Use of progestogens and the risk of intracranial meningioma: national case-control study
BMJ 2024; 384 doi: https://doi.org/10.1136/bmj-2023-078078 (Published 27 March 2024) Cite this as: BMJ 2024;384:e078078
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Dear Editor,
We read with interest your recently published case-control study examining the association of intracranial meningioma with use of different classes of progestins. We are concerned regarding the conclusion with medroxyprogesterone (marketed as Depo Provera and abbreviated DMPA).
The study represents a carefully thought-out approach to leveraging a large database of discharge diagnoses and documented medication exposure. In addition, authors raise important points regarding the biological plausibility of the effect of different progestins on the pathogenesis of meningioma. Given that interval meningioma growth has been noted during pregnancy and regression is observed in the non-pregnant state, endogenous progesterone may play a role in disease progression. Additionally, the heterogeneity of the different progestins suggest that a differential response based on chemical structure and receptor affinity may offer a plausible explanation.
However, we strongly urge caution with regard to concluding causation from an observational study with a small number of total patients. In this large review, which identified more than 18,000 patients affected by intracranial meningioma, only 9 had received IM medroxyprogesterone, as opposed to hundreds who had received other forms of progesterone with no association in disease progress. To draw a conclusion of disease causation from the observation of nine patients is premature. In addition, using such decisive language is potentially more detrimental to the ability of patients to access contraception and providers to confidently prescribe.
In calculating the number needed to harm, more than 2300 persons would need to use medroxyprogesterone for one associated case of meningioma according to Roland et al. In comparison, this contraceptive method is estimated to be more than 95% effective, which reliably protects users against pregnancy and its associated health risk. Authors point out the importance of identifying DMPA as a potential risk factor for meningioma development as it is a method more likely to be used by marginalized users. However we would like to offer a strong counter to this perspective by underscoring that the morbidity and mortality associated with unplanned or mistimed pregnancy occurs at a significantly greater frequency than that of intracranial meningioma. The causal conclusions offered by this study are premature and potentially threaten the availability of this critical contraceptive agent.
Competing interests: No competing interests
Dear Editor
The content of this article is also important for the Ophthalmologist, since in daily practice, sometimes women who have symptoms that could be caused by an intracranial meningioma, such as headache and ocular symptoms, undergo an eye examination.
In these cases, the ocular symptoms may also be poorly defined or subtle, e.g. difficult focusing of images, fleeting doubling, or sudden chromatic alteration; or more pronounced, such as the reduction of the visual field, diplopia, pain and swelling of the upper lid, ptosis, high eye pressure.
Even more attention is paid to patients who present with symptoms such as Visual Aura, both for new-onset cases and for those who have suffered from it previously and are already taking the related therapy, but despite treatment, they find a resurgence of Aura and Migraine.
In one article, the Authors highlight the mistake of not recognizing that a Meningioma was the true cause of some of the clinical pictures they mentioned [1].
In other research it is highlighted that it is quite frequent for the Meningioma of the sphenoidal ridge, parasellar area, and occiput to produce visual deficits, but in almost one half of these patients, the visual deficit was initially misdiagnosed [2].
A further report about the lack of initial diagnostic recognition of Meningiomas concerns those of the optic nerve sheath [3].
Knowing that the patient presents the aforementioned symptoms and is undergoing progestogen hormone therapy, which could increase the risk of developing an intracranial meningioma [4], should prompt us to pursue timely and thorough diagnostic procedures to investigate the suspected neurological pathology. This can prevent dangerous delays instead of attributing all symptoms to stress and fatigue.
These observations could also be useful for those who do not practise ophthalmology when they find a patient with the coincidence of the ocular symptoms and concomitant progestin therapy: Easier access to neuro-ophthalmologists, improved diagnostic strategies, and education regarding neuroimaging should help prevent diagnostic errors [3].
Reference:
[1] Anderson D, Khalil MK. Meningioma and the ophthalmologist: diagnostic pitfalls. Can J Ophthalmol. 1981 Jan;16(1):10-5. PMID: 7193508.
