Etiology

Elevated prolactin (PRL) levels are found in several pathologic conditions and physiologic states. One retrospective multicenter study of 1234 patients with hyperprolactinemia showed that 56.2% had prolactinomas, 14.5% had drug-induced hyperprolactinemia, 9.3% had macroprolactinemia, 6.6% had nonfunctioning pituitary adenomas, 6.3% had primary hypothyroidism, 3.6% had idiopathic hyperprolactinemia, and 3.2% had acromegaly.[12] Thus, the etiology of hyperprolactinemia can be categorized as pathologic, physiologic, pharmacologic, or idiopathic.

Pathologic

Pathologic hyperprolactinemia is mainly due to PRL-secreting pituitary adenomas (prolactinomas), masses compressing the pituitary stalk (due to inhibition of dopamine transport from the hypothalamus to lactotroph cells), pituitary adenomas cosecreting growth hormone (GH), hypothyroidism (due to increased hypothalamic synthesis of thyrotropin-releasing hormone), and chronic renal failure (due to decreased PRL clearance).

Tumor pathologies

  • Prolactinomas, 90% of which are microprolactinomas (tumors <10 mm in diameter), account for 25% to 30% of functioning pituitary tumors and are the most common cause of hyperprolactinemia. Macroprolactinomas (tumors >10 mm in diameter) are relatively uncommon and make up the remainder of prolactinomas.[Figure caption and citation for the preceding image starts]: MRI showing macroprolactinomaFrom the collection of Faidon Harsoulis, MD; used with permission [Citation ends].com.bmj.content.model.assessment.Caption@22dd6238 Macroprolactinomas present more frequently in men, possibly due to delayed diagnosis in this patient group.[3][13] Serum PRL levels usually parallel tumor size, and it is rare for a prolactinoma to expand significantly without a marked increase in PRL.

  • Most patients with PRL levels >150 micrograms/L have a prolactinoma. Macroprolactinomas usually present with PRL concentrations >250 micrograms/L, and sometimes >1000 micrograms/L.[1][13] Patients presenting with a pituitary macroadenoma and mild hyperprolactinemia (<100 micrograms/L) most likely have a nonsecreting pituitary tumor rather than a prolactinoma.[14] Nonetheless, these associations are not absolute.[1][13]

  • Most prolactinomas secrete only PRL, but approximately 5% contain somatotroph cells and thus also secrete GH.[15] They can rarely produce thyroid-stimulating hormone and adrenocorticotropic hormone.

  • Masses affecting the hypothalamus and compressing the pituitary stalk usually result in PRL levels of <250 micrograms/L. These include nonfunctioning adenomas, craniopharyngiomas, gliomas, and metastatic disease.[1][2][3]

  • Tumors that produce GH may also secrete PRL in nearly 25% of cases. These include mixed cell adenomas, acidophil stem cell-derived adenomas, mammosomatotroph cell-derived adenomas, and stalk compression by a solely GH-secreting macroadenoma.[16] These tumors are associated with both acromegaly and hyperprolactinemia, either by cells cosecreting GH and PRL or by the coexistence of two different cell populations, one secreting GH and the other PRL.

Nontumor pathologies affecting the pituitary gland

  • Traumatic sectioning of the pituitary stalk.

  • Lymphocytic hypophysitis is caused by autoimmune conditions of the pituitary with lymphocytic infiltration. This state usually, but not exclusively, occurs at the end of gestation or in the early postpartum period. It may coexist with other autoimmune diseases such as autoimmune thyroid diseases (mainly Hashimoto thyroiditis), Addison disease, type 1 diabetes mellitus, hypoparathyroidism, and autoimmune hepatitis. It can also be part of the autoimmune polyendocrinopathy syndrome.[1][2][17]

  • Granulomatous hypophysitis is caused by sarcoidosis and other granulomatous disorders such as tuberculosis, syphilis, histiocytosis X, and idiopathic granulomatous hypophysitis.[18]

Primary hypothyroidism

  • Results in mild elevation of PRL levels (<50 micrograms/L) in 8% of cases.[19] PRL levels normalize following thyroid hormone replacement therapy.

  • Among consecutive patients presenting with thyroid-related problems, PRL levels were elevated in 21% of patients with overt hypothyroidism and 8% of those with subclinical hypothyroidism.[20]

  • Hypothyroidism is also associated with thyrotroph (as well as lactotroph) cell hyperplasia leading to significant pituitary enlargement. This can be radiologically confused with a prolactinoma.

