ProlactinomasEpidemiology and aetiology

Prolactinomas are the most common adenoma type in CYP, occurring in approximately 0.1 million children every year3. However, prolactinomas are exceptionally rare before puberty, when corticotrophinomas are more common. In a series of 136 CYP presenting with pituitary adenomas before 20 years of age, 53% had prolactinomas, but 93% of these presented after 12 years of age. Pituitary adenomas were 3 times4,5,6 to 4.5 times7 more common in female patients than in male patients. Although patients can present with prolactinomas within the first decade of life4,5,8, an adolescent presentation is more typical4,6,7,8,9,10. Median duration of symptom history before diagnosis is 12 months3,11. Of note, macroprolactinomas or giant prolactinomas, which can exert secondary mass effects that compromise growth, puberty and vision, also occur more frequently in CYP than in adults6,12. In a study of CYP with macroprolactinomas, 46% had overweight or obesity at diagnosis and, of these, 23% cited weight gain as one of the reasons for seeking medical advice10. A small percentage of paediatric prolactinomas are related to familial isolated pituitary adenoma or syndromic disease (multiple endocrine neoplasia type 1 syndrome (MEN1), MEN1-like or phaeochromocytoma–paraganglioma-related pituitary disease), even without a known family history13. Therefore, genetic testing should be considered (see Part 1: R11 in ref. 2).

Diagnosis: clinical features

Part 2: R1. Offer serum prolactin measurement in CYP presenting with one or more of the following signs and symptoms: delayed puberty; galactorrhoea; visual field loss; growth or pubertal arrest; or girls with menstrual disturbance (strong recommendation, moderate-quality evidence).

High serum levels of prolactin inhibit gonadotrophin secretion via inhibition of the hypothalamic hormone kisspeptin14. Paediatric patients with hyperprolactinaemia might therefore present with delayed (>2 standard deviations (SD) later than mean population age for sex) or arrested puberty, growth failure or short stature, primary amenorrhoea, galactorrhoea, menstrual disturbance or secondary amenorrhoea (in post-menarcheal girls)3,6. Boys might present with gynaecomastia as a result of hypogonadism. Mass effects, occurring more commonly in boys than girls, include headache and visual field loss15. Obesity, gynaecomastia, constitutional delay in growth and puberty in boys, and menstrual disturbance in girls are common physiological variations that are very rarely caused by prolactinoma. However, the cost of measuring prolactin is offset by the benefits of an early diagnosis and timely treatment.

Diagnosis: biochemical evaluation

Part 2: R2. In CYP with signs or symptoms of hyperprolactinaemia, offer prolactin measurement in a single blood sample collected at any time of day (strong recommendation, high-quality evidence).

Part 2: R3. Consider investigating modestly elevated serum prolactin levels by serial measurements over time to exclude the effect of stress and prolactin pulsatility (moderate recommendation, low-quality evidence, Delphi 87%).

A single prolactin measurement taken at any time of the day is sufficient to assess hyperprolactinaemia16,17. As prolactin secretion also rises in response to stress, in patients with elevated baseline prolactin (up to five times of the upper limit of normal18), sampling can be repeated on a different day with two or three samples at 20–60 min intervals, using an indwelling cannula, to differentiate stress-related hyperprolactinaemia from organic disease16,18.

Part 2: R4. The diagnosis of hyperprolactinaemia in CYP requires age-specific and sex-specific prolactin reference ranges and the exclusion of confounding conditions such as hypothyroidism, renal and/or hepatic impairment, and use of medications that cause hyperprolactinaemia (strong recommendation, moderate-quality evidence).

Serum prolactin concentrations vary with age and sex. They are highest in the first 2 years of life and fall to a nadir in mid-childhood, to rise again in adolescence when they are higher in girls than in boys. Paediatric cohort studies of prolactinomas report diagnostic serum prolactin concentrations usually above 4,000 mU/l (188 µg/l)4,8,10, although lower levels can be seen in patients with microprolactinomas3. To rule out mixed prolactin and GH hypersecretion, age-dependent and sex-dependent insulin-like growth factor 1 (IGF1) evaluation should always accompany prolactin assessment in CYP with prolactinomas.

