By: Gemvi, CNEGM, CNGOF, FNCGM, CNPGO-GM, Seud

In recent years, the mismanagement of meningioma (although very low in absolute value) associated with three synthetic progestins and in particular with cyproterone acetate have led to recommendations for daily practice aimed at supervising their prescription. If these recommendations, particularly for cyproterone acetate, have enabled a re-evaluation of the individual benefit-risk balance of these molecules (which is obviously favorable in many indications validated by the ANSM itself), the entire community of clinicians is alarmed on recent recommendations, published on March 2, 2023, called "preliminary" . These recommendations which concern all the progestins currently reimbursed as well as natural progesterone are not based, in fact, to date that on some reported cases of meningioma, in the absence of any scientific study.

Should we recall for good health policies and in the interest of each person, the need for evidence-based medicine, widely taught for several years in our faculties and even being the subject specifically of an examination to the national classifying exam (ECN) called critical article of article!

The mission of the new temporary specific committee (CST) of the ANSM questions in this regard. Indeed, it has been installed with the specific objective of developing: “ Recommendations [which] will address healthcare professionals in order to better protect people using these drugs. They will be published and disseminated pending the results of new epidemiological studies which will allow to demonstrate or invalidate the risk of meningioma ”.

In fact, the question that must be asked is that of the consequences of this media coverage of preliminary recommendations without any assessment of a level of risk for designated progestins (Diénogest, Dydrogesterone, Médrogestone) and on natural progesterone .

It is already probably important to take into account the duration (or the cumulative dose [?] Of progestins), this question not resolved to date is however fundamental for clinicians.

Finally, putting synthetic progestins and natural progesterone on the same level is questionable to say the least in terms of activity and pharmacokinetics. Progesterone, a molecule secreted by the ovary, has a major role for the preparation of the endometrium of a future pregnancy and a rapid metabolism, therefore a half-life that has nothing to do with that of synthetic (progestogen) molecules.

It is also essential to know that progesterone and progestogens have a major role in the prevention of endometrium cancer and in the treatment of benign gynecological diseases. Their use for many years has significantly reduced the use of hysterectomy.

The use of progestins and progesterone therefore covers an important field of gynecology with essential uses. Let us quote some representative examples.

• The majority use of progesterone in the field of medical assistance to procreation (luteal phase support after intrauterine and vitro ) whose indications have been considerably extended since the publication of the new bioethics law. Usefulness proven by many randomized studies and meta-analyzes without real replacement molecule.
• The hormonal management of menopause is specifically based on the use of a treatment associating the 17beta-estradiol and natural progesterone, an association whose balances-risk profits is the subject of recommendations from learned companies in many countries (including the recommendations for French clinical practice developed jointly by the GEMVI and the CNGOF in 2021). All these companies notably American (North American Menopause Society, Endocrine Society, etc.) now specifically recommend this molecule having regard to its balance of risk-risk, probably the most optimal of the hormonal treatment of menopause.
• The same is true for treatment, among other things, of women with hypogonadotropic hypogonadism or premature ovarian insufficiency for which the use of hormonal treatment combining estradiol with progesterone or progestin is essential to limit early mortality linked to estrogen deficiency. Will we have to hysterectomize all of these women to prevent the occurrence of endometrial cancer induced by the use of estrogens without the addition of progesterone?
• In the 2018 international recommendations published under the aegis of the eShre, women suffering from SOPK (15 % of women in industrialized countries) and with cycle disorders must be able to benefit from hormone treatment containing progestins to limit the risk of endometrium hyperplasia and especially endometrium cancer. What will we offer to these women, especially when they have contraindications to estroprogestative contraceptions (unfortunately frequent situation in this pathology)?
• Finally, concerning the management of endometriosis, the development of low-dose progestin therapeutics showing employment of employment on the vascular risk is already to be avoided?

So many clinical situations would leave patients without any therapeutic resources if it is not to increase the prevalence of hysterectomies and help alter the quality of life of women when our country has been that in the world for many years where the number of hysterectomies and where the incidence of endometrium cancer are the lowest? Will it have to orient them towards treatments whose balance of global risk-risk is less favorable individually or remains to be demonstrated?

If the use of progesterone worries about our authorities with the risk of meningioma, would it not be more useful to look at the current scientific literature concerning women who have children (whose progesterone levels are multiplied by a factor 6 to 8 during their pregnancy) compared to nulliparous women. In this regard, the study by Jenny Pettersson-Segerlind published very recently in the prestigious review of the Nature ( Scientific Reports 2021) shows no risk of meningioma in multi-pore women compared to nulliparous women. And not to mention that no country to the world has to date have raised the question of such an association while synthetic progestins or progesterone are largely prescribed.

Finally, let us recall that the use of any therapeutic-whether it is a progestogen or any other molecule-is always the subject when prescribing an evaluation of its balance of individual profits. We can consider raising awareness among health professionals for long periods of use of progestins (in high doses) but let us stop worrying women on "suggestions" of risk not evaluated.