Pituitary News, Issue 5 - Autumn 1997.

The most common type of Pituitary tumour secretes an excess of Prolactin and is known as a Prolactinoma. This article focuses on some of the many letters The Foundation receives about the medications used to treat prolactinoma.

Dr John Bevan, Consultant Endocrinologist at Aberdeen Royal Infirmary and Trustee to The Pituitary Foundation

Prolactin is the name given to the milk hormone produced by the Pituitary gland. The most common type of pituitary tumour secretes an excess of prolactin and is known as a prolactinoma. Usually, these tumours are very small and called microprolactinomas (less than one centimetre in diameter). Twenty percent of women attending an infertility clinic with infrequent or absent periods will turn out to have a raised prolactin level in the blood, often due to a Microprolactinoma.

There is much useful information in The Pituitary Foundation booklet entitled 'Prolactinoma' (read this online) and it is not my intention to duplicate that material in this article. Rather, I should like to focus on some of the many letters The Foundation receives about the medications used to treat prolactinomas.

As explained in 'Prolactinomas', most patients with a prolactinoma (whatever its size) will be treated with tablets. Under normal circumstances, the bottom part of the brain (Hypothalamus) produces a chemical known as dopamine which reduces prolactin secretion by the pituitary. It is therefore logical that the medicines used to treat prolactinoma mimic the actions of this natural substance, dopamine. In the UK there are three medicines with a licence for the treatment of prolactin problems: Bromocriptine (Parlodel), cabergoline (Dostinex) and quinagolide (Norprolac). Bromocriptine has been in clinical use since the early 1970s, whereas the other two medicines received their full licence much more recently (1994).

Member's questions on prolactinoma fall into two broad groups. First, the short-term and longer-term side-effects of the dopamine-like medicines. Second, the safety of these treatments for mother and baby during pregnancy, together with any implications for breast feeding. I shall address each of these areas using some of the letters received from members, as illustration. I am very grateful to these ladies for their stimulating and challenging questions!

What side-effects may be expected?

Dopamine-like medicines are well tolerated by most patients. They should be taken with meals to avoid the nausea and tummy upset which sometimes occur if the tablets are taken on an empty stomach. Your doctor will give you instructions on how to build up the dose slowly, again to minimse side-effects, particularly dizziness. If you are on a once-daily medication it's a good idea to take it with a snack just before you go to bed; this again helps any tendency to dizziness. Occasionally these medications may cause constipation, but this can usually be cured by increasing your dietary fibre. Other less common side-effects are nasal stuffiness and Raynaud's phenomenon (you may notice 'white fingers' in cold weather - the circulation returns to normal as your hands warm up).

Bromocriptine is usually given two or three times daily, quinagolide once daily and cabergoline once or twice weekly. Your hospital specialist will help you decide the best drug to start on. If you experience some of the early side-effects described above he or she will probably change you to another tablet. For example, a patient who has side-effects with bromocriptine may have no side-effects or minimal discomfort with cabergoline or quinagolide (see MD letter). The fact that you have no side-effects at all doesn't mean the tablets aren't working. Apart from the three medicines with UK licences for the treatment of prolactinoma, there are several other drugs with prolactin-lowering action. One of these is called pergolide (Celance) (see HP and CG letters). This drug lowers prolactin satisfactorily but has a UK licence for the treatment of only Parkinson's disease and not prolactinoma; the recent licensing of cabergoline and quinagolide means that the use of pergolide as an alternative treatment for prolactinoma will become less frequent. It is, however, another medication which has to be taken only once daily.

CG raises the important issue of longer term side-effects. Many prolactinoma patients take these drugs for several years, so this is a relevant point. Fortunately, the evidence seems very reassuring. Some patients have now been taking bromocriptine for over 20 years without any adverse effects. There is less known about the long-term effects of the newer drugs cabergoline and quinagolide, but each has been used in clinical trials for over 10 years without any sign of serious problems. Very rarely, lung inflammation and mood disturbances have been recorded with all the dopamine-like medicines, but these are confined largely to patients taking the drugs for other medical indications and in doses at least five times those used in patients with prolactin problems.