Unexplained, persistently mildly or moderately elevated prolactin in blood samples taken after rest could be due to the stalk effect (disconnection hyperprolactinaemia, pituitary stalk compression from mass lesions disrupting the dopaminergic inhibition of lactotroph cells). In adult patients with stalk effect, prolactin levels are reported above the normal range but not higher than 2,000 mU/l; 94 µg/l (ref. 19) or six times above the upper limit of normal18. Even if no corresponding symptoms of hyperprolactinaemia, hypopituitarism or a pituitary mass are observed, pituitary imaging should be considered. If hyperprolactinaemia is due to a pituitary mass, baseline and dynamic pituitary assessment can identify a potential lack or excess of other anterior pituitary hormones.

Severe primary hypothyroidism can be accompanied by hyperprolactinaemia, probably due to compensatory thyrotropin-releasing hormone hypersecretion and pituitary hyperplasia; care should be taken to distinguish such pituitary enlargement from a true prolactinoma20,21. Severe and prolonged primary hypothyroidism in children can disrupt kidney and liver function as well as delay growth and puberty. In a large cohort of 2,848 adults, hyperprolactinaemia was reported in 43% of women and 40% of men presenting with frank primary hypothyroidism, in 36% of women and 32% of men with subclinical hypothyroidism, and only in around 2% of euthyroid individuals21. Hyperprolactinaemia is reported in 30–65% of adult patients with chronic kidney disease due to increased prolactin secretion and reduced renal clearance22. Severe liver disease is also associated with hyperprolactinaemia in adults18. Intracranial hypotension can cause hyperprolactinaemia18. Although we could find no parallel data describing the prevalence of hyperprolactinaemia in these clinical scenarios in CYP, the Guideline Development Group (GDG)2 recommends the exclusion of confounding diseases. Up to 80% of patients with tetrahydrobiopterin deficiencies (a group of rare neurometabolic disorders characterized by insufficient synthesis of monoamine neurotransmitters, including dopamine) can have hyperprolactinaemia (10–30 fold elevation of prolactin), usually from the teenage years; development of a microprolactinoma has been also described in case reports23,24. While less likely in the CYP population, pregnancy should not be overlooked as a cause of hyperprolactinaemia18.

Medications are one of the most common causes of hyperprolactinaemia in adults through direct prolactin stimulatory pathways or by antagonizing inhibitory dopaminergic tone25. Medication-induced hyperprolactinaemia is also well described in CYP (Supplementary Table 3). The role of synthetic oral oestrogens (for example, contraceptive pills) in causing mild elevation of prolactin is controversial.

Part 2: R5. Assess baseline macroprolactin levels where serum prolactin is found to be mildly or incidentally elevated (strong recommendation, low-quality evidence, GDG consensus).

In addition to monomeric prolactin (23 kDa), dimeric (48–56 kDa) and polymeric (>100 kDa) forms (usually associated with an antibody) can circulate (‘macroprolactin’, which has low biological activity), with or without excess monomeric prolactin. No routine assays distinguish between monomeric prolactin and macroprolactin; therefore, prompt and appropriate secondary analysis should be undertaken to detect the possible presence of macroprolactin in the initial investigation of asymptomatic CYP with hyperprolactinaemia26,27. In large retrospective cohorts of adults with hyperprolactinaemia, macroprolactinaemia was present in 10–40% of individuals with hyperprolactinaemia17,26,27, 20% of whom had galactorrhoea, 45% oligo-amenorrhoea and 20% pituitary adenomas. Few patients with macroprolactinaemia are reported in the paediatric literature. In a cohort of five patients aged 11–18 years with an incidental finding of hyperprolactinaemia due to macroprolactinaemia, none developed clinical features of prolactin excess during an observation period ranging from 3 months to 8 years28. In another report, one of six CYP with macroprolactinaemia was asymptomatic; the other five had either headache, menstrual disturbance, short stature, increased hair growth or early puberty. Four of those with symptoms underwent pituitary MRI and a microadenoma was identified in two (one with headache and one with oligomenorrhoea)29. Given these data and the current widespread clinical practice6, the GDG strengthened R5.

