What causes elevated prolactin (PRL) and macroprolactin?

From the Guidelines

Elevated prolactin (PRL) and macroprolactin levels can be caused by various factors, including prolactinomas, thyroid disorders, and certain medications 1. As a precautionary measure, it is recommended to:

• Repeat the prolactin test to confirm the elevated levels, as stress and prolactin pulsatility can affect serum prolactin levels 1
• Check for macroprolactin using polyethylene glycol (PEG) precipitation test to rule out macroprolactinemia, a condition where elevated prolactin levels are due to the presence of macroprolactin, a complex of prolactin and IgG antibody 1
• Perform a thorough medical history and physical examination to identify any potential causes of elevated prolactin, such as:
  • Thyroid disorders, like primary hypothyroidism, which can cause hyperprolactinaemia due to compensatory thyrotropin-releasing hormone hypersecretion and pituitary hyperplasia 1
  • Renal disease, like chronic kidney disease, which can cause hyperprolactinaemia due to increased prolactin secretion and reduced renal clearance 1
  • Medications, like risperidone, metoclopramide, or verapamil, which can cause hyperprolactinaemia through direct prolactin stimulatory pathways or by antagonizing inhibitory dopaminergic tone 1
• Consider imaging studies, such as MRI, to rule out prolactinomas or other pituitary disorders, especially if pituitary stalk compression is suspected 1
• If macroprolactinemia is confirmed, no treatment is usually necessary, but monitoring of prolactin levels is recommended 1
• If a prolactinoma is suspected, treatment with dopamine agonists like cabergoline (0.5-2 mg/week) or bromocriptine (2.5-10 mg/day) may be initiated, with regular monitoring of prolactin levels and tumor size 1

From the FDA Drug Label

As with other drugs that antagonize dopamine D2 receptors, RISPERIDONE elevates prolactin levels and the elevation persists during chronic administration. RISPERIDONE is associated with higher levels of prolactin elevation than other antipsychotic agents. The cause of elevated prolactin (PRL) is the antagonism of dopamine D2 receptors by RISPERIDONE.

• Main cause: Dopamine D2 receptor antagonism
• Effect on prolactin levels: Elevated prolactin levels that persist during chronic administration There is no information in the provided drug labels about macroprolactin. 2

From the Research

Causes of Elevated Prolactin (PRL) and Macroprolactin

• Elevated prolactin (PRL) levels can be caused by various physiological, pharmacological, and pathological factors, including stress, prolactinomas, hypothyroidism, renal and hepatic failure, intercostal nerve stimulation, and polycystic ovary disease 3
• Macroprolactin, an antigen-antibody complex of higher molecular mass than prolactin, can also contribute to elevated PRL levels, particularly in cases where the concentration of macroprolactin exceeds 60% of the total serum prolactin concentration 3
• The presence of macroprolactin can lead to mild hyperprolactinemia due to its reduced clearance from the circulation and inactivity of the hypothalamic negative feedback mechanism 3
• Macroprolactinemia, a condition characterized by high levels of macroprolactin, can be a benign clinical condition in patients with normal concentrations of bioactive monomeric prolactin, but may also occur in patients with conventional symptoms of hyperprolactinemia 3

Pathogenesis of Macroprolactin

• The pathogenesis of macroprolactin is not fully understood, but it is thought to involve changes in the pituitary prolactin molecule that increase its antigenicity to the immune system, leading to the production of anti-prolactin antibodies 3
• The large molecular size of macroprolactin may prevent its passage through the capillary endothelium to target cells, resulting in reduced bioactivity and a lack of hyperprolactinemic symptoms 3

Diagnosis and Management of Hyperprolactinemia

• The diagnosis of hyperprolactinemia involves measurement of serum prolactin levels, as well as dynamic tests with dopamine antagonists 4
• However, these tests may not be able to determine the presence of macroprolactin molecules in the serum, leading to potential misdiagnosis 4
• Management of hyperprolactinemia depends on the underlying cause and may involve pharmacological intervention with dopamine agonists, such as bromocriptine, quinagolide, and cabergoline 5, 6
• Surgery may be considered in certain circumstances, but dopamine agonists are often sufficient to alleviate symptoms and restore normal prolactin levels 5