Hyperprolactinaemia
Key points
- Hyperprolactinaemia: an elevated serum prolactin, from physiological, drug-induced, or pathological causes, most importantly a prolactinoma - the commonest functioning pituitary tumour.
- Mechanism: prolactin secretion is normally under constant inhibitory control by hypothalamic dopamine. Anything that reduces dopamine tone, blocks its receptor, or autonomously secretes prolactin raises the level.
- Causes: prolactinoma, physiological (pregnancy, breastfeeding, stress, sleep), drugs (antipsychotics, metoclopramide, domperidone), primary hypothyroidism, stalk compression by any large non-functioning tumour, renal failure and PCOS.
- Presentation in women: oligo/amenorrhoea, galactorrhoea, infertility, reduced libido and, if prolonged, osteoporosis from oestrogen deficiency.
- Presentation in men: erectile dysfunction, reduced libido, gynaecomastia and infertility. Galactorrhoea is less noticeable, so men often present later with mass effect from a macroprolactinoma.
- Interpreting the level: mild rises (under around 1,000 mU/L) suggest stress, drugs or stalk effect; very high levels, often over 5,000 mU/L, suggest a macroprolactinoma.
- Before diagnosing a prolactinoma: exclude pregnancy, hypothyroidism (TSH) and renal failure, and consider macroprolactin as a cause of a spuriously high result.
- Management: dopamine agonists (cabergoline or bromocriptine) are first line even for large tumours - they shrink the tumour and normalise prolactin in the majority. Surgery is reserved for resistant disease or acute visual compromise.
Introduction
Prolactin is secreted by lactotroph cells of the anterior pituitary and its principal physiological role is to stimulate milk production during lactation. Unlike every other anterior pituitary hormone, prolactin secretion is under tonic (constant) inhibitory control by hypothalamic dopamine, which travels down the pituitary stalk to suppress lactotroph activity.1 This has an important practical consequence: anything that interrupts dopamine's inhibitory signal, rather than an activating signal, raises prolactin - which is why so many unrelated conditions and drugs can cause hyperprolactinaemia.
Prolactinoma is the commonest functioning pituitary adenoma, and hyperprolactinaemia in general is the commonest pituitary hormone disturbance encountered in clinical practice.1 Most prolactinomas in women are diagnosed as microadenomas (under 1 cm), because symptoms of oestrogen deficiency and menstrual disturbance appear early; men are more often diagnosed with macroadenomas (1 cm or more), because the equivalent symptoms in men attract less attention.
Causes
Prolactin can be raised for physiological, pharmacological, or pathological reasons, and a systematic approach is needed before assuming a prolactinoma.
| Category | Cause | Notes |
|---|---|---|
| Pathological - pituitary | Prolactinoma | The commonest functioning pituitary tumour; secretes prolactin autonomously |
| Stalk compression ('stalk effect') | Any large non-functioning pituitary adenoma (or other sellar/suprasellar mass) can compress the pituitary stalk, interrupting dopamine delivery and causing a mild-to-moderate rise in prolactin, even though the tumour itself does not secrete it | |
| Physiological | Pregnancy, breastfeeding, stress (including venepuncture itself), exercise, sleep, sexual intercourse, nipple stimulation | Usually mild and transient; repeat the test under calmer conditions if suspected |
| Drug-induced | Antipsychotics (especially risperidone, amisulpride, first-generation agents), metoclopramide, domperidone, other dopamine antagonists, some antidepressants, oestrogens, opioids, verapamil | The commonest cause of a pathologically raised prolactin encountered in general practice; all act by blocking dopamine D2 receptors on the lactotroph4 |
| Endocrine | Primary hypothyroidism | Raised TRH (compensating for low thyroid hormone) also stimulates prolactin release - always check TSH |
| Polycystic ovary syndrome (PCOS) | Mildly raised prolactin is seen in a minority of patients | |
| Renal/hepatic | Chronic kidney disease | Reduced renal clearance of prolactin |
| Chest wall | Chest wall trauma, surgery, or herpes zoster | Stimulates the nipple stimulation reflex arc |
| Artefact | Macroprolactinaemia | A large, biologically inactive prolactin-immunoglobulin complex that is measured by standard assays but does not cause symptoms - see below |
Clinical features
Prolactin excess causes symptoms in two ways: directly, through galactorrhoea, and indirectly, because prolactin suppresses GnRH pulsatility, causing secondary hypogonadism (low LH/FSH and low sex steroids). A macroprolactinoma can additionally cause mass effect (headache, visual field loss) as described for pituitary tumours generally.
