Understanding Prolactin and Its Regulation
Prolactin is a hormone produced by the pituitary gland [1.4.3]. Its primary function is to initiate and maintain lactation in women, but it also plays a role in gonadal function and libido in both sexes [1.4.3]. The secretion of prolactin is primarily regulated by dopamine, which acts as an inhibitor [1.3.5]. When dopamine binds to D2 receptors on the pituitary gland's lactotroph cells, prolactin release is suppressed [1.3.3]. Any medication that interferes with this dopamine pathway can lead to elevated prolactin levels, a condition known as hyperprolactinemia [1.3.5, 1.3.7].
The Mechanism: How Medications Increase Prolactin
The most common way medications cause hyperprolactinemia is by blocking dopamine D2 receptors in the pituitary gland [1.3.3, 1.3.6]. This action removes the inhibitory effect of dopamine, leading to increased synthesis and release of prolactin [1.3.4]. This is the primary mechanism for antipsychotic drugs [1.3.3]. Other mechanisms include depleting dopamine (e.g., methyldopa) or stimulating the hormones that release prolactin, such as serotonin [1.3.4, 1.3.5]. For instance, antidepressants with serotoninergic activity can increase prolactin [1.2.4]. Drug-induced hyperprolactinemia typically results in prolactin levels between 25 and 100 ng/mL, though some drugs like risperidone and metoclopramide can cause levels to exceed 200 ng/mL [1.6.1].
Key Medication Classes That Cause High Prolactin
Several classes of drugs are known to cause hyperprolactinemia. Antipsychotics are the most frequent cause, but other common medications can also be responsible [1.3.3, 1.3.4].
Antipsychotics (Neuroleptics)
Antipsychotics are the most common pharmacological cause of hyperprolactinemia [1.2.5, 1.3.3].
- Typical (First-Generation) Antipsychotics: These drugs are potent dopamine D2 receptor blockers and frequently cause sustained high prolactin levels [1.3.3, 1.3.5]. Examples include Haloperidol, Chlorpromazine, Fluphenazine, and Thioridazine [1.2.5, 1.3.2]. The incidence of hyperprolactinemia with these agents can be as high as 90% [1.3.4].
- Atypical (Second-Generation) Antipsychotics: The effect of these drugs on prolactin varies. Risperidone and its metabolite paliperidone are well-known for causing significant and sustained hyperprolactinemia, similar to typical antipsychotics [1.2.4, 1.3.5]. Amisulpride also causes marked prolactin elevation [1.2.4]. In contrast, agents like Aripiprazole, Quetiapine, and Clozapine are considered "prolactin-sparing" because they cause minimal or only transient increases [1.2.4, 1.3.4, 1.5.5]. Olanzapine may cause a transient increase, which often returns to normal with continued treatment [1.3.5].
Antidepressants
Certain antidepressants, particularly those that affect serotonin, can lead to elevated prolactin.
- Selective Serotonin Reuptake Inhibitors (SSRIs): Drugs like Fluoxetine, Sertraline, and Paroxetine can cause hyperprolactinemia [1.2.2, 1.2.5].
- Tricyclic Antidepressants (TCAs): Amitriptyline, Clomipramine, and Amoxapine have been shown to cause sustained and symptomatic hyperprolactinemia [1.2.5, 1.2.8].
- Monoamine Oxidase Inhibitors (MAOIs): This class of antidepressants can also raise prolactin levels [1.2.4].
Other Common Medications
- Antihypertensives: Certain blood pressure medications like Methyldopa and Verapamil are known culprits [1.2.3, 1.2.5].
- Gastrointestinal (Prokinetic) Agents: Metoclopramide and Domperidone, used for nausea and gastric motility, are strong dopamine antagonists and frequently raise prolactin [1.2.2, 1.2.3, 1.2.5].
- H2 Receptor Antagonists: Cimetidine and Ranitidine, used for acid reflux, have been reported to cause hyperprolactinemia [1.2.3, 1.2.5].
- Opiates: Morphine and other opiates can stimulate prolactin release [1.2.5, 1.3.5].
- Estrogens: Found in oral contraceptives, estrogens can promote prolactin synthesis [1.2.3, 1.2.9].
