Researchers in France have suggested that prolonged use of certain progestogen hormone drugs might be associated with an increased risk of developing a type of brain tumour known as an intracranial meningioma.
Their study is the first to assess the risk associated with progestogens used by millions of women worldwide.
However, they said further studies were urgently needed to gain a better understanding of this risk, they wrote of their findings, published in The BMJ.
Progestogens are similar to the natural hormone progesterone, commonly 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) covering 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, the 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 three-five 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 three 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 it 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 74m 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.
Study details
Use of progestogens and the risk of intracranial meningioma: national case-control study
Noémie Roland, Anke Neumann, Léa Hoisnard, Lise Duranteau, Sébastien Froelich, Mahmoud Zureik, Alain Weill.
Published in The BMJ on 27 March 2024
Abstract
Objective
To assess the risk of intracranial meningioma associated with the use of selected progestogens.
Design
National case-control study.
Setting
French National Health Data System (ie, Système National des Données de Santé).
Participants
Of 108 366 women overall, 18 061 women living in France who had intracranial surgery for meningioma between 1 January 2009 and 31 December 2018 (restricted inclusion periods for intrauterine systems) were deemed to be in the case group. Each case was matched to five controls for year of birth and area of residence (90 305 controls).
Main outcome measures
Selected progestogens were used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and intrauterine levonorgestrel. For each progestogen, use was defined by at least one dispensation within the year before the index date (within three years for 13.5 mg levonorgestrel intrauterine systems and five years for 52 mg). Conditional logistic regression was used to calculate odds ratio for each progestogen meningioma association.
Results
Mean age was 57.6 years (standard deviation 12.8). Analyses showed excess risk of meningioma with use of medrogestone (42 exposed cases/18 061 cases (0.2%) v 79 exposed controls/90 305 controls (0.1%), odds ratio 3.49 (95% confidence interval 2.38 to 5.10)), medroxyprogesterone acetate (injectable, 9/18 061 (0.05%) v 11/90 305 (0.01%), 5.55 (2.27 to 13.56)), and promegestone (83/18 061 (0.5%) v 225/90 305 (0.2 %), 2.39 (1.85 to 3.09)). This excess risk was driven by prolonged use (≥one year). Results showed no excess risk of intracranial meningioma for progesterone, dydrogesterone, or levonorgestrel intrauterine systems. No conclusions could be drawn concerning dienogest or hydroxyprogesterone because of the small number of individuals who received these drugs. A highly increased risk of meningioma was observed for cyproterone acetate (891/18 061 (4.9%) v 256/90 305 (0.3%), odds ratio 19.21 (95% confidence interval 16.61 to 22.22)), nomegestrol acetate (925/18 061 (5.1%) v 1121/90 305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18 061 (3.5%) v 946/90 305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use.
Conclusions
Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningioma. The increased risk associated with the use of injectable medroxyprogesterone acetate, a widely used contraceptive, and the safety of levonorgestrel intrauterine systems are important new findings.
See more from MedicalBrief archives:
Blood clot risk rises with Pill/painkiller combo – Danish study
Breast cancer risk upped by contraceptive pill use – UK meta-analysis
Link confirmed between the Pill and clot risk
Contraception with fewer hormones still effective – Philippines modelling study