This is defined as a raised level of prolactin in the blood:

• Prolactin levels are normally high during pregnancy and lactation, but also in severe stress.
• Abnormally high levels of prolactin may be caused by a prolactin-secreting pituitary tumour or by a non-secreting pituitary tumour that prevents dopamine (prolactin release-inhibiting hormone) from reaching normal prolactin-producing cells.

Aetiology

Epidemiology

Prevalence

This is a common problem and is more common in women. The prevalence of hyperprolactinaemia ranges from 0.4% in an unselected normal adult population to as high as 9-17% in women with reproductive disorders.¹

Risk factors

There is a significant risk of tumour enlargement in pregnancy, particularly with macroadenoma.

Prolactinoma classification

• Microadenomas: <10 mm
• Macroadenomas: >10 mm
• Giant pituitary adenomas: >40 mm
• Malignant prolactinomas (rare)

Some pituitary tumours may occur as part of a clinical syndrome. In multiple endocrine neoplasia type 1 (MEN 1), an autosomal dominant genetic disorder, pituitary adenomas (most often prolactinomas) occur in association with tumours of the parathyroid and pancreatic islet cells.

Presentation

The behaviour of prolactin-secreting tumours is determined by their size at presentation; microprolactinomas rarely expand to become macroprolactinomas.

Symptoms

• Growth failure and delayed puberty are possible presentations in children.
• Up to 90% of women and 10-20% of men present with galactorrhoea.
• Headaches may be noted.
• Women frequently complain of oligomenorrhoea, amenorrhoea, or irregular menstrual cycles (95%), infertility, hirsutism and reduced libido - this allows the diagnosis to be made early.
• In men, prolactinomas tend to present late with erectile dysfunction and loss of libido - the hormonal effects of raised prolactin levels are subtle and develop slowly.

Signs

• With macroadenomas mass effects are seen - visual field defects (classically a bitemporal hemianopia or upper temporal quadrantanopia) or hypopituitarism. This is more common in men.
• Cranial nerve palsies may be seen.
• Occasionally there may be a cerebrospinal fluid (CSF) leak or secondary meningitis.

Investigations

• Check visual fields.
• Serum prolactin: note that the stress of taking a sample can cause mild increase so there is a need to check 2-3 times, preferably using an indwelling cannula after half an hour.
• There is a good correlation between the size of the prolactinoma and the degree of elevation of the serum prolactin:
  • ≥3,000 mU/l - either microprolactinoma or macroadenoma.
  • ≥6,000 mU/l - macroprolactinoma.
  • 3,000-6,000 mU/l - either macroprolactinoma or macroadenoma.
• To differentiate between microprolactinoma/macroadenoma, perform an MRI scan and then treat with a dopamine agonist and re-scan after 6 weeks; microprolactinoma will shrink, but not the macroadenoma (needs surgery).
• Thyroid and renal function - exclude hypothyroidism.
• Can use dynamic testing, i.e. response to hypothalamic/pituitary triggers, e.g. thyrotropin-releasing hormone (TRH).²
  • Dopamine antagonist test - 10 mg metoclopramide IV - at least 2 x rise in prolactin when not caused by prolactinoma.
  • Blunted prolactin response and/or marked rise in TSH when due to prolactinoma.
  • TRH test - TRH 200 μg IV measure prolactin at 0, 20, 60 minutes. Blunted rise in prolactin with prolactinomas.
  • Of these, the prolactin response to a dopamine agonist is the most clinically useful.³
• Idiopathic hyperprolactinaemia - around 50% remain stable, 33% normalise and 10-15% show further rise in prolactin levels
• MRI scan - microadenomas usually appear within the pituitary as hypointense lesions on T1-weighted images. If none seen, use gadolinium contrast enhancement.

Management

Many hormonally nonfunctioning pituitary tumours, causing no mass effects can be safely managed by follow-up surveillance alone. Where appropriate, treatment should be related to any underlying condition. The following suggestions refer specifically to the management of prolactinoma.

Microadenomas can be safely monitored, with no active management unless oral contraceptives or testosterone are needed for hypogonadism.^4,5

