VOLUME 40 : NUMBER 6 : DECEMBER 2017 ARTICLE Hyperprolactinaemia Angela X Chen Endocrine advanced SUMMARY trainee1 Associate lecturer2 Serum prolactin should only be measured in patients with a pituitary mass or the clinical Morton G Burt symptoms and signs of hyperprolactinaemia. 1 Endocrinologist There are many causes of hyperprolactinaemia, including drugs. It is important to identify the Associate professor2 underlying cause to guide appropriate treatment. 1 Southern Adelaide Hyperprolactinaemia can cause galactorrhoea and impair reproductive function. It can accelerate Diabetes and Endocrine bone loss if it is associated with sex hormone deficiency. Services Repatriation General Most prolactinomas are microprolactinomas. They usually do not grow sufficiently to cause Hospital hypopituitarism or visual field loss. 2 School of Medicine Flinders University Patients with a prolactinoma are usually successfully treated with a dopamine agonist such Adelaide as cabergoline. Keywords Introduction Estimates suggest that at least 10% of dopamine agonist, hyperprolactinaemia is secondary to hyperprolactinaemia, A high prolactin concentration in blood 1 prolactin, prolactinoma (hyperprolactinaemia) is a relatively common macroprolactinaemia. This arises when immunoglobulins endocrine abnormality. The causes range from in serum bind prolactin to create high-molecular-weight benign conditions requiring no treatment to major forms of prolactin. As clearance of these macroprolactin Aust Prescr 2017;40:220–4 medical problems necessitating immediate therapy. molecules is slower than monomeric prolactin, the https://doi.org/10.18773/ Hyperprolactinaemia can also be an adverse effect of serum prolactin concentration increases. Macroprolactin austprescr.2017.060 some drugs. is largely biologically inactive, so most patients with macroprolactinaemia are asymptomatic. Physiology Prolactin is a polypeptide hormone that is synthesised Pathological causes and secreted by lactotroph cells in the anterior Prolactinomas are tumours arising from the pituitary gland. The secretion of prolactin is primarily prolactin-secreting cells in the pituitary. Most regulated by dopamine, which is produced in the prolactinomas (90%) are microadenomas (<1 cm in hypothalamus and inhibits prolactin secretion. The diameter), which are 10 times more common in women hypothalamic hormone thyrotropin-releasing hormone than in men. Microadenomas cause a moderate stimulates prolactin secretion. elevation in prolactin that can be associated with Prolactin exerts its effects by binding to prolactin symptoms of hyperprolactinaemia, but they usually do receptors. These are located on the cell membrane of not grow and cause a mass effect or hypopituitarism.2 many cells, particularly in the breast and pituitary. In Macroadenomas (>1 cm in diameter) are less common the breast, prolactin stimulates glandular proliferation and giant prolactinomas (>4 cm in diameter) are rare. during pregnancy and breast milk production Compared with women, men are nine times more likely postpartum. In the pituitary gland, prolactin inhibits to present with a macroadenoma. These tumours cause gonadotrophin secretion. marked hyperprolactinaemia – a prolactin concentration Aetiology of hyperprolactinaemia more than 10 000 mIU/L almost always indicates a macroprolactinoma. They can cause hypopituitarism There are physiological, pathological and drug-related and visual field loss or ocular palsies by compressing causes of hyperprolactinaemia (Table 1). the optic chiasm or the cranial nerve nuclei. Physiological causes Other hypothalamic and pituitary masses can also Pregnancy, suckling and lactation, exercise, coitus and cause hyperprolactinaemia. As dopamine inhibits stress can all increase prolactin. These increases are prolactin secretion, any mass or infiltrative lesion transient, and usually do not exceed twice the upper that compresses the pituitary stalk can attenuate limit of normal reference ranges. dopamine’s action and cause hyperprolactinaemia. 220 Full text free online at nps.org.au/australianprescriber VOLUME 40 : NUMBER 6 : DECEMBER 2017 ARTICLE However, hyperprolactinaemia from stalk compression Table 1 Causes of hyperprolactinaemia is usually below 2000 mIU/L, allowing distinction 3 from a macroprolactinoma. Cause Examples Several illnesses can cause hyperprolactinaemia. Physiological Pregnancy Prolactin is predominantly renally cleared, so renal (transient Lactation impairment can increase prolactin concentration. hyperprolactinaemia) Excercise As thyrotropin-releasing hormone stimulates Coitus prolactin secretion, hypothyroidism can also cause Chest wall/nipple stimulation hyperprolactinaemia. Seizures can cause a transient Stress increase in prolactin. Seizure Drug-related