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A study published in the BMJ looks at an association between progesterone hormones and brain tumour risk.
Dr Mangesh Thorat, Honorary Reader in Wolfson Institute of Population Health, Queen Mary University of London and Consultant Breast Surgeon, Homerton University Hospital, said:
“This large study using French national database confirms association between certain progestogens and meningioma risk and it also shows similar association, albeit at a much lower level, with three additional progestogens. These results however do not give any reasons for women using progestogens to panic.
What are progestogens?
“Progestogens are medicinal analogues of naturally produced female hormone progesterone. These are a common component of contraceptive agents, hormone replacement therapy and other hormonal treatments. Two important things to know about these are: first, effects of different formulations vary sometimes substantially and second, the effect of individual drug varies on different organs within our body. Therefore, it is important to consider which specific drug is being used by an individual.
What is meningioma?
“Meningioma is a tumour of coverings of our brain and more than 90% of these are not cancerous. This is a rare tumour, for example, breast cancer is 10-times more common and it is even rarer in young individuals. A proportion of these need to be treated surgically as they increase pressure on the brain and / or nerves. The most common symptoms are persistent headache, and feeling sick all the time often with drowsiness.
How much of the risk is attributable to these drugs?
“Recent studies showed that three out of more than a dozen progestogen formulations to be associated with significant increase in the risk of developing meningioma. However, these 3 drugs put together account for (as a cause) just over 10% of all meningiomas in women. This study shows that 3 additional drugs to be associated with meningioma risk, but the magnitude of increase in the risk is much smaller. Furthermore, these 3 additional drugs put together account for (as a cause) only half percent of all meningiomas in women. In other words, a vast majority of meningioma would occur without use of such drugs.
Importantly, this study also shows that many progestogens, for example commonly used intrauterine contraceptive coil Mirena to be completely safe, without any increase in the risk of meningioma.
What should individuals using progestogens do?
“Talk to your healthcare provider regarding the drug you are using. If it is associated with an increased risk of meningioma, this can be changed to a safer alternative. There is no reason to panic as the risk is very small and even in those who developed meningioma, stopping the specific drug has shown to cause regression in the size of meningioma.
More research is needed:
“Although this is a large study, all studies have limitations. This study could not investigate long-term exposure beyond a few years, or the over-the-counter use of contraceptives. Furthermore, the study cannot provide information on the formulations not commonly used in France but used in other countries. This therefore underscores the need for further research using similar databases in other nations.”
Prof Sebastian Brandner (Head of Division), Professor of Neuropathology, Department of Neurodegenerative Disease, University College London (UCL), said:
“Key point of my statements below:
It must be emphasised that this study examines the risk of meningioma incidence/growth in the context of hormone treatment. There is no indication that testing of meningiomas for the presence of the receptors can inform of recurrence risk or treatment options.
“To summarise the key points of the study:
What are the important caveats?
“Meningiomas express receptors for progesterone. This is a well-established fact (cited in the study). However, it is important to understand and to communicate to the public that measuring these receptors on meningioma tumour samples has no diagnostic, prognostic, or predictive value (PMID: 38101773 ; 34678411). This is distinctively different from breast cancer, where measuring these receptors (by histological stains on tumour tissue sections) has an important diagnostic and prognostic value that can influence therapy. In breast cancer these receptors are established treatment targets.
“Therefore, testing for progesterone or estrogen receptor expression on meningiomas as a basis for antihormonal treatment is discouraged for the clinical routine and should only be considered in the context of clinical trials. It is not recommended and in fact actively discouraged to attempt testing of these receptors on meningioma tissue samples.
Why is it important to stress these facts?
“We (as diagnostic neuropathology department) occasionally receive requests from surgeons, oncologists and sometimes also patients to test meningioma for the presence of oestrogen and progesterone receptors. Whilst this can technically be done (using the same tests that are used routinely in breast cancer), the test result is neither validated nor standardised. Every time these tests are requested, we spend considerable time explaining that these tests have no value for the protection of recurrence and must not be used as basis of any further treatment. There is a risk that wide media coverage can confuse the risk of developing meningioma during hormone treatment, with the test of the progesterone receptor on tumour samples. This could lead to a significant increase of such requests across the NHS, with pathology departments being flooded with requests and requiring responses every time such requests are made. Importantly, this test is not in the NHS England genomic test directory and therefore not funded as standard of care (SOC) (for a very good reason, as explained).