How safe are these treatment during pregnancy?

Dopamine-like medicines are a very effective treatment for women with reduced fertility due to a prolactinoma. However, a pregnancy should be planned with care since increased Oestrogen levels may, occasionally, cause a prolactinoma to increase in size. Even the normal pituitary gland increases in size during pregnancy, due to an increase in the number and activity of the prolactin-producing cells.

The risk of important tumour enlargement is very low indeed for patients with a microprolactinoma (less than 2%). Even for larger prolactinomas the risk is much lower than previously thought; for women treated with a dopamine-like medicine for at least 6 months before contraception, the risk is probably substantially less than 15% (see KB letter).

Your doctor will probably ask you to stop taking bromocriptine or quinagolide as soon as a pregnancy is confirmed (see ME letter). This is on the general principle that all drug treatment should be reduced to a minimum during pregnancy. Many thousands of 'bromocriptine babies' have now been born; there has been no increased incidence of malformation and the children have developed normally (see MP and LJ letters). Furthermore, the pregnancies have not been associated with an increased miscarriage rate. The same is true for quinagolide but the number of pregnancies is much lower because it's a newer drug (176 pregnancies up until 1996).

The situation is slightly different for cabergoline because it is such a long-acting drug (and therefore stays in the body for a few weeks after it's stopped), and also newly introduced. Your specialist will probably recommend you stop treatment one month before attempting to conceive. If you have been on the medicine for several months, normal egg-releasing cycles can persist for 3-6 months after stopping treatment. Having said this, as of early 1997, 277 pregnancies have been reported in women taking cabergoline at the time of conception. These pregnancies seem to have been just as successful as for bromocriptine and quinagolide so it's likely that the 'one month rule' will be withdrawn eventually, provided this early success is maintained.

Any women with a prolactinoma who falls pregnant will be advised to inform her specialist without delay should she experience unusually severe headache or visual disturbance; these may be signs of tumour expansion. If necessary, magnetic resonance imaging (MRI) of the pituitary can be performed safely during pregnancy (since this technique does not expose the baby to X-rays). If significant prolactinoma enlargment is confirmed, bromocriptine will probably be restarted. This drug seems to be safe even when given throughout pregnancy and is likely to cause the prolactinoma to shrink again (see ME letter). There are virtually no data on cabergoline or quinagolide being given throughout pregnancy, so bromocriptine is the drug of choice in this situation. Bromocriptine would usually be restarted only for prolactinoma enlargement and not simply for a rise in prolactin level which occurs in all women during pregnancy, whether they have a prolactinoma or not (see MP letter).

If your medication is withdrawn and you have undergone an uneventful and successful pregnancy, it is likely that you will be able to breast-feed without any difficulty (see KB letter). After all, you have plenty of the milk hormone, prolactin! If, however, you have to restart your medication and the prolactin level is low or undetectable, you may have difficulty producing enough milk to satisfy your baby. Once you have finished breast-feeding your specialist will probably see you in clinic and recheck the prolactin level. In a small proportion of patients with a microprolactinoma the problem seems to disappear after a pregnancy: we don't know why this happens. If the prolactin level remains high, further drug therapy may be necessary. A further pregnancy should be straightforward if that is what you and your partner wish (see RP letter). If a further pregnancy is not desired you should discuss contraception with your doctor at an early stage: most of the usual types can be used, including the birth control pill.

In summary, dopamine-like medicines have revolutionised the treatment of prolactinoma. They are usually well tolerated and there are now three to choose from, if there are side-effects. They enable most patients to keep healthy and a pregnancy can be achieved in a high proportion of women with a prolactinoma. The medicines have a good safety profile for both mother and baby.

For those who want some further facts and figures from a more detailed article, I would recommed the one written by Dr Jonathan Webster who is a Consultant Endocrinologist working in Sheffield: A comparative review of the tolerability profiles of dopamine agonists in the treatment of Hyperprolactinaemia and inhibition of puerperal lactation. Drug Safety (1996), volume 14(4), pages 228-238.