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Management of postmenopausal women: Collège National des Gynécologues et Obstétriciens Français (CNGOF) and Groupe d'Etude sur la Ménopause et le Vieillissement (GEMVi) Clinical Practice Guidelines

  • Author Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    F.A. Trémollieres
    Correspondence
    Corresponding author at: Centre de Ménopause et Maladies Osseuses Métaboliques, Hôpital Paule-de-Viguier, CHU Toulouse, 330, avenue de Grande-Bretagne, TSA 70034, 31059 Toulouse, France.
    Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    Affiliations
    Centre de Ménopause et Maladies Osseuses Métaboliques, Hôpital Paule-de-Viguier, CHU Toulouse, 330, avenue de Grande-Bretagne, TSA 70034, 31059 Toulouse, France

    Inserm U1048-I2MC-Equipe 9, Université Toulouse III Paul-Sabatier, 1, avenue du Professeur-Jean-Poulhes, BP 84225, 31432 Toulouse cedex 4, France
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    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    N. Chabbert-Buffet
    Footnotes
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    Affiliations
    Service de gynécologie obstétrique, médecine de la reproduction, APHP Sorbonne Universitaire, Site Tenon, 4, rue de la Chine, 75020 Paris, France
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  • Author Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    ,
    Author Footnotes
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    G. Plu-Bureau
    Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    Affiliations
    Unité de gynécologie médicale, Hôpital Port-Royal, 123 boulevard de Port-Royal, 75014 Paris, France

    Université de Paris, Paris, France

    Inserm U1153 Equipe EPOPEE, Paris, France
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  • Author Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    ,
    Author Footnotes
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    C. Rousset-Jablonski
    Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    Affiliations
    Département de chirurgie oncologique, Centre Léon Bérard, 28, Promenade Léa-et-Napoléon-Bullukian, 69008 Lyon, France

    Département d'obstétrique et gynécologie, Hospices Civils de Lyon, CHU Lyon Sud, 165, Chemin du Grand-Revoyet, 69310 Pierre-Bénite, France

    Université Lyon, EA 7425 HESPER-Health Services and Performance Research, 8, avenue Rockefeller, 69003 Lyon, France
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  • J.M. Lecerf
    Affiliations
    Service de nutrition et activité physique, Institut Pasteur de Lille, 1, rue du Professeur-Calmette, 59019 Lille cedex, France

    Service de médecine interne, CHRU Lille, 2, avenue Oscar-Lambret, 59000 Lille, France
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  • M. Duclos
    Affiliations
    Service de médecine du sport et des explorations fonctionnelles, CHU Clermont-Ferrand, 63003 Clermont-Ferrand, France

    Clermont Université, Université d'Auvergne, UFR Médecine, BP 10448, 63000 Clermont-Ferrand, France

    INRAE, UMR 1019, UNH, CRNH Auvergne, 63000 Clermont-Ferrand, France
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  • Author Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    J.M. Pouilles
    Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    Affiliations
    Centre de Ménopause et Maladies Osseuses Métaboliques, Hôpital Paule-de-Viguier, CHU Toulouse, 330, avenue de Grande-Bretagne, TSA 70034, 31059 Toulouse, France
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    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    A. Gosset
    Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    Affiliations
    Centre de Ménopause et Maladies Osseuses Métaboliques, Hôpital Paule-de-Viguier, CHU Toulouse, 330, avenue de Grande-Bretagne, TSA 70034, 31059 Toulouse, France
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    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    G. Boutet
    Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    Affiliations
    AGREGA, Service de chirurgie gynécologique et médecine de la reproduction, Centre Aliénor d'Aquitaine, Hôpital Pellegrin, 33000 Bordeaux, France
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    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    ,
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    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    C. Hocke
    Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    Affiliations
    Service de chirurgie gynécologique et médecine de la reproduction, Centre Aliénor d'Aquitaine, CHU de Bordeaux, Place Amélie-Raba-Léon, 33076 Bordeaux cedex, France
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    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    E. Maris
    Footnotes
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    Affiliations
    Département d'obstétrique et gynécologie, CHU Montpellier, Université Montpellier, Montpellier, France
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  • J. Hugon-Rodin
    Affiliations
    Unité de gynécologie médicale, Hôpital Port-Royal, 123 boulevard de Port-Royal, 75014 Paris, France
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  • Author Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    L. Maitrot-Mantelet
    Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    Affiliations
    Unité de gynécologie médicale, Hôpital Port-Royal, 123 boulevard de Port-Royal, 75014 Paris, France
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    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    G. Robin
    Footnotes
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    Affiliations
    Service de gynécologie médicale, orthogénie et sexologie, UF de gynécologie endocrinienne, Hôpital Jeanne-de-Flandre, CHU de Lille, avenue Eugène-Avinée, 59037 Lille cedex, France
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    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    G. André
    Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    Affiliations
    15, boulevard Ohmacht, 67000 Strasbourg, France
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    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    ,
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    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    N. Hamdaoui
    Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    Affiliations
    Centre Hospitalier Universitaire Nord, Assistance publique–Hôpitaux de Marseille, Chemin des Bourrely, 13015 Marseille, France
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    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    C. Mathelin
    Footnotes
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    Affiliations
    Institut de cancérologie Strasbourg Europe, 17, rue Albert-Calmette, 67200 Strasbourg, France

    Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France

    Institut de génétique et de biologie moléculaire et cellulaire (IGBMC), CNRS UMR7104 Inserm U964, 1, rue Laurent-Fries, 67400 Illkirch-Graffenstaden, France
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    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    ,
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    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    P. Lopes
    Footnotes
    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    Affiliations
    Nantes, France Polyclinique de l'Atlantique Saint Herblain, 44819 St Herblain, France

    Université ́de Nantes, 44093 Nantes cedex, France
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    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    O. Graesslin
    Footnotes
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    Affiliations
    Département de gynécologie-obstétrique, Institut Mère–Enfant Alix de Champagne, Centre Hospitalier Universitaire, 45, rue Cognacq-Jay, 51092 Reims cedex, France
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    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    X. Fritel
    Footnotes
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
    Affiliations
    Service de gynécologie-obstétrique et médecine de la reproduction, CHU de Poitiers, 2, rue de la Milétrie, 86000 Poitiers, France
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    1 Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVi).
    2 Collège National des Gynécologues et Obstétriciens Français (CNGOF).
Open AccessPublished:June 09, 2022DOI:https://doi.org/10.1016/j.maturitas.2022.05.008

      Highlights

      • The focus of the first menopause consultation is to address and provide answers to women's questions about menopause.
      • At menopause, improving lifestyle and nutrition, avoiding risk factors (notably smoking), and promoting physical activity could help limit the long-term impact of estrogen deficiency.
      • In women with moderate to severe vasomotor symptoms and in the absence of contraindications, it is recommended to prescribe menopausal hormone therapy (MHT) as first-line treatment.
      • For the management of genitourinary syndrome of menopause, vaginal treatment is recommended as first-line treatment.
      • In early postmenopausal women at low to moderate risk of fracture, it is recommended that MHT be proposed as first-line treatment to prevent osteoporosis.
      • To limit the excess risk of breast cancer associated with MHT, it is recommended that estradiol be combined with progesterone or dydrogesterone.
      • Current data do not allow the recommendation of an optimal duration of MHT, which must take into account its initial indication and its benefit–risk balance.

      Abstract

      Aim

      The aim of these recommendations is to set forth an individualized approach to the management of early postmenopausal women (i.e., within the first 10 years after natural menopause) covering all aspects of lifestyle and therapeutic management, with or without menopause hormone therapy (MHT).

      Materials and methods

      Literature review and consensus of French expert opinion. Recommendations were graded according to the HAS methodology and levels of evidence derived from the international literature, except when there was no good-quality evidence.

      Summary recommendations

      The beginning of menopause is an ideal time for each woman to evaluate her health status by assessing her bone, cardiovascular, and cancer-related risk factors that may be amplified by postmenopausal estrogen deficiency and by reviewing her lifestyle habits. Improving lifestyle, including nutrition and physical activity, and avoiding risk factors (notably smoking), should be recommended to all women. MHT remains the most effective treatment for vasomotor symptoms but it could be also recommended as first-line treatment for the prevention of osteoporosis in early postmenopausal women at low to moderate risk for fracture. The risks of MHT differ depending on its type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is used. There is reasonable evidence that using transdermal estradiol in association with micronized progesterone or dydrogesterone may limit both the venous thromboembolic risk associated with oral estrogens and the risk of breast cancer associated with synthetic progestins. Treatment should be individualized to each woman, by using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation of its benefit–risk balance. For bothersome genitourinary syndrome of menopause (GSM) symptoms, vaginal treatment with lubricants and moisturizers is recommended as first-line treatment together with low-dose vaginal estrogen therapy, depending on the clinical course. No recommendation of an optimal duration of MHT can be made, but it must take into consideration the initial indication for MHT as well as each woman's benefit–risk balance. Management of gynecological side-effects of MHT is also examined.
      These recommendations are endorsed by the Groupe d'Etude sur la Ménopause et le Vieillissement hormonal (GEMVI) and the Collège National des Gynécologues-Obstétriciens Français (CNGOF).

      Keywords

      1. Introduction

      Menopause is a physiologic event defined by the loss of ovarian follicular function and the final menstruation period. The average age of menopause has been remarkably stable over time and varies little between ethnic groups. In France, it is 51 years of age. Menopause is considered natural (or physiologic) when it occurs spontaneously after the age of 45 years. It is surgical when the ovarian insufficiency results from bilateral oophorectomy or iatrogenic (e.g., by chemotherapy or pelvic radiation) when it occurs in a woman of childbearing age.
      Menopause is described as early when it occurs in women aged 40 to 45 years. It must be differentiated from premature ovarian failure, which occurs before the age of 40. The terms early menopause and premature menopause are no longer used in this situation, and premature ovarian failure implies the need to seek its etiology.
      Menopause is said to be late when it occurs after the age of 55. Perimenopause is defined as the onset of abnormal cycles and the occurrence of climacteric signs until ovarian activity stops completely. It begins on average at 47 years of age and lasts on average 4 years [
      • Harlow S.D.
      • Gass M.
      • Hall J.E.
      • Lobo R.
      • Maki P.
      • Rebar R.W.
      • Sherman S.
      • Sluss P.M.
      • de Villiers T.J.
      STRAW + 10 collaborative group, executive summary of the stages of reproductive aging workshop + 10: addressing the unfinished agenda of staging reproductive aging.
      ].

      2. Objectives

      The objectives of this work were to establish recommendations for the management of early postmenopausal women, i.e., within the first 10 years after the onset of physiologic postmenopausal amenorrhea. These recommendations do not concern the field of premature ovarian failure.
      The questions were chosen to help healthcare providers involved in these women's care in all aspects of menopause, including lifestyle issues and therapeutic management (including vasomotor symptoms (VMS), genitourinary syndrome of menopause (GSM) and osteoporosis prevention), especially with menopause hormone treatment (MHT). Recommendations for the management of climacteric syndrome were limited to vasomotor symptoms, in the absence of sufficient data for other types of symptoms.

