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Factsheet 6 Prolactin levels are normally high during pregnancy and lactation. Abnormally high levels of prolactin at other times may be caused by a prolactin-secreting Pituitary tumour or by a non-secreting pituitary tumour that prevents dopamine (prolactin release-inhibiting hormone) from the Hypothalamus reaching normal prolactinproducing cells (lactotrophs) of the pituitary. Raised prolactin levels are also sometimes found in Cushing’s syndrome, Hypothyroidism and polycystic ovarian disease. A number of drugs increase prolactin levels by blocking the action of dopamine, e.g., metoclopramide, domperidone, some anti-depressants and the phenothiazines. Stress raises prolactin levels so the very act of venepuncture can
result in high levels.
The behaviour of prolactin-secreting tumours is defined by their size at presentation. Microprolactinomas (less than 10mm in diameter) rarely expand to become macroprolactinomas. In men, prolactinomas tend to present late, because reduced potency and loss of libido - the hormonal effects of raised prolactin levels - are subtle and develop slowly. In women, absent periods and/or inappropriate production of breast milk often allow the diagnosis to be made early.
There should be a low threshold for referral for any patient with any Hyperprolactinaemia, as the greatest challenge in the diagnosis of hyperprolactinaemia is thinking of the disease. Once suspected biochemical confirmation or exclusion of the disease is usually straightforward. See ‘Who and When to Refer’ (factsheet 15). 
PRESENTING SYMPTOMS INVESTIGATIONS
Useful GP screening tests include basal prolactin, thyroid function tests, a careful drug history and exclusion of pregnancy. If prolactin (normal range <400 mU/l) is mildly elevated (400-1000 mU/l) it should be repeated before referral. Dynamic prolactin stimulation tests such as the TRH test have no part in the investigation of hyperprolactinaemia. Measurement of serum prolactin on three separate occasions (at least 2 hours after rising and when patient rested) provides all the information necessary. A prolactin level >5000 mU/l usually indicates a true Prolactinoma rather than a functionless tumour causing a raised prolactin. Specialist tests include pituitary imaging (preferably MRI) and visual field testing if indicated (macroadenomas) and assessment of pituitary function. Macroprolactin is a biologically inactive form of prolactin that causes no clinical problem, other than being detected in prolactin assays resulting in spurious elevation of serum prolactin levels. Macroprolactin should be suspected in any patient with an elevated prolactin but no associated signs or symptoms. Most laboratories can test for macroprolactin. Please see ‘Who and When to Refer’ (factsheet 15). TREATMENT OBJECTIVES AND POSSIBILITIES
Osteoporosis is a concern in any patient with Hypogonadism " manifest clinically as amenorrhoea or erectile dysfunction. In any patient with one year of hypogonadism a bone density scan should be performed and a major goal in the treatment of hyperprolactinaemia is the prevention of osteoporosis. In addition treatment should stop galactorrhoea and restore Oestrogen levels in women, and hence menstruation, fertility, libido and vaginal lubrication to normal. In men treatment of high prolactin should normalise Testosterone levels, and hence erectile function and libido. For macroprolactinomas, an additional objective is to shrink the tumour in order to reduce any pressure effects, such as visual failure.
