Prolonged Use of Progestogens May Be Linked to Increased Risk of Brain Cancer

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Prolonged use of selected progestogen agents may be associated with an increased risk of developing intracranial meningioma, according to a recent study published by Roland et al in the BMJ.


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

Intracranial meningioma tumors are found in the meninges covering the brain and spinal cord. Factors such as older age, female sex, and exposure to high doses of the progestogens nomegestrol, chlormadinone, and cyproterone acetate are known to increase the risk of intracranial meningioma—a majority of which are noncancerous.

There are currently many other progestogens for which the risk of intracranial meningioma associated with their individual use has not yet been estimated.

Study Methods and Results

In the recent study, investigators used data from the French National Health Data System to examine the outcomes of 18,061 female patients (average age, 58) who underwent surgery for intracranial meningioma between 2009 and 2018 and 90,305 birth year– and area of residence–matched controls. They sought to determine the real-life risk of intracranial meningioma associated with the use of several progestogens: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and levonorgestrel intrauterine systems.

For each of the progestogens, use was defined as at least one prescription within 1 year prior to hospital admission or within 3 to 5 years of hospital admission for levonorgestrel intrauterine systems. Use of at least one of the three high-dose progestogens known to increase the risk of intracranial meningioma in the 3 years prior to hospital admission was also recorded to minimize bias.

After considering other potential influential factors, the investigators found that the use of promegestone, medrogestone, or medroxyprogesterone acetate injection for at least 1 year was associated with a respective 2.7-, 4.1-, and 5.6-fold increased risk of intracranial meningioma requiring surgery. Additionally, there was an excess risk of intracranial meningioma among the patients exposed to chlormadinone acetate, nomegestrol acetate, and cyproterone acetate—all of which have been shown to increase the risk of the disease.

There appeared to be no risk of intracranial meningioma requiring surgery following progestogen use for less than 1 year. There was no excess risk of intracranial meningioma among those who used progesterone, dydrogesterone, or the widely used hormonal intrauterine systems—regardless of the dose of levonorgestrel they contained.

The investigators noted that the number of patients exposed to dienogest and hydroxyprogesterone was too small to draw conclusions regarding the risk of intracranial meningioma.


The investigators emphasized that because the study was observational, they couldn’t establish cause and effect. Further, the French National Health Data System lacked information regarding the clinical details and medical indications for which progestogens were prescribed. They were also unable to account for genetic predisposition and exposure to high-dose radiation.

However, they estimated that medroxyprogesterone acetate was used for birth control among 74 million women around the world. As a result, the number of attributable intracranial meningiomas may be high.

The investigators concluded that further studies using other sources of data may be needed to better understand the risk of intracranial meningiomas after the long-term use of progestogens.

Disclosure: The research in this study was funded by the French National Health Insurance Fund and the French National Agency for Medicines and Health Products Safety via the Health Product Epidemiology Scientific Interest Group. For full disclosures of the study authors, visit

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