      3. Methodology and organization

      These guidelines were developed according to the method described in the HAS (Haute Autorité de Santé, national authority for health) methodological guide, available on its website: https://www.hassante.fr/upload/docs/application/pdf/201802/good_practice_guidelines_cpg_method.pdf.
      This is a rigorous method based on:
      • -
        Transparency with regard to the critical analysis of the literature, the essential debates and decisions made by the members of the working group, the opinions of the members of the reading group, and all the participants in the different groups;
      • -
        Independence in the development of recommendations;
      • -
        The management of the financial interest disclosure declared by the experts of the working group.
      The literature search was systematic, prioritized, and structured. Each scientific article selected was analyzed according to the principles of critical reading of the literature, focusing first on evaluating the study method used, then the results, and finally the benefits or risks for the patient. The drafting of the scientific argument was based both on the critical analysis and synthesis of the literature performed by the editors and the opinions of the working group.
      In accordance with the HAS recommendations, and depending on their level of evidence, their expected benefit for patients, and their feasibility in clinical practice, recommendations were rated from A to C such as:
      • Grade A was based on studies with a high level of evidence (LE1): high powered randomized controlled trials without major bias, meta-analyses of randomized trials, decision analysis on well-conducted studies;
      • Grade B was based on a scientific presumption derived from studies of intermediate level of evidence (LE2), such as low-powered randomized controlled trials, well-conducted non-randomized studies or cohort studies;
      • Grade C was based on studies with a lower level of evidence, such as case-control studies (LE3), retrospective studies, case series or comparative studies with significant bias (LE4);
      Expert opinion: in the absence of (conclusive) studies, the recommendations resulted from an agreement between experts of the working group and after consultation with the reading group.
      The project and the working group were coordinated by Nathalie Chabbert, Xavier Fritel, Olivier Graesslin, Patrice Lopès, Geneviève Plu-Bureau and Florence Trémollieres. This organizing committee, which was appointed by the Collège National des Gynécologues-Obstétriciens Français (CNGOF) and the Groupe d'Etudes sur la Ménopause et le Vieillissement hormonal (GEMVI), defined the scope of the recommendations and the list of topics to be covered.
      A working group was set up with experts in women's midlife health from a wide range of specialties. They devoted significant time and effort to ensuring the accuracy and relevance of each key point and clinical recommendation (see the list of authors). Authors of every section were selected from this working group. They met several times to develop the initial version of the recommendations [
      • Rousset-Jablonski C.
      How to diagnose menopause? Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Lecerf J.-M.
      Nutritional advices for postmenopausal woman. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Duclos M.
      Effects of physical activity and decreased sedentary behaviours in menopausal women. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Pouillès J.-M.
      • Gosset A.
      • Trémollieres F.
      Menopause, menopause hormone therapy and osteoporosis. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Plu-Bureau G.
      • Mounier-Vehier C.
      Menopausal hormone therapy an cardiovascular risk. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Gosset A.
      • Robin G.
      • Letombe B.
      • Pouillès J.-M.
      • Trémollieres F.
      Menopause hormone treatment in practice. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Raccah-Tebeka B.
      • Boutet G.
      • Plu-Bureau G.
      Non-hormonal alternatives for the management of menopausal hot flushes. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Hocké C.
      • Diaz M.
      • Bernard V.
      • Frantz S.
      • Lambert M.
      • Mathieu C.
      • Grellety-Cherbero M.
      Genitourinary menopause syndrome. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Maris E.
      • Salerno J.
      • Hédon B.
      • Mares P.
      Management of vulvovaginal atrophy: physical therapies. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Hugon-Rodin J.
      • Perol S.
      • Plu-Bureau G.
      Menopause and risk of thromboembolic events. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Poudou C.
      • Baffet H.
      • Nadeau C.
      • Rolland A.-L.
      • Catteau-Jonard S.
      • Robin G.
      Benefit-risk balance of hormone replacement therapy: cancers and mortality. Postmenopausal women management - CNGOF and GEMVi clinical practice guidelines.
      ,
      • André G.
      Menopause hormone therapy and cognition. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Maitrot-Mantelet L.
      • Perol S.
      • Plu-Bureau G.
      Differential diagnosis of vasomotor symptoms. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Hamdaoui N.
      • Boubli L.
      Management of side effects under hormonal replacement therapy in menopausal women: abnormal uterine bleeding. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Mathelin C.
      The HRT follow-up consultation. What to do in case of breast pain. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Mathelin C.
      • Molière S.
      The HRT follow-up consultation. What to do in case of breast tumour (clinical or radiological) and microcalcifications. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ] based on the rationale provided by the writers, which was then submitted to the reading group (see list of reviewers at the end of the text). The members of the working group and the Scientific Bureau of the CNGOF and GEMVi validated the final version of these guidelines. Funding was provided by the CNGOF and GEMVI.

      4. Clinical practice guidelines

      4.1 The menopause diagnosis

      In physiologic situations, when there are no or minimal climacteric complaints, it is not necessarily useful to know the woman's menopausal status. However, some situations may require a diagnosis [
      • Rousset-Jablonski C.
      How to diagnose menopause? Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ].

      4.1.1 In the physiological situation

      The diagnosis of menopause is clinical and is made retrospectively after 12 months of amenorrhea without any other obvious cause [
      • Harlow S.D.
      • Gass M.
      • Hall J.E.
      • Lobo R.
      • Maki P.
      • Rebar R.W.
      • Sherman S.
      • Sluss P.M.
      • de Villiers T.J.
      STRAW + 10 collaborative group, executive summary of the stages of reproductive aging workshop + 10: addressing the unfinished agenda of staging reproductive aging.
      ,
      • Harlow S.D.
      • Crawford S.
      • Dennerstein L.
      • Burger H.G.
      • Mitchell E.S.
      • Sowers M.-F.
      ReSTAGE collaboration, recommendations from a multi-study evaluation of proposed criteria for staging reproductive aging.
      ]. It occurs at an average age of 51 but can vary widely from 45 to 55 years. The associated climacteric signs (e.g., hot flushes, night sweats, and vaginal dryness) are variable, and they are not essential to establish this diagnosis [
      • Gold E.B.
      • Colvin A.
      • Avis N.
      • Bromberger J.
      • Greendale G.A.
      • Powell L.
      • Sternfeld B.
      • Matthews K.
      Longitudinal analysis of the association between vasomotor symptoms and race/ethnicity across the menopausal transition: study of women's health across the nation.
      ,
      • Avis N.E.
      • Crawford S.L.
      • Greendale G.
      • Bromberger J.T.
      • Everson-Rose S.A.
      • Gold E.B.
      • Hess R.
      • Joffe H.
      • Kravitz H.M.
      • Tepper P.G.
      • Thurston R.C.
      Study of women's health across the nation, duration of menopausal vasomotor symptoms over the menopause transition.
      ].
      No study has evaluated the predictive value of the progestin test for the diagnosis of menopause. It consists of giving a progestin (typically, 20 mg/day of dydrogesterone) for 10 days to a woman with an amenorrhea period of less than 12 months. The test is considered positive if withdrawal bleeding occurs when the progestin is stopped, indicating that the endometrium is still under estrogen influence. On the other hand, a negative test (no withdrawal bleeding) suggests the absence of ovarian activity but does not necessarily define menopause. The number of negative tests to be repeated to diagnose menopause is not clearly defined.
      In the perimenopausal period, phases of transient hypoestrogenism are frequent and resolve spontaneously.
      Although fertility decreases with age, especially in the last stages before menopause, the risk of pregnancy is not null, but rather in the order of 1 to 5/1000 woman-years, in women over the age of 50 years [

      Fécondité selon l’âge détaillé de la mère | Insee, Données annuelles 2011 et 2021, (n.d.). https://www.insee.fr/fr/statistiques/2381386 (accessed March 18, 2022).

      ,
      • Baldwin M.K.
      • Jensen J.T.
      Contraception during the perimenopause.
      ].
      In physiological situations, no additional evaluation is required to diagnose menopause (grade A). The progestin test is not recommended for this diagnosis (expert opinion).

      4.1.2 In women using hormonal contraception

      Neither hormone assays [
      • Baldwin M.K.
      • Jensen J.T.
      Contraception during the perimenopause.
      ,
      • Creinin M.D.
      Laboratory criteria for menopause in women using oral contraceptives.
      ,
      • Castracane V.D.
      • Gimpel T.
      • Goldzieher J.W.
      When is it safe to switch from oral contraceptives to hormonal replacement therapy?.
      ] nor pelvic ultrasound has been shown to be useful for the diagnosis of menopause in women using hormonal contraception (level of evidence [LE3]).
      Their use cannot be recommended in routine practice to decide whether or not hormonal contraception may be stopped (grade C).
      When needed, the strategy that could be proposed is to discontinue hormonal contraception and set up a clinical follow-up (onset of amenorrhea) (expert opinion); during this period, non-hormonal contraception (most often a barrier method) may be used until one year of amenorrhea, when it may be discontinued (expert opinion).

      4.1.3 In women with a history of hysterectomy (without bilateral oophorectomy) or endometrectomy, followed by amenorrhea

      When necessary and in the absence of evaluable clinical symptoms (amenorrhea), repeated FSH assays (≥30 IU/L) associated with low estradiol (<20 pg/mL) for at least 3 months after surgery could be helpful for the diagnosis of menopause [
      • Henrich J.B.
      • Hughes J.P.
      • Kaufman S.C.
      • Brody D.J.
      • Curtin L.R.
      Limitations of follicle-stimulating hormone in assessing menopause status: findings from the National Health and nutrition examination survey (NHANES 1999–2000)*.
      ,
      • Qu X.
      • Cheng Z.
      • Yang W.
      • Xu L.
      • Dai H.
      • Hu L.
      Controlled clinical trial assessing the effect of laparoscopic uterine arterial occlusion on ovarian reserve.
      ,
      • Hehenkamp W.J.K.
      • Volkers N.A.
      • Broekmans F.J.M.
      • de Jong F.H.
      • Themmen A.P.N.
      • Birnie E.
      • Reekers J.A.
      • Ankum W.M.
      Loss of ovarian reserve after uterine artery embolization: a randomized comparison with hysterectomy.
      ] (expert opinion). Nevertheless, in symptomatic women, use of MHT may be discussed even if the diagnosis of menopause is not fully confirmed.

      4.1.4 In women treated for cancer (excluding breast cancer)

      The ovarian toxicity of chemotherapy varies with the type of cytotoxic agent, cumulative dose, and the patient's ovarian reserve at the time of treatment (which is age-dependent) [
      • Levine J.
      • Canada A.
      • Stern C.J.
      Fertility preservation in adolescents and young adults with cancer.
      ,
      • Mulder R.L.
      • Font-Gonzalez A.
      • Hudson M.M.
      • van Santen H.M.
      • Loeffen E.A.H.
      • Burns K.C.
      • Quinn G.P.
      • van Dulmen-den Broeder E.
      • Byrne J.
      • Haupt R.
      • Wallace W.H.
      • van den Heuvel-Eibrink M.M.
      • Anazodo A.
      • Anderson R.A.
      • Barnbrock A.
      • Beck J.D.
      • Bos A.M.E.
      • Demeestere I.
      • Denzer C.
      • Iorgi N.Di
      • Hoefgen H.R.
      • Kebudi R.
      • Lambalk C.
      • Langer T.
      • Meacham L.R.
      • Rodriguez-Wallberg K.
      • Stern C.
      • Stutz-Grunder E.
      • van Dorp W.
      • Veening M.
      • Veldkamp S.
      • van der Meulen E.
      • Constine L.S.
      • Kenney L.B.
      • van de Wetering M.D.
      • Kremer L.C.M.
      • Levine J.
      • Tissing W.J.E.
      PanCareLIFE Consortium
      Fertility preservation for female patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group.
      ,
      • Metzger M.L.
      • Meacham L.R.
      • Patterson B.
      • Casillas J.S.
      • Constine L.S.
      • Hijiya N.
      • Kenney L.B.
      • Leonard M.
      • Lockart B.A.
      • Likes W.
      • Green D.M.
      Female reproductive health after childhood, adolescent, and young adult cancers: guidelines for the assessment and management of female reproductive complications.
      ,
      • Green D.M.
      • Sklar C.A.
      • Boice J.D.
      • Mulvihill J.J.
      • Whitton J.A.
      • Stovall M.
      • Yasui Y.
      Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the childhood cancer survivor study.
      ,
      • Chemaitilly W.
      • Mertens A.C.
      • Mitby P.
      • Whitton J.
      • Stovall M.
      • Yasui Y.
      • Robison L.L.
      • Sklar C.A.
      Acute ovarian failure in the childhood cancer survivor study.
      ]. Radiation therapy also increases primordial follicle atresia; its toxicity is modulated by age, dose, and the radiation field [
      • Wallace W.H.B.
      • Thomson A.B.
      • Saran F.
      • Kelsey T.W.
      Predicting age of ovarian failure after radiation to a field that includes the ovaries.
      ].
      Amenorrhea is common during chemotherapy; the time to resumption of cycles is variable and sometimes very late after chemotherapy ended. Even after a prolonged period of amenorrhea, ovarian activity may resume, especially in women who were treated before the age of 40 years [
      • Bidet M.
      • Bachelot A.
      • Bissauge E.
      • Golmard J.L.
      • Gricourt S.
      • Dulon J.
      • Coussieu C.
      • Badachi Y.
      • Touraine P.
      Resumption of ovarian function and pregnancies in 358 patients with premature ovarian failure.
      ,
      • Sukumvanich P.
      • Case L.D.
      • Van Zee K.
      • Singletary S.E.
      • Paskett E.D.
      • Petrek J.A.
      • Naftalis E.
      • Naughton M.J.
      Incidence and time course of bleeding after long-term amenorrhea after breast cancer treatment: a prospective study.
      ]. Again, in symptomatic women, use of MHT can be discussed even if there is no confirmation of the premature ovarian failure diagnosis. In the youngest, the need for contraception has to be considered.
      The clinical criterion of 12 months of amenorrhea cannot be used for the diagnosis of menopause in women who have received gonadotoxic treatment for cancer (expert opinion). No additional evaluation can be recommended to confirm a diagnosis of menopause after gonadotoxic chemotherapy (expert opinion).

