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EXPERT REACTION: Common contraceptive hormone linked to increased brain tumour risk

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A French study has found that prolonged use of progesterone-like hormones which are found in some contraceptive injections and hormone treatments, are linked to an increased risk of developing a type of brain tumour called a meningioma. The study looked at a range of progesterone-like hormones that have different uses including as contraception, menopausal hormone therapies, and to treat endometriosis. They found that using some of the hormones for a year or more was linked with an increased risk of intracranial meningioma requiring surgery, although the cancer is a rare one so the absolute risk was still low. The authors say that one of these hormones, medroxyprogesterone acetate, is estimated to be used for birth control by 74 million women worldwide, so the number of attributable meningiomas may be high.

Journal/conference: The BMJ

Link to research (DOI): 10.1136/bmj-2023-078078

Organisation/s: French National Agency for Medicines and Health Products Safety

Funder: This research was funded by the French National Health Insurance Fund (Cnam) and the French National Agency for Medicines and Health Products Safety (ANSM) via the Health Product Epidemiology Scientific Interest Group (ANSM-Cnam EPI-PHARE Scientific Interest Group). NR, AN, and AW are employees of the French National Health Insurance Fund, MZ is an employee of the French National Agency for Medicines and Health Products Safety.

Media release

From: BMJ Group

Prolonged use of certain hormone drugs linked to increased brain tumour risk

First study to assess risk associated with widely used progestogens

Prolonged use of certain progestogen hormone drugs is associated with an increased risk of developing a type of brain tumour known as an intracranial meningioma, finds a study from France published by The BMJ today.

The researchers say this study is the first to assess the risk associated with progestogens used by millions of women worldwide, and further studies are urgently needed to gain a better understanding of this risk.

Progestogens are similar to the natural hormone progesterone, which are widely used for gynaecological conditions such as endometriosis and polycystic ovary syndrome, and in menopausal hormone therapy and contraceptives.

Meningiomas are mostly non-cancerous tumours in the layers of tissue (meninges) that cover the brain and spinal cord. Factors such as older age, female sex, and exposure to three high-dose progestogens (nomegestrol, chlormadinone, and cyproterone acetate) are already known to increase the risk of meningioma.

But there are many other progestogens for which the risk of meningioma associated with their use has not been estimated individually.

To address this knowledge gap, researchers set out to evaluate the real life risk of intracranial meningioma requiring surgery in women associated with use of several progestogens with different routes of administration.

They used data from the French national health data system (SNDS) for 18,061 women (average age 58) who underwent intracranial meningioma surgery from 2009-18.

Each case was matched to five control women without intracranial meningioma (total 90,305) by year of birth and area of residence.

The progestogens examined were progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and levonorgestrel intrauterine systems.

For each progestogen, use was defined as at least one prescription in the year before hospital admission or within 3-5 years for levonorgestrel intrauterine systems.

Use of at least one of the three high-dose progestogens known to increase the risk of meningioma in the 3 years before hospital admission was also recorded to minimise bias.

After taking account of other potentially influential factors, prolonged use (a year or more) of medrogestone was associated with a 4.1-fold increased risk of intracranial meningioma requiring surgery. Prolonged use of medroxyprogesterone acetate injection was associated with a 5.6-fold increased risk, and prolonged use of promegestone was linked to a 2.7-fold increased risk.

There appeared to be no such risk for less than one year of use of these progestogens.

As expected, there was also an excess risk of meningioma for women exposed to chlormadinone acetate, nomegestrol acetate, and cyproterone acetate, all of which are known to increase the risk of meningioma.

However, results showed no excess risk of meningioma for progesterone, dydrogesterone, or the widely used hormonal intrauterine systems, regardless of the dose of levonorgestrel they contained.

No conclusions could be drawn about dienogest or hydroxyprogesterone as the number of exposed individuals was too small.

This is an observational study so can’t establish cause and effect, and the authors acknowledge that the SNDS database lacked information on all the clinical details and medical indications for which progestogens are prescribed. Nor were they able to account for genetic predisposition and exposure to high dose radiation.

However, they say, given that medroxyprogesterone acetate is estimated to be used for birth control by 74 million women worldwide, the number of attributable meningiomas may be potentially high.

