Best Practice & Research Clinical Obstetrics and Gynaecology

Vol. 22, No. 2, pp. 341353, 2008

doi:10.1016/j.bpobgyn.2007.08.002
available online at http://www.sciencedirect.com

7
Hyperprolactinaemia
V.K.B. Prabhakar

MBBS, MRCP(UK)

Specialist Registrar

J.R.E. Davis *

MD, PhD, FRCP

Professor of Medicine
Department of Endocrinology, Manchester Royal Infirmary, Manchester M13 9WL, UK

Hyperprolactinaemia is a frequent cause of reproductive problems encountered in clinical

practice. A variety of pathophysiological conditions can lead to hyperprolactinaemia; therefore,
pregnancy, drug effects, hypothyroidism and polycystic ovary syndrome should be excluded before investigating for prolactin-secreting pituitary tumours. Prolactinomas are mainly diagnosed
in women aged 2040 years. They present with clinical features of hyperprolactinaemia (galactorrhoea, gonadal dysfunction), and more rarely with large tumours, headache and visual field
loss due to optic chiasm compression. Medical therapy with dopamine agonists is the treatment
of choice for both micro- and macroprolactinomas. Tumour shrinkage and restoration of gonadal function are achieved in the majority of cases with dopamine agonists. A trial of withdrawal
of medical therapy may be considered in many patients with close follow-up. Pituitary surgery
and radiotherapy currently have very limited indications. Pregnancies in patients with prolactinomas need careful planning and close monitoring.
Key words: dopamine agonists; hyperprolactinaemia; pituitary; prolactin; prolactinomas.

The term hyperprolactinaemia refers to an increase in circulating prolactin (PRL)

levels, and is a frequent cause of reproductive problems, particularly anovulatory infertility in women. It is the most common pituitary hormone abnormality seen in clinical
practice. In this review, current knowledge about the biology of PRL will be outlined
briefly, followed by a discussion of the causes, clinical features and current management of hyperprolactinaemia.

* Corresponding author. Tel.: 44 (0)161 275 5181; Fax: 44 (0)161 275 5958.
E-mail address: julian.davis@manchester.ac.uk (J.R.E. Davis).
1521-6934/$ - see front matter 2007 Elsevier Ltd. All rights reserved.

342 V. K. B. Prabhakar and J. R. E. Davis

PRL BIOLOGY
PRL is a peptide hormone evolutionarily related to growth hormone (GH) and structurally similar; its identification as a separate hormone in the early 1970s following the
introduction of a specific radio-immunoassay1 paved the way for further understanding
of this hormone and the associated pathophysiological conditions. Human PRL is a single-chain polypeptide of 199 amino acids2, with three intramolecular disulphide bonds
between six cysteine residues3 and a molecular weight of 23 kDa. Its three-dimensional structure consists of four major a helices arranged in anti-parallel fashion4, similar to many other cytokines. Several variants of PRL are known to exist, produced as
a result of translational changes.
The PRL gene in man is located on chromosome 6, comprises five coding exons and
four introns5, is 10 kb in size and encodes a single PRL in humans.6 The PRL gene has
40% homology to the pituitary GH gene on chromosome 17.7 In the pituitary, PRL
gene expression is dependent on the pituitary-specific transcription factor Pit-18,
while in the extrapituitary tissues such as uterus and T-lymphocytes, gene expression
is driven by an alternative upstream promoter.9,84 PRL mRNA expression is found at
its highest level in pituitary lactotrophs, and usually at lower levels in extrapituitary
sites.10
The PRL receptor (PRL-R) is a transmembrane protein belonging to the cytokine
receptor superfamily.11,12 It is encoded by a single gene located on chromosome 5,
close to the GH receptor gene.13 PRL-R and its mRNA are predominantly present
in breast tissue and ovary14, but a wide variety of peripheral tissues also express
PRL-R.15
Biological effects of PRL
PRL, traditionally named from its lactogenic action (mammogenesis and galactopoiesis
included), is now recognized from animal studies to have over 300 identifiable bioactivities corresponding to the wide distribution of PRL-Rs, including osmoregulation,
reproduction, behaviour modification and immune modulation.15 Many of these functions are difficult to discern in man, however, where the reproductive roles of PRL are
the most evident in terms of clinical disease.
While the tumour-promoting potential of locally produced PRL in breast16,17 and
prostate18 tissues is firmly established in the animal models, such evidence is currently
not available in humans. However, local production of PRL is demonstrated in human
tissues, including breast19 and prostate.20 Although the emerging epidemiological evidence seems to suggest that raised PRL is a risk factor for human breast cancer21,22,
and perhaps prostate cancer23, the exact roles of systemic and locally produced PRL
need further clarification.
Pituitary PRL secretion and control
Pituitary PRL secretion follows a circadian rhythm with the highest plasma PRL concentration seen during sleep, and the lowest during waking periods.24 This circadian
rhythm is independent of sleep and is thought to involve both the central circadian
pacemaker in the hypothalamic suprachiasmatic nucleus, and direct effects of pineal
melatonin secretion on the pituitary.25

