High Prolactin Without a Pituitary Tumour: Causes

Prolactin is a hormone made by the lactotroph cells of the anterior pituitary. The main regulator is dopamine from the hypothalamus, which acts as a brake - when dopamine falls or its action is blocked, prolactin rises. Physiologically its level rises in pregnancy, during breastfeeding, during sleep, after exercise, in stress and after nipple stimulation. The role of prolactin in women is greatest in lactation, but its excess also suppresses the hypothalamic-pituitary-ovarian axis, which leads to menstrual and fertility problems.

Reference ranges depend on the laboratory, sex and method; roughly, the upper limit of normal is about 25 ng/ml in women, and lower values (of the order of 15-20 ng/ml) in men. Units: in Poland ng/ml or µg/l are often used, and also mIU/l; the conversion depends on the standard used and is taken roughly as 1 ng/ml ≈ 21-36 mIU/l, so always compare with the range on your own report. A general principle (not an absolute rule): a small rise, up to a few times the upper limit, more often has causes unrelated to a tumour, whereas very high values (several hundred ng/ml) more often point to prolactinoma. The 2011 Endocrine Society guideline describes management that covers assessing the cause of hyperprolactinaemia, treating drug-induced hyperprolactinaemia and managing prolactinomas in non-pregnant and pregnant women.

Macroprolactin consists of large complexes of prolactin, most often bound to immunoglobulin G (antibodies against prolactin), which circulate in the blood for a long time and are biologically barely active. The standard test measures them together with true, monomeric prolactin, so the result looks raised although there is enough active prolactin. The effect: a woman with 'high' prolactin has no symptoms, or symptoms from other causes, yet ends up having an MRI and drugs she does not need.

The frequency of macroprolactinaemia depends on the assay: in an Irish study of 670 sera with hyperprolactinaemia measured with one assay (Tosoh), after PEG precipitation monomeric prolactin was normal in 165 (24.6%), indicating macroprolactinaemia; with an assay of lower cross-reactivity with macroprolactin (Roche) the frequency was 6.2%. Practical conclusion: different laboratories can give different results in the same person, and screening for macroprolactin is a cheap way of avoiding a wrong diagnosis. If prolactin is moderately raised and there are no or only non-specific symptoms, ask for a PEG-precipitation measurement (or for information on whether the laboratory performs such screening).

Drugs are one of the most common causes of raised prolactin. The mechanism rests on blocking dopamine D2 receptors on lactotroph cells, which removes dopamine's inhibitory effect. A review of drug-induced hyperprolactinaemia indicates that the most important groups are classic antipsychotics and some atypical ones (amisulpride, risperidone, paliperidone), as well as some antidepressants, antihypertensives and prokinetics (for example metoclopramide). The strength of the effect depends on affinity for the D2 receptor, penetration of the blood-brain barrier and the dose.

For antipsychotics, a French review states that all of them block the D2 receptor and can cause hyperprolactinaemia, but they can be divided into prolactin-raising (classic neuroleptics, amisulpride, risperidone) and prolactin-sparing (clozapine, aripiprazole, olanzapine). In an English study cited there, 18% of men and 47% of women treated for severe mental illness had prolactin above the normal range. Hyperprolactinaemia can be asymptomatic, but higher concentrations more often cause symptoms.

Primary hypothyroidism can raise prolactin because raised TRH (thyrotropin-releasing hormone) also stimulates lactotroph cells. For this reason TSH is routinely measured with any abnormal prolactin - treating hypothyroidism often normalises prolactin. We describe this more broadly in the knowledge-base entries on hypothyroidism and on TSH and thyroid hormones. Neglecting this step is a common mistake: a woman with raised prolactin and undetected hypothyroidism ends up with a pituitary MRI instead of thyroid treatment.

Chronic kidney disease reduces the clearance of prolactin and increases its production, and advanced liver disease disturbs its metabolism, which can lead to raised concentrations. In some women with polycystic ovary syndrome prolactin is slightly raised, overlapping with cycle disturbance; this does, however, call for assessing the whole picture rather than attributing prolactin solely to PCOS. We describe PCOS in the knowledge-base entry. Irritation of the chest wall (for example after surgery, shingles or tight clothing) can reflexively raise prolactin through nerve stimulation, as can repeated touching of the nipples.