      4.1.5 In women treated for breast cancer

      Antiestrogenic hormone therapies used in the management of breast cancer are not gonadotoxic [
      • Anderson R.A.
      • Themmen A.P.N.
      • Al-Qahtani A.
      • Groome N.P.
      • Cameron D.A.
      The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer.
      ]. They can nonetheless cause amenorrhea, although not necessarily related to ovarian failure.
      The hormonal status to be considered for the choice of antiestrogen therapy is that observed at the time of breast cancer diagnosis; a woman may be considered menopausal if she had an amenorrhea period of more than 12 months before the start of treatment and an age compatible with physiological menopause (>45 years). Hormonal assessments may be made in women who have undergone hysterectomy, and the decision will be based on a set of clinical data including age and climacteric symptoms (expert opinion).
      If at the time of breast cancer diagnosis, the menopausal status is not known because of hormonal contraception, it is preferable to consider that the woman is not menopausal [
      • Gradishar W.J.
      • Anderson B.O.
      • Abraham J.
      • Aft R.
      • Agnese D.
      • Allison K.H.
      • Blair S.L.
      • Burstein H.J.
      • Dang C.
      • Elias A.D.
      • Giordano S.H.
      • Goetz M.P.
      • Goldstein L.J.
      • Isakoff S.J.
      • Krishnamurthy J.
      • Lyons J.
      • Marcom P.K.
      • Matro J.
      • Mayer I.A.
      • Moran M.S.
      • Mortimer J.
      • O’Regan R.M.
      • Patel S.A.
      • Pierce L.J.
      • Rugo H.S.
      • Sitapati A.
      • Smith K.L.
      • Smith M.L.
      • Soliman H.
      • Stringer-Reasor E.M.
      • Telli M.L.
      • Ward J.H.
      • Young J.S.
      • Burns J.L.
      • Kumar R.
      Breast cancer, version 3.2020, NCCN clinical practice guidelines in oncology.
      ] (expert opinion).
      In women treated with GnRH agonists or tamoxifen, no additional evaluation (hormone assays or ultrasound) [
      • Berliere M.
      • Duhoux F.P.
      • Dalenc F.
      • Baurain J.-F.
      • Dellevigne L.
      • Galant C.
      • Van Maanen A.
      • Piette P.
      • Machiels J.-P.
      Tamoxifen and ovarian function.
      ,
      • Welt C.K.
      • Pagan Y.L.
      • Smith P.C.
      • Rado K.B.
      • Hall J.E.
      Control of follicle-stimulating hormone by estradiol and the inhibins: critical role of estradiol at the hypothalamus during the luteal-follicular transition.
      ] can be recommended to make a diagnosis of menopause (expert opinion).

      4.2 The first menopause consultation

      The focus of this first consultation is to address and provide answers to women's questions about menopause. It is also the ideal time to screen for clinical risk factors for the different disorders that may be worsened by the estrogen deficiency of menopause. Finally, this consultation gives healthcare providers the opportunity to promote healthy lifestyle changes [
      • Lecerf J.-M.
      Nutritional advices for postmenopausal woman. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Duclos M.
      Effects of physical activity and decreased sedentary behaviours in menopausal women. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ] and advise the avoidance of toxic substances (e.g., tobacco and alcohol).
      Among the pathologies whose incidence significantly increases after menopause, postmenopausal osteoporosis and cardiovascular disease (CVD) are the most emblematic. For a 50-year-old woman, the lifetime risk of having an osteoporotic fracture is about 40%, with an estimated risk of a hip fracture around 17% [
      • Grange L.
      • Chales G.
      • Alliot Launois F.
      Livre blanc des êtats généraux de l’ostéoporose.
      ]. At the age of 50, the lifetime risk of dying from CVD is about 45% [
      • Lloyd-Jones D.M.
      • Leip E.P.
      • Larson M.G.
      • D’Agostino R.B.
      • Beiser A.
      • Wilson P.W.F.
      • Wolf P.A.
      • Levy D.
      Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age.
      ].
      Various clinical risk factors have been associated with the risks of CVD and osteoporosis. Some of these factors, especially aging, are common to both, but most will be accentuated by postmenopausal estrogen deficiency. Screening for these different risk factors at the beginning of menopause enables the implementation of preventive measures whenever necessary.

      4.2.1 Evaluation of the risk of osteoporosis

      This consultation should include the identification of clinical risk factors that contribute to bone loss and increased fracture risk (Table 1) and measurement of bone mineral density (BMD) at the spine and femur by DXA. The risk of osteoporotic fracture increases exponentially with the number of risk factors [
      • Kanis J.A.
      • Borgstrom F.
      • De Laet C.
      • Johansson H.
      • Johnell O.
      • Jonsson B.
      • Oden A.
      • Zethraeus N.
      • Pfleger B.
      • Khaltaev N.
      Assessment of fracture risk.
      ,
      • Cauley J.A.
      • Wu L.
      • Wampler N.S.
      • Barnhart J.M.
      • Allison M.
      • Chen Z.
      • Jackson R.
      • Robbins J.
      Clinical risk factors for fractures in multi-ethnic women: the Women’s health initiative.
      ,
      • Chen Y.-T.
      • Miller P.D.
      • Barrett-Connor E.
      • Weiss T.W.
      • Sajjan S.G.
      • Siris E.S.
      An approach for identifying postmenopausal women age 50–64 years at increased short-term risk for osteoporotic fracture.
      ,
      • Waugh E.J.
      • Lam M.-A.
      • Hawker G.A.
      • McGowan J.
      • Papaioannou A.
      • Cheung A.M.
      • Hodsman A.B.
      • Leslie W.D.
      • Siminoski K.
      • Jamal S.A.
      Perimenopause BMD guidelines Subcommittee of Osteoporosis Canada, risk factors for low bone mass in healthy 40–60 year old women: a systematic review of the literature.
      ] and the decrease in BMD [
      • Kanis J.A.
      • Cooper C.
      • Rizzoli R.
      • Reginster J.-Y.
      Scientific advisory Board of the European Society for clinical and economic aspects of osteoporosis (ESCEO) and the committees of scientific advisors and National Societies of the international osteoporosis foundation (IOF), european guidance for the diagnosis and management of osteoporosis in postmenopausal women.
      ,
      • Kanis J.A.
      • McCloskey E.V.
      • Johansson H.
      • Oden A.
      • Melton L.J.
      • Khaltaev N.
      A reference standard for the description of osteoporosis.
      ] [LE1]. Moreover, they act synergistically on the gradient of risk [LE2].
      • -
        The clinical risk factors, taken alone or in combination in different clinical scores or fracture-probability algorithms (the only one currently used in France is the FRAX), perform poorly in predicting fractures among early postmenopausal women [
        • Marques A.
        • Ferreira R.J.O.
        • Santos E.
        • Loza E.
        • Carmona L.
        • da Silva J.A.P.
        The accuracy of osteoporotic fracture risk prediction tools: a systematic review and meta-analysis.
        ,
        • Viswanathan M.
        • Reddy S.
        • Berkman N.
        • Cullen K.
        • Middleton J.C.
        • Nicholson W.K.
        • Kahwati L.C.
        Screening to prevent osteoporotic fractures: updated evidence report and systematic review for the US preventive services task force.
        ,
        • Beaudoin C.
        • Moore L.
        • Gagné M.
        • Bessette L.
        • Ste-Marie L.G.
        • Brown J.P.
        • Jean S.
        Performance of predictive tools to identify individuals at risk of non-traumatic fracture: a systematic review, meta-analysis, and meta-regression.
        ] [LE2]. Their value is limited, as is that of the clinical FRAX score in predicting low BMD (T-score < −2.5) in these women, given its low specificity (around 50%) for a sensitivity of around 50–60% [LE1] [
        • Viswanathan M.
        • Reddy S.
        • Berkman N.
        • Cullen K.
        • Middleton J.C.
        • Nicholson W.K.
        • Kahwati L.C.
        Screening to prevent osteoporotic fractures: updated evidence report and systematic review for the US preventive services task force.
        ,
        • Leslie W.D.
        • Lix L.M.
        • Johansson H.
        • Oden A.
        • McCloskey E.
        • Kanis J.A.
        Manitoba bone density program, selection of women aged 50–64 yr for bone density measurement.
        ,
        • Crandall C.J.
        • Larson J.
        • LaCroix A.
        • Cauley J.A.
        • LeBoff M.S.
        • Li W.
        • LeBlanc E.S.
        • Edwards B.J.
        • Manson J.E.
        • Ensrud K.
        Predicting fracture risk in younger postmenopausal women: comparison of the garvan and FRAX risk calculators in the Women’s health initiative study.
        ].
      • -
        Dual X-ray absorptiometry (DXA) is the gold standard for measuring BMD [
        • Kanis J.A.
        • Cooper C.
        • Rizzoli R.
        • Reginster J.-Y.
        Scientific advisory Board of the European Society for clinical and economic aspects of osteoporosis (ESCEO) and the committees of scientific advisors and National Societies of the international osteoporosis foundation (IOF), european guidance for the diagnosis and management of osteoporosis in postmenopausal women.
        ]. The two reference bone measurement sites are the lumbar spine and the upper femur (femoral neck or total hip). The BMD result in g/cm2 is converted to the difference in standard deviations from the mean of the young adult, i.e., the T-score. The WHO definition of osteoporosis is a T-score ≤ 2.5 at, at least one of the bone sites measured [
        • Kanis J.A.
        • Borgstrom F.
        • De Laet C.
        • Johansson H.
        • Johnell O.
        • Jonsson B.
        • Oden A.
        • Zethraeus N.
        • Pfleger B.
        • Khaltaev N.
        Assessment of fracture risk.
        ,
        • Sornay-Rendu E.
        • Duboeuf F.
        • Boutroy S.
        • Chapurlat R.D.
        How to predict fragility fracture beyond 10 years?The OFELY study.
        ].
      Table 1Clinical risk factors for fracture.
      Nonmodifiable risk factorsModifiable risk factors
      • Age
      • Personal history of fracture
      • Family history of vertebral or hip fracture
      • History of early hypogonadism (before 40 years)
      • History of demineralizing endocrinopathies or pathologies
      • Low BMI (<19 kg/m2)
      • Tobacco
      • Systemic corticosteroid treatment (more than 7.5 mg prednisone equivalent for more than 3 months)
      • Demineralizing treatments (e.g., aromatase inhibitors)
      BMD is strongly correlated with both in vitro and in vivo bone strength. More than 20 prospective epidemiologic studies have established a strong relation between decreased BMD and increased fracture incidence [
      • Kanis J.A.
      • Cooper C.
      • Rizzoli R.
      • Reginster J.-Y.
      Scientific advisory Board of the European Society for clinical and economic aspects of osteoporosis (ESCEO) and the committees of scientific advisors and National Societies of the international osteoporosis foundation (IOF), european guidance for the diagnosis and management of osteoporosis in postmenopausal women.
      ,
      • Kanis J.A.
      • McCloskey E.V.
      • Johansson H.
      • Oden A.
      • Melton L.J.
      • Khaltaev N.
      A reference standard for the description of osteoporosis.
      ]. BMD measurement by DXA in early postmenopausal women is predictive of the 10-year—and even up to 20-year—risk of osteoporotic fractures [
      • Sornay-Rendu E.
      • Duboeuf F.
      • Boutroy S.
      • Chapurlat R.D.
      How to predict fragility fracture beyond 10 years?The OFELY study.
      ,
      • Kröger H.
      • Huopio J.
      • Honkanen R.
      • Tuppurainen M.
      • Puntila E.
      • Alhava E.
      • Saarikoski S.
      Prediction of fracture risk using axial bone mineral density in a perimenopausal population: a prospective study.
      ,
      • Stewart A.
      • Kumar V.
      • Reid D.M.
      Long-term fracture prediction by DXA and QUS: a 10-year prospective study.
      ,
      • Abrahamsen B.
      • Rejnmark L.
      • Nielsen S.P.
      • Rud B.
      • Nissen N.
      • Mosekilde L.
      • Bärenholdt O.
      • Jensen J.-E.B.
      Ten-year prediction of osteoporosis from baseline bone mineral density: development of prognostic thresholds in healthy postmenopausal womenThe Danish Osteoporosis Prevention Study.
      ,
      • Trémollieres F.A.
      • Pouillès J.-M.
      • Drewniak N.
      • Laparra J.
      • Ribot C.A.
      • Dargent-Molina P.
      Fracture risk prediction using BMD and clinical risk factors in early postmenopausal women: sensitivity of the WHO FRAX tool.
      ,
      • Greendale G.A.
      • Huang M.
      • Cauley J.A.
      • Harlow S.
      • Finkelstein J.S.
      • Karlamangla A.S.
      Premenopausal and early postmenopausal trabecular bone score (TBS) and fracture risk: study of Women’s health across the nation (SWAN).
      ] [LE2]. Its sensitivity is about of 60% and its specificity of 70% [
      • Trémollieres F.A.
      • Pouillès J.-M.
      • Drewniak N.
      • Laparra J.
      • Ribot C.A.
      • Dargent-Molina P.
      Fracture risk prediction using BMD and clinical risk factors in early postmenopausal women: sensitivity of the WHO FRAX tool.
      ].
      To date, no data formally demonstrate the impact of BMD testing at the beginning of menopause on the subsequent fracture and mortality rates [LE2]. The majority of international guidelines recommend BMD testing by DXA in postmenopausal women less than 65 years old who have clinical risk factors for fracture [
      • Kanis J.A.
      • Cooper C.
      • Rizzoli R.
      • Reginster J.-Y.
      Scientific advisory Board of the European Society for clinical and economic aspects of osteoporosis (ESCEO) and the committees of scientific advisors and National Societies of the international osteoporosis foundation (IOF), european guidance for the diagnosis and management of osteoporosis in postmenopausal women.
      ,
      • Silverman S.L.
      • Cummings S.R.
      • Watts N.B.
      Consensus panel of the ASBMR, ISCD, and NOF, recommendations for the clinical evaluation of agents for treatment of osteoporosis: consensus of an expert panel representing the american Society for Bone and Mineral Research (ASBMR), the International Society for Clinical Densitometry (ISCD), and the National Osteoporosis Foundation (NOF).
      ,
      • Force U.S.Preventive Services Task
      • Curry S.J.
      • Krist A.H.
      • Owens D.K.
      • Barry M.J.
      • Caughey A.B.
      • Davidson K.W.
      • Doubeni C.A.
      • Epling J.W.
      • Kemper A.R.
      • Kubik M.
      • Landefeld C.S.
      • Mangione C.M.
      • Phipps M.G.
      • Pignone M.
      • Silverstein M.
      • Simon M.A.
      • Tseng C.-W.
      • Wong J.B.
      Screening for osteoporosis to prevent fractures: US preventive services task force recommendation statement.
      ,
      Management of osteoporosis in postmenopausal women: the 2021 position statement of The North American Menopause Society.
      ]. Accordingly, systematic testing of the risk of osteoporosis by DXA at menopause cannot thus be recommended in the general population (grade B). Nevertheless, in some women, knowledge of BMD value may contribute to the management of menopause, especially with MHT. BMD may also be considered an important determinant of the benefit-risk balance of MHT, given the positive associations between high BMD and increased risk of breast cancer or on the other hand, osteoporosis and increase risk of cardiovascular disease.
      At the time of menopause, screening for clinical risk factors for fracture is recommended (grade A).
      Measurement of bone mineral density by dual X-ray absorptiometry is recommended in early postmenopausal women with one or more clinical risk factors for fracture (grade A).
      It could also be proposed on a case-by-case basis when knowledge of the level of bone mineral density is likely to affect a woman's management at menopause, in particular, the individual benefit-risk balance of menopause hormone treatment (expert opinion).