Hyperprolactinaemia 343

Pituitary PRL is mainly under inhibitory control exerted by the hypothalamus. The
dopaminergic neurons of the periventricular and arcuate nuclei of the medial basal hypothalamus provide dopamine to the pituitary gland through the hypothalamohypophyseal portal blood. Dopamine is the main PRL inhibitory factor, while neuropeptides
such as thyrotrophin-releasing hormone (TRH), oxytocin, vasopressin and vasoactive
intestinal polypeptide promote PRL secretion.
CLINICAL FEATURES OF HYPERPROLACTINAEMIA
Persistent hyperprolactinaemia interrupts the pulsatile secretion of gonadotrophinreleasing hormone, inhibits the release of luteinizing hormone and follicle-stimulating
hormone26, and directly impairs gonadal sex steroid production. Collectively, these
result in clinical features attributable to hyperprolactinaemia (Box 1).
Box 1. Clinical features of hyperprolactinaemia






Reduced libido, infertility, decreased bone density (both sexes)

Galactorrhoea, oligo-/amenorrhoea (women)
Galactorrhoea, gynaecomastia (very rarely in men)
Delayed puberty (in adolescents)
Mass effects such as headaches, visual field changes, cranial nerve palsies and
anterior hypopituitarism (with macroprolactinomas)

In hyperprolactinaemic women, the incidence of galactorrhoea is up to 80%, depending on the diligence with which galactorrhoea is sought.27,28 Hyperprolactinaemia
may be found in 30% of women with secondary amenorrhoea, and in 75% of women
with both amenorrhoea and galactorrhoea.27 In men, on the other hand, galactorrhoea usually only occurs with extremely high PRL levels. Gynaecomastia is a manifestation of secondary hypogonadism rather than raised PRL levels per se.
While weight gain is noted to be associated with hyperprolactinaemia, normalization of PRL level resulted in weight loss in one study29, but another retrospective
study found no correlation between the two.30 Further data are needed to help
understand this better. Hyperprolactinaemia may be associated with subtle psychological symptoms such as anxiety, depression and hostility that occasionally persist even
after successful treatment of elevated PRL.31,32
CAUSES OF HYPERPROLACTINAEMIA
Various causes of hyperprolactinaemia are listed in Boxes 2 and 3. The most common
reasons in clinical practice are a variety of pharmacotherapeutic agents that reduce hypothalamic secretion of dopamine or its action in the pituitary, which typically cause
mild to moderate hyperprolactinaemia (Box 3). Mild stress, including the stress of
venepuncture, can induce transient elevations in serum PRL, which needs to borne
in mind before making a firm diagnosis and proceeding to further investigation. Mild
hyperprolactinaemia is seen in a proportion of cases of polycystic ovary syndrome
(PCOS), usually with no pituitary lesion, although PCOS and prolactinoma may coexist and may need to be treated independently.33

344 V. K. B. Prabhakar and J. R. E. Davis

Box 2. Causes of hyperprolactinaemia

Physiological







Pregnancy
Lactation
Breast stimulation
Stress
Sexual intercourse
Exercise

Pathological
 Functioning pituitary tumours
Prolactinomas
Mixed GH/PRL and adrenocorticotrophic hormone/PRL adenomas
 Non-functioning pituitary tumours/pituitary stalk disconnection