[2] Anderson D, Khalil M. Meningioma and the ophthalmologist. A review of 80 cases. Ophthalmology. 1981 Oct;88(10):1004-9. doi: 10.1016/s0161-6420(81)80028-0. PMID: 7335302.
[3] Kahraman-Koytak P, Bruce BB, Peragallo JH, Newman NJ, Biousse V. Diagnostic Errors in Initial Misdiagnosis of Optic Nerve Sheath Meningiomas. JAMA Neurol. 2019 Mar 1;76(3):326-332. doi: 10.1001/jamaneurol.2018.3989. PMID: 30556835; PMCID: PMC6439718.
[4] Use of progestogens and the risk of intracranial meningioma: national case-control study. BMJ 2024; 384 doi: https://doi.org/10.1136/bmj-2023-078078 (Published 27 March 2024) BMJ 2024;384:e078078.
Competing interests: No competing interests
Dear Editor
This is an important article showing an increased likelihood of meningioma surgery with previous exposure to certain progesterone products including medroxy progesterone which is a common injectable contraception. The most likely explanation is that the exposure accelerates growth in very small meningiomas that would never present clinically to tumours that required surgery. This is plausible as many women are diagnosed with meningioma which are asymptomatic when scanned for other symptoms and most meningiomas have progesterone receptors and can be driven by progesterone. Thus the increased incidence in women of diagnosed tumours in adulthood despite boys having a higher risk than girls. Whilst these results need validation women with NF2 related schwannomatosis should avoid injectable medroxy progesterone acetate and both sexes cyproterone acetate.
Competing interests: No competing interests
Advanced age is a risk factor for the onset of Meningiomas: increased exposure to ionizing radiation over the years?
Dear Editor
It is known that with aging there is a greater need for diagnostic and therapeutic procedures related to the onset of various pathologies, often with consequent exposure to ionizing radiation. Such radiation can affect the skull, even if not directly addressed to this body area, especially if specific protections are not adopted to shield ionizing emissions.
In addition, in the healthcare sector, X-rays taken for ordinary dental care must be taken into account, as they are becoming more and more numerous with advancing years.
Finally, as one of the events to which we run the risk of exposure in daily life, we contemplate radiation emitted by natural sources, such as cosmic rays (such as high-altitude air travel) or radiation from elements underground, such as Radon gas [1].
Radon gas penetrates buildings from the ground and poses a real danger to people's health if the necessary preventive measures are not put in place in homes [1].
For this reason, it is necessary to take Radon into account when certain oncological or degenerative pathological events develop, the onset of which is favored by exposure to ionizing radiation [1,2,3].
This hypothesis becomes more suggestive in the case of the presence of a particular type of cataract, called posterior subcapsular [4], which occurs due to several etiological factors, including exposure to radiant energy [5]; however, it is necessary to specify that it is not pathognomonic of this condition.
REFERENCES:
[1] World Health Organization. Radon. https://www.who.int/news-room/fact-sheets/detail/radon-and-health
[2] Corrales L, Rosell R, Cardona AF, Martín C, Zatarain-Barrón ZL, Arrieta O. Lung cancer in never smokers: The role of different risk factors other than tobacco smoking. Crit Rev Oncol Hematol. 2020 Apr;148:102895. doi: 10.1016/j.critrevonc.2020.102895. Epub 2020 Jan 31. PMID: 32062313.
[3] Brenner DJ, Sachs RK. Domestic radon risks may be dominated by bystander effects--but the risks are unlikely to be greater than we thought. Health Phys. 2003 Jul;85(1):103-8. doi: 10.1097/00004032-200307000-00018. PMID: 12852476.
[4] Zuccheri Gianni. Subcapsular cataract: is there radon in the building? English version. 3 April 2024. Zuccheriperlasalute
[5] Richardson RB, Ainsbury EA, Prescott CR, Lovicu FJ. Etiology of posterior subcapsular cataracts based on a review of risk factors including aging, diabetes, and ionizing radiation. Int J Radiat Biol. 2020 Nov;96(11):1339-1361. doi: 10.1080/09553002.2020.1812759. Epub 2020 Sep 22. PMID: 32897800.
Competing interests: No competing interests