Pituitary apoplexy is one of the most dramatic emergencies in endocrinology — it causes sudden severe headache (thunderclap onset, maximal at onset), often with diplopia (CN III, IV, VI — passing through the cavernous sinus immediately lateral to the pituitary), visual field defects, and profound adrenal insufficiency (the posterior pituitary is usually spared, but anterior pituitary destruction causes acute cortisol deficiency). The headache pattern can mimic subarachnoid haemorrhage. The key GP action is 999/A&E without delay; give hydrocortisone 100 mg parenterally per the emergency protocol if adrenal insufficiency is suspected or the patient is unstable — do not delay transfer. Any patient with a known pituitary adenoma who develops acute severe headache with or without visual symptoms should be treated as pituitary apoplexy until proved otherwise. The importance of prolactin sample conditions: prolactin is a stress-hormone that rises in response to venepuncture, exercise, sexual activity and breast/nipple stimulation; fasting is not routinely required. A single elevated prolactin result in a patient who was anxious, had a difficult venepuncture, or had a breast examination beforehand may be a false positive. Measure prolactin according to the local laboratory protocol: the patient should be rested and the sample is preferably taken at least 2 hours after waking. A single result above the reference range may establish hyperprolactinaemia, but a mildly elevated or unexpected result should be repeated under rested conditions, ideally via an indwelling cannula if venepuncture stress is suspected. Many apparent hyperprolactinaemia cases are artefactual. On NICE NG12 (updated April 2026): hyperprolactinaemia itself has no suspected-cancer criterion, and none should be invented — prolactinomas are benign, and the urgent routes here are visual and endocrine. The one genuine cancer adjacency is in the galactorrhoea assessment: bilateral milky discharge fits prolactin, but discharge, retraction or other change of concern in one nipple only in someone aged 50 or over meets the NG12 breast criterion for a suspected cancer pathway referral. A non-prolactinoma sellar mass found on imaging is managed as a brain tumour by neurosurgery and endocrinology, not on a primary care cancer route.

The hypothyroidism-prolactin connection is one of the most commonly missed causes of apparent hyperprolactinaemia — TRH (thyrotropin-releasing hormone), raised in primary hypothyroidism, stimulates both TSH and prolactin release, so primary hypothyroidism can cause clinically significant hyperprolactinaemia. Treatment of the hypothyroidism with levothyroxine normalises the prolactin completely. This is why TSH must always be checked before investigating hyperprolactinaemia further. Macroprolactinaemia is the most important cause of false-positive hyperprolactinaemia — it is a common finding in patients referred for hyperprolactinaemia investigation and is caused by immunoglobulin binding to prolactin molecules, creating large biologically inactive complexes that are measured by immunoassay but cannot bind to prolactin receptors in tissues (therefore no clinical effect). The macroprolactin complex is too large to be filtered by the kidney and accumulates in the serum. A patient with macroprolactinaemia has a high measured prolactin but no symptoms (no amenorrhoea, no galactorrhoea, no infertility, no headache). The PEG precipitation test identifies macroprolactin — it should be requested particularly where prolactin is raised but symptoms are absent or disproportionate, and interpreted by the laboratory's criteria (post-PEG monomeric prolactin).

The prolactin cannula technique is the gold standard for accurate prolactin measurement — a sample taken immediately after the stress of venepuncture will contain stress-released prolactin in addition to the baseline. The correct protocol: (1) insert cannula at the start of the consultation; (2) allow patient to sit quietly and rest quietly; (3) draw blood at the end of the rest period through the cannula without any new needle insertion. This eliminates the venepuncture stress response. A cannula is not needed routinely and fasting is not required, but the patient should be rested and the sample preferably taken at least 2 hours after waking; use a cannula when venepuncture stress is suspected. Request macroprolactin analysis where prolactin is raised but symptoms are absent or disproportionate. Interpret results against the laboratory's sex-specific reference range and units — do not use universal cut-offs without confirming the local assay. A prolactin above approximately 5000 mIU/L is strongly suggestive of a prolactinoma, but a symptomatic patient may need imaging at a much lower level; MRI thresholds follow the local endocrine/radiology pathway.

The prolactin level at which macroprolactinoma vs stalk compression can be distinguished is clinically important — a prolactin result above approximately 5000 mIU/L is strongly suggestive of a prolactinoma (the pituitary cells secreting prolactin, not just compression releasing the inhibition on normal cells). Stalk compression by non-prolactin-secreting tumours may produce prolactin in the approximate range 400–2000 mIU/L, but this does not reliably distinguish lesions in every patient. This matters for treatment: prolactinomas respond to cabergoline (which directly suppresses prolactin secretion from the tumour and causes tumour shrinkage); non-functioning adenomas with stalk compression do not respond to cabergoline and require surgical decompression. Getting the diagnosis right prevents both under-treatment (missing a cabergoline-responsive prolactinoma) and inappropriate treatment (giving cabergoline to a patient with a non-functioning adenoma requiring surgery).