      4.2.2 Evaluation of the cardiovascular risk

      Major risk factors for CVDs in both sexes are listed in Table 2. In postmenopausal women, the other risk factors include time since menopause and an age over 60 years [LE1], as well as a history of preeclampsia or gestational diabetes [
      • Plu-Bureau G.
      • Mounier-Vehier C.
      Menopausal hormone therapy an cardiovascular risk. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ,
      • Cho L.
      • Davis M.
      • Elgendy I.
      • Epps K.
      • Lindley K.J.
      • Mehta P.K.
      • Michos E.D.
      • Minissian M.
      • Pepine C.
      • Vaccarino V.
      • Volgman A.S.
      ACC CVD womens committee members, summary of updated recommendations for primary prevention of cardiovascular disease in women: JACC state-of-the-art review.
      ,
      • Agarwala A.
      • Michos E.D.
      • Samad Z.
      • Ballantyne C.M.
      • Virani S.S.
      The use of sex-specific factors in the assessment of Women’s cardiovascular risk.
      ,
      • El Khoudary S.R.
      • Aggarwal B.
      • Beckie T.M.
      • Hodis H.N.
      • Johnson A.E.
      • Langer R.D.
      • Limacher M.C.
      • Manson J.E.
      • Stefanick M.L.
      • Allison M.A.
      American Heart Association prevention science Committee of the Council on epidemiology and prevention; and council on cardiovascular and stroke nursing, menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association.
      ] [LE2].
      Table 2Clinical risk factors for cardiovascular disease.
      (Adapted from the French society for arterial hypertension
      • Mounier-Vehier C.
      HTA, hormones et femme : un consensus d’experts de la Société française d’hypertension artérielle (SFHTA) pour optimiser la prise en charge du risque cardiovasculaire des femmes.
      .)
      CVD risk levelRisk factors
      High to very high
      • -
        Coronary or neurovascular disease
      • -
        Obliterative arterial disease of the lower limbs or abdominal aortic aneurysm
      • -
        Moderate or severe renal impairment; or microalbuminuria (>30 mg/g)
      • -
        Diabetes
      Moderate

      ≥2 major risk factors
      Standard risk factors

      • -
        Current smoking or cessation < 3 years
      • -
        Uncontrolled treated hypertension
      • -
        Treated and untreated dyslipidemia
      • -
        1st degree family history of CVD <55 years in men and <65 years in women
      • -
        Abdominal obesity waist circumference (≥88 cm)
      Emerging risk factors or conditions

      • -
        History of pregnancy hypertension (preeclampsia, HELLP syndrome) or gestational diabetes
      • -
        Sedentariness
      • -
        Metabolic syndrome
      • -
        Systemic autoimmune disease or chronic inflammatory disease
      • -
        Atrial fibrillation
      • -
        Subclinical atherosclerosis
      • -
        Poor cardiovascular adaptation to exercise
      Low to moderate
      • -
        Treated, uncomplicated hypertension with no other associated risk factors
      • -
        Optimal lifestyle
      It is recommended that women be asked about symptoms that could point to coronary artery disease (chest pain that is often atypical at rest or with exercise; worsening fatigue or dyspnea with exercise; digestive signs such as epigastralgia or nausea; palpitations at rest or with exercise).
      The level of cardiovascular risk is classified as high, intermediate, or low (Table 2).
      At menopause, individual assessment of the cardiovascular risk is recommended (grade A).

      4.3 Lifestyle and menopause

      At menopause, improving lifestyle which includes healthy nutrition [
      • Lecerf J.-M.
      Nutritional advices for postmenopausal woman. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ] and the promotion of physical activity [
      • Duclos M.
      Effects of physical activity and decreased sedentary behaviours in menopausal women. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ] and avoiding risk factors (smoking) could help limit the long-term impact of estrogen deficiency as well as that of aging on the development of several pathologies.

      4.3.1 Nutrition

      4.3.1.1 Weight gain

      Longitudinal studies have shown that weight gain begins well before the onset of menopause and continues thereafter with great interindividual variability [
      • Davies K.M.
      • Heaney R.P.
      • Recker R.R.
      • Barger-Lux M.J.
      • Lappe J.M.
      Hormones, weight change and menopause.
      ]. The role of energy expenditure is primordial and excess intake may be both relative and absolute. Only a chronically positive balance likely promotes weight gain, which means that only repeated excesses and/or a chronic quantitative and qualitative dietary imbalance are usually the cause of weight gain [
      • Mozaffarian D.
      • Hao T.
      • Rimm E.B.
      • Willett W.C.
      • Hu F.B.
      Changes in diet and lifestyle and long-term weight gain in women and men.
      ,
      • Rautiainen S.
      • Wang L.
      • Lee I.-M.
      • Manson J.E.
      • Buring J.E.
      • Sesso H.D.
      Dairy consumption in association with weight change and risk of becoming overweight or obese in middle-aged and older women: a prospective cohort study.
      ].
      The causes of these excesses and/or imbalance include sleep deprivation and, more broadly, disturbances in the rhythm of life, stress and its consequences on eating, physical inactivity and sedentariness, socio-economic conditions, and psychological factors [
      • Lecerf J.-M.
      Nutritional advices for postmenopausal woman. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ].
      In overweight postmenopausal women, a moderate reduction in energy intake together with increased physical activity is recommended to limit lean body mass loss (grade C).

      4.3.1.2 Cardiometabolic risk

      Nutrition plays a role in preventing cardiovascular risk in postmenopausal women in the same way as in the general population.
      In the case of excess abdominal weight, priority should be given to moderate weight loss (5 to 10% of body weight) through moderate overall energy reduction (of lipids and carbohydrates), associated with an increase in physical activity [
      • Wing R.R.
      • Matthews K.A.
      • Kuller L.H.
      • Meilahn E.N.
      • Plantinga P.L.
      Weight gain at the time of menopause.
      ,
      • Wildman R.P.
      • Schott L.L.
      • Brockwell S.
      • Kuller L.H.
      • Sutton-Tyrrell K.
      A dietary and exercise intervention slows menopause-associated progression of subclinical atherosclerosis as measured by intima-media thickness of the carotid arteries.
      ].

      4.3.1.3 Osteoporosis risk

      Given the hormonal determinism of early postmenopausal bone loss, the preventive impact of nutritional measures is relatively weak, although some deficits are likely to amplify postmenopausal bone loss; its beneficial impact on the risk of fracture later in life could justify the implementation of nutritional measures together with an increase in physical activity [
      • Khan B.
      • Nowson C.A.
      • Daly R.M.
      • English D.R.
      • Hodge A.M.
      • Giles G.G.
      • Ebeling P.R.
      Higher dietary calcium intakes are associated with reduced risks of fractures, cardiovascular events, and mortality: a prospective cohort study of older men and women.
      ,
      • Howe T.E.
      • Shea B.
      • Dawson L.J.
      • Downie F.
      • Murray A.
      • Ross C.
      • Harbour R.T.
      • Caldwell L.M.
      • Creed G.
      Exercise for preventing and treating osteoporosis in postmenopausal women.
      ].
      Postmenopausal women should have a sufficiently diversified intake of proteins and of calcium, preferably dietary calcium (dairy products), as well as sufficient intake of vitamin D, 80% of which is provided by skin synthesis of vitamin D through the effect of ultraviolet light (grade C).

