Prolactinoma

Dr Sarah Olson, Neurosurgeon, Princess Alexandra Hospital, Brisbane 
FRACS, MBChB, MPhil, and

Dr Ross Cuneo, Endocrinologist, Princess Alexandra Hospital, Brisbane 
FRACP, MBBS, PhD

Contents

 

Introduction

The pituitary gland plays a critical role in regulating growth and development, metabolism and reproduction.  It produces prolactin and a variety of other important hormones. Prolactin normally stimulates the breast to produce milk during pregnancy.

6 - 25% of people are shown to have a pituitary tumour at autopsy and many are prolactinomas.  The majority of such incidentially discovered tumours appear not to have been clinically significant for the patient.  Based on size prolactinomas can be classified as microprolactinoma (<10mm) or macroprolactinoma (>10mm). Clinically significant pituitary tumours occur in 0.01 % of the population.  Prolactinomas constitute approximately 25% of clinically significant tumours.  Sometimes Growth Hormone producing tumours also secrete prolactin.

Most pituitary tumours are sporadic and are not genetically passed from parent to child.  They are most common in the 3rdand 4th decade and equally effect males and females. The incidence is increased in families with Multiple Endocrine Neoplasia (MEN) Type 1, which is an autosomally dominant condition (50% probability of an affected parent passing the syndrome on to an offspring) associated with parathyroid hormone excess (causing elevated blood calcium levels, kidney stones, and osteoporosis), pancreatic tumours (causing an aggressive peptic ulcers, low blood glucose or diarrhoea), and pituitary tumours (prolactinomas, acromegaly, Cushing’s disease or non functioning tumours).

Symptoms

With any pituitary tumour symptoms can be related to three things. 

  1. Hormone excess
  2. Hormone depletion
  3. Pressure on or invasion of surrounding structures, particularly the nerves to the eyes and the cavernous sinus.


The main action of prolactin is to stimulate the breast to produce milk.  In women this manifests as breast milk unrelated to breast feeding.  This may be quite embarrassing if milk is produced spontaneously, or it may only be evident with expression.  In either case, this is termed galactorrhoea.  In men, breast milk production may occur, but is very uncommon due to a lack of developed breast tissue.

In both sexes, even modest elevations of prolactin cause impairment of the pituitary control of reproductive function.  In women this results in loss or irregularity of periods, and in reduced fertility.  Women may experience features of oestrogen deficiency (similar to that seen in menopause) which include vaginal dryness, moodiness, loss of skin elasticity, breast atrophy and osteoporosis.

In men prolactin excess results in reduction of testicular function, producing androgen deficiency, loss of sperm production, and a shrinkage in the size of the testicles.  Androgen deficiency (or low testosterone levels) produces reduced energy, reduced libido (but usually not erectile dysfunction), reductions in muscle size and strength, reduced beard growth and loss of body hair, and osteoporosis.  Loss of sperm production may come to light during the investigation of infertility. 

The differences in symptoms between men and women probably explain why tumours tend to be large in males and small in females when first seen.  Women are attuned to report menstrual irregularity, whereas men are often more reluctant to seek medical attention for sexual dysfunction, or attribute symptoms to “ageing”. 

Under-activity of the remainder of the pituitary may occur if the pituitary tumour grows and “squashes” the normal part of the gland.  This not uncommonly occurs in macroadenomas, and is caused in part because the pituitary is enclosed within a bony space (sella turcica).  Deficiencies of ACTH and cortisol, TSH and thyroid hormone, LH/FSH and sex steroids, and Growth Hormone may be clinically evident or found during investigations.

Expansion of a pituitary tumour may be silent or be associated with headache, which is fairly non-specific or described as “behind the eyes”.  Should the tumour extend upwards and compress the optic nerves patients may notice loss of vision out to the side (and bump into doorways or not notice moving people or cars that “suddenly appear”).  Detailed vision (reading print material for example) may also be lost.  Uncommonly the tumour can cause double vision.

Diagnosis

Your Doctor will arrange a number of blood tests to check the pituitary function.  They will ask about other conditions and medications known to raise prolactin levels.  Prolactin levels can be raised (without there being a pituitary tumour) by oestrogen-containing contraceptive pills, certain pain-killers, antidepressants, anti-psychotics and some antihypertensives, during normal pregnancy and lactation, with low thyroid function, and a number of other conditions.  Sometimes what is measured in blood as prolactin may not function as such, and the compound measured is termed “macroprolactin”, describing a clump of several prolactin molecules or other unrelated substances.

