PITUITARY

Prolactin disorders
Jeannie F Todd

Secretion of prolactin by lactotrophs in the anterior pituitary gland

is inhibited by dopamine acting via D2 receptors on the lactotroph
cells. Therefore, any process that disrupts dopamine secretion or
interferes with delivery of dopamine to the portal vessels may
cause hyperprolactinaemia. The primary action of prolactin is
to stimulate lactation, but hypersecretion of prolactin leads to
infertility and gonadal dysfunction because of its inhibitory effects
on gonadotropin-releasing hormone and pituitary gonadotrophin
release, and impairment of gonadal steroidogenesis.

Aetiology and differential diagnosis

Normal prolactin levels in women and men are less than 625 mU/
litre and less than 375 mU/litre, respectively. Because prolactin
gene expression and synthesis are controlled by oestrogen, prolactin levels are higher in premenopausal women than in men, and
physiological hyperprolactinaemia, leading to a tenfold increase
in circulating prolactin levels, can occur during pregnancy and
lactation. Prolactin levels also increase after meals, after exercise,
and during physical and psychological stress.
Iatrogenic hyperprolactinaemia can be caused by drugs that
block D2 receptors, such as the major tranquillizers (e.g. phenothiazines, butyrophenones) and anti-emetics (e.g. metaclopramide). Risperidone, monoamine oxidase inhibitors and tricyclic

Whats new ?
Cabergoline is now the first-line treatment for
microprolactinoma and macroprolactinoma
MRI of the pituitary has superseded CT as the first-line
investigation
Continuation of cabergoline therapy is advisable during
pregnancy in patients with a macroprolactinoma, but
can be stopped in those with a microprolactinoma

Jeannie F Todd is Consultant Endocrinologist and Senior Lecturer in

Imperial College Faculty of Medicine at Hammersmith Hospital, London,
UK. She qualified from Kings College Hospital, London. Her research
interests include neuroendocrine control of pituitary function, and
neuroendocrine tumours. Conflicts of interest: none declared.

MEDICINE 33:11

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2005 The Medicine Publishing Company Ltd

PITUITARY

Dopamine agonist therapy, usually with bromocriptine or

cabergoline, is the primary therapy for microprolactinomas and
macroprolactinomas. These drugs reduce both prolactin secretion
and the size of the tumour.
Bromocriptine is a D2 receptor agonist. Therapy should be
started at a dose of 0.625 mg at night; after 1 week, a morning
dose of 1.25 mg can be added. The dose should be increased by
1.25 mg per week; a daily dose of 57.5 mg is usually required to
restore menses and normalize prolactin levels. Side-effects including nausea, orthostatic hypotension and depression are minimized
by taking the drug at night.
Cabergoline is a long-acting D2 receptor agonist that is taken
once or twice per week. It is more effective in reducing prolactin
and restoring ovulatory cycles (90% and 85% of patients, respectively) than is bromocriptine (59% and 52%) at doses of 2.55 mg
twice daily.1 Cabergoline also reduces the size of macroadenomas
in 90% of patients, and is better tolerated than bromocriptine,
with fewer and milder side-effects. Therapy is started at a dose of
0.25 mg per week and increased to a maximal 1 mg twice weekly;
0.250.5 mg is usually sufficient to normalize prolactin levels.
Pregnancy the risk of symptomatic enlargement of a microadenoma during pregnancy is about 13%, so dopamine agonists
can be stopped once pregnancy is confirmed. However, macroadenomas carry a greater risk of growth during pregnancy (reported
rates are 1535%) and therefore dopamine agonist therapy should
be continued. Although carbergoline is not licensed in pregnancy,
no adverse effects have been reported.2

antidepressants can also cause hyperprolactinaemia. Oestrogen

therapy causes mild increases in prolactin.
Hyperprolactinaemia can occur as part of a pathological process such as pituitary stalk compression or in the presence of a
prolactin-secreting tumour or prolactinoma. Prolactinomas are
benign tumours that account for 40% of pituitary tumours; more
than 90% are intrasellar microprolactinomas (< 10 mm) that
seldom increase in size.
Primary hypothyroidism and chronic renal failure may lead
to hyperprolactinaemia as a consequence of increased synthesis
of thyrotrophin-releasing hormone and reduced clearance of the
hormone, respectively.
Pathological hyperprolactinaemia should be suspected in
patients with a prolactin concentration of consistently more than
700900 mU/litre with no identified physiological or drug cause.

Clinical features
The clinical features of hyperprolactinaemia vary with the patients
sex and age, and the size of the tumour.
Hypogonadism is the most common presenting feature in
premenopausal women with a delayed menarche, menstrual disturbance such as oligomenorrhoea or amenorrhoea, and infertility.
Galactorrhoea is present in about 3080% women; this may reflect
the duration of gonadal dysfunction, because women with longstanding oestrogen deficiency are less likely to have galactorrhoea.
Most prolactinomas in women are small at the time of diagnosis,
and headaches and neurological deficits are rare.
Men may also present with symptoms of hypogonadism such
as loss of libido, impotence and infertility. However, both men and
postmenopausal women often come to medical attention because
of symptoms of a pituitary mass (e.g. headache, visual loss, cranial
nerve dysfunction) or symptoms suggesting hypopituitarism (e.g.
hypoadrenalism, hypothyroidism).
In both sexes, long-standing hyperprolactinaemia leads to low
bone mineral density.

Trans-sphenoidal surgery is an option in infertile patients who

cannot tolerate or are resistant to dopamine agonists.

Investigations
A single measurement of prolactin level is usually adequate to
diagnose hyperprolactinaemia. When the result is borderline, it
is worth repeating the test, because of the effects of stress. Most
causes of hyperprolactinaemia can be excluded on the basis of the
history (including drug history), examination, pregnancy testing
and assessment of thyroid and renal function.
When other causes of hyperprolactinaemia have been excluded,
the diagnosis of prolactinoma is confirmed by gadoliniumenhanced pituitary MRI, though CT with contrast is an alternative.
Prolactinomas are classified as microadenomas if less than 10 mm
in diameter and macroadenomas if 10 mm or more. Patients with
macroadenomas that extend beyond the sella should undergo
formal visual field testing to exclude visual field defects, and
dynamic testing of the anterior pituitary function to exclude
hypopituitarism.

REFERENCES
1 Webster J, Piscitelli G, Polli A et al. A comparison of cabergoline and
bromocriptine in the treatment of hyperprolactinemic amenorrhea.
N Engl J Med 1994; 331: 9049.
2 Robert E, Musatti L, Piscitelli G et al. Pregnancy outcome after
treatment with the ergot derivative, cabergoline. Reprod Toxicol
1996; 10: 3337.
FURTHER READING
Molitch M E. Disorders of prolactin secretion. Endocrinol Metab Clin
North Am 2001; 30: 585610.
Rains C P, Bryson H M, Fitton A. Cabergoline. A review of its
pharmacological properties and therapeutic potential in the
treatment of hyperprolactinaemia and inhibition of lactation. Drugs
1995; 49: 25579.
Schlechte J A. Prolactinoma. N Engl J Med 2003; 349: 202333.

Management
The aim of treatment is to reduce the size of the tumour and to
restore gonadal function.

MEDICINE 33:11

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2005 The Medicine Publishing Company Ltd