Suckling

stimulus
-

Sleep
+

Stress

Hypothalamus
TRH
+

Dopamine
-

Anterior
pituitary
Prolactin
Mammary gland

Stimulates development
Epithelial cell proliferation

Other effects
Major
Suppression of LH and FSH production
Potential or minor
Regulation
of
lymphocytes
Osmoregulation
Maintenance of the corpus luteum
Steroidogenesis in testis and ovary

in

the

ovary

Initiates and maintains lactation

Synthesis of casein and lactalbumin Synthesis
of lactose
Synthesis of free fatty acids
Synergized by glucocorticoids
Inhibited by oestrogen and progesterone
Figure 5.10 Summary of the regulation and effects of prolactin. For the influences on the hypothalamus,
the + and - symbols reflect their net effect on prolactin secretion. The bold arrow for dopamine reflects its predominance as a
regulatory factor compared to thyrotrophin releasing hormone (TRH). LH, luteinizing hormone; FSH, follicle stimulating hormone.

Investigation and diagnosis

Diagnosing
hyperprolactinaemia
requires
several
blood samples to avoid the risk of raised PRL
secondary to stress from a single painful
venesection
leading to a false diagnosis. Also, on occasion,
large
forms of PRL, called macroprolactin (do
not
confuse the word with macroprolactinoma),
are
detected by some PRL assays. Although
inactive
biologically, macroPRL creates the false
impression
of
hyperprolactinaemia.
If suspected,
additional

laboratory methods can remove it from the

assay.
These issues aside, the major challenge is to
tease

apart the differential diagnosis when serum PRL

is repeatedly above the normal range [i.e.>500
mU/L (25 ng/mL)] (Box 5.7).
The exclusion of pregnancy is mandatory to
avoid
further
unnecessary
investigation.
Otherwise,
the extent of the raised prolactin concentration
gives
a clue to the underlying diagnosis. PRL

secretion
from
microprolactinomas
and
macroprolactinomas
forms a continuum above the upper limit of
the
normal range. However, when PRL is only
relatively
modestly increased [500-2000 mU/L (25-100
ng/
mL)], other diagnoses need consideration,
such as

Chapter 5: The hypothalamus and pituitary gland / 85

Box 5.7 Hyperprolactinaemia

Commonly presents in women with
amenorrhoeagalactorrhoea
Confirm hyperprolactinaemia on several
stress-free blood tests
Differential diagnosis
Pregnancy
Prolactin moderately raised [5002000 mU/L (25-100 ng/mL)]:

Primary hypothyroidism ( TRH drive to

PRL secretion)

Stress
Drug treatment [e.g. dopamine receptor
antagonists antiemetics, antipsychotics,
antidepressants, certain
antihypertensives (-methyldopa,
reserpine), opioids and H 2 antagonists]

Chronic renal failure (reduced clearance)

and cirrhosis

Idiopathic (PRL levels frequently return

to normal)

Stalk disconnection
Acromegaly
Chest wall injury
Nipple stimulation
High prolactin [>3000 mU/L (>150 ng/mL)]:
icroprolactinoma
M
Very high prolactin [

>6000 mU/L (>300 ng/

mL)]:

acroprolactinoma

Treatment
Dopamine agonist (e.g. cabergoline)
Surgery and radiotherapy rarely needed

primary
hypothyroidism
causing
inadequate
feedback of thyroid hormone on TRH, raised
TRH and lactotroph (as well as
thyrotroph) stimulation. Renal disease
can compromise clearance, slightly
elevating
circulating
PRL
levels.
Therefore, serum urea and electrolyte
assays, and tests for pregnancy and
thyroid function should be performed.
A drug history is important as some
pharmaco-

logical agents can stimulate PRL

release.
For
example, any drug that inhibits
dopamine
synthesis
(e.g. l-methyldopa) or action (e.g.
dopamine recep-

tor antagonists used as antiemetics) can

increase
serum
PRL
and
cause
galactorrhoea.
Having excluded other causes, the
aetiology
is
likely to be a pituitary tumour, most
frequently
a
microprolactinoma,
which
is
the
commonest
scenario in women of reproductive age. With
pituitary
pathology,
especially
larger
macroprolactinomas,
other anterior pituitary axes need to be
assessed
as
they may be underactive. On occasion,
acromegaly
may be suspected as some pituitary
tumours
can
secrete both GH and PRL, possibly
reflecting
the
shared developmental origin of the
somatotroph
and
lactotroph. There is also the possibility of
stalk
disconnection syndrome where a pituitary
tumour
(especially
if
superiorly
positioned),
previous
surgery
or trauma can block hypothalamic
dopaminergic
neurones from reaching the lactotrophs,
causing
a
mild rise in PRL. However, serum PRL
concentration above 2000 mU/L (100 ng/mL)
most
likely
indicates a prolactinoma. Thereafter,
serum
levels
tend to correlate with size and can
exceed
100,000 mU/L (5000 ng/mL) in large
tumours.

