Hyperprolactinaemia

Elevated circulating prolactin, arising from a range of physiological, pharmacological and pathological causes. Prolactinoma (a prolactin secreting pituitary adenoma) is the commonest pathological pituitary cause.

However, a broad differential must be systematically considered before a specific pathological diagnosis is confirmed:

• physiological causes (pregnancy, breastfeeding, stress)
• medication effects (particularly dopamine antagonist antipsychotics and certain antiemetics, given the normal inhibitory dopaminergic control of prolactin secretion)
• primary hypothyroidism (through elevated thyrotropin releasing hormone driving prolactin co-secretion)
• the "stalk effect"

The "stalk effect" is compression of the pituitary stalk by any sellar or suprasellar mass lesion. This disrupts normal inhibitory dopaminergic transport from the hypothalamus and produces mild, secondary prolactin elevation. The mass need not itself be a prolactin secreting tumour.

Pathophysiology and the stalk effect

• Prolactin secretion is normally under predominant tonic inhibitory control from hypothalamic dopamine. Dopamine is delivered via the pituitary portal circulation through the pituitary stalk.
• Any process disrupting this inhibitory pathway can produce hyperprolactinaemia. One cause is a prolactin secreting tumour producing autonomous excess secretion. Another is an unrelated sellar or suprasellar mass compressing the stalk and disrupting dopamine delivery (the "stalk effect").
• The distinction matters because the clinical and management implications differ.
• The degree of prolactin elevation is an important clue to the mechanism. Very high levels (generally above 5000 mU per litre, or the locally relevant substantially elevated threshold) strongly support a significant prolactin secreting macroprolactinoma.
• More modest elevation is compatible with several causes: the stalk effect from a non-functioning or other sellar mass, medication effect, or a small microprolactinoma. The degree of elevation, considered with imaging findings, supports the distinction.

• In women, hyperprolactinaemia characteristically produces oligomenorrhoea or amenorrhoea. This reflects prolactin mediated suppression of normal gonadotropin releasing hormone pulsatility and downstream gonadotropin secretion.
• Galactorrhoea (inappropriate breast milk production) occurs in a proportion, though not all, of affected women. Over time, associated hypogonadism reduces bone density.
• In men, hyperprolactinaemia more typically presents with reduced libido, erectile dysfunction, and, less commonly, galactorrhoea.
• Diagnosis is frequently delayed compared with women, because these symptoms are less immediately apparent. Men with prolactinoma more commonly present late with a larger macroadenoma and mass effect symptoms (headache, visual disturbance), rather than through early recognition of the hormonal symptoms.
• Macroprolactinoma may present with mass effect symptoms alongside the hormonal manifestations. These are headache and visual field compromise from optic chiasm compression, as in pituitary adenoma generally.
• Establish a relevant medication history, particularly antipsychotic or antiemetic use. Also establish symptoms or history suggesting primary hypothyroidism, and pregnancy status in women of childbearing age. These identify a non-tumoural cause of the elevated prolactin.

• Serum prolactin measurement confirms hyperprolactinaemia, and the degree of elevation provides diagnostic guidance.
• Ideally sample without preceding breast examination, sexual activity, or significant physical or emotional stress. All of these can produce transient, modest prolactin elevation.
• Consider macroprolactin screening, particularly where the degree of elevation seems discordant with the clinical picture, such as a significantly elevated result in an entirely asymptomatic patient.
• Macroprolactin is a larger, biologically less active prolactin complex. It can produce a spuriously elevated result on standard assay without genuine clinical hyperprolactinaemia. Recognising it avoids unnecessary investigation and treatment.
• Obtain thyroid function tests and a full medication history in every patient. These identify common, readily addressed alternative causes before pituitary imaging.
• Magnetic resonance imaging of the pituitary is indicated where a pituitary cause is suspected: significantly elevated prolactin, or persistent elevation after exclusion of the alternative causes.
• It characterises any pituitary lesion and its size. It helps distinguish a genuine prolactinoma from the stalk effect of an alternative non-functioning sellar mass.

• Medication induced hyperprolactinaemia is managed, where clinically feasible, by discontinuing the causative medication or switching to one with lower prolactin elevating potential. The underlying indication guides this. Specialist psychiatric input may be needed on alternative antipsychotics.
• Primary hypothyroidism related hyperprolactinaemia resolves with appropriate levothyroxine replacement, as for hypothyroidism. No separate prolactin directed treatment is needed.
• Prolactinoma, whether micro or macroadenoma, is treated first line with dopamine agonist therapy. Cabergoline is generally preferred, with superior efficacy and tolerability compared with bromocriptine.
• Cabergoline typically starts at a low dose such as 0.25 mg twice weekly, titrated according to prolactin response.
• This is an important exception to the generally surgery first approach for other pituitary adenoma subtypes. Prolactinomas respond excellently and reliably to this therapy.
• In the great majority of patients it normalises prolactin and, for macroprolactinoma, produces substantial tumour shrinkage.
• Surgical resection is reserved for the uncommon scenario of dopamine agonist intolerance or resistance. Rarely, urgent decompression is required for significant, acute visual compromise not responding rapidly enough to medical therapy alone.
• This contrasts with the primary surgical approach for other functioning and non-functioning pituitary adenoma subtypes.
• Pregnancy planning in women with prolactinoma needs specific consideration. In women with microprolactinoma, dopamine agonist therapy is generally discontinued once pregnancy is confirmed, given the very low risk of clinically significant tumour growth in this smaller tumour category.
• Women with macroprolactinoma need closer monitoring during pregnancy, including visual field assessment and a lower threshold for continuing or restarting dopamine agonist therapy. The risk of clinically significant tumour growth is somewhat higher, though still generally modest, in the hyperprolactinaemic and oestrogen rich state of pregnancy.
• Regular monitoring of serum prolactin underpins ongoing management. For macroadenoma, or where visual pathways were initially involved, add periodic imaging and visual field reassessment.
• Consider a trial of dopamine agonist dose reduction or discontinuation after a period of sustained normoprolactinaemia and, for macroadenoma, significant tumour shrinkage. A proportion of patients maintain durable remission after withdrawal following a sufficiently prolonged treatment course.