causes Macroprolactinaemia Immunoglobulin (IgG) binding prolactin A number of drugs impair hypothalamic dopamine Hypothalamic/ Prolactinoma release leading to increased secretion of prolactin pituitary lesions Non-functioning masses: (prolactin 500–4000 mIU/L). Hyperprolactinaemia • adenoma develops in patients taking antipsychotics such as • craniopharyngioma risperidone. It can also develop, to a lesser extent, • meningioma with some selective serotonin reuptake inhibitors.4,5 • Rathke’s cleft cyst Other drugs may cause hyperprolactinaemia less Inflammatory/infiltrative lesions: frequently (Table 1). If hyperprolactinaemia is drug- • lymphocytic hypophysitis induced, concentrations usually normalise if the drug • Langerhan’s cell histiocytosis is ceased for 72 hours. Other illness Hypothyroidism Clinical features Chronic renal failure In some patients hyperprolactinaemia causes no Drugs Antipsychotics (risperidone, amisulpride, paliperidone, haloperidol) symptoms, but it can affect breast and reproductive Antiemetics (metoclopramide, domperidone) function (Table 2 and Fig. 1). In women, it can cause Antidepressants (uncommon) oligo-amenorrhoea, infertility and galactorrhoea. In men, Opioids hyperprolactinaemia can result in erectile dysfunction, Oestrogens infertility and gynaecomastia. Galactorrhoea is much Antihypertensives (verapamil) less common in men than in women.6 In both sexes, gonadal hormone deficiency can accelerate bone loss. Patients may present with symptoms or signs associated with the underlying cause of hyperprolactinaemia. For Table 2 Clinical features of hyperprolactinaemia example, headache and visual loss in a patient with a pituitary mass, and fatigue and cold intolerance in a Women Men patient with hypothyroidism. Breast Galactorrhoea Gynaecomastia Investigation Galactorrhoea It should be emphasised that prolactin should only Reproductive Oligo-amenorrhoea Erectile dysfunction be measured in patients with clinical symptoms or Infertility Infertility signs of hyperprolactinaemia or patients with a known Osteopenia/osteoporosis Osteopenia/osteoporosis pituitary mass. The diagnosis of hyperprolactinaemia can be based on a single measurement of serum prolactin that is prolactin, which is usually normal in patients with above the upper limit of normal. The venepuncture macroprolactinaemia. 5 must be performed without excessive stress. Once the diagnosis of hyperprolactinaemia has Macroprolactinaemia should be excluded, especially in been made, investigations are required to identify asymptomatic patients, by adding polyethylene glycol the underlying cause and associated complications. to a serum sample to precipitate macroprolactin.5 Women and men should have oestrogen and morning Many laboratories in Australia routinely screen testosterone measured respectively along with for macroprolactin in cases of apparent gonadotrophins. Thyroid and renal function should hyperprolactinaemia. Polyethylene glycol precipitation be assessed and pregnancy excluded in women of also allows for the measurement of monomeric childbearing age. Full text free online at nps.org.au/australianprescriber 221 VOLUME 40 : NUMBER 6 : DECEMBER 2017 ARTICLE Hyperprolactinaemia Unless another clear cause is identified, MRI of the the potential benefits, any hypogonadism can be pituitary is indicated. Patients with a pituitary mass treated with appropriate sex hormone replacement. more than 1 cm in diameter should have investigations Occasionally patients with galactorrhoea can be assessing other pituitary hormones and have visual prescribed a dopamine agonist, but this may impair field testing. Measure the bone mineral density of the primary action of the drug which has caused hypogonadal patients. the hyperprolactinaemia. For example, prescribing a dopamine agonist to a patient taking an antipsychotic Management drug could exacerbate their psychiatric condition. Some patients do not require treatment. Prolactinoma Patients with physiological hyperprolactinaemia, macroprolactinaemia, asymptomatic microprolactinoma The first-line treatment of a prolactinoma is a or drug-induced hyperprolactinaemia usually do not dopamine agonist. These are recommended in all require treatment. If hyperprolactinaemia is secondary patients with a macroprolactinoma and most patients to hypothyroidism, treating the patient with thyroxine with a symptomatic microprolactinoma. The two most should normalise prolactin. commonly used dopamine agonists in Australia are cabergoline and bromocriptine. Both drugs should Drug-induced hyperprolactinaemia be started at a low dose and titrated up as required In patients with symptomatic drug-induced to minimise gastrointestinal adverse effects and hyperprolactinaemia the first consideration is whether