Non-functioning pituitary adenoma

Craniopharyngioma
Germinomas
Meningiomas
Empty sella syndrome
Lymphocytic hypophysitis
Infiltrative conditions (sarcoidosis, tuberculosis, histiocytosis X, metastasis)
Irradiation to hypothalamo-pituitary region
Trauma to pituitary gland/hypothalamus

Pharmacological (see Box 3)

Others






Primary hypothyroidism
Chronic renal failure
Severe hepatic insufficiency
PCOS
Chest wall lesions (trauma, surgery, herpes zoster)

Sellar and parasellar lesions, including pituitary and non-pituitary tumours and infiltrative conditions, frequently cause hyperprolactinaemia through a functional disconnection that interrupts the normal dopaminergic inhibition of lactotroph cells,
causing raised serum PRL levels. In primary hypothyroidism, stimulatory effects of
elevated TRH on PRL secretion result in high PRL levels.34
Prolactinomas, the most common cause of tumoral hyperprolactinaemia, account
for nearly 30% of pituitary adenomas, and have an estimated prevalence of 100 per
1 million population.35 The great majority of prolactinomas are microadenomas
(<1 cm in size), presenting with clinical features secondary to hyperprolactinaemia,

Hyperprolactinaemia 345

Box 3. Drugs causing hyperprolactinaemia

 Antipsychotics
Phenothiazines, haloperidol
Risperidone (atypical agent)
 Antidepressants
Tricyclic and tetracyclic agents
Monoamine oxidase inhibitors
Selective serotonin re-uptake inhibitors
 Anti-emetics
Metoclopramide, domperidone
 Antihypertensives
Methyldopa, verapamil
 Opiates
Morphine, methadone
 Others
Oestrogens
Cocaine
Cimetidine

whereas macroadenomas (>1 cm in size) may, in addition, present with mass effects
(Box 1). Prolactinomas are usually diagnosed in females between the third and fifth decades of life; after 50 years of age, the frequency is similar in both sexes.36 Men tend to
present relatively late and typically have macroadenomas.37 Prolactinomas may infrequently present as a component of multiple endocrine neoplasia type 1.38
EVALUATION OF PATIENTS WITH HYPERPROLACTINAEMIA
Clinical assessment
Initial assessment of a patient with hyperprolactinaemic symptoms and persistently
elevated serum PRL should include a detailed clinical history, careful drug history, physical examination including direct confrontation testing of visual fields, pregnancy test,
routine blood tests (renal and hepatic function), thyroid function testing and a consideration of PCOS. A single PRL measurement is usually sufficient for diagnosis, but a repeat blood sample taken without significant venepuncture stress may be necessary.
Biochemical evaluation: interpretation of serum PRL
In the commonly used assays, normal PRL levels in men and women are usually quoted
as being <20 mg/L and <25 mg/L, respectively (1 mg/L equivalent to 21.2 mU/L).

