Medications for Pituitary Tumours

Dr Stephen Thornley, Consultant Endocrinologist, Miranda NSW.

Contents

Introduction

This talk will firstly address the use of medication in the treatment of pituitary tumours, and later attempt to briefly cover the large topic of replacement therapy for hormone deficiencies.

Medication is commonly used in the therapy of two types of pituitary tumours; firstly, Prolactin secreting pituitary tumours (Prolactinoma), where either Bromocriptine or Cabergoline are used, and in Growth Hormone secreting pituitary tumours (Acromegaly), where Octreotide and long-acting Octreotide are used. In these conditions, these medications are either used to complement surgery and radiotherapy, or may be used as the sole therapy in some patients.

Prolactinoma

Medication has been used for many years to treat Prolactinoma, and is often effective in avoiding the need for surgery or radiotherapy. Prolactin is produced by cells called Lactotrophs, and the major role of Prolactin in humans is to facilitate lactation (the production of breast milk). It has no other known actions in humans.

The two drugs that are commonly used both mimic the way that Dopamine acts on the pituitary. Normally when we produce Dopamine in the hypothalamus it travels down the pituitary stalk to inhibit Prolactin production in the pituitary. If a large tumour puts pressure on the pituitary stalk this negative feedback does not happen and too much Prolactin is produced. Therefore medication with ‘Dopamine-agonist’ drugs reduces the production of Prolactin. Reducing Prolactin to normal levels may restore the menstrual cycle and improve fertility in women. In men it may increase the testosterone level, libido and well being. These drugs may also work to reduce tumour size, thus avoiding the need for surgery.

In many cases of Prolactinoma medical therapy is appropriate just as the sole therapy, where there is no need for surgery or radiotherapy. Prolactinomas are unique in the fact that they are the only form of pituitary tumour where medication alone can control both tumour size and production of excess hormone.

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The two medications used for Prolactinoma are:

  • Bromocriptine (trade names Parlodel, Kripton, Bromohexal, Bromolactin) – generally taken once or twice daily
  • Cabergoline (trade names Dostinex, Cabaser) – taken once or twice a week

In women who are trying to fall pregnant Bromocriptine is more appropriate because it has been around for longer and we know more about its use in this context. Outside of this situation however, Cabergoline however has the advantages that in many cases it doesn’t need to be taken as often, has less side effects and so is usually the preferred drug.

Adverse effects of these drugs are similar and include nausea, vomiting, headaches, dizziness and low blood pressure and fatigue. They are best taken with food to minimise these side effects, and if possible at bedtime (to minimise the tendency towards dizziness and low blood pressure while lying flat) and so reduce disruption to daily function. If side effects are a major problem, the dose could be reduced and then slowly increased over time. In rare cases the drugs are not tolerated, in which case surgery and radiotherapy may need to be discussed. Also if the tumour is very large and possibly encroaching on surrounding structures, surgery and radiotherapy are likely to be used.

Acromegaly

Medical therapy also plays a major role in the management of Acromegaly (Growth Hormone secreting pituitary tumours). Excess Growth Hormone leads to a variety of clinical features including soft tissue thickening, especially of the hands, feet and tongue; heart disease and high blood pressure; and an increased risk of cancers such as bowel cancer. Pressure effects of the tumour on surrounding structures also need to be considered. Therefore treatment is important.

Normally Growth Hormone Releasing Hormone (GHRH) is produced by the hypothalamus to simulate Growth Hormone (GH) production from the pituitary. To keep this in balance a feedback loop exists where the liver and, to a lesser extent, other body tissues produce IGF-1, and the hypothalamus produces Somatostatin (Growth Hormone Inhibiting Hormone – GHIH) to decrease GH production.

In Acromegaly medication is less commonly the sole therapy (compared with Prolactinoma), but is usually used in combination with surgery and radiotherapy. Surgery is generally considered to be the first line of treatment. It is sometimes combined with radiotherapy and/or medication if a cure is not achieved with surgery alone.    

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Medications used in treating acromegaly are;

  • Bromocryptine and Cabergoline are also used in treating Acromegaly, but are less effective than Octreotide. They are only used occasionally.
  • Pegvisomant works to prevent growth hormone binding to receptors in the bodies’ tissues, thereby preventing the adverse effects of excess growth hormone secretion. IGF levels tend to fall with this therapy, however growth hormone levels can elevate.  It has no effect on pituitary tumour size.  This is not available in Australia at this point.
  • Octreotide (Sandostatin) – injected under the skin three times per day
  • Octreotide long acting (Sandostatin LAR) – injected once per month
  • Somatuline LA or Somatuline Autogel (both presentations contain the active ingredient lanreotide) are injected every 14 days and 28 days respectively. Somatuline Autogel is packaged in a pre-filled syringe, ready to be injected. 
     

Lanreotide and Octreotide work to lower GH hormone levels, improving symptoms such as headache, sweating, etc and more importantly they do reduce the risk of early death by heart disease and possibly cancer. They may also reduce tumour size.

Adverse effects of Octreotide can include the inconvenience of multiple daily injections if using the short-acting Octreotide, mild temporary discomfort at the site of injection in the case of long-acting Octreotide, nausea, diarrhoea or mild malabsorption of nutrients in the large intestine and gallstones or gall bladder ‘sludge’. To assist monitoring of the gall bladder, all patients commencing on Octreotide of any type should have a baseline abdominal ultrasound. Routine screening with ultrasound is presently not considered essential unless symptoms consistent with gallstones develop (right upper abdominal pain, nausea, vomiting, and fever).


