Hyperprolactinaemia and prolactinoma

What is hyperprolactinaemia?¹

Hyperprolactinaemia is defined as a raised level of prolactin in the blood. Note that prolactin levels are normally high during pregnancy and lactation, and also in severe stress.

Prolactinomas are benign, prolactin-producing tumours of the pituitary gland.

Prolactin is produced in the lactotroph cells of the anterior pituitary gland, under inhibitory control by dopamine. Prolactin production can be stimulated by various factors: dopamine receptor antagonists, thyrotropin-releasing hormone (TRH), vasoactive intestinal peptide (VIP) or epidermal growth factor, and by suckling an infant.²

Prolactin is also produced outside the pituitary gland (extra-pituitary prolactin), including hair follicles, adipose tissue and immune cells.

Effects of raised prolactin

• In women, hyperprolactinaemia inhibits gonadotrophin secretion (follicle-stimulating hormone (FSH) and luteinising hormone (LH)), leading to menstrual dysfunction. It also may cause galactorrhoea.

• In men, hyperprolactinaemia has a direct, reversible effect on the hypothalamus, causing secondary hypogonadism which results in reduced libido and erectile dysfunction.

Causes of hyperprolactinaemia (aetiology)^{1 3 4 5 6}

Common causes are prolactinomas, hypothyroidism, and drug-induced (eg, antipsychotics).

High levels of prolactin may be caused directly by a prolactin-secreting pituitary tumour; or indirectly by a non-secreting pituitary tumour that prevents dopamine (which inhibits prolactin release) from reaching the normal prolactin-producing cells.

'Physiological' causes

• Pregnancy.

• Puerperium.

• Breast stimulation.

• Stress - physical (including excessive exercise) or psychological - including venepuncture.

• Macroprolactinaemia:
  

  • This refers to prolactin of high molecular mass, mostly complexes of monomeric prolactin with immunoglobulins (prolactin autoantibody complexes).

  • These larger molecules have low bioactivity and a prolonged clearance rate similar to that of immunoglobulins.

  • Depending on the immunoassay used, macroprolactinaemia may account for 25% of laboratory documented hyperprolactinaemia.

  • Consider this cause in an asymptomatic patient with hyperprolactinaemia and consult laboratory staff (see 'Investigations', below).

Intracranial causes

• Pituitary tumours:
  

  • 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.

  • Prolactinomas:
    

    • Microprolactinomas (the most common, approximately 90%).

    • Macroprolactinomas (>10 mm size - approximately 10%).

    • Pituitary or hypothalamic tumour compressing the pituitary stalk - eg, craniopharyngioma.

    • Prolactinomas occur in about 20% of patients with multiple endocrine neoplasia type 1 (MEN1).

• Head injury (eg, due to disruption of the pituitary stalk).

• Brain surgery and radiotherapy.

• Post-ictal - within hours of a seizure.

Endocrine and metabolic causes

• Hypothyroidism (due to increased synthesis of TRH).

• Cushing's syndrome.

• Liver cirrhosis.

• Polycystic ovary syndrome.

• Coeliac disease (possibly).⁷

Drugs

• Dopamine receptor antagonists - eg, domperidone, metoclopramide, neuroleptics/anti-psychotics:

  • 40-90% of patients taking typical antipsychotics - eg, phenothiazines or butyrophenones.

  • 50-100% of patients taking risperidone.

• Dopamine-depleting agents - eg, methyldopa.

• Antidepressants - eg, tricyclic antidepressants, monoamine-oxidase inhibitors, serotonin reuptake inhibitors.

• Verapamil (affects 8.5% of patients).

• Opiates.

• Protease inhibitors.

• Bezafibrate.

• Omeprazole.

• H₂-receptor antagonists.

• Oestrogens, anti-androgens.

• Cyproheptadine.

• Cocaine.

Other causes

• Chest wall surgery or trauma.

• Sarcoidosis.

• Langerhans' cell histiocytosis.

• Idiopathic - a diagnosis of exclusion.

Prolactinoma classification³

• Microadenomas: <10 mm.

• Macroadenomas: >10 mm.

• Giant pituitary adenomas: >40 mm.

• Malignant prolactinomas (very rare).

Some pituitary tumours may occur as part of a clinical syndrome. In multiple endocrine neoplasia type 1 (MEN1), an autosomal-dominant genetic disorder, pituitary adenomas (most often prolactinomas) occur in association with parathyroid tumours and pancreatic islet cell tumours.