346 V. K. B. Prabhakar and J. R. E. Davis

However, the reference range for most laboratories is skewed, and a reference range
up to 35 mg/L (700 mU/L) may be more appropriate in premenopausal women.39
While the values are certainly not absolute, the recently published guidelines from
the Pituitary Society40 suggest that PRL values up to 100 mg/L (2000 mU/L) may be due
to psychoactive drugs, oestrogens, idiopathic causes or even microprolactinomas,
whereas macroprolactinomas are typically associated with levels >25 mg/L
(>5000 mU/L). Recent evidence from a large series suggests that PRL level in nonfunctioning pituitary adenomas (causing stalk disconnection hyperprolactinaemia) is
almost always <100 mg/L (<2000 mU/L).41
Patients with a large pituitary mass should be investigated for anterior hypopituitarism. In the authors unit, initial basal determinations of pituitary and target organ hormones, as well as insulin-like growth factor-1, are measured routinely in order to rule
out possible secondary hypoadrenalism and hypothyroidism associated with significant
pituitary disease, and to exclude excess GH co-secretion from mammosomatotroph
pituitary tumours.
PRL may form immune complexes, generally with an immunoglobulin G antibody, to
produce a biologically inactive form called macroprolactin42, which has a molecular
mass of more than 150 kDa. This is registered by most PRL immunoassays and hence
serum PRL levels are reported to be high. Since misdiagnosis of hyperprolactinaemia
due to the presence of macroprolactin may lead to patient mismanagement, this possibility should be considered in cases with no apparent hyperprolactinaemic symptoms.
Polyethylene glycol precipitation is the method of choice to confirm macroprolactinaemia, which in itself has no clinical significance, although it should be remembered that
genuine pituitary pathology may co-exist in nearly 5% of such cases.43
Radiological assessment
Patients with persistent hyperprolactinaemia should be investigated for possible structural pathology in the hypothalamo-pituitary region, after other common causes have
been excluded.
Magnetic resonance (MR) scanning is currently the radiological investigation of choice44,
with the use of gadolinium enhancement increasing the detection of microadenomas. If MR
imaging is contra-indicated or inappropriate, a computed tomography scan with intravenous contrast is the best available option, although frequently repeated scans do entail a significant radiation dose, particularly important with regard to the eyes. Patients with
macroadenomas that might impinge on the optic apparatus should undergo formal visual
field assessment (e.g. by Goldmann perimetry or by computerized charting).
Pituitary microadenomas are found in 1020% of the normal population as judged
by autopsy studies. Therefore, the presence of an MR-scan-detected pituitary
adenoma in a patient with hyperprolactinaemia is suggestive but not absolutely diagnostic that the lesion is a prolactinoma. On the other hand, no demonstrable lesion
may be seen in these patients even on high-resolution imaging, suggesting that they
either harbour a microadenoma <2 mm in diameter, or that they have lactotroph
hyperplasia or idiopathic non-tumoral hyperprolactinaemia.
TREATMENT OF HYPERPROLACTINAEMIA
The objectives of treatment of hyperprolactinaemia are to normalize serum PRL levels
in order to restore gonadal function and stop galactorrhoea, and in the case of

Hyperprolactinaemia 347

prolactinomas, also to reduce tumour mass, preserve residual pituitary function and
prevent disease progression. Recognized indications for therapy include hypogonadism
(oligo-/amenorrhoea, infertility, impotence, osteoporosis/osteopenia), tumour mass
effect, and significant or troublesome galactorrhoea.
Asymptomatic patients may not require treatment45, and periodic observation
should then suffice. Studies examining the natural history of untreated microprolactinomas have shown that significant growth of these tumours is uncommon.46 Women
with hyperprolactinaemia but normal regular menses are not at risk of osteoporosis
and, again, periodic observation should suffice.39
Medical therapy
Dopamine agonists (DAs) play a major role in the management of both idiopathic/nontumoral and prolactinoma-related PRL excess. These agents act on dopamine D2-type
receptors on pituitary lactotroph cells, resulting in a decrease in synthesis and release
of PRL.47,48 By mechanisms yet to be fully understood, DA therapy is known to cause
marked and sometimes dramatic reductions in prolactinoma tumour volume.45
Three DAs have been licensed for use in the UK, namely bromocriptine (BC),
cabergoline (CAB) and quinagolide. While all three lower serum PRL on oral administration and also reduce tumour size, they differ in their affinity for D2 receptors and
plasma half-life. CAB has the highest affinity and greatest selectivity for D2 receptors.49 The half-lives of CAB, quinagolide and BC are 65 h49, approximately 24 h
and 812 h, respectively, thereby influencing the dosing regimen.
BC was developed in the 1970s as the first of the DAs to be introduced for pituitary disease, and there is a wealth of data regarding its safety and efficacy50 in addition
to clinical experience. BC is known to normalize PRL levels in 8090% of patients with
microprolactinomas and nearly 70% of those with macroprolactinomas, together with
tumour shrinkage.5052 However, nearly 60% of patients develop side-effects53, mainly
gastrointestinal (nausea, dyspepsia, abdominal pain). Other common problems include
postural hypotension, dizziness and headache. In the past 20 years, agents with better
side-effect profiles have been developed, notably CAB and quinagolide. CAB has been
found to be better tolerated than BC, and more efficient in normalizing PRL level, improving gonadal function and achieving comparable tumour shrinkage.54,55 Quinagolide
also provides a safe therapeutic option, and is efficacious in patients with BC intolerance/resistance.56,57
Resistance to DAs
Resistance to DAs in prolactinomas, defined as failure to normalize serum PRL levels
and failure to reduce tumour size, is thought to relate to a low density of membrane
D2 receptors on some lactotroph tumours.58 A recent review by Olafsdottir and
Schlechte59 indicated that nearly 20% of patients treated with BC for microprolactinoma/idiopathic hyperprolactinaemia, and 30% treated for macroprolactinoma, failed
to normalize serum PRL, whereas the corresponding figures for CAB were better
at 10% and 20%, respectively. With regard to tumour size, <10% of CAB-treated patients with microadenomas and macroadenomas failed to show tumour reduction of
more than 3050%. It should be noted that some DA-resistant patients normalize
PRL levels on therapy with no change in tumour size, and vice versa. Prolactinomas
in men are more often resistant to BC60, and invasiveness of these tumours is a negative predictor of response to DAs.61