MRI will delineate the size of the

pituitary
tumour
and any impact on the surrounding
structures.
Where there is extensive growth close
to
the
optic
chiasm,
formal
visual
field
assessment
is
very
important.

Treatment

The
major
reasons
for
treating
hyperprolactinaemia are to prevent inappropriate
lactation, restore fertility and prevent
bone demineralization from inadequate
oestrogen in women or testosterone in
men (see Chapter 7).
Treatment is by cause. If secondary to
offending drugs, these should be
withdrawn
or
changed
wherever possible. This is frequently difficult
with
antipsychotic medication and treatment
changes should be discussed with the
mental
health
team.
Primary
hypothyroidism
is
treated
with
thyroxine.
Prolactinomas
are
exquisitely
sensitive
to
dopamine
agonists.
Therefore,
prolactinomas
of
all
sizes should be treated with medical
therapy
in
the
first instance, even in the presence of
optic
chiasm
compression and visual field loss.
Surgery
and/or
radiotherapy are only very rarely
required.
Upon
dopamine agonist treatment, PRL falls,
tumour
cells shrink quickly and sight is
commonly restored.

86 / Chapter 5: The hypothalamus and pituitary gland

Historically, bromocriptine has been

used;
however,
it is frequently associated with nausea
because
of
its
action on other dopamine receptor subtypes.
Better
alternatives now include cabergoline,
taken
orally,
usually twice weekly. By treating for 5
years,
the
majority of microprolactinomas are
cured,
i.e.
PRL
remains
in
the
normal
range
permanently
after
withdrawal of therapy. This is not true
of
large
macroprolactinomas, which are more
likely
to
require on-going treatment. In recent
years,
there
has been concern over drugs derived
from
ergot
alkaloids, like cabergoline, causing
sclerotic
heart
valve pathology. However, the data
emanate
from
use in Parkinson disease at much higher
dose
than
commonly
prescribed
for
hyperprolactinaemia
(e.g.
cabergoline 250 g twice weekly).
The management of prolactinomas
in
pregnancy can potentially be difficult.
Although
there
is
little evidence of a teratogenic effect,
dopamine
agonists
are
usually
stopped.
However,
the
lactotroph population normally increases
significantly
during pregnancy and there is a risk of
excessive
tumour
growth,
especially
from
macroadenomas.
Headaches and visual disturbance are
very
important symptoms. One strategy is to
conduct
visual
field analyses in each trimester. In

addition,
within
a specialist setting, observing serum
PRL
measurements broadly commensurate with
the
stage
of
pregnancy is reassuring that very
large
tumour
growth has not occurred. If necessary,
MRI
and
potential reinstitution of dopamine
agonist
therapy
can be considered.
Breast cancer
Epidemiological studies have linked
higher
levels
of PRL with increased risk of breast
cancer,
treatment failure and worse survival, but
whether
therapeutic lowering of PRL alters these
outcomes
is
unknown.
Hypoprolactinaemia
Low serum prolactin from loss of
lactotrophs in hypopituitarism has no
known clinical consequence beyond
failure of lactation and thus inability
to breast-feed. This demonstrates the
questionable
significance of PRL in humans other than
on
lactation
and
gonadotrophin
production.

Answers, see p. 97

Case history 5.3

A 16-year-old girl was referred to the
gynaecologist with a history of primary
amenorrhoea, tiredness and poor growth. She
was receiving no medication. She
was not sexually active. She was short.
Investigations showed raised PRL
[2000 mU/L (100 ng/mL)] and MRI
revealed an enlarged pituitary. Her renal
function was normal. A diagnosis of
prolactinoma was made and she was
treated with cabergoline. She started to
have periods but did not grow. Repeat
imaging of her pituitary showed no
change. At this point she was referred to
the endocrinologist who performed further
investigations and realized that the initial
diagnosis was wrong. Her treatment was
altered and she started to grow. Her
pubertal development continued and,
furthermore, there was complete
resolution of the abnormality on MRI.
What are the possible causes of
hyperprolactinaemia?
What investigation made the diagnosis?
Why did the pituitary enlargement on MRI
regress with treatment?

Adrenocorticotrophic hormone
ACTH is a short peptide of
39
amino
acids.
Residues 1-24 are highly conserved and
confer
full activity, such that synthetic
ACTH(1-24)
is used clinically to test adrenocortical
function
(see Chapter 6). ACTH comes from
the
proopiomelanocortin gene (POMC), which
encodes
the
POMC
protein
that
is
cleaved
enzymatically
into
many
potential
products
(Figure
5.11).
These
include several forms of melanocytestimulating
hormone (MSH) and -endorphin with
morphinelike activities that may inhibit pain
signals
to
the
brain. The enzyme that cleaves POMC
to yield