Progesterones and meningiomas

A new study has hit the main stream media about meningiomas in women. Meningiomas are usually non cancerous (benign) tumours of the lining of the brain or spinal cord, however there is a rare type which is cancerous. They are relatively common with 2-3% of the population having one without it causing any symptoms, and therefore they are often only picked up when the person is having a scan for another reason. They are twice as common in women as they are in men. The incidence of meningioma increases with age, rising sharply after the age of 65 years. Conversely, meningiomas are rare before the age of 35.

It has been observed that meningiomas can increase in size during pregnancy, when there is a high level of progesterone in the blood, and then reducing again after delivery when levels drop back to normal. Previous studies have shown that use of 2 different progestogens, cyproterone acetate (found in Dianette) and nomegestrol acetate (found in Zoely), has been associated with an increased risk of meningiomas, and as in pregnancy they will shrink when these medications are stopped.

The new study aimed to assess the real-life risk of intracranial meningioma associated with the use of progestogens from an extensive list (progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and levonorgestrel intrauterine systems) with different routes of administration (oral, percutaneous, intravaginal, intramuscular, and intrauterine). Norgestimate, gestodene, desogestrel and norethisterone were not studied, neither was the contraceptive implant (etonorgestrel).

Of these, only medroxyprogesterone, which is used in the depot contraceptive injection, was found to have an increase between the study group and the control group, with a 0.04% increase in risk an extra 4 in women would be found to have a meningioma for every 1,000 taking medroxyprogesterone for more than 12 months.

It is important to bear in mind that ‘association does not imply causation’. Suppose we observe that people who daily drink more than 4 cups of coffee have a decreased chance of developing skin cancer. This does not necessarily mean that coffee confers resistance to cancer; one alternative explanation would be that people who drink a lot of coffee work indoors for long hours and thus have little exposure to the sun, a known risk. If this is the case, then the number of hours spent outdoors is a confounding variable—a cause common to both observations. In such a situation, a direct causal link cannot be inferred; the association merely suggests a hypothesis, such as a common cause, but does not offer proof. In addition, when many variables in complex systems are studied, spurious associations can arise. Thus, association does not imply causation. We know that meningiomas can have receptors for progesterone, with anywhere between 48% and 100% of the tumours having a progesterone receptor. Interestingly the more progesterone receptors the tumour has the better the prognosis. With progesterone and meningiomas it is thought that progesterone may increase the size of a meningioma which would otherwise have remained too small to be detect, but that it does not cause the meningioma to occur in the first place. However more evidence is required about the link between progesterone and meningiomas.

As the risk of meningioma increases with age this information is more relevant to women over the age of 40 having progesterone as part of contraception, or as part of HRT. It is reassuring the the Mirena coil and micronised progesterone were not shown to have any associations and patient’s using these as part of HRT treatment can be reassured.

The FSRH previously advised that Zoely (Estradoil 1.5mg, Nomogestrel acetate 2.5mg) and Dianette (Cyproterone acetate 2 mg, Ethinylestradiol 35 microgram) should not be used by individuals who have or have had meningioma. It has added “The FSRH CEU recommends no significant change to current practice currently but does suggest that this information is included in individual discussions with patients regarding risks and benefits of various contraceptive methods…..The FSRH CEU will continue to monitor the evidence regarding progestogen use and the risk of meningioma.”

References

Omulecka A, Papierz W, Nawrocka-Kunecka A, Lewy-Trenda I. Immunohistochemical expression of progesterone and estrogen receptors in meningiomas. Folia Neuropathol. 2006;44(2):111-5. PMID: 16823693.

Roland N, Neumann A, Hoisnard L, Duranteau L, Froelich S, Zureik M et al. Use of progestogens and the risk of intracranial meningioma: national case-control study BMJ 2024; 384 :e078078

FSRH CEU Statement: New manufacturer/MHRA advice regarding nomegestrol acetate – how does this affect prescribing of Zoely®? (April 2023)

FSRH CEU Statement: New advice from the MHRA regarding cyproterone acetate: how does this affect prescribing of Co-cyprindiol/Dianette® for acne/hirsutism? (July 2020)