Researchers identify increased brain tumor risk with specific contraceptive use

By Pooja Toshniwal PahariaReviewed by Lily Ramsey, LLMMar 28 2024

In a recent study published in BMJ, researchers evaluated the intracranial meningioma risk associated with progestogen use.

Study: Use of progestogens and the risk of intracranial meningioma: national case-control study. Image Credit: fongbeerredhot/Shutterstock.com

Background

Meningiomas are primary central nervous system tumors that can compress nearby brain tissue, necessitating surgical decompression.

Age, female sex, neurofibromatosis type 2, ionizing radiation exposure, and long-term usage of high-dose progestogens such as nomegestrol, chlormadinone, and cyproterone acetate are all risk factors for intracranial meningioma. Discontinuing these progestogens minimizes meningioma volume, avoiding surgery and its risks.

However, meningioma risk related to other progestogens is uncertain, and there is no apparent link between exogenous female hormones and meningioma risk for hormonal contraceptives.

Further, the evidence regarding hormone replacement therapy for menopause is conflicting. Discontinuing these progestogens minimizes meningioma volume, preventing surgery and related risks.

About the study

In the present observational and population-based study, researchers investigated whether certain progestogens increased intracranial meningioma risk and related delivery routes.

The researchers analyzed data from France's National Health Information System [i.e., Système National des Données de Santé (SNDS)]. Among 108,366 females, 18,061 residing in France and operating for intracranial meningioma from January 2009 to December 2018 were cases.

The researchers matched each case to five control individuals by birth year and residence area (90,305 controls), excluding women with pregnancies commencing two years before hospitalization for meningioma surgery.

Progestogens used included hydroxyprogesterone, progesterone, medrogestone, dydrogesterone, promegestone, medroxyprogesterone acetate, levonorgestrel, and dienogest. The administration routes investigated were oral, intramuscular, intravaginal, percutaneous, and intrauterine.

The team defined progestogen use by one drug dispensation within 12 months before hospitalization (within three and five years for intrauterine levonorgestrel systems in doses of 13.50 mg and 52 mg, respectively).

The researchers used the World Health Organization's (WHO) Anatomical, Therapeutic, and Chemical (ATC) classification to define progestogen exposure. They used conditional logistic regressions to determine the odds ratios (OR) for analysis. Study covariates included residence, age, type 2 neurofibromatosis, and, for meningioma cases only, surgery year, tumor site, and grade.

The team obtained adjuvant radiation data between three months before and six months after hospitalization. They also evaluated the patients for all-cause death two and five years after the hospitalization date and antiepileptic medicine use three years after surgery.

In addition, they performed sensitivity analyses, stratifying the data by patient age, tumor location, and severity.

Results

The mean participant age was 58 years, and the most common tumor site was the skull base (56%). Most cases were benign (92%), with 5.8% atypical and 1.9% malignant tumors. Among the cases, 29% of women consumed antiepileptic medications after three years of surgery.

Mortality rates were higher among cases than controls, with 2.8% of cases dying within two years and 5.3% within five years. Of 18,061 cases, 1.8% used oral or intravaginal progesterone, and 1.5% used spironolactone.

0.9% used dydrogesterone, 0.9% used medroxyprogesterone acetate, 0.5% used percutaneous progesterone, 0.2% used medrogestone, 0.1% used dienogest, and 0.5% used promegestone.

The team noted excess meningioma risk related to medrogestone use [42/18,061 cases (0.20%) vs. 79/90,305 control individuals (0.10%), OR 3.5], promegestone [83/18,061 (0.5%) vs. 225/90,305 (0.2%), OR 2.4], and medroxyprogesterone acetate [injectable route, 9/18,061 (0.05%) vs. 11/90,305 (0.01%), OR 5.6]. The excess meningioma risk was associated with progestogen use for ≥12 months.

In contrast, there was no excess meningioma risk for dydrogesterone, progesterone, and levonorgestrel intrauterine medications. The team could not conclude hydroxyprogesterone or dienogest use due to the limited sample size of drug recipients.

They observed a considerably elevated risk of intracranial meningioma for nomegestrol acetate [5.1% (925 cases) vs. 1.2% (1,121 controls), OR 4.9], cyproterone acetate [4.9% (891 cases) vs. 0.3% (256 controls), OR 19.2], and chlormadinone [3.5% (628 cases) vs. 1.0% (946 controls), OR 3.9], which were positive controls.

The sensitivity analyses showed a high excess meningioma risk for the middle of the skull tumors (OR 8.3), with a slightly higher risk among women aged 45–54 years.

The excess meningioma risk related to promegestone use was marginally higher among individuals aged above 65 years (OR 3.2) and for tumors in the middle or front of the skull (ORs of 3.0 and 3.2, respectively).

Conclusions

The study findings showed prolonged usage of medrogestone (oral, 5.0 mg), medroxyprogesterone acetate (injectable, 150 mg), and promegestone (oral, 0.10/0.50 mg) was associated with increased meningioma risk.

However, there was no excess meningioma risk related to progesterone (oral, percutaneous, and intravaginal; 25, 100, and 200 mg), dydrogesterone (10 mg, combined with estrogen: 5, 10 mg), spironolactone (25, 50, 75 mg), and levonorgestrel (intrauterine, 13.5 mg and 52 mg) use.

Future studies should investigate the relationship between progestogen duration and meningioma risk, broaden the topic to include dienogest and hydroxyprogesterone and evaluate meningioma risk with medroxyprogesterone acetate, a second-line injectable contraceptive infrequently used in France.

Further research from nations with a larger population and vulnerable groups is required to improve understanding of the dose-response relationship of this medication.