In many of these situations mild hyperprolactinaemia needs no separate treatment - it is enough to deal with the cause. If, however, the rise is marked, accompanied by symptoms, or no explanation can be found, further work-up is needed, including pituitary imaging.

Prolactin rises during sleep (with a peak at night and in the early morning hours), after physical exercise, after a high-protein meal, in physical and mental stress and after nipple stimulation. The review of drug-induced hyperprolactinaemia draws attention to the role of psychological and post-traumatic stress in regulating prolactin secretion. In practice this means the stress of the blood draw itself - fear of the needle, rushing, trouble with the vein - can temporarily raise the result, especially in sensitive people.

It is worth remembering that repeating the test under correct conditions and with macroprolactin measured often closes the matter. If the second result is normal and periods are regular, further work-up is usually unnecessary. If the result is still raised, the next steps are TSH, creatinine, a pregnancy test (in women of reproductive age), a medication review and assessment of symptoms.

Excess prolactin suppresses secretion of gonadotropin-releasing hormones, which lowers LH, FSH and oestradiol. In women this leads to irregular periods, scanty periods or their absence, infertility due to lack of ovulation, and galactorrhoea (milk discharge from the breasts outside pregnancy and breastfeeding). Prolonged hyperprolactinaemia with low oestradiol raises the risk of bone loss. In men it shows as lowered libido, erectile dysfunction, infertility and, less often, gynaecomastia and galactorrhoea.

Symptoms are not always present, and their absence does not mean the result is meaningless. In women with regular periods and a small rise in prolactin, significant hyperprolactinaemia is rarely the issue. Conversely, in a woman with absent periods, galactorrhoea and prolactin above the upper limit, broader work-up is necessary. Prolactin is always assessed together with other cycle hormones - we write about their role in other articles in the series, and in men in the context of sex hormones and fertility.

A pituitary MRI is ordered when hyperprolactinaemia is confirmed (after excluding macroprolactinaemia, drugs, hypothyroidism, pregnancy and other causes), is marked or is accompanied by symptoms (headaches, visual disturbance, signs of deficiency of other pituitary hormones), and also when no other explanation can be found. A rise clearly higher than is typical for drug or thyroid causes increases the likelihood of an adenoma, although this is a general rule, not an absolute threshold. It is worth knowing about the 'hook' effect: with very large tumours prolactin can be falsely low if the sample was not diluted.

Treating hyperprolactinaemia is not necessary just because a number is above the range. The indications are symptoms (menstrual disturbance, infertility, troublesome galactorrhoea, signs of hypogonadism, bone loss) and also pregnancy planning. In drug-induced hyperprolactinaemia the first step is a review of the drug, and in hypothyroidism, treatment of the thyroid. Dopamine agonists, for example cabergoline, are used according to the doctor's indications; the Endocrine Society guideline describes management including treatment of drug-induced hyperprolactinaemia and prolactinoma. Macroprolactinaemia in which active prolactin is normal usually needs no treatment.

What this text does not cover: it does not describe treatment of pituitary adenomas or the details of imaging, does not give doses of prolactin-lowering drugs and does not replace a consultation. Prolactin ranges, units and thresholds differ between laboratories; the figures quoted (for example the frequency of macroprolactinaemia) come from specific studies in particular populations and assays and need not carry over to every laboratory. The reviews of drug-induced hyperprolactinaemia are narrative reviews.

Raised prolactin is a result that should most often set off an orderly procedure, not panic. We recommend three things: repeat the test under correct conditions, ask for macroprolactin and TSH, and write down all your drugs. Only after that is it worth deciding on an MRI and treatment. We particularly warn against stopping psychotropic drugs on your own and against buying 'prolactin-lowering' supplements - they have no reliable evidence of effectiveness, and a wrong intervention can do harm.