      4.3.2 Physical activity

      It must be adapted to the risk profile of each patient, bearing in mind that the benefits of physical activity of moderate intensity will be the greatest in women at risk for CVD [
      INSERM EC
      Activité physique. Prévention et traitement des maladies chroniques.
      ,
      Actualisation des repères du PNNS
      Révisions des repères relatifs à l’activité physique et à la sédentarité.
      ] [LE1]. The benefit is less for the prevention of osteoporosis and fractures, particularly at the beginning of the menopause, given the strong estrogen dependence of bone loss [LE1], or when the risk of fracture is already increased [
      • Howe T.E.
      • Shea B.
      • Dawson L.J.
      • Downie F.
      • Murray A.
      • Ross C.
      • Harbour R.T.
      • Caldwell L.M.
      • Creed G.
      Exercise for preventing and treating osteoporosis in postmenopausal women.
      ,
      Actualisation des repères du PNNS
      Révisions des repères relatifs à l’activité physique et à la sédentarité.
      ] [LE2]. Its benefit is clearer later in life, particularly if the risk of fracture is low to moderate [LE2], which justifies promoting physical activity from the beginning of menopause. It is also likely to increase the beneficial effect of MHT on bone density [
      • Wolff I.
      • van Croonenborg J.J.
      • Kemper H.C.
      • Kostense P.J.
      • Twisk J.W.
      The effect of exercise training programs on bone mass: a meta-analysis of published controlled trials in pre- and postmenopausal women.
      ] [LE1].

      4.3.2.1 Impact on mortality and cardiovascular risk

      Regular moderate physical activity significantly decreases overall and cardiovascular mortality in postmenopausal women [LE1]; most studies also show the protective role of low-intensity physical activity and decreased sedentary behavior [
      INSERM EC
      Activité physique. Prévention et traitement des maladies chroniques.
      ] [LE2].
      After menopause, regular low to moderate physical activity and reduction of sedentary lifestyle is recommended to decrease mortality and cardiovascular risk (grade A).

      4.3.2.2 Impact on osteoporosis risk

      Combined exercises associating weight-bearing exercises with impact and muscle strengthening are the most effective in decreasing postmenopausal bone loss and fracture incidence (around 10%, particularly later in life) [LE2]. This benefit is less than that of preventing overall and cardiovascular mortality and significantly less than any pharmacological intervention for osteoporosis prevention. It also raises the question of long-term adherence [
      • ANSES
      Actualisation des repères du PNNS-révision des repères relatifs à l’activité physqieu et à la sédentarité.
      ].
      At menopause, in women at risk for osteoporosis, physical activity combining weight-bearing and muscle-strengthening exercises and reducing sedentariness are recommended (grade B).

      4.3.2.3 Impact on body composition

      All intervention studies in postmenopausal women have shown that regular endurance/aerobic type physical activity without dietary restriction significantly but only moderately decreases total body fat (on average −3%) [LE2]. Only muscle strengthening or combined training (aerobic/endurance + muscle strengthening) with high loads have been shown to be effective in slowing down muscle mass loss (or even increasing muscle mass). However, there is evidence to suggest that even short-term compliance with such intense exercise is low and that many women drop out of training after only a few weeks. In addition, some women may have a physical disability that prevents them from following such a training program [
      • Ambikairajah A.
      • Walsh E.
      • Tabatabaei-Jafari H.
      • Cherbuin N.
      Fat mass changes during menopause: a metaanalysis.
      ] [LE1].

      4.4 Management of symptomatic postmenopausal women

      Climacteric disorders include hot flushes and night sweats, sleep disturbances, mood disorders, arthralgia, and genitourinary syndrome of menopause (GSM). Vasomotor symptoms are very common, affecting approximately 80% of Western postmenopausal women, 25% of whom experience severe disability [
      • Avis N.E.
      • Crawford S.L.
      • Greendale G.
      • Bromberger J.T.
      • Everson-Rose S.A.
      • Gold E.B.
      • Hess R.
      • Joffe H.
      • Kravitz H.M.
      • Tepper P.G.
      • Thurston R.C.
      Study of women's health across the nation, duration of menopausal vasomotor symptoms over the menopause transition.
      ,
      • Sussman M.
      • Trocio J.
      • Best C.
      • Mirkin S.
      • Bushmakin A.G.
      • Yood R.
      • Friedman M.
      • Menzin J.
      • Louie M.
      Prevalence of menopausal symptoms among mid-life women: findings from electronic medical records.
      ,
      • Woods N.F.
      • Mitchell E.S.
      Symptoms during the perimenopause: prevalence, severity, trajectory, and significance in women's lives.
      ,
      • Thurston R.C.
      • Joffe H.
      Vasomotor symptoms and menopause: findings from the study of Women’s health across the nation.
      ]. They last on average 5 to 7 years but can persist more than 15 years [
      • Avis N.E.
      • Crawford S.L.
      • Greendale G.
      • Bromberger J.T.
      • Everson-Rose S.A.
      • Gold E.B.
      • Hess R.
      • Joffe H.
      • Kravitz H.M.
      • Tepper P.G.
      • Thurston R.C.
      Study of women's health across the nation, duration of menopausal vasomotor symptoms over the menopause transition.
      ,
      • Dennerstein L.
      • Lehert P.
      • Guthrie J.R.
      • Burger H.G.
      Modeling women’s health during the menopausal transition: a longitudinal analysis.
      ].

      4.4.1 Menopause hormone treatment (MHT): general principles

      Prescription of MHT (specific substance, route of administration, regimen) [
      • Gosset A.
      • Robin G.
      • Letombe B.
      • Pouillès J.-M.
      • Trémollieres F.
      Menopause hormone treatment in practice. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ] is underpinned, on one hand, by the benefit-risk balance (see Section 4.6) and the risk of adverse effects (see Section 4.8), and on the other hand by its clinical tolerance, which is a key factor for adherence and continuation.
      Because of the possibility of persistent ovarian activity or transient resumption of ovarian activity during the menopausal transition, which would contribute to hyperestrogenism-related side effects such as breast tenderness/pain or abnormal uterine bleeding in a treated woman, it is recommended that MHT not be prescribed until the diagnosis of menopause is confirmed. On the other hand, given the increase in the cardiovascular risk associated with MHT when it is started 10 years or more after menopause (see Section 4.6.2), it is recommended that MHT be used within the first 10 years after menopause.
      In women with a uterus, MHT requires the combination of estrogens with progesterone/dydrogesterone or a synthetic progestin, the duration of which partly determines the benefit-risk balance (see Section 4.6), as does the occurrence of withdrawal bleeding. In France, only estradiol and estradiol valerate are available estrogen compounds.
      In hysterectomized women, it is not necessary to combine a progestin with estrogen. In some cases, particularly in women with a history of endometriosis, the combination of progestin and estrogen may be preferred even in the case of hysterectomy [
      • Collinet P.
      • Fritel X.
      • Revel-Delhom C.
      • Ballester M.
      • Bolze P.A.
      • Borghese B.
      • Bornsztein N.
      • Boujenah J.
      • Brillac T.
      • Chabbert-Buffet N.
      • Chauffour C.
      • Clary N.
      • Cohen J.
      • Decanter C.
      • Denouël A.
      • Dubernard G.
      • Fauconnier A.
      • Fernandez H.
      • Gauthier T.
      • Golfier F.
      • Huchon C.
      • Legendre G.
      • Loriau J.
      • Mathieu-d’Argent E.
      • Merlot B.
      • Niro J.
      • Panel P.
      • Paparel P.
      • Philip C.A.
      • Ploteau S.
      • Poncelet C.
      • Rabischong B.
      • Roman H.
      • Rubod C.
      • Santulli P.
      • Sauvan M.
      • Thomassin-Naggara I.
      • Torre A.
      • Wattier J.M.
      • Yazbeck C.
      • Bourdel N.
      • Canis M.
      Management of endometriosis: CNGOF/HAS clinical practice guidelines - short version.
      ].
      Given the risk of hyperestrogenism related to the persistence (or transient resumption) of ovarian activity, it is recommended that menopause hormone treatment be started only after clinical confirmation of menopause (grade B).
      It is recommended that menopause hormone treatment not be started more than 10 years after the beginning of menopause (grade B).
      17Beta-estradiol or estradiol valerate with micronized progesterone or dydrogesterone at least 12 days per month is recommended as menopause hormone treatment (grade B); in women who have had hysterectomies, estradiol or estradiol valerate alone without progesterone or progestin is recommended (grade B).
      The choice between sequential or combined regimens should consider the patient's desire to have or not have withdrawal bleeding. The combined regimen is the most commonly used because of its endometrial protection benefit [LE1] and most patients' desire to avoid withdrawal bleeding [LE3] [
      • Beral V.
      Million women study collaborators, breast cancer and hormone-replacement therapy in the million women study.
      ,
      • Olsson H.L.
      • Ingvar C.
      • Bladström A.
      Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden.
      ,
      • Stahlberg C.
      • Pedersen A.T.
      • Lynge E.
      • Andersen Z.J.
      • Keiding N.
      • Hundrup Y.A.
      • Obel E.B.
      • Ottesen B.
      Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe.
      ,
      • Lacey J.V.
      • Brinton L.A.
      • Lubin J.H.
      • Sherman M.E.
      • Schatzkin A.
      • Schairer C.
      Endometrial carcinoma risks among menopausal estrogen plus progestin and unopposed estrogen users in a cohort of postmenopausal women.
      ,
      • Allen N.E.
      • Tsilidis K.K.
      • Key T.J.
      • Dossus L.
      • Kaaks R.
      • Lund E.
      • Bakken K.
      • Gavrilyuk O.
      • Overvad K.
      • Tjønneland A.
      • Olsen A.
      • Fournier A.
      • Fabre A.
      • Clavel-Chapelon F.
      • Chabbert-Buffet N.
      • Sacerdote C.
      • Krogh V.
      • Bendinelli B.
      • Tumino R.
      • Panico S.
      • Bergmann M.
      • Schuetze M.
      • van Duijnhoven F.J.B.
      • Bueno-de-Mesquita H.B.
      • Onland-Moret N.C.
      • van Gils C.H.
      • Amiano P.
      • Barricarte A.
      • Chirlaque M.-D.
      • Molina-Montes M.-E.
      • Redondo M.-L.
      • Duell E.J.
      • Khaw K.-T.
      • Wareham N.
      • Rinaldi S.
      • Fedirko V.
      • Mouw T.
      • Michaud D.S.
      • Riboli E.
      Menopausal hormone therapy and risk of endometrial carcinoma among postmenopausal women in the European prospective investigation into cancer and nutrition.
      ,
      • Trabert B.
      • Wentzensen N.
      • Yang H.P.
      • Sherman M.E.
      • Hollenbeck A.R.
      • Park Y.
      • Brinton L.A.
      Is estrogen plus progestin menopausal hormone therapy safe with respect to endometrial cancer risk?.
      ,
      • Mørch L.S.
      • Løkkegaard E.
      • Andreasen A.H.
      • Krüger-Kjaer S.
      • Lidegaard O.
      Hormone therapy and ovarian cancer.
      ,
      • Koskela-Niska V.
      • Pukkala E.
      • Lyytinen H.
      • Ylikorkala O.
      • Dyba T.
      Effect of various forms of postmenopausal hormone therapy on the risk of ovarian cancer–a population-based case control study from Finland.
      ,
      • Shi L.
      • Wu Y.
      • Li C.
      Hormone therapy and risk of ovarian cancer in postmenopausal women: a systematic review and meta-analysis.
      ].
      A continuous combined regimen should be preferred if hot flushes recur upon discontinuation of treatment or in the case of symptoms related to hormonal variations (migraines) or difficulties in complying with a sequential regimen (expert opinion).