Part 2: R6. Perform serial dilutions of serum for prolactin measurement in CYP with large pituitary lesions and normal or mildly elevated prolactin levels (strong recommendation, moderate-quality evidence).

Serum prolactin levels directly correlate with prolactinoma size and are important markers of treatment response. Based on adult data, approximately 5% of patients with macroprolactinomas and a paradoxically modest serum concentration of hyperprolactinaemia have grossly elevated prolactin concentrations following serum dilution30. When prolactin is measured in two-site immunoradiometric assays, very high concentrations of prolactin could saturate the signalling antibody, making it less available for binding to the coupling antibody, resulting in artificially low measurements16. This phenomenon has been described as the ‘high-dose hook effect’30 and is well recognized. Some prolactin assay manufacturers have put specific mitigating factors in place, such as large linear ranges or automatic dilution steps, in many modern assays. However, the potential remains for this effect to be a source of anomalous results31. Thus, contact with the clinical biochemist to request manual dilution is advised when a discrepancy exists between a large pituitary adenoma on imaging and only modestly elevated prolactin concentrations on initial biochemistry. Of note, inconsistent symptoms and laboratory results can occasionally arise due to biotin exposure or heterophilic anti-animal antibodies18.

Treatment

Part 2: R7. In CYP with prolactinoma, offer a dopamine agonist as first-line therapy to reduce serum prolactin concentrations and induce tumour shrinkage; cabergoline is the dopamine agonist of choice given its superior effectiveness and lower adverse effect profile (strong recommendation, moderate-quality evidence).

Part 2: R8. In CYP with prolactinoma, offer cabergoline as first-line therapy, even in the presence of visual disturbance and pituitary apoplexy, while carefully monitoring for any deterioration in vision, pituitary function or general status (strong recommendation, low-quality evidence, Delphi 100%).

Dopamine agonists reduce pituitary-origin hyperprolactinaemia of any cause18. In adults with prolactinoma, dopamine agonists induce normalization of the prolactin level (median: 68% of patients; range: 40–100%), tumour shrinkage (62%; 20–100%), resolution of visual field defects (67%; 33–100%), normalization of menses (78%; 40–100%), fertility (53%; 10–100%) and sexual function (67%; 6–100%), and resolution of galactorrhoea (86%; 33–100%)11,32,33. In both adults and CYP with prolactinoma, cabergoline is the dopamine agonist of choice3,11,12. Cabergoline has a longer half-life and greater affinity for the dopamine receptor than other dopamine agonists. In a randomized controlled trial of adult women with prolactinoma, cabergoline was superior to bromocriptine in normalizing prolactin (83% versus 59%), resuming ovulatory cycles or achieving pregnancy. Adverse events were more commonly reported with bromocriptine than with cabergoline (72% versus 52%)34.

In studies of CYP with prolactinomas, dopamine agonists lower prolactin concentrations in 60–70% of patients3,4,8,10,11,35, reduce tumour size by 80–88%3,11, improve visual deficits36, resolve pubertal delay and eliminate headache11. In an observational study of 28 paediatric patients, CYP with prolactinomas smaller than 13.5 mm in diameter (13 patients) achieved normalization of prolactin levels without surgery, using conventional cabergoline doses (up to 2 mg/week)12. Moreover, another series of 22 CYP with prolactinomas reported that all tumours of >20 mm diameter required surgery6. Although successful dopamine agonist discontinuation has been achieved in CYP, younger patients and those with high serum prolactin concentrations at diagnosis (a marker of adenoma size) are less likely to achieve complete remission and euprolactinaemia3,11,37.

