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Reference Section
Hyperprolactinaemia in Children – A Common Diagnostic Dilemma
a report by
F r a n c e s c o M a s s a r t and G i u s e p p e S a g g e s e
Fellow, Postgraduate Paediatric Residency School, and Full Clinical Professor and Chief Director,
Department of Paediatrics, University of Pisa DOI:10.17925/EE.2006.00.02.1j
Prolactin (PRL) is a peptide hormone secreted by
lactotroph cells of the anterior pituitary.1 PRL is
predominantly under inhibitory influence of
hypothalamic dopamine, whereas thyrotropinreleasing hormone (TRH), among other endogenous
substances, is the main PRL-releasing factor. In
physiological conditions, PRL secretion is also affected
by numerous exogenous influences, such as stress,
physical effort, hypoglycaemia, lactation and sleep.1
The main activity of PRL is its influence on the
mammary gland (the so-called mammotrophic and
lactotrophic effect) and the gonads, inhibiting the
pulsatile excretion of gonadotropin-releasing hormone
(GnRH) and the secretion of follicle-stimulating
hormone (FSH) and luteinising hormone (LH).1
Since human PRL was purified in 1972,2 the
clinical syndrome of hyperprolactinaemia has been
characterised extensively, the predominant symptoms
being galactorrhoea, oligomenorrhoea or secondary
amenorrhoea, infertility in women and reduced libido,
impotence and gynaecomastia in men.3 In children and
adolescents, major clinical signs of hyperprolactinaemic
syndrome are delayed puberty, gynaecomastia,
galactorrhoea and primary amenorrhoea.
Hyperprolactinaemia represents a common
diagnostic dilemma due to the fact that it is often
encountered in clinical practice even in the absence
of significant pathology. An elevated PRL value, also
in asymptomatic patients, creates the need to rule out
diverse organic and functional aetiologies of
hyperprolactinaemia (see Table 1). Therefore,
differential diagnosis of hyperprolactinaemia may be
difficult and undiscounted – especially in children
and adolescents, in whom the stress of venipuncture
even causes mild PRL increase.
and another pituitary hormone, e.g. growth hormone
(GH), or from two distinct adenomas producing
various hormones. From this point of view, these
hyperprolactinaemic syndromes may overlap other
endocrine conditions with affected pituitary function.
For pituitary prolactinoma, the clinical syndrome
traditionally described in children is caused
by functional alterations resulting from hyperprolactinaemia (i.e. galactorrhoea, gynaecomastia,
amenorrhoea and delayed puberty) and/or by the mass
effect of the tumour (i.e. headaches, visual field
abnormalities, etc.).5–6 Interestingly, there is a
predominance of macroprolactinoma over microprolactinoma in most paediatric studies; at the time of
diagnosis, males present mainly with neurophthalmologic abnormalities secondary to tumoural
growth, whereas in females, endocrine-gynaecological
symptoms are predominant.6
The absolute PRL levels have considerable diagnostic
and predictive value because the serum PRL
concentrations are consistently elevated in patients
with prolactinoma. For many years, it has been
argued that PRL values above 100ng/ml are
suggestive of organic pathology, while values below
that level are indicative of functional alteration.4 The
most likely cause of a PRL level above 250ng/ml is a
PRL-secreting tumour, whereas tumours causing
compression of the pituitary stalk show only
moderate elevation of PRL resulting from an
insufficient dopamine supply. In children and
adolescents with prolactinoma, serum PRL levels are
10 times higher in macroadenoma than in
microadenoma.7 Indeed, a PRL concentration of
more than 600ng/ml is always due to a
macroprolactinoma.5,7 However, many patients
affected by prolactinoma have PRL levels below
100ng/ml in the first measurement.6
Prolactinomas
Prolactinomas, the most common functioning pituitary
tumours, are the most frequent cause of hyperprolactinaemia in patients aged two to 80 years;
however, these tumours are less frequent in children.4–5
Also, hyperprolactinaemia may derive from a pituitary
tumour that contains bipotential cells secreting PRL
The PRL response to TRH is characteristically
blunted in patients with prolactinoma, but the
response may be normal. In addition, prolactinoma
patients with normal basal PRL levels may have PRL
values that are more than three times elevated after
stimulation.8 Finally, the usefulness of dynamic tests
of the PRL axis is highly controversial.9
BUSINESS BRIEFING: EUROPEAN ENDOCRINE REVIEW 2006
Francesco Massart
Giuseppe Saggese
Francesco Massart is a fellow of the
Postgraduate Paediatric Residency
School of the University of Pisa.