Cushing’s Disease

This is caused by an ACTH secreting pituitary tumour, leading to elevated blood cortisol levels. Treatment is surgery +/- radiotherapy. In select situations, a variety of medications have been used in the treatment of Cushing’s disease, includingketaconazole, mitotane, aminiglutethimide and metyrapone. These medications all work to lower the production of cortisol by the adrenal glands and do not to reduce pituitary ACTH production. They all have significant side effects and are therefore not widely used.


Advantages and disadvantages

The main advantages of medical therapy for treatment of pituitary tumours (in preference to surgery or radiotherapy) are that treatment is reversible when ceased, the medications have a rapid onset of action and other pituitary hormones are not affected (no hypopituitarism). In fact, in some cases other hormone levels that have been affected may actually return to normal after medical treatment, eg in Prolactinoma in men the testosterone level may return to normal after medication.


Disadvantages include the side-effects of medication; the need for long-term medication which may be life-long and thus can be costly, especially in the case of short and long acting Octreotide (many thousands of dollars per year); and the fact that it may not be curative (more often the case in GH secreting tumours than Prolactinomas.)


Replacement Therapy

Hypopituitarism is often the end result of surgery or radiotherapy for a pituitary tumour, or a complication of a large tumour. Rarely, other conditions can cause Hypopituitarism. Hypopituitarism can affect production of any/all of the following hormones: Thyroid Stimulating Hormone (affecting T4 and T3 production from the thyroid gland), LH and FSH (which stimulate Oestrogen and Progesterone/Testosterone), ACTH (which causes Cortisol production from the adrenal glands), Growth Hormone and Anti-Diuretic Hormone (ADH/Vasopressin – from the posterior pituitary). Pituitary hormones may be deficient in any combination and can become so in any order. The pituitary is remarkable in that even if it is squashed into virtual non-existence, or parts of it are removed by surgery, it can still produce adequate levels of hormones. We actually only need about 10% of normal pituitary tissue for us to have normal pituitary function.


The need for replacement therapy will be assessed in most patients with pituitary disease at the time of diagnosis. This is generally done with blood and urine tests. The tests should be repeated after new surgery, when there are clinical changes or progression of the disease, and on a regular basis in patients who have had radiotherapy (hormone levels can become deficient up to ten years after radiotherapy). Your Endocrinologist will advise you if you require investigation, how often, and whether all or only some of your hormones need testing.


If there are pituitary hormone deficiencies we need to replace them. Some of the pituitary hormones can be made synthetically so that we can directly replace them. But in some cases, instead of replacing the pituitary hormone, it is easier to replace the hormone that the pituitary would normally stimulate.


Medications used as replacement therapy include:

Thyroxine (tablets; Oroxine, Tertroxin) – TSH is not given. It is easier to give Thyroxine itself. It is usually simple to find the right dose and administer. It is best taken in the morning before food. A 75 mcg thyroxine tablet is now available, in addition to the existing 50, 100 and 200 mcg strengths.


Cortisol (tablets; Prednisone, Cortate, Hydrocortisone or others) – again the pituitary hormone ACTH is not given, but Cortisol is used instead. It requires closer monitoring of dosages than other replacement drugs, and may need to be taken at various times through the day. Sometimes the highest dose is taken in the morning to mimic the Cortisol boost we would normally get at the start of the day. It is a dangerous situation if it is not taken. Wearing a MedicAlert bracelet or carrying similar information about your mediation is advisable. You can also teach carers how to give an injection in emergencies.

Oestrogen & Progesterone (tablets, patches, gel preparations, injections, implants) – you get a better clinical effect from giving these medications than from giving LH and FSH alone. The sex hormones are especially important in women to reduce menopausal symptoms and particularly to reduce the risk of fractures due to osteoporosis. You should discuss the need for regular breast checks and pap smears etc. with your doctor.


Testosterone (tablets, gel, patches, injections and implants). Tablets are generally not used, as the liver tends to destroy much of the testosterone given in this way. The gel is a good option of treatment as it has a much lower incidence of skin irritation compared to the patches. Injections are another option, a long lasting product (reandron) only needs to be administered every 3 months, compared to every 3 weeks with the older products. Implants, where testosterone pellets are inserted under the skin in a minor procedure, are occasionally used.


Anti-Diuretic Hormone (nose-spray, injections; DDAVP, Minirin, Octostim) – Desmopressin is a modified synthetic form of the original hormone Vasopressin. Injections may be given if there are problems with the nose (eg, if the nose is packed with bandages after surgery).


Growth Hormone – is now available for adult patients who are Growth Hormone deficient, but not widely prescribed due to its cost. Because it is a protein it cannot be taken orally (it is broken down in the stomach too quickly, before it can be effective) so it is given as an injection.


Questions & Answers

Q – Are there any long term effects of DDAVP?

A – There are no long-term adverse effects of DDAVP to my knowledge. Short-term effects can include fluid retention, rapid heart rate, low blood pressure, headache, nausea, intestinal cramps, sore eyes, nose bleeds and nasal congestion.



Q – Why has it taken so long to approve Growth Hormone in Australia?

A – The government is very slow to approve medications. They are very fussy and this is the case for many medications.

 


This article updated: January 2009