Further studies using other sources of data are urgently needed to gain a better understanding of this risk, they conclude.

[Ends]

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Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Professor John Funder AC is a Distinguished Scientist from The Hudson Institute, and also from the Centre for Neuroscience at The University of Melbourne

The paper from France on the use of progestagens and the increased risk of meningioma pinpoints those which do and those which don't, providing clear evidence for change. One quirk is that drospirenone - which is not reimbursed in France - was not studied but in its place spironolactone was. Higher doses of spironolactone may cause breast enlargement, but to the best of my reading no other potentially relevant side-effects. In particular, it has no place as a contraceptive or in post-menopausal women. It may, however, help those with low renin hypertension and/or primary aldosteronism.

Last updated: 28 Mar 2024 10:37am

Declared conflicts of interest:

None declared.

Gino Pecoraro OAM is Associate Professor of Obstetrics and Gynaecology at the University of Queensland and President of the National Association of Specialist Obstetricians and Gynaecologists (NASOG). He is also a practising obstetrician and gynaecologist in private practice in Brisbane.

Meningioma is a benign tumour of the membranes covering the brain and spinal cord.

Although slow-growing, it can cause symptoms requiring surgery. More than half of these tumours have progesterone receptors present and previous studies have shown that at least three known progestogens (synthetic analogues of the natural hormone progesterone) have been associated with an increased risk of developing the condition.

This new French study comparing 18,000 women who had had surgery for meningioma with 90,000 women who do not, matched for age and area of residence, found an association with previous prolonged (a year or more) exposure to a further three progestogens not previously studied.

Of the hormones found to have an increased risk of meningioma, two are not available in Australia.

The third however is available in Australia and consists of a depot injection given intramuscularly every three months containing the active drug medroxyprogesterone acetate150mg (DepotProvera). The intrauterine levonorgestrol system (Mirena), increasingly being used in Australia did not show an excess risk of meningioma.

This should be reassuring to Australian women that the vast majority of contraceptives available and used in this country are not associated with an increased risk of developing meningioma.

The release of these findings should also be a timely reminder to women to review their contraceptive needs periodically to make sure they are still using the best product available for them.

Last updated: 27 Mar 2024 3:57pm

Declared conflicts of interest:

I sit on advisory boards and give sponsored educational sessions for pharma companies that produce and market a number of the hormones mentioned in the study.

Dr Susan Evans is a gynaecologist and pain physician with expertise in endometriosis and pelvic pain. She is Chair of the Pelvic Pain Foundation of Australia and an Associate Professor at the University of Adelaide

Progestogen medications are medications that mimic progesterone in the body. Each progestogen has its own characteristics. This is important information to guide health practitioners when prescribing hormonal therapies. Importantly, the use of intrauterine devices, including Mirena, were not found to increase meningioma risk.

This information will further speed the changing preference from oral hormonal medications to intrauterine devices.

The Kaiser Family Foundation in the United States found that IUD use increased from 2% - 14% of contraceptive use, while oral contraceptive use fell from 31% to 22% over the time period 1995-2017. This data will further speed this change.

The authors of the paper have reported on an epidemiological study of 108,000 women. This included 18,000 women with intracranial meningioma.

It is therefore a large sample size, well able to consider outcomes of low frequency. They have not put forward a reason for their findings.

We know that different progestogen medications react differently at multiple hormonal receptors in the body. We also know that some progestogens, including medroxyprogesterone acetate and cyproterone acetate disrupt the androgen receptor.

This study should be a prompt for research considering different progestogens and their interaction with a full range of hormonal and endocrine receptors including androgen receptors

Last updated: 28 Mar 2024 9:54am

Declared conflicts of interest:

I am founder and shareholder of Alyra Biotech, which is developing a novel intrauterine device to reduce pelvic pain in women through modulation of the immune system. I am a very minor shareholder in Havah Therapeutics which is developing a therapy to reduce breast cancer using androgens and aromatase inhibitors to reduce breast density. I have also published on the evolutionary aspect of androgen disruption in the development of endometriosis - and on the association between low androgens and pain symptoms in women.

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