Pharmacological

• In both microprolactinomas and macroprolactinomas the aim of treatment is to restore gonadal function.
• Dopamine agonist suppresses prolactin in most patients and normalises gonadal function and stops galactorrhoea.
• In macroprolactinomas there is also a need to reduce the tumour size and prevent its expansion (it will continue to expand and lead to pressure effects if untreated).
• Most patients are treated medically with cabergoline, quinagolide or bromocriptine; all reduce prolactin levels, allow oestrogen levels to rise and greatly reduce the size of the tumour.
• Cabergoline is more effective than bromocriptine (83% vs 59% normalisation of prolactin in microprolactinoma).⁶
• The treatment needs to be continued in the long-term, although recent studies have indicated successful withdrawal of these agents in a subset of patients, challenging the previous belief that medical therapy is lifelong.⁴
• These drugs can be associated with some dizziness and nausea. There is also a risk of excessive daytime sleepiness.
• The Committee on Safety of Medicines (CSM) has also advised that these drugs are associated with pulmonary, retroperitoneal and pericardial fibrosis. Although there is insufficient evidence to support an association between treatment with cabergoline and clinically significant valvular heart disease, mild and moderate tricuspid regurgitation, aortic valve calcification and mitral valve tenting have been described.⁷ Erythrocyte sedimentation rate (ESR) and serum creatinine should be monitored, as should CXR and lung function. Echocardiography is recommended before starting dopamine agonists and during treatment. The frequency should be dictated by the dose.
• This can be limited by taking the medicine last thing at night and by starting at a low dose.
• Tumour shrinkage is variable and needs careful monitoring.

Surgical

• Surgery is used to reduce tumour size, but much more rarely.
• It is only indicated for patients who do not respond to or cannot tolerate a dopamine agonist.⁸
• With macroprolactinomas there is only 30% cure rate.
• With microprolactinomas there is >80% cure rate, but risk of hypopituitarism and recurrence make it second choice.

Radiotherapy

This is used to reduce the chance of recurrence.

• Pituitary irradiation produces reduction in prolactin over years in most patients and needs to be concurrent with dopamine agonist treatment.
• It may be useful for macroprolactinomas, after the tumour has been shrunk away from the chiasm.

However, pituitary irradiation can cause hypopituitarism.

Good practice points

• Refer to hospital urgently if vision deteriorates.
• Remember that successful treatment usually results in restoration of fertility (particularly in microprolactinomas).
• Patients may be predisposed to osteoporosis.
• Ask about erectile function. Reassure that it is part of the disease and that it can be treated.

Pregnancy

• Bromocriptine may be necessary to enable ovulation and conception; as a result, it is often taken in early pregnancy until the pregnancy is known and after that cessation is usually advised.⁴
• There is no evidence of any increased incidence of malformation or miscarriage with bromocriptine use and concomitant pregnancy.⁹
• However, there are less data available on cabergoline.
• During pregnancy there is a slight risk of tumour enlargement, particularly in patients with macroadenomas.
• Any patient who experiences severe headaches or visual disturbances should be referred back to their specialist.

Prognosis

Microprolactinoma spontaneously resolve in around a third of women, especially after the menopause or pregnancy. Treatment should be discontinued intermittently to see if it is still needed.

Dose may be decreased slowly over time.

Document references

1. Biller BM, Luciano A, Crosignani PG, et al; Guidelines for the diagnosis and treatment of hyperprolactinemia. J Reprod Med. 1999 Dec;44(12 Suppl):1075-84. [abstract]
2. Le Moli R, Endert E, Fliers E, et al; Evaluation of endocrine tests. A: the TRH test in patients with hyperprolactinaemia. Neth J Med. 2003 Feb;61(2):44-8. [abstract]
3. Sawers HA, Robb OJ, Walmsley D, et al; An audit of the diagnostic usefulness of PRL and TSH responses to domperidone and high resolution magnetic resonance imaging of the pituitary in the evaluation of hyperprolactinaemia. Clin Endocrinol (Oxf). 1997 Mar;46(3):321-6. [abstract]
4. Gillam MP, Molitch ME, Lombardi G, et al; Advances in the treatment of Prolactinomas. Endocr Rev. 2006 May 26. [abstract]
5. Molitch ME; Drugs and prolactin. Pituitary. 2008 Apr 11. [abstract]
6. Webster J, Piscitelli G, Polli A, et al; A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group. N Engl J Med. 1994 Oct 6;331(14):904-9. [abstract]
7. Martin NM, Tan T, Meeran K; Dopamine agonists and hyperprolactinaemia. BMJ. 2009 Mar 3;338:b381. doi: 10.1136/bmj.b381.
8. Mah PM, Webster J; Hyperprolactinemia: etiology, diagnosis, and management. Semin Reprod Med. 2002 Nov;20(4):365-74. [abstract]
9. Webster J; A comparative review of the tolerability profiles of dopamine agonists in the treatment of hyperprolactinaemia and inhibition of lactation. Drug Saf. 1996 Apr;14(4):228-38. [abstract]

Internet and further reading

• Segu VB; Prolactinoma, eMedicine, Sep 2009
• Mulinda JR; Pituitary Macroadenomas, eMedicine, Mar 2010
• Pituitary Disease Factfile for General Practitioners, The Pituitary Foundation

Acknowledgements