He is a member of several
professional organisations and
scientific societies, such as the
Italian Society of Paediatrics and
the Italian Society of Paediatric
Endocrinology & Diabetology.
Dr Massart has published several
original manuscripts, reviews and
abstracts in scientific journals and
has contributed to more than five
books. He is a manuscript reviewer
for several journals, including Fertility
& Sterility, Journal of Perinatology and
Gynecological Endocrinology.
Giuseppe Saggese is Full Clinical
Professor of Paediatrics and Chief
Director of the Department of
Paediatrics at the University of Pisa.
He is also Director of the
Postgraduate Paediatric Residency
School of the University of Pisa and
Clinical Chairman of the Tuscany
Paediatric Endocrine Centre. Professor
Saggese is President of the Italian
Society of Paediatrics and Past
President of the Italian Society of
Adolescent Medicine. He is an invited
lecturer at various national university
and teaching hospitals and has
published more than 600 original
manuscripts, reviews and books.
Professor Saggese is manuscript
reviewer for several journals.
1
Reference Section
Table 1: The Most Common Causes of Hyperprolactinaemia in Children and
Adolescents
Nipple stimulation/sucking
Sexual intercourse
Stress
Pituitary prolactinomas
Head mass compressing pituitary stalk
Stalk section by heard injury or surgery
Empty sella syndrome
Polycystic ovary syndrome
Pregnancy
Chronic renal feature
Hypothyroidism
Macroprolactinaemia
Drug treatment with
Oestrogens
Opiates
Antidepressants
Tricyclic agents, monoamine oxidase inhibitors,
selective serotonin re-uptake inhibitors
Atypical antipsychotic drugs
Risperidone, amisulpride, thioridazine,
chlorpromazine, haloperidol, sulpiride,
fluphenazine, flupenthixol
Cardiovascular drugs
Verapamil, methyldopa
Dopamine receptor antagonists Metoclopramide, domperodone
GnRH agonists
Triptorelin
Protease inhibitors
Ritonavir, indinavir, zidovudine
Others
Omeprazole, bezafibrate, H2 antagonists
Misdiagnosis
On the other hand, not all hyperprolactinaemic
patients with uncertain pituitary imaging have an
adenoma. Peillon et al.10 reported a pseudotumoural
appearance of the pituitary on computed tomography
(CT) or magnetic resonance imaging (MRI) scans in
five women with functional hyperprolactinaemia. In
these cases, the tissue pathology showed lactotroph
hyperplasia, which is also found in physiological
conditions such as pregnancy or lactation. It is
important
to
recognise
that
functioning
hyperprolactinaemia may mimic PRL-secreting
adenoma on CT and MRI scans.10 Follow-up CT and
MRI brain scans at regular intervals (initially at one
year, then every two years thereafter) are necessary to
monitor for the development of pituitary tumour.