| Sex | Features |
|---|---|
| Women | Oligomenorrhoea or amenorrhoea, galactorrhoea (spontaneous or expressible milky nipple discharge, uni- or bilateral), infertility from anovulation, reduced libido, and, if hypogonadism is prolonged, osteoporosis from oestrogen deficiency |
| Men | Erectile dysfunction, reduced libido, gynaecomastia, infertility from impaired spermatogenesis, and loss of body hair. Galactorrhoea is uncommon and often unnoticed because the male breast is not primed by oestrogen |
Investigations
Confirm and interpret the prolactin level
Take a single fasting sample, avoiding recent breast examination, exercise or stress where possible, and repeat if mildly raised before pursuing further investigation.1 The magnitude of the result is itself diagnostically useful:
| Level | Likely cause |
|---|---|
| Mildly raised (roughly up to 1,000 mU/L) | Physiological cause, drug effect, stalk compression, hypothyroidism, PCOS or renal impairment - a prolactinoma is less likely |
| Moderately raised (roughly 1,000-5,000 mU/L) | Microprolactinoma, or a more marked drug effect (particularly antipsychotics, which can occasionally push levels quite high) |
| Markedly raised (often over 5,000 mU/L) | Macroprolactinoma - a very high level in the presence of a large pituitary mass is essentially diagnostic |
Exclude secondary causes
- Pregnancy test in any woman of reproductive age
- TSH - to exclude primary hypothyroidism
- U&Es - to exclude renal impairment
- Full drug history - review for dopamine-antagonist drugs; if a causative drug can safely be stopped or switched, prolactin is rechecked afterwards rather than proceeding straight to imaging
Macroprolactin
Macroprolactin is a large complex of prolactin bound to immunoglobulin that is detected by standard prolactin immunoassays but has little biological activity and does not cross capillary walls effectively.1 It is a recognised cause of a spuriously raised prolactin in an asymptomatic patient. Where hyperprolactinaemia is found without any of the expected symptoms, the laboratory can perform a polyethylene glycol (PEG) precipitation test - if most of the prolactin precipitates out as macroprolactin, no further endocrine work-up is needed.
Imaging
If secondary causes are excluded and the prolactin remains raised, arrange MRI pituitary to look for a prolactinoma or a non-functioning tumour causing stalk effect.2 Formal visual field testing is required if imaging shows a macroadenoma close to the optic chiasm. The rest of the anterior pituitary profile (as for any pituitary mass) should also be checked to screen for co-existing hypopituitarism or, rarely, co-secretion of another hormone.
Management
Management depends on the underlying cause.
Prolactinoma
Dopamine agonists are first-line treatment for essentially all prolactinomas, including large macroadenomas with mass effect - this is a genuinely distinctive point compared with other functioning pituitary tumours, where surgery is usually first line.2,3 Dopamine agonists restore the normal inhibitory tone on the lactotroph, which both suppresses prolactin secretion and, characteristically, shrinks the tumour itself, often substantially and within weeks.
| Drug | Notes |
|---|---|
| Cabergoline | First choice for most patients - more effective, better tolerated and requires less frequent dosing (once or twice weekly) than bromocriptine4 |
| Bromocriptine | Preferred choice when pregnancy is being planned or occurs, because it has a longer track record of safety data in pregnancy; also an option where cabergoline is not tolerated |
With treatment, prolactin normalises and the tumour shrinks in the large majority of patients, menstruation and fertility are usually restored in women, and visual field defects typically improve as the tumour regresses. Treatment is often continued for at least 2 years before a cautious, monitored dose reduction or withdrawal is considered, particularly for microprolactinomas that have normalised on imaging.
Surgery
Trans-sphenoidal surgery is reserved for:2
- Resistance or intolerance to dopamine agonists
- Acute visual compromise that is not improving rapidly on medical therapy
- Patient preference after full discussion, in selected cases
Other causes
- Drug-induced - stop or switch the causative drug where clinically safe to do so (never stop an antipsychotic unilaterally; discuss with psychiatry), and recheck prolactin
- Hypothyroidism - treat with levothyroxine; prolactin normalises as thyroid function is corrected
- Stalk effect from a non-functioning tumour - treat the underlying mass as for a non-functioning adenoma; the prolactin rise resolves once the compression is relieved
- Macroprolactinaemia - no treatment required; reassure the patient
Pregnancy
Oestrogen physiologically stimulates lactotroph growth, so pregnancy carries a small risk of prolactinoma growth, higher for macroadenomas than microadenomas.2 Dopamine agonists are usually stopped once pregnancy is confirmed in women with a microprolactinoma, with clinical monitoring for symptoms of tumour growth (headache, visual disturbance) through pregnancy. Women with a macroprolactinoma are monitored more closely, sometimes with visual field testing each trimester, and the dopamine agonist may need to be continued or restarted if the tumour grows.
Complications
- Infertility - from anovulation in women and impaired spermatogenesis in men, usually reversible with treatment
- Osteoporosis - from prolonged oestrogen or testosterone deficiency if hypogonadism goes untreated; consider bone density assessment in longstanding disease
- Mass effect - visual field loss and headache from a macroprolactinoma, as for pituitary tumours generally
- Hypopituitarism - from compression of the surrounding normal gland by a macroprolactinoma
- Psychological impact of infertility, galactorrhoea and sexual dysfunction, which should not be overlooked
Red flags
Prognosis
The prognosis for hyperprolactinaemia is generally excellent. Most microprolactinomas remain stable or shrink with dopamine agonist therapy and rarely progress to macroadenomas. Dopamine agonists normalise prolactin and substantially shrink the tumour in the large majority of patients, restoring fertility and reversing galactorrhoea and hypogonadal symptoms.2,3 Even large macroprolactinomas with visual field loss often respond well enough to medical therapy alone that surgery can be avoided. Relapse after stopping treatment occurs in a proportion of patients, particularly those with larger tumours or persistently visible disease on imaging, so withdrawal is only attempted after a prolonged period of normal prolactin and radiological stability, with ongoing monitoring.
References
- Melmed S, Casanueva FF, Hoffman AR et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism. 2011. Available here
- Society for Endocrinology. Clinical guidance - hyperprolactinaemia and prolactinoma. Available here
- NICE Clinical Knowledge Summaries. Galactorrhoea. Available here
- BNF. Cabergoline and bromocriptine - indications and dosing. Available here
This article is written for revision and education. It is not clinical guidance and must not be used to make decisions about the care of a patient. Always check current NICE guidance and local protocols.