Aetiology

Elevated prolactin (PRL) levels are found in several pathological conditions and physiological states. One retrospective multicentre study of 1234 patients with hyperprolactinaemia showed that 56.2% had prolactinomas, 14.5% had drug-induced hyperprolactinaemia, 9.3% had macroprolactinaemia, 6.6% had non-functioning pituitary adenomas, 6.3% had primary hypothyroidism, 3.6% had idiopathic hyperprolactinaemia, and 3.2% had acromegaly.[12] Thus, the aetiology of hyperprolactinaemia can be categorised as pathological, physiological, pharmacological, or idiopathic.

Pathological

Pathological hyperprolactinaemia 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 co-secreting growth hormone (GH), hypothyroidism (due to increased hypothalamic synthesis of thyrotropin-releasing hormone), and chronic renal failure (due to decreased PRL clearance).

Tumour pathologies

  • Prolactinomas, 90% of which are microprolactinomas (tumours <10 mm in diameter), account for 25% to 30% of functioning pituitary tumours and are the most common cause of hyperprolactinaemia. Macroprolactinomas (tumours >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@61e35841 Macroprolactinomas present more frequently in men, possibly due to delayed diagnosis in this patient group.[3][13] Serum PRL levels usually parallel tumour size, and it is rare for a prolactinoma to expand significantly without a marked increase in PRL.

  • Most patients with PRL levels >6522 picomol/L (150 micrograms/L) have a prolactinoma. Macroprolactinomas usually present with PRL concentrations >10,870 picomol/L (250 micrograms/L), and sometimes >43,478 picomol/L (1000 micrograms/L).[1][13] Patients presenting with a pituitary macroadenoma and mild hyperprolactinaemia <4348 picomol/L (100 micrograms/L) most likely have a non-secreting pituitary tumour 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 adrenocorticotrophic hormone.

  • Masses affecting the hypothalamus and compressing the pituitary stalk usually result in PRL levels of <10,870 picomol/L (250 micrograms/L). These include non-functioning adenomas, craniopharyngiomas, gliomas, and metastatic disease.[1][2][3]

  • Tumours 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 tumours are associated with both acromegaly and hyperprolactinaemia, either by cells co-secreting GH and PRL or by the co-existence of two different cell populations, one secreting GH and the other PRL.

Non-tumour 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 postnatal period. It may co-exist with other autoimmune diseases such as autoimmune thyroid diseases (mainly Hashimoto's thyroiditis), Addison's 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 (<2174 picomol/L [50 micrograms/L]) in 8% of cases.[19] PRL levels normalise 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 tumours such as parathyroid tumours, enteropancreatic tumours (insulinomas, gastrinomas), or adrenal adenomas.[1]

Polycystic ovary syndrome (PCOS)

  • Hyperprolactinaemia, associated with PRL levels <2174 picomol/L (50 micrograms/L), is estimated to occur in 11% to 37% of women with PCOS, although the pathophysiological mechanism behind this link is poorly understood.[19][21][22] In one study of 122 women with PCOS and hyperprolactinaemia, around 60% had normal prolactin levels after polyethylene glycol precipitation, 27% were diagnosed with a pituitary adenoma, and 13% had idiopathic hyperprolactinaemia 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 hyperprolactinaemia 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 hyperprolactinaemia due to a reflex mediated through the mammary nerve.[1][2][3] This reflex is also the mechanism responsible for the hyperprolactinaemia associated with idiopathic granulomatous mastitis.[24]

Ectopic hyperprolactinaemia

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

  • Surgical resection of the causative tumour normalises PRL levels.

Pharmacological

Drug-induced hyperprolactinaemia is usually associated with PRL levels of <4348 picomol/L (100 micrograms/L).

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

Although the highest PRL elevations were noticed with the first-generation anti-psychotics, the second-generation ones can also cause hyperprolactinaemia. 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 favourable 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 hyperprolactinaemia 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])

  • Oestrogen

  • Alcohol (excessive intake).

Physiological

Macroprolactinaemia

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

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

  • In the general population, the prevalence of macroprolactinaemia 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 hyperprolactinaemia and has been reported in specific hyperprolactinaemia-related conditions such as antipsychotic-induced hyperprolactinaemia.[36]

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

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

  • PRL levels are usually <4348 picomol/L (100 micrograms/L), with only 8.5% to 20.0% of patients having a PRL level 4348 picomol/L (100 micrograms/L).[19][38]

Physiological stress

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

Pregnancy, lactation, and nipple stimulation

  • In pregnancy, the rising oestrogen 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 oestrogens and progesterone, the decline of which in the postnatal period allows lactation to occur.[39]

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

Other physiological causes include:

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

Idiopathic

Rarely, the underlying cause of hyperprolactinaemia (usually to levels of 4348 picomol/L [100 micrograms/L]) cannot be determined, and this condition is termed idiopathic hyperprolactinaemia.[1][2][3]

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

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