The Relationship Between Medroxyprogesterone Acetate and Intracranial Meningioma: A Review of Current Evidence and Recommendations for Future Study

Outcome: Meningioma

Intracranial meningioma is a typically benign neoplasm originating in the arachnoid mater of the meninges that surround the brain. Meningiomas are frequently slow-growing and asymptomatic, detected incidentally on imaging for other purposes, with 80-90% being classified as Grade 1 in the 2021 World Health Organization Classifications of Central Nervous System Tumors (Park, 2025a). However, these tumors can cause a wide range of symptoms depending on their size and location, with 30% of patients presenting with seizures (Park, 2025a). The focal neurological deficits that a patient presents with depend on the brain area adjacent to a meningioma. These deficits can include sensory changes; the loss of vision, hearing, or smell; altered mental status; headache; and weakness in the extremities (Park, 2025a). Depending on their size, location, and the severity of symptoms, meningiomas may be managed conservatively with surveillance or with surgery and/or radiation (gross total resection is typically curative for WHO CNS Grade 1 neoplasms) (Park, 2025b).

Meningiomas are the most common primary brain tumors, accounting for approximately 8 cases per 100,000 people (Reuter et al., 2025). These tumors are associated with genetic conditions, such as Neurofibromatosis Type 2 and Multiple Endocrine Neoplasia Type 1, and exposure to ionizing radiation (Park, 2025a). Of note, meningiomas are rare among prepubertal patients and are estimated to be twice as common in females as they are in males, with the female-to-male ratio being highest during peak years of reproduction (Park, 2025a). Additionally, progesterone and androgen receptors are present in over 60% of meningiomas, with estrogen receptors being positive in a smaller portion (Blankenstein et al., 2000). This pattern has led to an ongoing investigation as to whether sex hormones, physiologic or exogenous, including estrogen and progesterone, influence the development of meningiomas.

Evidence from prior studies is mixed as to whether there is a causal relationship between exogenous estrogen and/or progestin exposure and the risk of meningioma (Park, 2025a). Some data suggest that menopausal hormone therapy and use of progestin-containing contraceptives are associated with a small but statistically significant increase in the risk of meningioma (Park, 2025a). A recent study renewed public interest in this topic after demonstrating a small but statistically significant association between the progestin birth control injection and meningioma (Roland et al., 2024). This precipitated active discourse on social media, with many people raising alarm and misinterpreting the findings. In light of the recent relevance of this topic, our report will specifically focus on the relationship between this progestin in the birth control injection, medroxyprogesterone acetate, and intracranial meningioma.

Exposure: Medroxyprogesterone Acetate

DepoProvera, more commonly known as the birth control shot, is an intramuscular injection of 150 mg/1 mL of depot medroxyprogesterone acetate (DMPA). This method of birth control has been approved since 1992. DMPA is a progestin, a synthetically derived version of the naturally occurring progesterone hormone that regulates the menstrual cycle (Kaunitz, 2024). One injection of DepoProvera is approved for contraceptive purposes for up to 14 weeks, but patients routinely receive follow-up injections at 3-month intervals. DMPA works by binding to the progesterone receptor in the brain’s hypothalamus, preventing the release of gonadotropin-releasing hormone. This disruption inhibits ovulation and thus protects the user against pregnancy with up to 99% effectiveness (Griffin, 2024). These characteristics make DepoProvera a reliable and convenient form of birth control used by 74 million women worldwide (Roland et al., 2024). The prevalence of DepoProvera use among reproductive-aged women varies around the world, from 1.8% in high-income countries to 8.7% in low-income countries.

A recent study by Roland et al. (2024) found a link between DMPA and intracranial meningioma, igniting public discourse on this common form of birth control. The American College of Obstetricians and Gynecologists (ACOG) released a statement in light of these findings, encouraging providers to prepare to discuss the results with patients. However, ACOG also cautioned that because the overall risk appears to be quite low, and the Roland et al. (2024) study had several limitations, providers should interpret the results with caution and continue a shared decision-making approach when counseling patients about DepoProvera (ACOG, 2025). This paper will review the existing literature on the relationship between DMPA and meningioma and suggest future work to establish more definitive evidence of the risk.