      4.4.2 Effectiveness of MHT on vasomotor symptoms (VMS)

      All molecules with estrogenic activity are effective in reducing the frequency and intensity of VMS, regardless of the route of administration (whether cutaneous or oral) [LE1]. The efficacy is dose-dependent as in most tissues with a hierarchy of estrogen sensitivity; breast, endometrium, and bone are the most estrogen-dependent tissues [
      • Barbieri R.L.
      Hormone treatment of endometriosis: the estrogen threshold hypothesis.
      ,
      • Mashchak C.A.
      • Lobo R.A.
      • Dozono-Takano R.
      • Eggena P.
      • Nakamura R.M.
      • Brenner P.F.
      • Mishell D.R.
      Comparison of pharmacodynamic properties of various estrogen formulations.
      ] [LE1].
      All doses of estrogen, including low doses, and all types of treatment regimens (combined or sequential, continuous or discontinuous) are effective in reducing the frequency and intensity of VMS [NP1].
      In women with moderate to severe vasomotor symptoms and in the absence of contraindications, it is recommended to prescribe menopause hormone therapy as first-line treatment (grade A).

      4.4.3 Nonhormonal alternatives to MHT

      Nonhormonal alternatives have been evaluated mainly in the management of VMS [
      • Raccah-Tebeka B.
      • Boutet G.
      • Plu-Bureau G.
      Non-hormonal alternatives for the management of menopausal hot flushes. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ]. Their efficacy (when documented) is lower than that of MHT; in randomized trials, the difference with placebo is small (on the order of 10 to 40% depending on the substance and dose). There is a placebo effect with a reduction in the frequency of VMS averaging 25 to 58% [
      • Sloan J.A.
      • Loprinzi C.L.
      • Novotny P.J.
      • Barton D.L.
      • Lavasseur B.I.
      • Windschitl H.
      Methodologic lessons learned from hot flash studies.
      ,
      • Boekhout A.H.
      • Beijnen J.H.
      • Schellens J.H.M.
      Symptoms and treatment in cancer therapy-induced early menopause.
      ,
      • MacLennan A.
      • Lester S.
      • Moore V.
      Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review.
      ] (LE1).

      4.4.3.1 Pharmacological interventions

      Apart from beta-alanine, none of the interventions listed below have a marketing authorization in France for treatment of VMS. There have been no head-to-head trials evaluating the effectiveness against VMS of the different nonhormonal alternatives. Their use is generally limited by their adverse effects.

      4.4.3.1.1 Phytoestrogens

      Phytoestrogens are plant compounds with estrogen-like properties. They have 2 major classes: isoflavones and lignans. Though much research has been devoted to determining whether phytoestrogens are well tolerated and effective in the treatment of VMS, study results have been inconclusive, and no consensus has been reached about their utility. Multiple factors may be responsible for the conflicting data, including variations in studies' inclusion criteria, types and dosages of phytoestrogens, a lack of appropriate study controls, control for the consumption of phytoestrogens from other sources, and differences in the outcome measures used. At high doses, genistein was shown to significantly reduce the frequency of hot flushes [
      • Lethaby A.
      • Marjoribanks J.
      • Kronenberg F.
      • Roberts H.
      • Eden J.
      • Brown J.
      Phytoestrogens for menopausal vasomotor symptoms.
      ,
      • Franco O.H.
      • Chowdhury R.
      • Troup J.
      • Voortman T.
      • Kunutsor S.
      • Kavousi M.
      • Oliver-Williams C.
      • Muka T.
      Use of plant-based therapies and menopausal symptoms: a systematic review and meta-analysis.
      ] [LE2].
      Given their mechanism of action through the estrogen receptor and even though this can be discussed, the French Food Safety Agency (AFSSA) has formally recommended that phytoestrogens not be used in women with estrogen-dependent disease [
      • AFSSA
      Sécurité et bénéfices des phyto-estrogènes apportés par l’alimentation- Recommandations.
      ].
      Placebo-controlled studies show no significant difference in the frequency and severity of VMS in women taking red clover [
      • Franco O.H.
      • Chowdhury R.
      • Troup J.
      • Voortman T.
      • Kunutsor S.
      • Kavousi M.
      • Oliver-Williams C.
      • Muka T.
      Use of plant-based therapies and menopausal symptoms: a systematic review and meta-analysis.
      ], black cohosh (or Cimicifuga racemosa) [
      • Leach M.J.
      • Moore V.
      Black cohosh (Cimicifuga spp.) for menopausal symptoms.
      ], or Chinese herbs [
      • Zhu X.
      • Liew Y.
      • Liu Z.L.
      Chinese herbal medicine for menopausal symptoms.
      ] [LE2].
      Use of phytoestrogens cannot to be recommended for the management of vasomotor symptoms although benefits derived from concentrates of genistein should be possible (grade B).

      4.4.3.1.2 Other compounds

      Only one small randomized trial has evaluated the efficacy of purified pollen extracts combining pollen, pistil extracts from a plant of the Poaceae family, and vitamin E. It showed significant decrease in VMS compared with placebo [
      • Winther K.
      • Rein E.
      • Hedman C.
      Femal, a herbal remedy made from pollen extracts, reduces hot flushes and improves quality of life in menopausal women: a randomized, placebo-controlled, parallel study.
      ] [LE3].
      Neither primrose oil [
      • Farzaneh F.
      • Fatehi S.
      • Sohrabi M.-R.
      • Alizadeh K.
      The effect of oral evening primrose oil on menopausal hot flashes: a randomized clinical trial.
      ] nor ginseng appears to be effective in reducing the frequency of VMS or improving the quality of life score in postmenopausal women [
      • Lee H.W.
      • Choi J.
      • Lee Y.
      • Kil K.-J.
      • Lee M.S.
      Ginseng for managing menopausal woman’s health: a systematic review of double-blind, randomized, placebo-controlled trials.
      ] [LE2].

      4.4.3.2 Nonpharmacological interventions

      Evaluation of the effectiveness of acupuncture on VMS is made difficult by the lack of a control group. Some uncontrolled trials have reported that it is effective in reducing the frequency and severity of VMS [
      • Dodin S.
      • Blanchet C.
      • Marc I.
      • Ernst E.
      • Wu T.
      • Vaillancourt C.
      • Paquette J.
      • Maunsell E.
      Acupuncture for menopausal hot flushes.
      ,
      • Chiu H.-Y.
      • Hsieh Y.-J.
      • Tsai P.-S.
      Acupuncture to reduce sleep disturbances in perimenopausal and postmenopausal women: a systematic review and meta-analysis.
      ] (LE3).
      Cognitive-behavioral therapy (CBT) [
      Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society.
      ,
      • Ye M.
      • Shou M.
      • Zhang J.
      • Hu B.
      • Liu C.
      • Bi C.
      • Lv T.
      • Luo F.
      • Zhang Z.
      • Liang S.
      • Feng H.
      • Qian C.
      • Cao S.
      • Liu Z.
      Efficacy of cognitive therapy and behavior therapy for menopausal symptoms: a systematic review and meta-analysis.
      ] [LE2], hypnosis [
      • Franco O.H.
      • Chowdhury R.
      • Troup J.
      • Voortman T.
      • Kunutsor S.
      • Kavousi M.
      • Oliver-Williams C.
      • Muka T.
      Use of plant-based therapies and menopausal symptoms: a systematic review and meta-analysis.
      ,
      • AFSSA
      Sécurité et bénéfices des phyto-estrogènes apportés par l’alimentation- Recommandations.
      ,
      • Leach M.J.
      • Moore V.
      Black cohosh (Cimicifuga spp.) for menopausal symptoms.
      ] [LE2] and yoga [
      • Zhu X.
      • Liew Y.
      • Liu Z.L.
      Chinese herbal medicine for menopausal symptoms.
      ] [LE3] appear to reduce the frequency and severity of VMS compared to placebo. Mindfulness therapies also appear to relieve the severity of hot flushes, but affect their frequency less [
      • van Driel C.M.
      • Stuursma A.
      • Schroevers M.J.
      • Mourits M.J.
      • de Bock G.H.
      Mindfulness, cognitive behavioural and behaviour-based therapy for natural and treatment-induced menopausal symptoms: a systematic review and meta-analysis.
      ] [LE2].
      Neither physical exercise nor relaxation had any significant effect on the frequency of VMS [
      • Saensak S.
      • Vutyavanich T.
      • Somboonporn W.
      • Srisurapanont M.
      Relaxation for perimenopausal and postmenopausal symptoms.
      ,
      • Daley A.
      • Stokes-Lampard H.
      • Macarthur C.
      Exercise for vasomotor menopausal symptoms.
      ,
      • Daley A.J.
      • Thomas A.
      • Roalfe A.K.
      • Stokes-Lampard H.
      • Coleman S.
      • Rees M.
      • Hunter M.S.
      • MacArthur C.
      The effectiveness of exercise as treatment for vasomotor menopausal symptoms: randomised controlled trial.
      ] [LE2].
      The small number of published studies on aromatherapy/essential oils and reflexology does not justify any conclusion about their efficacy in decreasing VMS [LE3].
      Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), gabapentin, oxybutynin, clonidine, genistein, cognitive-behavioral therapy (CBT), hypnosis and yoga have been shown to have some efficacy and can be discussed for the management of menopausal vasomotor symptoms (grade B).
      • In women with postmenopausal breast cancer and VMS
      When tamoxifen is used, it is recommended that fluoxetine, paroxetine, and sertraline not be used to treat vasomotor symptoms due to their interaction with cytochrome P450 2D6 (grade B).
      In women with postmenopausal breast cancer, it is recommended that phytoestrogens not be used to treat vasomotor symptoms (grade A).

      4.5 Management of genitourinary syndrome of menopause [
      • Maris E.
      • Salerno J.
      • Hédon B.
      • Mares P.
      Management of vulvovaginal atrophy: physical therapies. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ]

      The term genitourinary syndrome of menopause (GSM) has replaced the term vulvovaginal atrophy [
      • Portman D.J.
      • Gass M.L.S.
      Vulvovaginal atrophy terminology consensus conference panel, genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's sexual health and the North American Menopause Society.
      ]. Its prevalence varies according to studies from 27% to 70% [
      • Pastore L.M.
      • Carter R.A.
      • Hulka B.S.
      • Wells E.
      Self-reported urogenital symptoms in postmenopausal women: women's health initiative.
      ,
      • Nappi R.E.
      • Kokot-Kierepa M.
      Vaginal Health: Insights, Views & Attitudes (VIVA) - results from an international survey.
      ,
      • Moral E.
      • Delgado J.L.
      • Carmona F.
      • Caballero B.
      • Guillán C.
      • González P.M.
      • Suárez-Almarza J.
      • Velasco-Ortega S.
      • Nieto C.
      as the writing group of the GENISSE study, genitourinary syndrome of menopause. Prevalence and quality of life in Spanish postmenopausal women. The GENISSE study.
      ].
      GSM is defined as a collection of symptoms and signs associated with a decrease in estrogen and other sex steroids involving changes to the labia majora/minora, clitoris, vestibule/introitus, vagina, urethra, and bladder [
      • Portman D.J.
      • Gass M.L.S.
      Vulvovaginal atrophy terminology consensus conference panel, genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women's sexual health and the North American Menopause Society.
      ,
      • Palacios S.
      • Castelo-Branco C.
      • Currie H.
      • Mijatovic V.
      • Nappi R.E.
      • Simon J.
      • Rees M.
      Update on management of genitourinary syndrome of menopause: a practical guide.
      ,
      • Faubion S.S.
      • Sood R.
      • Kapoor E.
      Genitourinary syndrome of menopause: management strategies for the clinician.
      ]. The syndrome may include but is not limited to:
      • -
        vulvovaginal symptoms: dryness, pain, burning, irritation, pruritus;
      • -
        sexual symptoms: essentially dyspareunia of intromission, due to lack of lubrication and sometimes orifice stenosis.
      • -
        urinary symptoms, which may include polyuria, urinary urgency, or recurrent urinary infections (urinary burning).
      The clinical symptoms of GSM impair women's quality of life and worsen with age and duration of menopause, but decrease with the frequency of sexual intercourse [
      • Nappi R.E.
      • Palacios S.
      • Panay N.
      • Particco M.
      • Krychman M.L.
      Vulvar and vaginal atrophy in four European countries: evidence from the European REVIVE Survey.
      ]. Complementary examinations (pH, mucosal biopsy, microbiota assessment, etc.) are not useful in the diagnosis of GSM (LE2).
      The genitourinary syndrome of menopause is a clinical diagnosis. Women may present with some or all of the signs and symptoms which is sufficient to support the genitourinary syndrome of menopause. It is thus recommended that no additional tests be performed to confirm this diagnosis (grade B).
      Maintaining regular sexual activity provided that it remains painless increases vaginal vascularization, provides prostaglandins and fatty acids, and helps maintain vaginal flexibility (expert opinion).

