By Rebecca H. Allen, MD, MPH, Editor
SYNOPSIS: The authors of this study sought to determine whether there was a relationship between progestins and central nervous system meningiomas.
SOURCE: Roland N, Neumann A, Hoisnard L, et al. Use of progestogens and the risk of intracranial meningioma: National case-control study. BMJ 2024;384:e078078.
Meningiomas are the most common type of tumor found in the central nervous system. They typically are benign but may cause complications when they compress nearby structures.1 Whether progestins contribute to the development and growth of central nervous system meningiomas has been controversial. The one progestin most implicated is high-dose cyproterone acetate, which is a progestin not available in the United States but is used in Europe for prostate cancer among other indications. Two other high-dose progestins, nomegestrol acetate and chlormadinone acetate, also have been linked.2
The authors of this study sought to determine whether there was a relationship between other types of progestins and central nervous system meningiomas. This was a case-control study conducted using data from the French national health system, which includes more than 99% of the population in France. The system contains data on healthcare reimbursements and hospital discharges. Cases were women of all ages who underwent surgery for an intracranial meningioma between Jan. 1, 2009, and Dec. 31, 2018.
The date of surgery was considered the index date. Surgeries were identified by ICD-10 codes and procedure codes. Women with pregnancies within two years of the index date were excluded from the study. Controls were randomly matched 5:1 by year of birth and area of residence. Both cases and controls had to have at least one service reimbursed in each of the three years prior to the index date to make sure they were active in the system. Multiple types of progestins were evaluated as exposures: oral, intravaginal, and percutaneous progesterone; dihydrogesterone; hydroxyprogesterone; medrogestone; promegeston; depot medroxyprogesterone acetate (DMPA); dienogest (in association with 2 mg of estrogen); levonorgestrel (LNG) intrauterine system (IUS), both 13.5 mg and 52 mg; and spironolactone as a proxy for drospirenone, which was not used in France.
For oral, intravaginal, percutaneous, or intramuscular progestins, exposure was defined as at least one administration in the 365 days before the index date. For IUS, administration was within three years for the 13.5-mg device and within five years for the 52-mg device. Exposure was defined as any exposure to a progestin listed earlier, exposure within three years to at least one of the high-dose progestins associated with meningioma (nomegestrol acetate, cyproterone acetate, and chlormadinone acetate), or the absence of exposure to any progestins. Other data collected included sociodemographic and medical characteristics, and details of the surgery. Logistic regression analysis was conducted to estimate odds ratios (ORs) and their 95% confidence intervals (CIs).
A total of 18,061 cases were identified and matched to 90,305 controls. The mean age was 57.6 years (± 12.8 years). Most women were aged 45-54 years (26.7%), 55-64 years (26.4%), and 65-74 years (21.5%). Most of the meningiomas were benign (92.3%), 5.8% were atypical, and 1.9% were malignant. Among the 18,061 cases, 329 (1.8%) had used oral or intravaginal progesterone, 90 (0.5%) had used percutaneous progesterone, 156 (0.9%) had used dydrogesterone, 42 (0.2%) had used medrogestone, nine (< 0.1%) had used medroxyprogesterone acetate, 83 (0.5%) had used promegestone, three (< 0.1%) had used dienogest, and 264 (1.5%) had used spironolactone. For IUS, 566 (3.7%) had used the 52-mg LNG-IUS and 10 (0.2%) had used the 13.5-mg LNG-IUS. These numbers do not include the 2,999 individuals who had been exposed to nomegestrol acetate, cyproterone acetate, and chlormadinone acetate in the previous three years.