Comparison of Prolactin-Elevating Medications
| Medication Class | Specific Examples | Mechanism of Action | Degree of Prolactin Elevation |
|---|---|---|---|
| Typical Antipsychotics | Haloperidol, Chlorpromazine [1.2.5] | Dopamine D2 receptor blockade [1.3.3] | High and Sustained [1.3.5] |
| Atypical Antipsychotics | Risperidone, Paliperidone, Amisulpride [1.2.4, 1.5.5] | Dopamine D2 receptor blockade [1.2.4] | High and Sustained [1.2.4] |
| Prolactin-Sparing Antipsychotics | Aripiprazole, Quetiapine, Clozapine [1.5.5] | Partial dopamine agonism or rapid D2 dissociation [1.3.4] | Minimal to None / Transient [1.2.4, 1.3.4] |
| Antidepressants (SSRIs, TCAs) | Fluoxetine, Amitriptyline [1.2.2, 1.2.5] | Serotonergic stimulation / Catecholamine re-uptake inhibition [1.2.3, 1.2.4] | Mild to Moderate [1.6.1] |
| GI Motility Agents | Metoclopramide, Domperidone [1.2.5] | Dopamine D2 receptor blockade [1.2.3] | High [1.6.1] |
| Antihypertensives | Methyldopa, Verapamil [1.2.5] | Dopamine depletion or blockade [1.2.3, 1.2.5] | Mild to Moderate [1.2.5] |
Symptoms, Diagnosis, and Management
Symptoms
Symptomatic hyperprolactinemia results from hypogonadism (low sex hormones) and the direct effects of prolactin [1.3.5, 1.4.3].
- In Women: Symptoms include menstrual irregularities (oligomenorrhea or amenorrhea), infertility, galactorrhea (milky nipple discharge), and decreased libido [1.4.3, 1.4.7]. Long-term low estrogen can lead to decreased bone mineral density and osteoporosis [1.3.5, 1.4.2].
- In Men: Symptoms often include decreased libido, erectile dysfunction, infertility, and less commonly, gynecomastia (breast enlargement) and galactorrhea [1.4.3, 1.4.7].
Diagnosis
Diagnosis begins with a simple blood test to measure fasting prolactin levels [1.4.3]. It's crucial to rule out other causes like pregnancy, hypothyroidism, kidney failure, or a pituitary tumor (prolactinoma) [1.4.3, 1.5.4]. If a medication is suspected, a physician may temporarily stop the drug to see if prolactin levels normalize [1.5.3]. A pituitary MRI may be ordered if levels are exceptionally high (e.g., >100-200 ng/mL) or if a tumor is suspected [1.5.1, 1.5.4].
Management Strategies
Treatment is generally only required if the hyperprolactinemia is symptomatic [1.3.9, 1.5.6]. The approach depends on the severity of symptoms and the clinical need for the offending medication [1.5.4].
- Watch and Wait: For mild symptoms, monitoring may be sufficient [1.5.1].
- Dose Reduction or Discontinuation: If clinically feasible, reducing the dose or stopping the medication is a primary option [1.5.1, 1.5.4]. Prolactin levels typically normalize within a few weeks of stopping an oral medication [1.6.1].
- Switching Medications: For essential medications like antipsychotics, switching to a prolactin-sparing alternative (e.g., aripiprazole, quetiapine) is a highly effective strategy [1.5.3, 1.5.4].
- Adding Aripiprazole: For patients stable on a prolactin-raising antipsychotic, adding a low dose of aripiprazole can normalize prolactin levels due to its partial dopamine agonist activity [1.5.2, 1.5.4].
- Dopamine Agonists: In rare cases, a dopamine agonist like cabergoline or bromocriptine may be cautiously added. However, this can risk worsening psychotic symptoms and is not a first-line approach [1.5.3, 1.5.4].
Conclusion
Numerous common medications, with antipsychotics being the most prominent, can cause high prolactin levels by interfering with the brain's dopamine system [1.2.7, 1.3.3]. This can lead to significant side effects affecting reproductive and sexual health, as well as long-term bone density [1.4.5]. Awareness of what medications cause high prolactin allows for proper diagnosis and management, which may involve switching to a prolactin-sparing drug, reducing the dose, or adding an adjunctive treatment like aripiprazole [1.5.4, 1.5.5]. Collaborative management with a healthcare provider is essential to balance the benefits of the primary medication against the symptoms of hyperprolactinemia. For more information, you can visit the Pituitary Foundation.