Hyperprolactinaemia epidemiology

Prevalence

Hyperprolactinaemia is a relatively common problem and appears to be increasing. The prevalence of hyperprolactinaemia in a UK study was 0.23%.⁸ The rising prevalence is thought to be due to a combination of an increase in testing and an increase in drug-related causes.

In the same study the cause of hyperprolactinaemia was:

• Pituitary disorder 45.9%.

• Drug-induced 45.9%.

• Macroprolactin 7.5%.

• Hypothyroidism 6.1%.

• Idiopathic 15.0%.

Overall incidence of hyperprolactinaemia was 3.5 times higher in women than in men and the highest rates were in women aged 25-44.

Prolactinoma²

• Prolactinomas are the most common hormone-secreting pituitary tumours: 40% of all pituitary tumours are prolactinomas.

• Prevalence is variously reported to be from 6-50 per 100,000 population.⁴

• A possible explanation for the higher incidence of prolactinomas in premenopausal women is higher rates of diagnosis, as in this group there will be more obvious symptoms (oligomenorrhoea or infertility).³

• Giant prolactinomas are rare (2-3% of all prolactinomas) but are 9 times more common in men than in women.⁹

• Prolactinomas are very rare in children, representing 2% of all intracranial tumours.¹⁰

Risk factors

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

Hyperprolactinaemia symptoms^{1 3 4}

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

• Women:
  

  • Common symptoms of are amenorrhoea, oligomenorrhoea, anovulatory cycles and galactorrhoea.

  • They may also have infertility, hirsutism and reduced libido.

• Men:
  

  • The hormonal effects of raised prolactin levels are subtle and develop slowly.

  • Endocrine symptoms are reduced libido and erectile dysfunction, reduced beard growth, gynaecomastia and galactorrhoea and azoospermia.

  • Presentation is often late, and osteoporosis and atherosclerosis, as an indirect result of hypogonadism, may already be present at diagnosis.

• Children:¹⁰
  

  • Growth failure and delayed puberty are possible presentations in children.

  • (NB: 60% of normal adolescent boys develop pubertal gynaecomastia).

Symptoms due to tumour size (usually macroprolactinomas):

• Headache.

• Visual disturbances (classically, a bitemporal hemianopia (lateral visual fields) or upper temporal quadrantanopia).

• Cranial nerve palsies.

• Symptoms and signs of hypopituitarism.

• Rarely, cerebrospinal fluid (CSF) leak or secondary meningitis.

Investigations^{3 4 11}

Initial investigations

• TFTs.

• Exclude pregnancy.

• Basal serum prolactin:
  

  • Initial test can be taken at any time of day but testing should avoid excessive venepuncture stress.

  • If prolactin is mildly elevated (eg, 400-1000 mU/L, normal range <400 mU/L), it should be repeated before referral.

  • Dynamic prolactin stimulation tests, such as the TRH test, are not required. Measurement of serum prolactin on three separate occasions (at least two hours after rising and when the patient is rested) is sufficient.

  • A prolactin level >5000 mU/L usually indicates a true prolactinoma.

Further investigations

• Visual field testing.

• Pituitary imaging (preferably MRI).

• Assessment of pituitary function.

Diagnostic pitfalls

• Macroprolactinaemia (see 'Aetiology', above) - suspect this if there is a high prolactin level with no symptoms (eg, normal menstrual cycles). The serum sample should be treated with polyethylene glycerol (PEG) to precipitate out the macroprolactin so that free prolactin concentration can be assessed.

• The assay for prolactin has a 'high-dose hook effect' - there may be a falsely low prolactin result due to the behaviour of the assay. Therefore, if a large tumour is found in conjunction with relatively low prolactin levels, the laboratory should perform serial dilutions of the serum to exclude this effect.

Hyperprolactinaemia treatment and management^{1 3 5}

General

Treat the underlying cause if feasible.

The goals of treatment are:

• Relieve symptoms (if present).

• Prevent complications:
  

  • Prevent osteoporosis (due to hypogonadism).

  • For macroprolactinomas, shrink the tumour in order to reduce pressure effects - eg, vision loss.

• Restore fertility and sexual function.

Management of prolactinoma^{12 13}

Asymptomatic patients with hyperprolactinaemia +/- a prolactinoma do not have an absolute requirement for treatment; 90-95% of of prolactinomas never increase in size. Indications for treatment are:

• Adverse effects of tumour size.

• Adverse effects of hyperprolactinaemia.