348 V. K. B. Prabhakar and J. R. E. Davis

Management of DA resistance currently includes progressive increase in the DA

dosage, changing the DA, and resorting to trans-sphenoidal pituitary surgery if necessary. A novel class of compounds called PRL-R antagonists, akin to the GH-receptor
antagonist pegvisomant used in acromegaly, may have a future therapeutic role in
DA-resistant prolactinomas.62
Surgical treatment and radiotherapy
The efficacy of medical treatment in restoring a normoprolactinaemic state without
the risk of pituitary insufficiency has limited the indications for surgical resection of
prolactinomas. Surgery may achieve a long-term cure, but remission rates are no better than 60%.6365 Nowadays, surgery is usually reserved for cases of intolerance/resistance to medical therapy, persistent tumour mass effect despite maximal DA
treatment, and considered in patients who are dependent on antipsychotic medication. In young patients with microprolactinomas wishing to avoid long-term medical
therapy, curative surgery may be an option66 when neurosurgical expertise is locally
available.
Radiotherapy is used very infrequently; external beam radiotherapy to the hypothalamo-pituitary region has considerable side-effects including anterior hypopituitarism67, optic nerve damage and increased risk of cerebrovascular disease. It has
a role for macroprolactinomas that are not responsive to other modes of treatment,
or when medical and/or surgical therapies are contra-indicated/felt to be
inappropriate.
TREATMENT OF HYPERPROLACTINAEMIA: MANAGEMENT ISSUES
Pregnancy and the hyperprolactinaemic woman
DA therapy restores ovulation in about 90% of women with anovulatory infertility secondary to hyperprolactinaemia. Patients who do not wish to conceive should be advised
to use contraception, as return of fertility may not be immediately apparent. DAs are normally stopped following confirmation of pregnancy in order to avoid any possible teratogenic risk and so as not to prevent lactation at term. Even when DAs are
discontinued early, the fetus is probably exposed to these drugs for up to 34 weeks
of gestation; however, no adverse outcome has been reported during pregnancy68 or
childhood.69 Whereas BC has a proven safety record in pregnancy70, the data on CAB
and quinagolide are still limited. DAs impair lactation and hence are avoided in the postpartum period when breastfeeding is desired by the patient.
The pituitary gland normally enlarges during pregnancy due to the stimulatory
effects of oestrogen. According to a recently published meta-analysis71, the risk of symptomatic tumour enlargement is low (12.6%) in patients with microprolactinomas, and is
substantially higher (approximately 30%) in patients with macroprolactinomas. The overall risk declined to 5% if the macroprolactinomas were treated surgically or irradiated
before pregnancy.
Women should therefore be counselled about these risks before embarking on
pregnancy, and should be advised regarding close monitoring on clinical grounds. Visual
field testing can be a helpful guide, and there is limited value in measuring serum PRL
levels.72 Symptomatic tumour expansion needs confirmation with a MR scan, and duly