There was no significant association between the need for meningioma surgery and exposure to oral or vaginal progesterone (OR, 0.88; 95% CI, 0.78, 0.99) or exposure to percutaneous progesterone (OR, 1.11; 95% CI, 0.89, 1.40), dydrogesterone (OR, 0.96; 95% CI, 0.81, 1.14), and spironolactone (OR, 0.95; 95% CI, 0.84, 1.09). Exposure to dienogest was rare, with an OR of 1.48 (95% CI, 0.41, 5.35), and no exposed cases to hydroxyprogesterone were found. The risk of meningioma surgery was increased with the use of medrogestone (OR, 3.49; 95% CI, 2.38, 5.10), DMPA (OR, 5.55; 95% CI, 2.27, 13.56), and promegestone (OR, 2.39; 95% CI, 1.85, 3.09). The OR for the progestins known to be associated with meningiomas were elevated as expected (chlormadinone acetate [OR, 3.87; 95% CI, 3.48, 4.30], nomegestrel acetate [OR, 4.93; 95% CI, 4.5, 5.41], and cyproterone acetate [OR, 19.21; 95% CI, 16.61, 22.22]). A subset of intrauterine device (IUD) users was identified for a separate analysis with their controls. There was no excess risk of meningioma surgery with the use of the 52-mg LNG-IUS (OR, 0.94; 95% CI, 0.86, 1.04) nor with the 13.5-mg LNG-IUS (OR, 1.39; 95% CI, 0.70, 2.77). Exposure to copper IUDs showed an OR of 1.13 (95% CI, 1.01, 1.25).
COMMENTARY
There is biologic plausibility that hormones may play a role in meningioma development, since the incidence is higher in females compared to males and this ratio peaks in the reproductive years. In addition, meningiomas can contain androgen, progesterone, and estrogen receptors.2
Studies have been mixed on whether low-dose hormone replacement therapy or combined oral contraceptive use contributes to meningioma risk.3 But, as stated earlier, high-dose cyproterone (25 mg/day or more is associated with a small increased risk of meningioma, especially if taken over several years. And there have been studies showing that nomegestrol acetate and chlormadinone acetate also may be implicated. None of these progestins are used in the United States.
The authors opted to explore other progestins as well in this study. For progestins pertinent to the United States, the study shows that the levonorgestrel IUDs and spironolactone have no association. Dienogest was studied as part of a combined hormonal contraceptive pill that also contains estradiol valerate. This pill is available in the United States with the brand name Natazia. There were only three cases of dienogest use, which the authors noted was a very small number of people and led to a wide CI, but the OR was not significant. For DMPA, the OR was elevated (OR, 5.55; 95% CI, 2.27, 13.56) but, again, there is a wide CI because there were only nine people who used the medication. For DMPA, there were nine cases (0.05%) in DMPA users and 11 cases (0.01%) in the control group. All but two of these DMPA users had used the medication for more than a year.
In my opinion, it is difficult to interpret this association because the number of women exposed to DMPA was very small. In addition, the fact that the copper IUD had a positive significant association demonstrates that, in studies with large sample sizes overall, outcomes may be significant purely by chance as part of the statistical noise that exists in these types of studies. Limitations of the study include that the researchers could only evaluate meningiomas that led to intracranial surgery, so there may have been more meningiomas that were undetected. If there were more or fewer meningiomas in the control arm that were undetected, this could bias the results. The authors acknowledged that risk/benefit ratio for using progestins for various medical disorders and contraception could not be ascertained from the data.
In the end, if DMPA does indeed have an association with meningiomas, the absolute risk is very small. The population attributable fraction for DMPA was estimated to be 0.04%. This means that only 0.04% of the surgeries for intracranial meningiomas in France during the time period of the study could be attributed to DMPA. Nevertheless, other studies have documented a link between DMPA and meningioma risk, and more research needs to be performed.
REFERENCES
- Cao J, Yan W, Li G, et al. Incidence and survival of benign, borderline, and malignant meningioma patients in the United States from 2004 to 2018. Int J Cancer 2022;151:1874-1888.
- Hoisnard L, Laanani M, Passeri T, et al. Risk of intracranial meningioma with three potent progestogens: A population-based case-control study. Eur J Neurol 2022;29:2801-2809.
- Michaud DS, Gallo V, Schlehofer B, et al. Reproductive factors and exogenous hormone use in relation to risk of glioma and meningioma in a large European cohort study. Cancer Epidemiol Biomarkers Prev 2010;19:2562-2569.