New guidelines for the treatment of prolactinoma have been released for the first time in almost 20 years, instigating a fierce debate about the best way to treat these challenging tumours.
Know your prolactinoma
Prolactinomas are a relatively common tumour of the pituitary gland. They cause the gland to stop making sensible amounts of a variety of hormones and start producing excessive amounts of one particular hormone – prolactin.
While prolactin performs many useful functions in everyone’s body, it’s most well-known for its role in breastfeeding and maternal bonding. However, too much prolactin can cause men and women to lactate, lose sexual function, and become infertile. It can even cause weak bones. As the pituitary gland is located just below the brain and right next to the optic nerves, large tumours can also cause headaches and vision problems.
The agonies of agonists
For years, prolactinomas have mainly been treated with a type of medication called dopamine agonists. Dopamine agonists mimic dopamine by attaching to dopamine receptors, like chocolate coins mimic real coins when you put them in a parking metre. As one of dopamine’s jobs is to regulate hormones, tricking the tumour into thinking there’s more dopamine around suppresses its production of prolactin.
These drugs usually work pretty well to shrink the tumour and return prolactin levels to normal, but sometimes come with side-effects that people struggle to deal with.
Although dopamine agonists were designed to work on the brain, they can also be a pain in the butt. Common symptoms like nausea, insomnia, dizziness and headaches can make life unpleasant, but dopamine agonists also carry the risks of affecting overall mood, impairing impulse control and damaging heart valves. Dopamine agonist-induced impulse control disorders, while rare, can be insidiously destructive, resulting in patients compulsively overspending, gambling or becoming hyper-sexual.
These side-effects would be bearable if treatment was only a week. But dopamine agonists usually need to be taken for years, or even decades, to keep the tumour under control.
There’s a new guide in town
The new prolactinoma guidelines were developed by the Pituitary Society, an international body comprised of researchers and doctors working in pituitary disorders.
In a multi-day multi-disciplinary online workshop, 36 experts across 13 countries synthesised the latest prolactinoma research into a new document to help doctors provide the best treatments for their patients.
While dopamine agonists are still recommended as a first-line treatment, the new guidelines suggest that surgery also be offered to patients as an equally valid option. This represents a shift from recommending surgery as a backup for patients who haven’t had any luck with medication, to recommending surgery upfront.
Surgery: cutting edge or short cut?
In a correspondence piece to Nature Reviews Endocrinology, Associate Professor Sunita De Sousa of the Royal Adelaide Hospital, together with her endocrine and surgical colleagues, question the recommendation to routinely offer surgery to all patients without trying medication first.
She notes that while dopamine agonists have their drawbacks, surgery can also result in complications like eye damage, meningitis and hypopituitarism – the pituitary gland not producing enough of anything. These are potentially life-threatening and permanent conditions compared to the temporary side-effects of medication.
The main reason A/Prof De Sousa could see for the new guidelines is the potential risk of dopamine agonists causing tumours to scar up, becoming tough, fibrous, and harder to remove in surgery.
However, fibrous tumours were more characteristic of older medications like bromocriptine that aren’t usually used any more. Newer drugs like cabergoline don’t carry the same risk of the tumours growing scar tissue.
She was also wary about the Pituitary Society’s use of a meta-analysis of postoperative remission rates as a justification for its new recommendation.
The meta-analysis found that the success rates for surgery were lower when patients had previously taken dopamine agonists. But these were observational studies – it’s likely that people who needed both medication and surgery either had severe tumours that needed more aggressive treatment overall, or were patients for whom medication didn’t work.
A/Prof De Sousa argues that the meta-analysis couldn’t definitively show that using dopamine agonists before surgery was directly causing lower success rates because the patients who required medication before their surgery probably just had more difficult tumours to begin with.
Without randomised studies (such as the PRolaCT studies) comparing surgery without medication to surgery after medication, the correspondence piece urges caution in recommending surgery as a treatment without first looking into dopamine agonists.
Head to head
The guidelines themselves note that “whether to use preoperative medical therapy remains controversial.”
A reply to A/Prof De Sousa led by Professor Doctor Petersenn of the ENDOC Centre for Endocrine Tumours in Hamburg and the University of Duisburg-Essen argues that surgery is good actually.
They note that experienced pituitary surgeons do a pretty good job of removing tumours, with less than 2% of patients experiencing complications. Surgery can also be a one-and-done procedure compared to decades of pill-popping. Taking medication long-term can exact a heavy price – literally, for regular ECGs and check-ups with specialists, but also mentally for many patients. And thinking of surgery as a last resort, the authors argue, might lead patients to try one fruitless medication after another before staggering into a surgeon’s office anyway.
The authors also observe that bromocriptine is still used in some countries, so the risks of severe side effects and tumour fibrosis is still a reality for many.
Overall, they suggest that for some people, dopamine agonists might be too bitter a pill to swallow, and patients should be given all the information they need to make a choice that suits their circumstances.
Finding common ground with a common purpose
A/Prof De Sousa agrees that there are pros and cons to both surgery and medical therapy for prolactinomas. In an ideal world, every individual with a prolactinoma would have access to a specialised multidisciplinary team with expertise specifically in prolactinomas, including highly experienced neurosurgeons with spectacular cure rates.
However, most people with prolactinomas don’t have access to specialist pituitary multidisciplinary teams because prolactinomas are much more common than other pituitary tumours, and were usually just managed with medication until now. The resources just aren’t in place yet to offer everyone surgery.
In parting, A/Prof De Sousa notes that a lot more funding will be required to get all individuals with prolactinomas access to the most up-to-date counseling and management, which is something probably all prolactinoma experts and patients can agree on.