Literature Review

The literature on the relationship between DMPA and meningioma development is small but growing. All studies are observational, including case-control, retrospective cohort, and case series designs. Most data supports that the use of DMPA, especially for long periods, increases the risk of meningioma development. The existing literature is summarized in the table below. Of note, several additional studies are available as preprints online, but were excluded from this analysis as they have not yet undergone peer review.

Because meningiomas are a rare outcome, most studies identified were either case-control designs or case series. These types of observational studies are more suited to rare diseases than cohort studies because a cohort study would require following a large number of people to observe a few events. Roland et al. (2024), Griffin (2024), and Wahyuhadi et al. (2018) conducted case-control studies. While Wahyuhadi et al. (2018) found the high use of any hormonal contraceptive among meningioma patients compared to controls of 12.3 (p=.000), they interestingly did not specifically report the OR of DMPA use. However, comparing the odds of use of 3-month intervals DMPA injection birth control, they found that the 1-month DMPA formulation, progesterone pills, and combination pills were statistically significantly less likely to be associated with meningioma. The Roland et al. (2024) and Griffin (2024) studies had more robust methodological designs, with sample sizes many times larger than the 200 patients in the Wahyuhadi et al. study. However, it is important to note that since the Roland et al. (2024) study included exposure to other progestins, only 20 patients in the sample were exposed to DMPA, 9 of whom were cases; this is a small number to draw conclusions on. Roland et al. (2024) and Griffin (2024) were also more robust because they matched their cases to controls to limit the influence of confounders. Specifically, Roland et al. (2024) matched cases to controls based on birth year and area of residence, and Griffin (2024) matched based on age, year of enrollment, and duration of enrollment. Roland et al. (2024) found that the OR of DMPA was 5.62 (2.19 to 14.42), and Griffin (2023) found that DMPA exposure was associated with 76% increased odds of meningioma. Roland et al. (2024) did not compute an adjusted model, but Griffin (2024) found that their results persisted with statistical significance even after adjusting for age and comorbid conditions.

Abou-Al-Shaar et al. (2023) examined 25 cases of women with meningiomas who had previous long-term use of DMPA. Being a case series, this study confers the least ability to make causal conclusions. For instance, the shrinkage of meningiomas seen in five patients in this series after discontinuing DMPA upon their diagnosis could have been related to withdrawal of the hormone or other factors; the authors did not specify whether these patients were being concurrently treated with chemotherapy. Unlike the aforementioned studies that aimed to determine if DMPA is associated with a higher risk of meningioma, Dustur et al. (2022) conducted a retrospective cohort study of meningioma patients to determine whether the histological grade of the lesions differed between those exposed to DMPA and those who were unexposed. They found that no association between DMPA use and meningioma grade among patients taking DMPA contraception for <10 years and >10 years. Additionally, the methods section of this study was somewhat unclear, with no distinction as to whether the determination of DMPA exposure was made from an objective chart review or a self-report. If this data was obtained from self-report, it would be subject to recall bias. Because of these factors, we found this study somewhat less robust than the others mentioned previously.

A limitation common to several of these studies was that they were conducted at a single clinical center. Dustur et al. (2022) and Abou-Al-Shaar et al. (2023) took place at the same hospital in Indonesia, while Wahyuhadi et al. (2018) was conducted at a US facility. The single-center nature of these studies is significant because it may mean their results are not generalizable to other populations. On the other hand, Roland et al. (2024) and Griffin (2024) used databases with information about patients from across their respective countries; Roland et al. (2024) used a national French database, while Griffin (2024) collected data from the largest private-insurance claims database. Notably, the private insurance status of all the patients in the Griffin (2024) study could mean that the results would differ in an uninsured or Medicare/Medicaid insured population.

Most of these studies employed objective measures of both the outcome and exposure. For instance, Roland et al. (2024) and Griffin (2024) used databases rather than self-report measures to determine DMPA exposure. However, in Roland et al. (2024), exposure to DMPA was measured as “at least one dispensation of the medication within 365 days of the admission date,” which may not be an accurate measure of DMPA exposure. On the other hand, Abou-Al-Shaar et al. (2023), Dustur et al. (2022), and Wahyuhadi et al. (2018) were either unclear about how they determined DMPA exposure or they relied on self-reports from patients, which is known to be subject to information bias.