The antipsychotic switching dilemma for hyperprolactinaemia deserves specific attention — antipsychotic-induced hyperprolactinaemia is common, and the long-term consequences of sustained hyperprolactinaemia from antipsychotics include: osteoporosis (from hypogonadism), sexual dysfunction, infertility, and possible breast cancer risk (oestrogen-dependent; prolactin has growth-promoting effects on breast tissue). The evidence base: amisulpride and risperidone are the most potent prolactin-raising antipsychotics; aripiprazole is a partial D2 agonist that has negligible prolactin-raising effect and can even reduce prolactin when added to other antipsychotics (combination strategy without compromising antipsychotic efficacy). Quetiapine also has low prolactin-raising potential. GPs who identify patients on antipsychotics with symptomatic hyperprolactinaemia (amenorrhoea, galactorrhoea, sexual dysfunction, bone density concerns) should raise this with the prescribing psychiatrist — switching to aripiprazole or quetiapine is a clinically meaningful quality-of-life intervention that requires psychiatric team decision-making.

Cabergoline vs bromocriptine — the evidence clearly favours cabergoline for prolactinoma management: cabergoline is more effective than bromocriptine at normalising prolactin and restoring ovulation, and has far better tolerability (once or twice weekly dosing vs BD/TDS for bromocriptine; much lower rate of nausea, postural hypotension, and gastrointestinal side effects). The cardiac valvulopathy risk from cabergoline is principally established at the much higher doses used for Parkinson's disease — at the lower doses used for prolactinoma (typically 0.5–2 mg/week), the risk is low but not zero, so a baseline echocardiogram is followed by monitoring per the SfE/BSE/BHVS position statement (repeat at 5 years if ≤2 mg/week; annually if >2 mg/week) or the more intensive SmPC schedule, according to the local endocrine/cardiology pathway. Bromocriptine remains the preferred choice in women planning pregnancy because it has a much longer safety record in early pregnancy (established since the 1970s) — cabergoline is usually stopped when pregnancy is confirmed (in microprolactinoma patients) and restarted postpartum if required. The decision to stop or continue dopamine agonist during pregnancy in macroprolactinoma requires specialist input.

The fertility restoration rate with prolactin normalisation is one of medicine's most satisfying treatment outcomes — many women with hyperprolactinaemic amenorrhoea and infertility resume spontaneous ovulation once prolactin is normalised with cabergoline. This means that for most women with hyperprolactinaemia-related infertility, the treatment is cabergoline alone, not IVF. The sequencing is important: normalise prolactin first and allow time for ovulation to resume before adding ovulation induction (agreed with endocrinology/fertility services) — many women need only the prolactin-normalising treatment and nothing further. Adding clomifene or gonadotrophins while prolactin is still elevated will be ineffective because elevated prolactin suppresses the hypothalamic-pituitary-ovarian axis at a level upstream of where these drugs act.

The cabergoline withdrawal trial (attempting to stop cabergoline after 2+ years of normalised prolactin and stable MRI) is an important management option that is underutilised — some microprolactinoma patients achieve sustained remission after cabergoline withdrawal (prolactin remains normal without treatment). The predictors of successful withdrawal include: normalised prolactin for at least 2 years on treatment, no visible tumour on MRI (or dramatic tumour size reduction), and low pre-treatment prolactin. The Endocrine Society guideline (Melmed et al., 2011; international) and the Pituitary Society consensus (2023; international) support discussing withdrawal after about 2 years of stability — no UK national guideline covers hyperprolactinaemia. The protocol: the dose is reduced gradually under specialist supervision while monitoring prolactin, aiming for eventual cessation. If prolactin rises to above normal on dose reduction → continue treatment. If prolactin remains normal off treatment on the specialist's agreed checks → remission likely. This approach prevents patients from taking a lifelong drug when they may not need it.

The macroprolactinaemia explanation to patients requires care — patients who have been told their prolactin is 'high' and then are told 'actually it's a form of prolactin that doesn't matter' often feel confused or dismissed. The clear explanation is: 'There are different forms of prolactin in your blood. Standard blood tests measure all of them together, but one form — a larger version — attaches to other proteins and can't actually reach the cells that would respond to it. You have more of this inactive form, which makes the total reading look high. But your body is working perfectly normally — this is a characteristic of your blood chemistry, not a disease, and you don't need any treatment or follow-up unless you develop symptoms.' This explanation validates the patient's concern, explains why the test result is not as alarming as it appears, and prevents unnecessary anxiety about a finding that requires no action. It helps to acknowledge the oddness directly — "I know it's strange to be told this after being sent for tests" — and to invite questions. In the SCA the same skill is being marked: the candidate who gets the biochemistry right but leaves the patient confused has only done half the job.