Hyperprolactinaemia

Introduction

Prolactin is a hormone produced by the anterior pituitary gland, most commonly associated with lactation (milk production) in females. It is also produced in adipose (fat) tissue and hair follicles.

Hypoerprolactinaemia exists when the levels of prolactin in the blood are raised.

Hyperprolactinaemia can result in galactorrhea (milk production) and menstrual dysfunction in females, and reduced libido and erectile dysfunction in males.

The production of prolactin is controlled mainly by dopamine (an inhibitory effect). Prolactin production can be stimulated by dopamine antagonists, as well as physical stimulation by suckling of a baby at the breast. Other factors include thyrotropin release hormone (TRH) and vasoactive intestinal peptide (VIP).

Prolactin levels are raised physiologically during pregnancy and during times of stress.

The main pathological cause of raised prolactin is a prolactinoma – an otherwise benign adenoma of the anterior pituitary gland – which produces prolactin outside of the normal controls.

• Diagnosis of a prolactinoma is usually on the basis of prolactin levels and imaging of the brain
• Treatment usually involves the use of dopamine agonist medication and less commonly, surgical removal of the adenoma

Epidemiology and Aetiology

• Prevalence is about 0.25%
  • Increasing – thought to be drug related
• More common in women
  • M:F – 1 : 3.5
• Typical age of onset 25-45
• About half of cases are due to a pituitary adenoma
  • Usually a micro adenoma (<10mm diameter) – 90% of adenomas
  • Less commonly a macro adenoma (>10mm) – 10% of adeomas
  • Rarely, other types of pituitary tumour (nonfunctioning tumours) can cause hyperprolactinaemia through compression of the pituitary stalk – which decreases the flow of dopamine to the pituitary and thus reduces the dopamine suppression feedback
  • Multiple Endocrine Neoplasia (MEN) causes about 20% of cases of hyperprolactinaemia
• Drug – account for about 45% of cases
  • Anti-psychotics (e.h. haloperidol, risperidone)
  • Methyldopa
  • Opioids
  • Antidepressants including TCAs and SSRIs
  • Verapamil
• Hypothyroidism – about 5% of cases
  • Due to increased production of TRH
• Physiological causes
  • Pregnancy
  • Nipple stimulation
  • Stress
  • Excessive exercise
  • In neonates (<3m old)

Signs and Symptoms

• Galactorrhoea – milk production – is the most common symptoms
  • Can occur unman as well as women
  • Often intermittent and sporadic
• Women may also exhibit
  • Amenorrhoea or oligomenorrhea
  • Signs of hirsutism (male pattern hair growth, increased musculature) – which can make it difficult to distinguish from PCOS
• Men are more likely to present with:
  • Headaches
  • Visual disturbance
    • Consider checking visual fields for any signs of compression of the optic chasm
    • Bitemporal hemianopia (lateral visual fields) most commonly affected
  • Reduced libido
  • Erectile dysfunction
  • Symptoms in men tend to be more subtle and have slower onset

Investigations

• Prolactin level
  • >5x normal usually required to confirm diagnosis
  • Usually correlate to the size of the tumour – bigger tumour = greater prolactin level
• TFTs
  • To rule out hypothyroidism as the cause
• CT or MRI
  • To confirm the presence of adenoma
  • MRI preferred (higher resolution than CT, the pituitary gland is small!)

Management

The goal of management is to reduce symptoms and prevent complications. The most common complications are osteoporosis and visual loss.

For drug induced hyperprolactinaemia – cease the drug!

For hyperprolactinaemia caused by a tumour:

• Observation
  • Patients who are asymptomatic, with prolactin levels <100ng/ml can usually be observed with repeat prolactin levels every 3 months, and repeat imaging every 12 months
  • Prolactin levels often return to normal after several years
  • In women, 30% of cases spontaneously resolve
• Medical management
  • Dopamine agonists are mainstay of treatment (e.g. bromocriptine 1.25 – 5 mg BD, or cabergoline 0.25 – 1mg weekly or twice weekly)
    • Cabergoline has been shown to be more effective than bromocriptine
    • Have been associated with valvular heart disease when given long-term in high doses (usually only seen in Parkisnon’s disease, because doses used in hyperprolactinaemia are lower)
    • Consider echocardiogram monitoring
    • Other side effects include psychiatric effects – such as increased impulsive behaviour, and rarely, psychosis
  • Consider exogenous oestrogen for women who have low estradiol levels
    • Risk for tumour growth is very low
  • Dopamine agonists usually result in shrinkage of the adenoma
  • Treatment is required long term, but particularly for microadenomas, remission may occur if treatment is ceased. Advice is to consider a trial of treatment cessation after 3 years if prolactin levels are normal and the tumour has decreased in size. It important to continue to monitor the prolactin levels and the tumour size after cessation of treatment
  • They will not shrink a “nonfunctioning tumour” – these are tumours which cause hyperprolactinaemia through compression of the pituitary stalk. 
• Surgery
  • Considered for macroadenomas – particularly if they don’t shrink with medical therapy
• Radiation therapy
  • Considered for large nonfunctioning tumours to shrink them
  • Usually a last resort
  • Hypopituitarism is common – onset usually occurs several years after therapy

Indications for treatment

Women

• Amenorrhoea (or oligomenorrhoea)
  • If prolonged, increases the risk of osteoporosis
• Hirsutism
• Low libido
• Galactorrhoea (if bothersome)

Men

• Hypogonadism
• Erectile dysfunction
• Low libido
• Infertility

Pregnancy

• During pregnancy, adenomas can increase in size. Bother bromocriptine and cabergoline are safe to use during pregnancy
• Consider ceasing treatment during breast feeding

 

References

• Galactorrhoea – Merck Manual
• Hyperprolactinaemia and Prolactinoma – patient.info
• Murtagh’s General Practice. 6th Ed. (2015) John Murtagh, Jill Rosenblatt
• Oxford Handbook of General Practice. 3rd Ed. (2010) Simon, C., Everitt, H., van Drop, F.

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