If the prolactin level is high they will arrange an MRI.  A CT may also be ordered but it is less sensitive than an MRI for assessing pituitary tumours.  A large pituitary tumour, other than a prolactin-producing tumour, may raise the blood prolactin level by a modest degree to some degree.  This occurs because the tumours distort the pituitary stalk and reduces the transmission of a prolactin inhibiting agent (dopamine) that normally travels down the stalk from the hypothalamus to the pituitary.

If the prolactin is equal to or more than 10 times the upper limit of the normal range for prolactin one can fairly confidently assume that the tumour is a prolactinoma. Levels below this may be consistent with a small prolactinoma or a non-secretory pituitary tumour.

Your doctor may also request that you see an eye doctor to see if a tumour is affecting the nerves to the eyes.

Treatment

The goals of treatment are to return prolactin secretion to normal (thereby restoring sexual function and fertility), and to reduce the tumour size (aiming to correct any deficiencies in pituitary function and to correct any visual abnormalities). 

In general prolactinomas are a pituitary tumour that should be treated with medication rather than surgery intially.  Agents that act like dopamine are used to treat the tumour.  They shrink the tumour, sometimes quite dramatically and in a matter of days, and return prolactin levels to normal in 80% of patients.

The main agents are bromocriptine (Parlodel) and cabergoline (Dostinex), with quinagolide (Norprolac) being a recent addition.  Cabergoline in general is better tolerated than bromocriptine which can be associated with nausea and dizziness, depression and nightmares.  For this reason bromocriptine and cabergoline are usually started slowly and the dose titrated up.  A recent publication has raised concerns about the development of valvular problems in the heart in patients with Parkinson’s Disease treated with cabergoline.  In prolactinoma treatment the doses used are very much smaller and valvular dysfunction has not been observed.

Fertility may return following dopamine-type treatment, simply by returning prolactin levels to normal.  If not, assisted fertility procedures are available.  Correction of other pituitary hormone function may similarly ensure, or hormone replacement may be required.

Surgery is considered if medical therapy does not achieve the desired results or the patient is unable to tolerate the side effects of medications.  In small surgically amenable tumours surgery should have an 80% chance of returning the hormone level to normal.  Surgery may also be required in some larger tumours when a sudden bleed into the tumour causes the gland to enlarge rapidly and threaten vision.  Surgery however has added risks of damaging the normal pituitary gland.  Surgery is sometimes more difficult after treatment with cabergoline or bromocriptine as the tumour becomes more firm.

Radiation may also be required to control a prolactinoma if it has not responded to medical therapy or surgery.

Prolactinomas in pregnancy

Patients with prolactinomas may be able to conceive and have a normal pregnancy. They do however need close monitoring.  The normal pituitary gland enlarges during pregnancy, and prolactinomas may also increase in size.  A woman with a prolactinoma should discuss her plans to conceive with her physician.  Most endocrinologists consider that patients who had a macroprolactinoma (>10 mm diameter) should receive dopamine-like treatment throughout pregnancy, while microadenomas may simply require careful observation.  Bromocriptine has an extensive safety record in pregnancy, and emerging experience suggests cabergoline may also be quite safe.  Insufficient safety data with quinagolide preclude its use during pregnancy.  Patients should report headaches or visual changes and have visual fields checked several times during the pregnancy.

Osteoporosis

Because of the reduction in estrogen in women and testosterone in men with prolactinomas there is an increased risk of osteoporosis.  Patients may require measurement of bone density measurements.  Current recommendations for weight-bearing exercise, calcium intake and vitamin D assessment should be observed.

Prognosis

People with microprolactinom have an excellent prognosis.  In 95% of patients the tumour will be controlled.  Macroprolactinomas are somewhat more difficult to control and may require combination treatments, but still 80% of patients have control of tumour growth with medical therapy.  Medical therapy does not “kill” the tumour cells, explaining the current recommendations to continue such treatment indefinitely.  There are, however, emerging data to suggest that small tumours may only require such treatment for several years; drug withdrawal should be carefully supervised.