Multiple endocrine neoplasia syndrome type I

  • Prolactinomas can present as a component of this syndrome in association with other endocrine tumors such as parathyroid tumors, enteropancreatic tumors (insulinomas, gastrinomas), or adrenal adenomas.[1]

Polycystic ovary syndrome (PCOS)

  • Hyperprolactinemia, associated with PRL levels <50 micrograms/L, is estimated to occur in 11% to 37% of women with PCOS, although the pathophysiologic mechanism behind this link is poorly understood.[19][21][22] In one study of 122 women with PCOS and hyperprolactinemia, around 60% had normal prolactin levels after polyethylene glycol precipitation, 27% were diagnosed with a pituitary adenoma, and 13% had idiopathic hyperprolactinemia with a normal MRI scan.[22] PRL concentrations >85.2 micrograms/L in women with PCOS have been shown to be highly indicative of a prolactinoma (77% sensitivity, and 100% specificity).[21]

Chronic renal failure

  • Mild hyperprolactinemia is seen in 30% of patients with chronic renal failure.[23]

Cirrhosis

  • Causes a mild elevation in basal PRL in up to 20% of patients with cirrhosis.[1][2][3]

Chest wall trauma or surgery

  • Leads to hyperprolactinemia due to a reflex mediated through the mammary nerve.[1][2][3] This reflex is also the mechanism responsible for the hyperprolactinemia associated with idiopathic granulomatous mastitis.[24]

Ectopic hyperprolactinemia

  • This condition is a paraneoplastic manifestation in which PRL is produced by tumors deriving from tissues other than the pituitary gland, such as ovarian or mesenchymal (perivascular epithelioid cell) tumors.[25][26]

  • Surgical resection of the causative tumor normalizes PRL levels.

Pharmacologic

Drug-induced hyperprolactinemia is usually associated with PRL levels of <100 micrograms/L.

Antipsychotics (phenothiazines, thioxanthenes, butyrophenones, and atypical antipsychotics) are the most common cause of drug-induced hyperprolactinemia, with approximately 60% of women and 40% of men on these medications (also known as neuroleptics) being affected.[27]

Although the highest PRL elevations were noticed with the first-generation antipsychotics, the second-generation ones can also cause hyperprolactinemia. The highest rates have been reported with amisulpride, risperidone, and paliperidone (which raise PRL even at low doses), whereas aripiprazole and quetiapine have the most favorable profile. PRL elevations are usually observed at the initiation of treatment and are generally dose-dependent. Aripiprazole can even reduce PRL levels.[28]

Other drugs implicated in the development of hyperprolactinemia include:[29][30][31][32][33]

  • Drugs that block dopamine receptors (metoclopramide, domperidone, risperidone, phenothiazines, tricyclic antidepressants, cimetidine)

  • Drugs that interfere with the synthesis or storage of dopamine (e.g., methyldopa, monoamine oxidase inhibitors [MAOIs])[29]

  • Antidepressants (tricyclic and tetracyclic antidepressants, MAOIs, selective serotonin reuptake inhibitors, nefazodone, bupropion, venlafaxine)

  • Opiates and cocaine

  • Antihypertensives (e.g., verapamil, methyldopa)

  • Gastrointestinal drugs (metoclopramide, domperidone, histamine receptor [H2] blockers, protease inhibitors [conflicting data])

  • Estrogen

  • Alcohol (excessive intake).

Physiologic

Macroprolactinemia

  • High levels of macroprolactin lead to reduced clearance rates of the PRL-IgG complex.

  • The prevalence of macroprolactinemia in hyperprolactinemic sera ranges from 15% to 46%.[1][6][19] It is thought to be more common in women with hyperprolactinemia; however, it is unclear if this is a true difference.[34]

  • In the general population, the prevalence of macroprolactinemia was previously reported as 0.2% in women and 0.02% in men; however, the overall prevalence is now estimated to be 3.7% with no sex difference.[34][35]

  • Prevalent in idiopathic hyperprolactinemia and has been reported in specific hyperprolactinemia-related conditions such as antipsychotic-induced hyperprolactinemia.[36]

  • Present in up to 40% of patients with systemic lupus erythematosus, possibly due to anti-PRL autoantibodies.[37]

  • Suspected when a hyperprolactinemic patient lacks typical symptoms and/or radiographic evidence of a pituitary tumor. However, one isolated study of 106 participants found reports of amenorrhea, galactorrhea, and/or infertility in these patients.[38]

  • PRL levels are usually <100 micrograms/L, with only 8.5% to 20.0% of patients having a PRL level >100 micrograms/L.[19][38]

Physiologic stress

  • Hypoglycemia, myocardial infarction, and surgery may all cause high levels of PRL.

Pregnancy, lactation, and nipple stimulation

  • In pregnancy, the rising estrogen concentrations lead to high PRL levels via the direct stimulation of lactotroph cells. Increase in both the size and the number of lactotroph cells is observed during pregnancy. However, lactation is inhibited during pregnancy as a result of high levels of estrogens and progesterone, the decline of which in the postpartum period allows lactation to occur.[39]

  • Nipple stimulation leads to hyperprolactinemia due to a reflex mediated through the mammary nerve.

Other physiologic causes include:

  • Exercise, food ingestion, sexual intercourse, sleep, and psychological stress.[39]

Idiopathic

Rarely, the underlying cause of hyperprolactinemia (usually to levels of <100 micrograms/L) cannot be determined, and this condition is termed idiopathic hyperprolactinemia.[1][2][3]

Such patients may harbor microadenomas that are not detectable with computed tomography and magnetic resonance imaging scans.[40] Anti-PRL autoantibodies, without the presence of autoimmune disease, have been detected in approximately 16% of cases of idiopathic hyperprolactinemia.[40][41]

Use of this content is subject to our disclaimer