What causes elevated prolactin levels?

Causes of Elevated Prolactin Levels

Hyperprolactinemia results from prolactinomas, dopamine-antagonist medications, primary hypothyroidism, chronic kidney disease, hepatic disease, or pituitary stalk compression—with prolactinomas being the most common pathological cause and medications being one of the most frequent overall causes. 1

Pathological Causes

Prolactinomas

• Prolactinomas are the most common pathological cause of chronic hyperprolactinemia, with prolactin levels typically exceeding 4,000 mU/L (approximately 200 ng/mL) in children and adolescents. 1
• Prolactin levels directly correlate with tumor size—values >250 ng/mL are highly suggestive of prolactinomas and virtually exclude nonfunctioning pituitary adenomas. 2
• However, up to 25% of patients with microprolactinomas or cystic macroprolactinomas may present with prolactin <100 ng/mL, representing an important diagnostic pitfall. 2
• Approximately 93% of pediatric prolactinomas present after age 12, with a 3-4.5 times higher prevalence in females. 3

Pituitary Stalk Compression

• Mass lesions compressing the pituitary stalk interrupt the inhibitory dopaminergic tone on lactotroph cells, resulting in elevated prolactin levels (the "stalk effect"). 1
• Most patients with nonfunctioning pituitary adenomas causing stalk compression present with prolactin levels <100 ng/mL. 2
• A critical pitfall is the "hook effect"—falsely low prolactin levels in patients with large pituitary adenomas (≥3 cm) due to immunoassay saturation, occurring in approximately 5% of macroprolactinomas. 3, 2
• The hook effect should be excluded by performing serial serum dilutions (1:100) for prolactin measurement whenever large pituitary masses have disproportionately low prolactin levels. 1, 2

Medication-Induced Hyperprolactinemia

Medications are one of the most common causes of hyperprolactinemia, acting through direct prolactin stimulation or dopamine antagonism. 1

Antipsychotic Agents

• Typical antipsychotics and risperidone (an atypical agent) are the most frequent medication culprits causing hyperprolactinemia. 4, 5
• Other atypical antipsychotics like olanzapine and clozapine infrequently cause hyperprolactinemia. 5
• Women are more sensitive than men to the hyperprolactinemic effects of antipsychotics. 5

Other Medications

• Antidepressants with serotonergic activity (SSRIs, MAO inhibitors, some tricyclics) can elevate prolactin. 5
• Prokinetic agents (like prochlorperazine/Stemetil) cause hyperprolactinemia through dopamine antagonism. 1
• Additional culprits include antihypertensive agents, H2-receptor antagonists, opiates, estrogens, anti-androgens, and anticonvulsants. 4, 5

Endocrine and Systemic Causes

Primary Hypothyroidism

• Primary hypothyroidism causes hyperprolactinemia in 43% of women and 40% of men with frank disease, and in 36% of women and 32% of men with subclinical hypothyroidism. 1
• The mechanism involves compensatory hypersecretion of thyrotropin-releasing hormone (TRH), which stimulates prolactin release. 1
• Hypothyroidism may produce pituitary hyperplasia that mimics a prolactinoma on imaging. 1
• While prolactin elevation is generally modest (<100 ng/mL), rare cases with severe hypothyroidism have reached 323 ng/mL, particularly when combined with macroprolactinemia. 6

Chronic Kidney Disease

• Hyperprolactinemia occurs in 30-65% of adult patients with chronic kidney disease due to both increased prolactin secretion and reduced renal clearance. 1
• Prolactin values can exceed 250 ng/mL in chronic renal failure, potentially mimicking prolactinomas. 2

Severe Liver Disease

• Hepatic disease is associated with hyperprolactinemia in adults, though the mechanism is less well-defined than renal disease. 1

Other Causes

Macroprolactinemia

• Macroprolactinemia accounts for 10-40% of all hyperprolactinemia cases and represents the third most frequent cause after medications and prolactinomas. 7, 2
• Macroprolactin has low biological activity, yet up to 40% of macroprolactinemic patients present with hypogonadism symptoms, infertility, or galactorrhea. 2
• Approximately 20% of patients with macroprolactinemia have coexisting pituitary adenomas, making imaging still necessary in symptomatic cases. 7

Physiological and Stress-Related

• Pregnancy is a physiologic cause that must be excluded in women of reproductive age. 7
• Stress can elevate prolactin levels up to five times the upper limit of normal, necessitating serial measurements for modestly elevated levels. 1, 7

Rare Causes

• Intracranial hypotension, tetrahydrobiopterin deficiency, and chest wall lesions can cause hyperprolactinemia. 1

Diagnostic Algorithm

When evaluating hyperprolactinemia, the Endocrine Society recommends this systematic approach:

1. Exclude pregnancy in all women of reproductive age. 7
2. Review all medications for dopamine antagonists or serotonergic agents. 7
3. Measure TSH to exclude primary hypothyroidism. 7
4. Assess renal function (creatinine/eGFR) and liver function tests. 7
5. Test for macroprolactin using polyethylene glycol (PEG) precipitation when prolactin is mildly or incidentally elevated, especially in asymptomatic patients. 7
6. Obtain pituitary MRI after excluding secondary causes to evaluate for prolactinomas or other masses. 7
7. Perform serial dilutions if large pituitary masses have disproportionately low prolactin to exclude the hook effect. 7