Treat with dopamine agonists: cabergoline, bromocriptine or quinagolide. (Pergolide is not licensed for treating hyperprolactinaemia in the UK.)

• These reduce prolactin levels, allowing oestrogen levels to normalise.

• They lead to shrinkage of tumours in the majority of patients.

• They are highly effective in most patients.

• They may need to be continued on a long-term basis although withdrawal of treatment can be trialled after three years, but follow-up is essential.

• Cabergoline has been shown to be more effective than bromocriptine and, as it has a very long half-life, only needs be taken once or twice a week.

NB: with dopamine agonists (DAs), cautions are:¹⁴

• Exclude cardiac valve fibrosis and pulmonary fibrosis before starting treatment, then monitor for cardiac/retroperitoneal/pulmonary fibrosis (for details see the British National Formulary). However, there is thought to be less risk when DAs are used for this indication than in Parkinson's disease, as the doses involved are much lower.¹²

• Be aware that excess or sudden sleepiness is a possible side-effect as are impulse control disorders, including pathological gambling and binge eating.

• Hypotensive reactions can occur when starting treatment.

If DAs are ineffective, further treatment is by the following:

• Surgery - to reduce tumour size.

• Radiotherapy - rarely used due to significant adverse effects and lack of effectiveness.

• Women with hypogonadism and microprolactinomas who do not wish to become pregnant may be treated for their hypogonadism with oestrogen-containing contraception, as long as their prolactin levels (checked annually) do not increase substantially and there is no evidence of tumour enlargement.

During pregnancy

• There is a small risk of tumour enlargement, particularly with macroadenomas (one third will enlarge). Refer urgently if there are headaches or visual disturbance.

• Patients should be under an endocrinologist (ideally for pre-conception counselling too).

• Depending on the individual situation, management may be:

  • Omitting DAs for the duration of pregnancy and during lactation.

  • If treatment is required, bromocriptine and cabergoline appear to be safe during pregnancy - bromocriptine is the most 'tried and tested' in this scenario.

Drug-induced hyperprolactinaemia

This may be treated by withdrawing the drug (if feasible), with oestrogen/testosterone replacement, or with a cautious trial of a DA.¹⁵

Macroprolactinaemia

This condition usually requires no treatment and does not generally cause infertility.²

Good practice points

• Refer to hospital urgently if vision deteriorates.

• Remember that successful treatment usually restores fertility - so contraception must be used in patients wishing to avoid pregnancy.

• Ask about erectile function. Provide reassurance that it is part of the disease and that it can be treated.

• Prevent osteoporosis.

Complications¹²

These will depend on the underlying cause, endocrine function and the tumour size (if due to a pituitary tumour). Possible complications are:

Complications of hypogonadism

• Osteoporosis:

  • Bone loss occurs in about 25% of women with hyperprolactinaemia and doesn't necessarily improve when prolactin levels return to normal.⁴

  • A small retrospective study of men with prolactinoma demonstrated significant bone loss whether treatment was with surgery or medical therapy. The authors suggest that a prolactinoma, even when adequately treated, increases the risk of osteoporosis in men by about 5 times.¹⁶

• Reduced fertility.

• Erectile dysfunction, and infertility.

Complications relating to tumour size

• Visual loss.

• Headache.

• Pituitary apoplexy:¹²
  

  • This is the sudden onset of neurological symptoms (headache, visual symptoms, altered mental status, meningism) and hormonal dysfunction due to acute haemorrhage or infarction of a pituitary gland.

  • It is uncommon.

  • More likely in larger lesions.

  • May develop in patients with giant prolactinomas if their tumours do not reduce in size substantially with a chosen form of therapy.

• CSF rhinorrhoea may occur with rapid size reductions in large prolactinomas that are highly sensitive to DA therapy.

• Very rarely, prolactinomas may be malignant.

Prognosis¹²

This depends on the underlying cause.

In women microprolactinomas spontaneously resolve in around a third, especially after the menopause or pregnancy. Treatment should be discontinued intermittently to see if it is still needed. The treatment dose may be decreased slowly over time. It is reasonable to attempt DA withdrawal in all patients who have been treated for three years, if prolactin levels are normal and the tumour volume has markedly reduced.¹³

Five-year recurrence rates depend on the presence or absence of visible adenoma on MRI:

• Macroprolactinoma:

  • Without visible remnant 33%.

  • With visible remnant 78%.

• Microprolactinoma:

  • Without visible remnant 26%.

  • With visible remnant 42%.

Follow-up to detect recurrence of hyperprolactinaemia and tumour enlargement is essential.