      4.5.1 Local nonhormonal and nonphysical treatments for GSM

      Moisturizers and/or lubricants can be used in all women with GSM. Vaginal hyaluronic acid has been associated with significant improvement in GSM symptoms [LE3], but remains less effective than vaginal estrogen therapy [
      • Palacios S.
      • Castelo-Branco C.
      • Currie H.
      • Mijatovic V.
      • Nappi R.E.
      • Simon J.
      • Rees M.
      Update on management of genitourinary syndrome of menopause: a practical guide.
      ] [LE3].

      4.5.2 Hormonal treatments

      Systemic MHT, regardless of its route of administration and type of estrogen, and including tibolone, has a partial and inconsistent effect on GSM [LE2]. Low-dose vaginal estrogens are significantly superior to systemic MHT, particularly for urinary symptoms [
      • Cardozo L.
      • Bachmann G.
      • McClish D.
      • Fonda D.
      • Birgerson L.
      Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee.
      ,
      • Formoso G.
      • Perrone E.
      • Maltoni S.
      • Balduzzi S.
      • Wilkinson J.
      • Basevi V.
      • Marata A.M.
      • Magrini N.
      • D’Amico R.
      • Bassi C.
      • Maestri E.
      Short-term and long-term effects of tibolone in postmenopausal women.
      ] [LE1]. All low-dose vaginal estrogens, including estradiol and estriol, have been shown to improve GSM symptoms [
      • Lethaby A.
      • Ayeleke R.O.
      • Roberts H.
      Local oestrogen for vaginal atrophy in postmenopausal women.
      ] [LE2].
      The combination of estriol and lactobacilli appears to have synergistic effects [
      • Mueck A.O.
      • Ruan X.
      • Prasauskas V.
      • Grob P.
      • Ortmann O.
      Treatment of vaginal atrophy with estriol and lactobacilli combination: a clinical review.
      ] [LE2]. Pharmacological data are not available for promestriene. Prasterone (DHEA) is effective against GSM symptoms [
      • Labrie F.
      • Archer D.F.
      • Martel C.
      • Vaillancourt M.
      • Montesino M.
      Combined data of intravaginal prasterone against vulvovaginal atrophy of menopause.
      ] [LE2]. Herbal therapy has not been shown to be effective in managing this syndrome [
      • Dizavandi F.R.
      • Ghazanfarpour M.
      • Roozbeh N.
      • Kargarfard L.
      • Khadivzadeh T.
      • Dashti S.
      An overview of the phytoestrogen effect on vaginal health and dyspareunia in peri- and post-menopausal women.
      ] [LE3].
      Low-dose vaginal estrogens for durations of treatment of less than 2 years have not shown any effect on the endometrium [
      • Crandall C.J.
      • Hovey K.M.
      • Andrews C.A.
      • Chlebowski R.T.
      • Stefanick M.L.
      • Lane D.S.
      • Shifren J.
      • Chen C.
      • Kaunitz A.M.
      • Cauley J.A.
      • Manson J.E.
      Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study.
      ] [LE1]. Current data do not show an increased risk of breast cancer in women without a history of breast cancer [
      • Crandall C.J.
      • Hovey K.M.
      • Andrews C.A.
      • Chlebowski R.T.
      • Stefanick M.L.
      • Lane D.S.
      • Shifren J.
      • Chen C.
      • Kaunitz A.M.
      • Cauley J.A.
      • Manson J.E.
      Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women's Health Initiative Observational Study.
      ,
      • Lyytinen H.
      • Pukkala E.
      • Ylikorkala O.
      Breast cancer risk in postmenopausal women using estrogen-only therapy.
      ], but the safety of using this type of local treatment in women with a history of breast cancer is uncertain [
      • Sulaica E.
      • Han T.
      • Wang W.
      • Bhat R.
      • Trivedi M.V.
      • Niravath P.
      Vaginal estrogen products in hormone receptor-positive breast cancer patients on aromatase inhibitor therapy.
      ] [LE2].
      There is no predefined duration of treatment. Discontinuation of treatment is associated with a rapid recurrence of GSM symptoms [LE2].

      4.5.3 Physical methods for the treatment of GUSM [
      • Hugon-Rodin J.
      • Perol S.
      • Plu-Bureau G.
      Menopause and risk of thromboembolic events. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ]

      These are of more recent use, particularly lasers. Numerous studies have evaluated the efficacy of lasers (CO2 and Erb-Yag) on GSM symptoms. They are effective in reducing these symptoms compared with placebo [
      • Cruz V.L.
      • Steiner M.L.
      • Pompei L.M.
      • Strufaldi R.
      • Fonseca F.L.A.
      • Santiago L.H.S.
      • Wajsfeld T.
      • Fernandes C.E.
      Randomized, double-blind, placebo-controlled clinical trial for evaluating the efficacy of fractional CO2 laser compared with topical estriol in the treatment of vaginal atrophy in postmenopausal women.
      ,
      • Ruanphoo P.
      • Bunyavejchevin S.
      Treatment for vaginal atrophy using microablative fractional CO2 laser: a randomized double-blinded sham-controlled trial.
      ,
      • Paraiso M.F.R.
      • Ferrando C.A.
      • Sokol E.R.
      • Rardin C.R.
      • Matthews C.A.
      • Karram M.M.
      • Iglesia C.B.
      A randomized clinical trial comparing vaginal laser therapy to vaginal estrogen therapy in women with genitourinary syndrome of menopause: the VeLVET trial.
      ] [LE2]. However, there are still a lack of data confirming long term safety and efficacy.
      In cases of vulvar or vaginal stenosis, the use of vaginal dilators of progressively increasing size with lubricants is possible.
      For the management of genitourinary syndrome of menopause, vaginal treatment is recommended in first line (grade A). Lubricants and moisturizers should be recommended as first line treatment with low-dose vaginal hormonal treatment in second line depending on the clinical course (expert opinion).
      Pending confirmation of long-term safety and efficacy, lasers should not still be used as first-line treatment for the management of symptoms of genitourinary syndrome of menopause (grade C).

      4.6 The benefit-risk balance of menopausal hormone treatment

      The initial prescription of MHT and its renewal must be based on a prior assessment of its benefit-risk balance and a regular reassessment, particularly when the prescription is renewed.

      4.6.1 Bone beneficial effects [
      • Pouillès J.-M.
      • Gosset A.
      • Trémollieres F.
      Menopause, menopause hormone therapy and osteoporosis. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ]

      Estrogens are effective in preventing postmenopausal bone loss and microarchitectural degradations. After 12 to 18 months of treatment, bone remodeling stabilizes at a premenopausal level and BMD is maintained as long as estrogen treatment is continued [
      • Wells G.
      • Tugwell P.
      • Shea B.
      • Guyatt G.
      • Peterson J.
      • Zytaruk N.
      • Robinson V.
      • Henry D.
      • O’Connell D.
      • Cranney A.
      Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group, Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women.
      ,
      • Cranney A.
      The National Institutes of Health (NIH) Consensus Development Program: Osteoporosis Prevention, Diagnosis, and Therapy.
      ] [LE1].
      Estrogens have a dose-effect relation [LE1], but with great interindividual variability in the densitometric response to MHT [
      • Delmas P.D.
      • Pornel B.
      • Felsenberg D.
      • Garnero P.
      • Hardy P.
      • Pilate C.
      • Dain M.P.
      A dose-ranging trial of a matrix transdermal 17beta-estradiol for the prevention of bone loss in early postmenopausal women. International Study Group.
      ,
      • Heikkinen J.
      • Vaheri R.
      • Kainulainen P.
      • Timonen U.
      Long-term continuous combined hormone replacement therapy in the prevention of postmenopausal bone loss: a comparison of high- and low-dose estrogen-progestin regimens.
      ,
      • Lindsay R.
      • Gallagher J.C.
      • Kleerekoper M.
      • Pickar J.H.
      Effect of lower doses of conjugated equine estrogens with and without medroxyprogesterone acetate on bone in early postmenopausal women.
      ]. Neither the route of estrogen administration [
      • Stevenson J.C.
      • Cust M.P.
      • Gangar K.F.
      • Hillard T.C.
      • Lees B.
      • Whitehead M.I.
      Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women.
      ,
      • Hillard T.C.
      • Whitcroft S.J.
      • Marsh M.S.
      • Ellerington M.C.
      • Lees B.
      • Whitehead M.I.
      • Stevenson J.C.
      Long-term effects of transdermal and oral hormone replacement therapy on postmenopausal bone loss.
      ] nor the type of treatment regimen (with or without progesterone or a synthetic progestin) [
      Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI.
      ,
      • Figueras F.
      • Castelo-Branco C.
      • Pons F.
      • Sanjuán A.
      • Vanrell J.A.
      Effect of continuous and sequential oral estrogen-progestogen replacement regimens on postmenopausal bone loss: a 2-year prospective study.
      ] influences the bone response to MHT [LE1].
      MHT significantly decreases the risk of fracture at all bone sites in postmenopausal women, including women at low risk of fracture [
      • Gartlehner G.
      • Patel S.V.
      • Feltner C.
      • Weber R.P.
      • Long R.
      • Mullican K.
      • Boland E.
      • Lux L.
      • Viswanathan M.
      Hormone therapy for the primary prevention of chronic conditions in postmenopausal women: evidence report and systematic review for the US Preventive Services Task Force.
      ,
      • Banks E.
      • Beral V.
      • Reeves G.
      • Balkwill A.
      • Barnes I.
      Million Women Study Collaborators, Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women.
      ,
      • Cauley J.A.
      • Robbins J.
      • Chen Z.
      • Cummings S.R.
      • Jackson R.D.
      • LaCroix A.Z.
      • LeBoff M.
      • Lewis C.E.
      • McGowan J.
      • Neuner J.
      • Pettinger M.
      • Stefanick M.L.
      • Wactawski-Wende J.
      • Watts N.B.
      Women's Health Initiative Investigators, Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial.
      ,
      • Bouxsein M.L.
      • Eastell R.
      • Lui L.-Y.
      • Wu L.A.
      • de Papp A.E.
      • Grauer A.
      • Marin F.
      • Cauley J.A.
      • Bauer D.C.
      • Black D.M.
      FNIH bone quality project, change in bone density and reduction in fracture risk: a meta-regression of published trials.
      ,
      • Zhu L.
      • Jiang X.
      • Sun Y.
      • Shu W.
      Effect of hormone therapy on the risk of bone fractures: a systematic review and meta-analysis of randomized controlled trials.
      ] [LE1].
      Given the fact that to date, osteoporosis is a chronic disease that cannot be cured, the choice of the 1st treatment option should be made as part of a comprehensive long-term strategy. MHT represents a genuine preventive treatment option in early postmenopausal women found to be at low to moderate risk of fragility fracture over the next 10 years but who may have a much greater lifetime risk. In the absence of contraindication, MHT is a valuable option for the maintenance of bone health in those women where specific bone active medications are not warranted. It must be considered as a true primary preventive therapy to maintain bone mass and quality as well as decrease the risk of fracture at an age when this risk is not yet as high as later in life [
      • Rozenberg S.
      • Al-Daghri N.
      • Aubertin-Leheudre M.
      • Brandi M.-L.
      • Cano A.
      • Collins P.
      • Cooper C.
      • Genazzani A.R.
      • Hillard T.
      • Kanis J.A.
      • Kaufman J.-M.
      • Lambrinoudaki I.
      • Laslop A.
      • McCloskey E.
      • Palacios S.
      • Prieto-Alhambra D.
      • Reginster J.-Y.
      • Rizzoli R.
      • Rosano G.
      • Trémollieres F.
      • Harvey N.C.
      Is there a role for menopausal hormone therapy in the management of postmenopausal osteoporosis?.
      ,
      • Gosset A.
      • Pouillès J.-M.
      • Trémollieres F.
      Menopausal hormone therapy for the management of osteoporosis.
      ].
      In women at low to moderate risk of fracture, it is recommended that menopause hormone treatment be proposed as first-line treatment to prevent osteoporosis (grade A).
      This decision should consider other clinical risk factors for fracture and the individualized benefit-risk balance of menopause hormone treatment (grade C).
      In this situation, it is not possible to recommend a standard estrogen dose (Grade B).