Hyperprolactinaemia 349

responds to restarting a DA, but surgery is required on occasions when the lesions
become sight threatening.73
Hyperprolactinaemic women who have had a normal pregnancy may subsequently
normalize their PRL levels in nearly 35% of cases, compared with 14% in those who
had not been pregnant.74 This suggests that pregnancy may trigger a return of the pituitary to normality; therefore, it is important to review the PRL status several months
postpartum before re-instating any medical therapy.
Use of oral contraceptives (oestrogen)
When a woman with raised PRL does not wish to become pregnant or is intolerant to
various DAs, oestrogen-replacement therapy may be warranted to prevent osteoporosis or to improve libido. Hypogonadal women with microprolactinomas may therefore be treated for their hypogonadism with combined oral contraceptive agents75
when galactorrhoea is not a major problem. While published data on patients with
prolactinomas who are treated with oral contraceptives for hypogonadism have not
shown any substantial risk for tumour enlargement76, it is advisable to monitor patients who use oral contraceptives carefully with periodic measurement of PRL
levels.77
Menopause
Female patients with hyperprolactinaemia who go through the menopause have a significant chance of normalizing their PRL levels.78 The menopause is an indication for reassessment of the need to continue to treat with DAs. If galactorrhoea or pituitary
mass lesion are not significant problems, treatment may no longer be necessary. Hormone-replacement therapy with oestrogens can be considered if bone protection is
required, provided that PRL levels and pituitary anatomy are monitored.
Antipsychotic medication
In cases of hyperprolactinaemia due to psychoactive medications, it is considered unwise to initiate DA therapy for the fear of precipitating a psychotic crisis.79 In most
such situations, the role of the endocrinologist is limited to the exclusion of any significant co-existing hypothalamo-pituitary structural lesion. Occasionally, psychiatric
management can be adjusted and drugs substituted, for example olanzapine, which
is said to have a lesser effect on PRL secretion.80,81
Remission of hyperprolactinaemia and prolactinoma
As noted previously, remission of prolactinomas, which are inherently very indolent,
has been described as part of the natural history of untreated tumours.46 In addition,
follow-up studies of patients treated with DAs revealed remission of hyperprolactinaemia, without recurrence on discontinuation of therapy.74,82 A recent prospective
study83 on 200 patients treated with CAB for hyperprolactinaemia indicated that
the overall estimated rates of remission at 5 years were 76% among patients with
non-tumoral hyperprolactinaemia, 67% among those with microprolactinomas, and
57% among those with macroprolactinomas. The estimated rate of recurrence at
5 years was higher among patients with macroprolactinomas and those with

350 V. K. B. Prabhakar and J. R. E. Davis

microprolactinomas who had small remnant tumours visible on MR scan at the time of
treatment withdrawal than among patients whose scans showed no evidence of tumour
at the time of withdrawal.85 These data support a trial cessation of therapy in selected
cases, especially in patients with negative pituitary MR studies during treatment. Longer
follow-up is essential with close monitoring for recurrent hyperprolactinaemia and
renewed tumour growth.
SUMMARY
Hyperprolactinaemia is the most common pituitary hormone disorder encountered in
clinical practice, and is associated with anovulatory infertility, galactorrhoea and hypogonadism. The causes are numerous, with prolactinomas being the most frequent
form of pituitary disease. Medical therapy is successful in achieving normoprolactinaemia in most but not all patients, and other modes of treatment such as surgery and
radiotherapy have very limited indications. Newer DAs have fewer side-effects and
better tolerability compared with BC. Pregnancy is usually successful but demands
careful counselling and close follow-up. Drug treatment can be safely withdrawn in
some patients who have achieved good control of hyperprolactinaemia.
Research agenda





weight gain in hyperprolactinaemia

role of locally produced PRL in breast and prostate cancers
potential role of PRL-R antagonists as therapeutic agents
pathogenesis of hyperprolactinaemia and prolactinoma

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