PATIENT MANAGEMENT
Most patients are treated medically with the dopamine agonists cabergoline, or Bromocriptine, both of which reduce prolactin levels, allow oestrogen or testosterone levels to rise and greatly reduce the size of the tumour. Surgery to reduce tumour size, and Radiotherapy to reduce the chance of recurrence, are rarely required. Medical treatment with cabergoline, quinagolide, or bromocriptine controls prolactin and symptoms in the majority of patients, but needs to be continued long term. In patients with microprolactinomas an attempt to withdraw the medication can be made after 3 years. These drugs can be associated with some dizziness and nausea. This can be limited by taking the medicine in the middle of meals or last thing at night and by starting at low dose. Cabergoline is the most widely prescribed treatment for prolactinoma as it is more potent and associated with fewer side-effects. However, recent guidance suggests that patients taking cabergoline should have regular examination of the heart (echocardiography) and watch out for shortness of breath as cabergoline can cause (at higher dosage) fibrosis of the lungs and heart valves. PREGNANCY AND PROLACTINOMAS
Patients should be followed during pregnancy by an Endocrinologist. Ideally it is advisable for patients to have discussed pregnancy with their endocrinologist prior to conception. Most women are advised to cease taking dopamine agonists for the duration of pregnancy and during lactation. However, many thousands of babies have been born to mothers taking bromocriptine and there is no evidence of an increased incidence of malformation or miscarriage. Cabergoline treatment appears to be safe during pregnancy. During pregnancy, there is a slight risk of tumour enlargement, particularly in patients with macroadenomas. Any patient who experiences severe headaches or visual disturbances should be seen urgently by their specialist. WATCHPOINTS
Urgent - refer to hospital Non-urgent (but still very important) Remember that successful treatment usually results in restoration of fertility (particularly in microprolactinomas) Patients may be predisposed to problems related to osteoporosis Ask about erectile function. Reassure that it is part of the disease and that it can be treated
QUESTIONS PATIENTS MAY ASK Why do I have a discharge from my breasts?
Prolactin is normally required to initiate and maintain lactation. The secretion of prolactin from a pituitary tumour may have the same effect. Will a Microprolactinoma grow into a Macroprolactinoma?
In the vast majority of cases, no. This very rarely happens. Have I inherited this, will my children get it?
In all but very exceptional circumstances there is no hereditary link. Do all patients with prolactinomas need treatment?
Most do. If you have infertility problems, problems with lack of interest in sex (low libido) or impotence, excessive milk production or a large tumour causing pressure symptoms, then there is a clear case for treatment. If not, then the need may not seem so clear. However, prolonged sex-hormone deficiency (particularly oestrogen in women) causes thinning of the bones, or osteoporosis. Therefore, most doctors believe that women without regular periods should receive treatment. The same applies to men with low testosterone levels. How long will I have to take tablets for prolactinoma?
You will probably need to take these tablets for a relatively long time, with interruption during pregnancy as described earlier. If you have a microprolactinoma, many specialists withdraw treatment for a trial period every three years or so; in some patients the problem seems to disappear during prolonged tablet treatment. If you have a large tumour, your treatment courses may last several years; tumour control is maintained and side-effects during long-term treatment are not usually a problem. What are my fertility prospects as a man with prolactinoma?
Tablet treatment alone may improve your sperm count and lead to the return of normal fertility, although this may take several months. Additional treatment with hormone injections (FSH and LH) may also be necessary. Fertility is usually attainable. Is tablet treatment better than surgery for prolactinomas?
Tablet treatment is the accepted form of treatment. Occasionally (5-10%) patients have either severe side effects or do not respond to cabergoline. In these patients surgery may be advised although it is not always curative (70-80%) and the operation may cause hypopituitarism.
RESOURCES FOR PATIENTS
available from The Pituitary Foundation HelpLine or our website www.pituitary.org.uk or our Endocrine Nurse HelpLine Patient Information Booklet Prolactinoma
Other information and resource links available at www.pituitary.org.uk FOR GPs MORE SPECIALIST RESOURCES Management of Pituitary Tumors: The Clinician’s Practical Guide (2003) (Second Edition), Editors and authors Michael P. Powell, Stafford L. Lightman and Edward R. Laws. Humana Press, Totowa, New Jersey Pituitary Tumours. Recommendations for service provision and guidelines for management of patients. Consensus statement of a working party (1997) RN Clayton & JAH Wass (Eds) London: Royal College of Physicians The Diagnosis and Treatment of Pituitary Insufficiency (1997) Lamberts SWJ (Ed) Bristol, UK: BioScientifica Endocrinology (1997) Levy A & Lightman SL New York: Oxford University Press The Epidemiology, Pathogenesis and Management of Pituitary Tumours (1998) Webb SM (Ed) Bristol, UK: BioScientifica
©2011 Version 3 (To be reviewed by 2013)
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