Medication-induced shrinkage of prolactinomas that have invaded sphenoid bone can cause rhinorrhoea after a few months of drug administration (mean 3.3 months, range 3 days–17 months) due to a cerebrospinal fluid leak38, but this adverse effect can also occur during long-term treatment. Detection of β2-transferrin or β-trace protein (specific to cerebrospinal fluid) in nasal secretions confirms a cerebrospinal fluid leak39. Cerebrospinal fluid leak can require urgent intervention (for example, lumbar drain or surgical repair), with or without a temporary cessation in dopamine agonist therapy40. Apoplexy has been described during cabergoline therapy both in adults and CYP6.

Part 2: R9. For CYP resistant to standard doses of cabergoline, offer graduated dose increments of up to 3.5 mg per week or up to 7 mg per week in exceptional cases (strong recommendation, moderate-quality evidence, Delphi 100%).

Evidence indicates that adult patients with prolactinoma who are unresponsive to standard dopamine agonist doses (up to 1.5–2 mg of cabergoline per week) might respond to higher doses (3.5–7 mg per week), whilst even higher doses (up to 12 mg per week41,42 but below the 21 mg per week dose used for Parkinson disease) have been tried. High-dose cabergoline is reportedly well tolerated and doses of up to 7 mg per week have been used to successfully treat CYP with prolactinoma10,11. However, others report little benefit of cabergoline doses above 3.5 mg per week in adults41. Patients with cabergoline resistance or intolerance will require adjuvant therapy with surgery or radiotherapy42.

Part 2: R10.1. Following multidisciplinary discussion, for CYP with prolactinomas offer surgery when the patient is unable to tolerate or is resistant to high-dose cabergoline (strong recommendation, low-quality evidence, Delphi 95%).

Part 2: R10.2. Following multidisciplinary discussion, for CYP with prolactinomas offer surgery when the patient develops deteriorating vision on cabergoline (strong recommendation, low-quality evidence, Delphi 90%).

Part 2: R10.3. Following multidisciplinary discussion, for CYP with prolactinomas offer radiotherapy if surgery is not an option (strong recommendation, low-quality evidence, Delphi 100%).

Small nocturnal dose increments of cabergoline can effectively diminish the adverse effects of gastrointestinal intolerance and postural hypotension, thereby avoiding trials of less effective dopamine agonists (bromocriptine or quinagolide). Dose-independent psychological intolerance (mood changes, depression, aggression, hypersexuality and impulse control disorder) is similar between agents and described in adults as well as CYP37,43, but the frequency of these adverse events might be higher in CYP than in adults11,44. Dopamine agonist resistance is usually defined in adults and CYP as failure to achieve normoprolactinaemia (biochemical resistance) and less than 50% reduction in tumour area in the coronal plane and/or less than 30% reduction of the longest diameter of the tumour (tumour size resistance, assessed by Response Evaluation Criteria In Solid Tumours (RECIST) criteria) after 3–6 months of maximally tolerated dopamine agonist doses (at least 2 mg per week)18,41,45,46. In a paediatric macroprolactinoma cohort of patients who were unresponsive to 3 months of 15 mg per day bromocriptine, 600 µg per day quinagolide or 3.5 mg per week cabergoline, 26% were biochemically resistant and 24% were tumour-shrinkage resistant10. This resistance directly correlated with tumour size and prolactin levels (which in turn were closely correlated) but was independent of MEN1 mutation status10.

In CYP with prolactinoma, neurosurgical intervention should be considered if vision deteriorates or does not improve on medical therapy or if dopamine agonist resistance, escape or intolerance occurs. Careful multidisciplinary discussion is needed if the patient expresses a preference for surgery rather than long-term medication or is non-adherent to the latter.

Transsphenoidal surgery induced remission in 30–50% of adults with prolactinomas and any residual post-operative hyperprolactinaemia was subsequently more responsive to dopamine agonists than pre-operatively47. Tumour size negatively predicted surgical remission rates, with smaller adenomas being more often cured by surgery alone than larger ones