2
Furthermore, all hyperprolactinaemic syndromes
may be misdiagnosed as prolactinoma due to the
relatively common occurrence of pituitary
incidentaloma on imaging studies.11 A tiny pituitary
mass revealed by MRI scan is likely to be an
incidentaloma of little clinical significance. CT and
MRI imaging in the general population, undertaken
for reasons other than suspected pituitary disease,
indicate that 10–20% of such images are consistent
with the presence of a pituitary adenoma.11 Given
that up to 10% of a population may harbour an
asymptomatic adenoma, it is to be expected that
some patients will be identified who have both
hyperprolactinaemia and imaging findings consistent
with a pituitary adenoma. It has been suggested that
this may account for part of the failure of pituitary
microsurgery of prolactinoma.12
Hyperprolactinaemia is frequently reported in
patients with inherited endocrine syndromes, such as
Carney complex, McCune-Albright syndrome
(MAS) or multiple endocrine neoplasia type 1 (MEN
1), which share some endocrine and skin features.13,14
The vast majority of hyperprolactinaemic patients
with MAS or Carney complex have negative
pituitary gland imaging studies, whereas
prolactinomas are commonly present in kindreds
with MEN 1.15–17 Therefore, hyperprolactinaemia in
MEN 1, contrary to MAS and Carney complex, is a
clinically distinct entity due to pituitary adenoma and
constitutive activation of somatomammotroph cells,
respectively.16,17 It is always prudent to exclude these
inherited endocrine syndromes for all hyperprolactinaemic patients.
Polycystic Ovary Syndrome
Hyperprolactinaemia is the cause of 20–30% of
secondary amenorrhoea, a condition that affects at
least 3% of women in reproductive age, and
polycystic ovary syndrome (PCOS) is diagnosed
in 80% of patients with menstrual cycle
disturbances.18,19 Indeed, PCOS causes such as stress,
hypoglycaemia and obesity are reported as the main
causes of hyperprolactinaemia.8,18
PCOS is a chronic hyperandrogenous disease with
characteristic androgenic phenotype, disturbances of
the menstrual cycle, hirsutism and reduced hormonal
carbohydrate and lipid metabolism.18,19 There are also
reports of hyperinsulinism and insulin resistance in
PCOS.8,18 Hyperinsulinaemia is a reason for
hyperprolactinaemia in PCOS as well as in obesity;
hyperinsulinism may induce hyperandrogenaemia
through inhibition of androgen catabolism.19 Also,
oestrogens result from the aromatase conversion of
androgen excess. It should be noted that, among the
numerous factors stimulating PRL secretion,
oestrogens play a significant role, which is the case in
PCOS or obesity or after oral intake of oestrogens.18,19
Hyperoestrogenism may stimulate PRL release by
lactotrophs directly as well as inhibiting dopamine
secretion in the hypothalamus.8,19 Significantly higher
levels of PRL have been found in PCOS than in
control females with regular cycles and menstruation;
the highest PRL values are detected in women with
both PCOS and obesity.8,20 As the PCOS diagnosis
is straightforward and pharmacological treatment
leads to restoration of pituitary function,19 it is
mandatory to rule out PCOS in all young
hyperprolactinaemic females.
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Hyperprolactinaemia in Children – A Common Diagnostic Dilemma
Other Aetiologies of
Hyperprolactinaemia
Rarely, marginal increases in PRL levels accompany
other endocrine conditions, such as hypothyroidism.1,3
Due to the fact that TRH, among other endogenous
substances, is the main PRL-releasing factor, increased
PRL secretion may be due to primary hypothyroidism.1,3 Therefore, complete thyroid function
must be evaluated in all hyperprolactinaemic patients
because thyroid hormone replacement rapidly
normalises PRL function in these patients.21
Hyperprolactinaemia also results from conditions that
decrease dopamine action at the lactotroph cells, such
as pregnancy, seizures or drugs, and conditions in
which reduced clearance of PRL occurs, such as
chronic renal failure.3 Many pharmacological
treatments may also raise pituitary PRL release, such as
dopamine receptor antagonists, atypical antipsychotic
agents, antidepressants, oestrogens, opiates and
antihypertensive drugs.3 Furthermore, reversible
asymptomatic hyperprolactinaemia is reported as an
adverse effect during GnRH agonist (GnRHa)
treatment, such as triptorelin, in girls.22 Interestingly,
hyperprolactinaemic GnRHa-treated children show
PRL levels that are elevated by more than three times
after TRH stimulation. However, increased PRL
values rapidly normalise after GnRHa withdrawal.22
Transient increase in PRL levels has been confirmed
during and following seizures in both adults and
children.23 For PRL levels to increase postictally,
neuromuscular activity lasting for a minimum of 30
seconds is required.23 Febrile seizures are characterised
by their brief duration and benign, non-epileptic
nature; thus, the transient postictal PRL elevation of
epileptic seizures may not be obligatory.24 In addition
to the postictal hyperprolactinaemia, it has been
proposed that patients with epilepsy may have high
interictal PRL levels, but this has not been confirmed
worldwide.23,24 While high postictal PRL levels may
indicate a convulsive attack, a normal PRL value does
not guarantee its absence.24 Therefore, once drug
effects or seizure episodes have been excluded, it is
mandatory to check renal function and pregnancy
status in hyperprolactinaemic subjects.
