5–15 mg/day (divided doses) -
Cycloset (Type 2 Diabetes):
0.8 mg daily within 2 hours of waking; titrate up to 4.8 mg/day -
Dosing notes:
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Must be taken with meals
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Short half-life necessitates daily or twice-daily dosing
-
6. Clinical Monitoring
| Parameter | Frequency and Considerations |
|---|---|
| Serum prolactin levels | Every 4–8 weeks during dose titration |
| Pituitary MRI | Annually (for macroadenomas) |
| Visual field testing | If tumor involves optic chiasm |
| Cardiac valvulopathy | Baseline and periodic echocardiogram (cabergoline >2 mg/week) |
| Liver function tests | Periodically during long-term therapy |
| Pregnancy testing | Baseline and during therapy in women |
7. Adverse Effects
Common
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Gastrointestinal: nausea, vomiting, constipation
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Neurologic: dizziness, headache, fatigue
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Cardiovascular: orthostatic hypotension
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Psychiatric: hallucinations, depression, impulse control disorders (gambling, hypersexuality)
Serious
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Cardiac valvulopathy (cabergoline >2 mg/week): due to serotonin 5-HT2B agonism
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Fibrotic complications (retroperitoneal, pulmonary, cardiac)
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Pulmonary infiltrates
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Psychosis exacerbation in predisposed individuals
Cabergoline has a lower side effect profile than bromocriptine at therapeutic doses.
8. Contraindications
| Condition | Reason |
|---|---|
| Uncontrolled hypertension | Exacerbated by dopaminergic effects |
| Cardiac valvular disease | Risk of fibrotic valvulopathy |
| Psychotic disorders | May worsen hallucinations or mania |
| Hypersensitivity to ergot alkaloids | Both cabergoline and bromocriptine are ergot derivatives |
| Pregnancy (without monitoring) | Use only when benefits outweigh risks |
9. Drug Interactions
| Interacting Drug/Class | Effect | Clinical Concern |
|---|---|---|
| CYP3A4 inhibitors (e.g., ketoconazole, macrolides) | ↑ cabergoline levels | Increased risk of side effects |
| Antipsychotics (e.g., risperidone, haloperidol) | ↓ efficacy of prolactin inhibitors | Antagonize dopamine D2 receptors |
| Ergot alkaloids (e.g., ergotamine) | Additive vasoconstriction | Increased risk of hypertension or ischemia |
| Triptans (migraine drugs) | Vasospasm risk | Monitor blood pressure |
| SSRIs, SNRIs, TCA antidepressants | May mask hyperprolactinemia | Symptomatic overlap or PRL increase |
10. Use in Pregnancy and Lactation
| Parameter | Cabergoline | Bromocriptine |
|---|---|---|
| Pregnancy Category | B (US FDA) | B (US FDA) |
| Clinical Use | Discontinue if pregnancy occurs unless tumor control needed | May continue with close monitoring |
| Lactation | Contraindicated | Contraindicated |
11. Special Populations
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Elderly: Use lower starting doses; monitor blood pressure closely
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Hepatic impairment: Avoid or use cautiously (especially cabergoline)
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Renal impairment: No dose adjustment generally needed
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Adolescents: Used in prolactinoma with careful monitoring
12. Discontinuation Considerations
In long-term controlled hyperprolactinemia (e.g., ≥2 years), drug withdrawal may be attempted if:
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Prolactin levels are normalized
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Tumor has regressed or is no longer visible
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Patient is asymptomatic
Recurrence occurs in ~20–30% of cases; thus, regular follow-up is required.
13. Clinical Practice Guidelines
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Endocrine Society Guidelines recommend cabergoline over bromocriptine for most patients due to better efficacy and tolerability.
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In patients with large macroadenomas, medical therapy can reduce tumor size to avoid surgery.
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In resistant cases, surgery or radiotherapy may be considered.
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Cabergoline-resistant prolactinomas may require dose escalation or alternative treatment.
14. Comparison: Cabergoline vs. Bromocriptine
| Feature | Cabergoline | Bromocriptine |
|---|---|---|
| Dosing Frequency | Twice weekly | Daily or twice daily |
| Efficacy | Higher (85–95%) | Lower (70–85%) |
| Tolerability | Better | More GI and neuro side effects |
| Cardiac Safety Concern | Valvulopathy (high dose) | Less risk |
| Preferred Agent | Yes (first-line) | Second-line or when cabergoline unavailable |
15. Future Directions
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Non-ergot prolactin inhibitors (e.g., quinagolide analogues) under investigation
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Gene therapy targeting pituitary tumors
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Selective D2 receptor modulators with reduced systemic side effects
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