We don´t have elements to scare women who use oral contraceptives based on nomegestrol or chlormadinone about the risk of meningioma. Let's be careful and honest!

On 8 July 2022, the European Medicines Agency (EMA) safety committee (Pharmacovigilance Risk Assessment Committee, PRAC) recommended new measures to minimise the risk of meningioma with medicines containing nomegestrol acetate (NOMAc) or chlormadinone acetate (CMA) [1]. In the epidemiological studies presented by the PRAC and performed between 2007 and 2017 [2, 3], the correlation between the intake of NOMAc and CMA [two commonly used progestins in combination with oestradiol and ethinyl-oestradiol in oral contraceptives (OCs), respectively] and the risk of developing an intracranial meningioma was assessed. Following these studies, NOMAc and CMA are currently contraindicated in France for use in patients with a history of meningioma.

Meningiomas are neoplasms of the membranes covering the brain and spinal cord. They are not considered to be cancers but, due to their location in and around the brain and spinal cord, they can, in rare cases, cause serious problems. Meningiomas show an evident female predominance (a female-to-male ratio of 2.5:1), especially in women of reproductive age: the size of meningiomas increases during pregnancy and decreases after delivery [4]. Furthermore, a hormonal modulation, probably due to high doses of progesterone stimulation, has always been proposed. Previously, it has been shown that progesterone receptor expression may be involved in the occurrence of certain types of meningioma [5].

The PRAC has recommended that medicines containing high-dose NOMAc (3.75–5 mg) or high-dose CMA (5–10 mg) should be used at the lowest effective dose and for the shortest duration possible [1]. It must be noted that the marketed OCs with NOMAc and CMA contain lower doses of ‘indicted progestins’ (in particular, 2.5 mg of NOMAc and 2 mg of CMA). Furthermore, in the presented studies, practically all (95%) the women observed took the ‘indicted progestins alone’ (for menstrual regularisation during amenorrhoea and other menstrual disorders, for abnormal uterine bleedings, etc.) and not ‘in combination with oestrogens’ as occurs for OC purposes (in these women the risk was not shown to be increased [2,3]): this is a weighty omission in the EMA document!

How the risk of meningioma could change from ‘progestin-only therapy’ to ‘combined therapy’ has not been fully understood: central oestrogen modulation of risk could be very important and a real game changer in the cause–event hormonal effect, as we do not know any progestin-only pill containing these specific progestins in the market or in the experimental phase for contraceptive purposes. In fact, a recent meta-analysis including 13 studies (1,948,360 participants) reporting on the association between OC use and the risk of meningioma did not find evidence of any significant association between OC use and meningioma risk in female patients (relative risk = 0.99; 95% CI = 0.87–1.13; I² = 42.7%), while showing a reduction of glioma occurrence [6].

Interestingly, in past years a high risk of meningioma has been observed with the use of high doses (50 mg) of another progestin, cyproterone acetate (CPA) [7] and also in transgender individuals [8]. It is very intriguing to note that all these progestins are derived from progesterone [in particular, 17α-hydroxyprogesterone (CMA and CPA) and 19-norprogesterone (NOMAc)] and not from 19-nortestosterone as with many other progestins commonly used in OCs (levonorgestrel, gestodene, desogestrel, dienogest, norgestimate) [9]. The topic of a potential increased risk of meningioma with the use of high-dose synthetic progestins derived from progesterone, or perhaps even with the therapeutic use of progesterone itself, could be an element to be studied in depth in the coming years; however, this topic is more related to obstetric, gynaecological and perimenopausal drug therapy than to hormonal contraception.

In conclusion, with these data there is no evidence to scare women who use OCs containing NOMAc or CMA about the possible increased risk of meningioma, and even more so for those who are taking them for therapeutic benefits beyond safe contraception (polycystic ovarian syndrome, endometriosis, heavy menstrual bleeding treatment, etc.). All specific available progestins have their corollary of risks/benefits (venous thromboembolism risk, breast tissue stimulation, nuclear receptor activity, etc.); in all these fields evaluated, it is demonstrated that the effect of the specific progestin in OCs depends more on the balance with oestrogen than on its own activities. We should stop to consider different progestins from a single confused and supposed point of view!

Disclosure statement

Giovanni Grandi received honoraria for sponsored lectures and participation in advisory boards from Bayer AG, Italfarmaco, Theramex, Organon, Gedeon Richter and Exeltis, not related to this manuscript. The authors report no other potential conflicts of interest in relation to this work.