“Therefore, this study only provides information about the risk of the development of a meningioma in the context of hormone treatment, but it does not recommend testing of meningiomas for the presence of these receptors.”
Professor Paul Pharoah, Professor of Cancer Epidemiology, Cedars-Sinai Medical Center, said:
“This paper reports on a carefully conducted study using records from the French National health Data System to study the association of progestogen medications and risk of meningioma. An association of high doses of certain types of progestogens with meningioma has previously been reported, but these are rarely used in clinical practice. The aim of this study was to investigate more commonly used progestogens.
“The press release is a good summary of the findings. The authors note that causality cannot be determined in an observational study such as this but, given what we know about the risk factors for meningioma, it seems quite likely that the association reported for medroxyprogesterone acetate is causal. In particular, the size of the effect is quite large, there are no obvious confounders or biases, and the effect was seen for some medications and not others (any confounding and bias would be expected to affect all medications similarly).
“It is important to note that progestogens are an important component of many types of birth control pill (oral contraceptives) and hormone replacement therapy but there are many different types of progestogens and no association with meningioma was found for the types of progestogens commonly used in the United Kingdom. This means that women taking the commonly used birth control pills or hormone replacement therapy are not at increased risk of meningioma. It is important that women do not stop using their birth control pills without consulting their doctor.
“The notable exception is medroxyprogesterone acetate (also known as Depo Provera) which is sometimes used as an injectable form of contraception in the UK. Use of medroxyprogesterone acetate for more than one year was associated with a five-fold increase in risk of meningioma. While this sounds like a very large risk it is important to realise that meningioma is rare and a five-fold increase in a rare disease is still a rare disease. To put some numbers on this, based on UK cancer registration data, approximately 40 out of 10,000 30-year old women would be expected to be diagnosed with a meningioma before the age of 80. This increases to 200 in those who have used medroxyprogesterone acetate. This small increase in risk needs to be considered in relation to the benefits of using an injectable form of contraception.”
Professor David Parkinson, Professor of Neuroscience, Peninsula Medical School (Faculty of Health), Principal Investigator for the Brain Tumour Research Centre of Excellence at Plymouth University, said:
“This is a new and significant study that builds upon previous work and shows a significant association between developing a meningioma tumour and some types of progestogen treatment. The new paper shows that additional types of progestogens, including one that is widely used for birth control, may also increase the risk of developing a meningioma tumour. This new work highlights two things: Firstly, that use of a larger number of progestogens may be a distinct risk factor for some meningioma tumours, and secondly, by understanding the signalling through progesterone receptors in these tumour cells, we may be able to design ways to slow tumour growth in patients.”
Dr Karen Noble, Director of Research, Policy, and Innovation, Brain Tumour Research, said:
“Any increased understanding of the risk factors of brain tumours is beneficial to the brain tumour community; it may open doors to research on preventative measures, as well as increase our understanding of why these tumours arise in the first place. However, the public needs to be cautious when digesting the results from a study such as this before taking action. Although this study has linked certain progestogen treatments to an increased risk of meningioma, it has also demonstrated the safety of other progestogen treatments which were shown to not increase risk. If you are concerned, it is recommended that you speak to your GP before stopping any prescribed treatment.”
‘Use of progestogens and the risk of intracranial meningioma: national case-control study’ by name of Noémie Roland et al. was published in The BMJ at 22:30 hours UK time (GMT) Wednesday 27 March 2024.
DOI: 10.1136/bmj-2023-078078
Declared interests
Dr Thorat: No conflicts of interest.
Prof Brandner:
Prof Pharoah: No conflicts of interest.
For all other experts, no reply to our request for DOIs was received.