Ruling out Macroprolactinaemia
Finally, for all patients found to have hyperprolactinaemia, it is prudent to exclude macroprolactinaemia. There are three major molecular forms
of PRL in the circulation:
• monomeric PRL (little PRL; 23 kilo Daltons
(kDa));
• dimeric PRL (or big PRL; 45–50kDa); and
• macroprolactin (big-big PRL, 150–170kDa).25
Macroprolactin is a complex of immunoglobulin G
(IgG) and monomeric PRL with prolonged plasma
half-life due to delayed renal clearance. PRL mainly
circulates in the monomeric form (85–95%), but
occasionally, macroprolactin may be the predominant
form, such as in macroprolactinaemia. The estimated
prevalence of macroprolactin among patients with
hyperprolactinaemia ranges from 9% to 42%, and its
prevalence in healthy people is less than 1%.25,26
Although biological activity has been demonstrated in
vitro, it is generally believed the macroprolactin lacks
biological activity in vivo because it cannot cross the
endothelial lining and reach the cell surface
receptors.25,26 Therefore, macroprolactinaemia – the
presence of elevated levels of PRL of high molecular
mass with little, if any, bioactivity – is one aetiology of
hyperprolactinaemia that is considered benign.25
Unfortunately, macroprolactin is a significant source of
analytical error that is affecting most, if not all, of the
PRL assays in current use.27 Recent studies have
indicated that macroprolactinaemia accounts for up to
26% of biochemical hyperprolactinaemia depending
on the immunoassay in use and, thus, macroprolactinaemia represents a common diagnostic pitfall
that is responsible for frequent misdiagnosis and
mismanagement of hyperprolactinaemic patients.25,27 It
is advisable for clinicians to have some knowledge of
the assay proprieties used by their laboratories. One of
the commonly used methods to screen for
macroprolactinaemia is polyethylene glycol (PEG)
precipitation.27 PRL that is not precipitated by PEG is
considered as free and biologically active PRL.27
Knowing the level of monomeric PRL is desirable for
hyperprolactinaemic patient management as this is the
biologically active form, and monomeric PRL and
macroprolactin can occur simultaneously.25–27
However, despite convincing evidence of the
importance of ruling out macroprolactinaemia in
hyperprolactinaemic subjects, routine screening has not
yet been generally adopted.
Summary
In conclusion, although hyperprolactinaemia
represents a common problem encountered in clinical
practice, its diagnosis may be confused or overlooked.
Therefore, an accurate differential diagnosis is
mandatory in order to rule out the diverse aetiologies
of hyperprolactinaemia. In addition, although
dopamine agonist drugs, such as bromocriptine, are
often efficacious at reducing PRL levels in all
hyperprolactinaemic syndromes, both method and
duration of curative treatment largely depends on the
specific aetiology of the hyperprolactinaemia.
Failing to make a differential diagnosis, the hyperprolactinaemic condition could lead to unnecessary
and costly investigations, inappropriate intervention
and needless apprehension. ■
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3
Reference Section
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