These studies could be improved by controlling for additional confounding variables in their methods and analysis. As mentioned above, Roland et al. (2024) and Griffin (2024) both matched cases to controls, and Griffin (2024) also computed an adjusted analysis, but few variables were included. Importantly, they considered age, but other potential covariates could confound or moderate the relationship between DMPA and meningioma. Potential confounders of this relationship include age, socioeconomic status, reproductive history, race/ethnicity, and insurance status. Covariates include exposure to ionizing radiation, genetic predispositions for meningiomas, exposure to other hormones, and obesity.

Proposed Mechanism

Gaps and Proposed Study

As evidenced above, there are flaws in the current body of literature examining the association between DMPA and meningioma. We still lack precise estimates of the risk DMPA confers towards meningioma development. It is also important to note that the current knowledge base is drawn almost entirely from retrospective registry studies of tumors that required surgery, leaving the earliest, asymptomatic stages of lesion development uncharacterized. We know little about how genetic predisposition, body mass index, reproductive history, previous radiation exposure, or racial and ethnic background might modify the DMPA-meningioma relationship.

To address these gaps, we propose a multi-center prospective cohort study embedded in integrated health-care systems that links electronic pharmacy files, longitudinal clinical records, and research imaging. We will recruit 500,000 reproductive-age women using DMPA injections and 500,000 age-matched women who opted for a copper intrauterine device (IUD). The comparison group will be women with the copper IUD, rather than women not using birth control, because women who are not using birth control may differ from women using any form of birth control in certain behaviors or characteristics. We want to ensure that these factors are controlled for. Additionally, the copper IUD is locally acting and does not contain any progesterone, therefore it does not confer an increased risk of meningioma. Baseline data will include a detailed contraceptive history, parity, menarche, menopausal status, BMI, smoking, prior head irradiation, and germline variants in NF2 and DNA-repair genes. All participants will undergo a screening 3-Tesla brain MRI at enrolment and five-year intervals for 30 years; interim symptomatic scans will also be captured. Meningiomas, symptomatic or incidental, radiological or observed, will constitute the primary outcome. Time-to-event analyses with time-varying exposure will yield hazard ratios for DMPA vs the copper IUD. At the same time, expandable Cox models will test interactions with genetic background, BMI, and radiation history to identify modifiers of risk. By imaging every participant prospectively, we will characterize latent tumor development and define growth kinetics for DMPA patients. The cohort’s racially and socio-economically diverse membership will also reduce disparities in surveillance.

Conclusions

In sum, based on recent observational studies, growing evidence supports a connection between the use of DMPA and the risk of meningioma development. Additionally, this relationship is biologically plausible as prior research demonstrates that progesterone receptors are present in over 60% of meningiomas (Blankenstein et al., 2000). Undoubtedly, this connection should be explored with further research, but alarm should not be raised at this juncture. A physician in a letter to the editor of the journal in which the Roland et al. (2024) study was published highlights significant limitations in what is known so far. This doctor calls to attention that only nine patients with meningioma were exposed to DMPA. Additionally, this physician cautions that we should not abandon a reliable form of birth control that is over 95% effective and relied on by low-income patients, when the number needed to harm is so high; more than 2,300 people would need to be exposed to DMPA for one additional meningioma case to occur (Smith, 2024). The American College of Obstetricians and gynecologists also cautions against raising alarm on this association because although the relative risk of meningioma with DMPA exposure may be elevated, the absolute risk difference remains very low, from one out of 10,000 women not using the medication to five out of 10,000 women using DMPA (ACOG, 2025). Thus, it is important to place the link between DMPA and meningioma into context and assist patients in performing a cost-benefit analysis when deciding if this is the ideal form of birth control for them.

References

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American College of Obstetricians and Gynecologists. (2024). Guide for ob-gyns for patient counseling on birth control injection and meningioma. https://www.acog.org/clinical-information/patient-education-materials/tools-for-navigating-discussions/birth-control-injection-and-meningioma-counseling-guide?utm_source=redirect&utm_medium=web&utm_campaign=int

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