Hyperprolactinaemia: diagnosis and management

Raised prolactin levels and their management, including clinical presentations, recent research on dopamine agonists and when surgery may be indicated.

Coloured CR scan showing a side view of a tumour (orange) of the pituitary gland (Picture: Science Photo Library)
Coloured CR scan showing a side view of a tumour (orange) of the pituitary gland (Picture: Science Photo Library)

Hyperprolactinaemia is a raised level of prolactin in the blood. This hormone stimulates breast epithelial cell proliferation and induces milk production. However, excessive production of prolactin can lead to infertility and gonadal dysfunction.1

Prolactin suppresses gonadotrophin-releasing hormone (GnRH), resulting in suppression of ovulation in females and reduced testosterone levels and hypogonadism in males.

Causes

Prolactin levels are normally high during pregnancy and lactation. Levels also increase after meals, after exercise and during stress, as well as during sleep.

Abnormally high levels of prolactin may be caused by a prolactin-secreting pituitary tumour (prolactinoma), or by a non-secreting pituitary tumour that prevents dopamine (a prolactin release-inhibiting hormone) from reaching normal prolactin-producing cells.

Common and rarer causes

Prolactinomas are the most common cause of hyperprolactinaemia, although it has many different causes. They are benign tumours that account for 40% of pituitary tumours and are the most common type of pituitary adenomas. More than 90% are intrasellar microprolactinomas (<10mm) that seldom increase in size.

Common causes of hyperprolactinaemia1
  • Pituitary or hypothalamic tumour compressing stalk infiltration
  • Pregnancy or breast feeding
  • Co-secretion of prolactin in acromegaly
  • Hypothyroidism
  • Stress
  • Renal failure
  • Drugs

Primary hypothyroidism may lead to hyperprolactinaemia as a consequence of increased synthesis of thyrotropin-releasing hormone, which stimulates prolactin production.

Severe liver disease and chronic renal failure can also be causes. Head injuries, brain surgery and cranial radiotherapy can also cause hyperprolactinaemia.

Rarer causes
  • Head injury
  • Brain surgery and radiotherapy
  • Chronic renal failure
  • Severe liver disease
  • Sarcoidosis
  • Chest wall injury
  • Post-ictal

Drugs

The commonest medications to cause hyperprolactinaemia are antipsychotic drugs. Antidepressants, opiates, verapamil and oestrogens can also lead to hyperprolactinaemia.

Drugs that may cause hyperprolactinaemia
  • Antipsychotic drugs (phenothiazines, butyrophenones)
  • Dopamine antagonists (such as domperidone, metoclopramide)
  • Most other antiemetics (except cyclizine)
  • Oestrogen therapy (combined oral contraceptive pill)
  • Antidepressants (tricyclic antidepressants, MAO inhibitors)
  • Verapamil
  • Opiates
  • Cimetidine
  • Cocaine

Significance of prolactin levels

Mildly increased prolactin levels (400-600mu/L) may be physiological and asymptomatic but higher levels are usually pathological. Very elevated levels (above 5,000mu/L) usually imply a prolactin-secreting pituitary tumour. Most patients with a prolactinoma are women.

Clinical presentation

The clinical presentation in women is more obvious and so occurs earlier than in men. Women present most commonly with galactorrhoea (up to 90% of cases), menstrual disturbance, reduced fertility and libido. Men present with galactorrhoea (10-20% of men), loss of libido, erectile dysfunction and occasionally, reduced fertility and gynaecomastia.

In both sexes, a macroadenoma (>10 mm in diameter) can cause mass effects, which may result in visual-field defects or headache.

In both sexes, long-standing hyperprolactinaemia can lead to low bone mineral density with an increased risk of developing osteoporosis.

Investigations

A single measurement of prolactin level is usually adequate to diagnose hyperprolactinaemia. However, when the result is borderline, the test should be repeated. The pain/stress of venepuncture can actually elevate prolactin levels. Obviously, pregnancy must be excluded, if relevant. Renal and thyroid function tests should also be performed.

When other causes of hyperprolactinaemia have been excluded, the diagnosis of a prolactinoma is usually confirmed by a pituitary MRI scan.

Patients with macroadenomas that extend beyond the sella should undergo testing to exclude visual field defects, and also dynamic testing of the anterior pituitary function to exclude hypopituitarism.

Management

Treatment of hyperprolactinaemia will vary according to the cause - for example, a drug review may be required where it is drug-related. The aim of treatment is to improve symptoms and avoid the long-term effects of oestrogen deficiency in women or testosterone deficiency in men.

Dopamine agonists suppress prolactin in most patients, normalise gonadal function and stop galactorrhoea. In patients with prolactinomas, they reduce the size of the tumour.2

Cabergoline and bromocriptine are both ergot-based dopamine receptor agonists. Cabergoline is the first-line treatment for prolactinomas as it has greater efficacy in suppressing prolactin secretion. It is better tolerated and has a more convenient dosing regimen when compared with bromocriptine.

The MHRA issued a warning in the past about the safety of dopamine agonists for treating hyperprolactinaemia, due to concerns about an association with chronic pleuropulmonary, pericardial and retroperitoneal fibrosis, and particularly fibrotic valvular heart disease.3

However, recent studies have not shown a clinically significant association between the use of ergot-derived dopamine agonist drugs for the treatment of hyperprolactinaemia and valvulopathy.4,5

In some patients with microprolactinomas, withdrawal of treatment can be tried after three years, as microprolactinomas can spontaneously resolve, especially after the menopause or pregnancy. Transsphenoidal surgery is an option in infertile patients who cannot tolerate or are resistant to dopamine agonists. It may also be performed if a macroadenoma does not shrink with drug treatment.

Definitive treatment depends on the size of the tumour and the patient's wishes (including future fertility).

Prognosis

Over 90% of microadenomas remain stable or gradually reduce their secretion of prolactin. One third of patients with idiopathic hyperprolactinaemia improve without treatment. This is more common in women around their menopause.

However, recurrence rates of hyperprolactinaemia are as high as 80 per cent, and therefore the majority of patients require long-term medical treatment.

Key points
  • Hyperprolactinaemia can be physiological, caused by stress or exercise or occurring after meals.
  • Very elevated levels are usually due to a prolactin-secreting pituitary tumour.
  • Hyperprolactinaemia should be treated to restore gonadal function.
  • Medical treatment with dopamine agonists is the most common management.
  • Dr  Newson is a GP in the West Midlands

This is an updated version of an article that was first published in September 2009.

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References

  1. Capozzi A, Scambia G, Pontecorvi A, Lello S. Gynecol Endocrinol. 2015; 31(7): 506-10
  2. Mehta GU, Lonser RR. Neuro Oncol 2016 doi:10.1093/neuonc/now130
  3. MHRA Ergot-derived dopamine agonists: risk of fibrotic reactions. 2008
  4. Drake W, Stiles C, Bevan J et al. J Clin Endocrinol Metab 2016; 101(11): 4189-4194
  5. Vroonen L, Lancellotti P, Garcia MT, et al. Endocrine 2016; 55(1): 239-245.

Useful website:
Pituitary Foundation - www.pituitary.org.uk

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