      4.6.2 Cardiovascular impact [
      • Plu-Bureau G.
      • Mounier-Vehier C.
      Menopausal hormone therapy an cardiovascular risk. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ]

      Although the incidence of ischemic arterial diseases (including myocardial infarction (MI) and ischemic stroke) is lower than that of men before menopause, its incidence quickly rises after menopause to reach that of men resulting in the leading cause of death among postmenopausal women in France.
      Randomized trials in postmenopausal women with a history of one or more coronary events (the HERS study in secondary prevention) and in healthy postmenopausal women (primary prevention) [
      • Hulley S.
      • Grady D.
      • Bush T.
      • Furberg C.
      • Herrington D.
      • Riggs B.
      • Vittinghoff E.
      Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.
      ], in particular the Women's Health Initiative (WHI) [
      • Rossouw J.E.
      • Anderson G.L.
      • Prentice R.L.
      • LaCroix A.Z.
      • Kooperberg C.
      • Stefanick M.L.
      • Jackson R.D.
      • Beresford S.A.A.
      • Howard B.V.
      • Johnson K.C.
      • Kotchen J.M.
      • Ockene J.
      Writing Group for the Women's Health Initiative Investigators
      Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women'’s health initiative randomized controlled trial.
      ], have largely called into question the expected benefit of MHT on the CVD risk [
      • Boardman H.M.P.
      • Hartley L.
      • Eisinga A.
      • Main C.
      • Cosp X.Bonfill
      • Sanchez R.Gabriel
      • Knight B.
      • Roqué i Figuls M.
      Hormone therapy for preventing cardiovascular disease in post-menopausal women.
      ]. It should be noted that almost all these trials have evaluated the combination of oral conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA).

      4.6.2.1 Myocardial infarction (MI)

      Overall, no increase in the risk of MI with the use of CEE associated with MPA has been observed for any duration of use [
      • Boardman H.M.P.
      • Hartley L.
      • Eisinga A.
      • Main C.
      • Cosp X.Bonfill
      • Sanchez R.Gabriel
      • Knight B.
      • Roqué i Figuls M.
      Hormone therapy for preventing cardiovascular disease in post-menopausal women.
      ] [LE1]. Nevertheless, the risk of a first coronary event has been reported to rise the first year of use [
      • Hulley S.
      • Grady D.
      • Bush T.
      • Furberg C.
      • Herrington D.
      • Riggs B.
      • Vittinghoff E.
      Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.
      ,
      • Rossouw J.E.
      • Anderson G.L.
      • Prentice R.L.
      • LaCroix A.Z.
      • Kooperberg C.
      • Stefanick M.L.
      • Jackson R.D.
      • Beresford S.A.A.
      • Howard B.V.
      • Johnson K.C.
      • Kotchen J.M.
      • Ockene J.
      Writing Group for the Women's Health Initiative Investigators
      Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women'’s health initiative randomized controlled trial.
      ] [LE2].
      The risk of MI was not increased [LE1] and indeed appeared significantly reduced when MHT is used within the first 10 years after menopause [LE2] or before the age of 60 years [LE3]. It is therefore important to consider the timing hypothesis in the evaluation of the benefit-risk balance of MHT.
      In older women who reached menopause more than 15 years earlier, the risk of MI rises with the initiation of MHT [
      • Boardman H.M.P.
      • Hartley L.
      • Eisinga A.
      • Main C.
      • Cosp X.Bonfill
      • Sanchez R.Gabriel
      • Knight B.
      • Roqué i Figuls M.
      Hormone therapy for preventing cardiovascular disease in post-menopausal women.
      ,
      • Bassuk S.S.
      • Manson J.E.
      The timing hypothesis: Do coronary risks of menopausal hormone therapy vary by age or time since menopause onset?.
      ] [LE1].
      The risk of MI does not differ by type of estrogen [LE2], route of estrogen administration (LE3), or type of progestin [
      • Oliver-Williams C.
      • Glisic M.
      • Shahzad S.
      • Brown E.
      • Pellegrino Baena C.
      • Chadni M.
      • Chowdhury R.
      • Franco O.H.
      • Muka T.
      The route of administration, timing, duration and dose of postmenopausal hormone therapy and cardiovascular outcomes in women: a systematic review.
      ] [LE3].
      No randomized trial has analyzed the impact of progesterone or progestins given alone.
      Given the current state of knowledge, menopause hormone treatment is not recommended for the prevention of myocardial infarction (grade B).

      4.6.2.2 Ischemic stroke

      The risk of ischemic stroke rises significantly with oral estrogens, whether taken alone or in combination with a progestin [LE1]; risk increases with the estrogen dose [
      • Rossouw J.E.
      • Anderson G.L.
      • Prentice R.L.
      • LaCroix A.Z.
      • Kooperberg C.
      • Stefanick M.L.
      • Jackson R.D.
      • Beresford S.A.A.
      • Howard B.V.
      • Johnson K.C.
      • Kotchen J.M.
      • Ockene J.
      Writing Group for the Women's Health Initiative Investigators
      Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women'’s health initiative randomized controlled trial.
      ,
      • Kim J.-E.
      • Chang J.-H.
      • Jeong M.-J.
      • Choi J.
      • Park J.
      • Baek C.
      • Shin A.
      • Park S.M.
      • Kang D.
      • Choi J.-Y.
      A systematic review and meta-analysis of effects of menopausal hormone therapy on cardiovascular diseases.
      ] [LE2]. An excess risk of ischemic stroke is associated with MHT regardless of age and years since menopause [LE1]. The absolute risk of ischemic stroke nonetheless remains low in early postmenopausal women [LE1].
      Transdermal estrogen therapy in low or moderate doses combined with oral natural progesterone does not seem to be associated with the risk of ischemic stroke [
      • Renoux C.
      • Dell’aniello S.
      • Garbe E.
      • Suissa S.
      Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study.
      ,
      • Canonico M.
      • Carcaillon L.
      • Plu-Bureau G.
      • Oger E.
      • Singh-Manoux A.
      • Tubert-Bitter P.
      • Elbaz A.
      • Scarabin P.-Y.
      Postmenopausal hormone therapy and risk of stroke: impact of the route of estrogen administration and type of progestogen.
      ] [LE3].
      To limit the risk of ischemic stroke associated with oral menopause hormone therapy, it is recommended that a combination of transdermal estradiol and oral progesterone be preferred (grade B).

      4.6.2.3 Venous thromboembolic risk [
      • Hugon-Rodin J.
      • Perol S.
      • Plu-Bureau G.
      Menopause and risk of thromboembolic events. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines.
      ]

      Venous thromboembolic disease (VTE) includes deep vein thrombosis and pulmonary embolism. The incidence of VTE increases with age [
      • Zöller B.
      • Li X.
      • Sundquist J.
      • Sundquist K.
      Age- and gender-specific familial risks for venous thromboembolism: a nationwide epidemiological study based on hospitalizations in Sweden.
      ].
      Oral estrogens (CEE and estradiol) multiply the risk of VTE in the general population by a factor of 1.7 compared with placebo [
      • Rovinski D.
      • Ramos R.B.
      • Fighera T.M.
      • Casanova G.K.
      • Spritzer P.M.
      Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: a systematic review and meta-analysis.
      ] [LE1]. The risk appears to be greater with CEE than with estradiol [LE2] and to be modulated by the type of progestin [
      • Vinogradova Y.
      • Coupland C.
      • Hippisley-Cox J.
      Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases.
      ] [LE2].
      Transdermal estradiol does not appear to increase the risk of VTE in the general population [LE2]. This risk appears to be neutral with the combination of transdermal estradiol and oral micronized progesterone, dydrogesterone, chlormadinone acetate, medrogestone, cyproterone acetate, and medroxyprogesterone acetate, but increases with nomegestrol acetate and promegestone in the general population [
      • Kim J.-E.
      • Chang J.-H.
      • Jeong M.-J.
      • Choi J.
      • Park J.
      • Baek C.
      • Shin A.
      • Park S.M.
      • Kang D.
      • Choi J.-Y.
      A systematic review and meta-analysis of effects of menopausal hormone therapy on cardiovascular diseases.
      ,
      • Rovinski D.
      • Ramos R.B.
      • Fighera T.M.
      • Casanova G.K.
      • Spritzer P.M.
      Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: a systematic review and meta-analysis.
      ,
      • Vinogradova Y.
      • Coupland C.
      • Hippisley-Cox J.
      Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases.
      ,
      • Canonico M.
      • Oger E.
      • Plu-Bureau G.
      • Conard J.
      • Meyer G.
      • Lévesque H.
      • Trillot N.
      • Barrellier M.-T.
      • Wahl D.
      • Emmerich J.
      • Scarabin P.-Y.
      Estrogen and Thromboembolism Risk (ESTHER) Study Group
      Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study.
      ,
      • Canonico M.
      • Fournier A.
      • Carcaillon L.
      • Olié V.
      • Plu-Bureau G.
      • Oger E.
      • Mesrine S.
      • Boutron-Ruault M.-C.
      • Clavel-Chapelon F.
      • Scarabin P.-Y.
      Postmenopausal hormone therapy and risk of idiopathic venous thromboembolism: results from the E3N cohort study.
      ] [LE3].
      In women with a personal history of VTE (deep vein thrombosis or pulmonary embolism), oral estrogen therapy increases the risk of VTE recurrence [
      • Olié V.
      • Canonico M.
      • Scarabin P.-Y.
      Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women.
      ] [LE1]. Transdermal estradiol does not further increase the risk of VTE recurrence [
      • Olié V.
      • Plu-Bureau G.
      • Conard J.
      • Horellou M.-H.
      • Canonico M.
      • Scarabin P.-Y.
      Hormone therapy and recurrence of venous thromboembolism among postmenopausal women.
      ] [LE2], but women with a history of VTE have an increased risk of further VTE given their history.
      Obesity increases the risk of VTE. The use of oral estrogens in obese women is associated with an increased risk of VTE [
      • Curb J.D.
      • Prentice R.L.
      • Bray P.F.
      • Langer R.D.
      • Van Horn L.
      • Barnabei V.M.
      • Bloch M.J.
      • Cyr M.G.
      • Gass M.
      • Lepine L.
      • Rodabough R.J.
      • Sidney S.
      • Uwaifo G.I.
      • Rosendaal F.R.
      Venous thrombosis and conjugated equine estrogen in women without a uterus.
      ,
      • Cushman M.
      • Kuller L.H.
      • Prentice R.
      • Rodabough R.J.
      • Psaty B.M.
      • Stafford R.S.
      • Sidney S.
      • Rosendaal F.R.
      Women's Health Initiative Investigators
      Estrogen plus progestin and risk of venous thrombosis.
      ,
      • Sweetland S.
      • Beral V.
      • Balkwill A.
      • Liu B.
      • Benson V.S.
      • Canonico M.
      • Green J.
      • Reeves G.K.
      Million Women Study Collaborators
      Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study.
      ] [LE1]. Transdermal estradiol does not appear to be associated with an increased risk of VTE regardless of BMI [
      • Vinogradova Y.
      • Coupland C.
      • Hippisley-Cox J.
      Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases.
      ,
      • Canonico M.
      • Oger E.
      • Conard J.
      • Meyer G.
      • Lévesque H.
      • Trillot N.
      • Barrellier M.T.
      • Wahl D.
      • Emmerich J.
      • Scarabin P.Y.
      EStrogen and THromboEmbolism Risk (ESTHER) Study Group
      Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study.
      ] [LE2].
      In women with a factor V Leiden mutation or a G20210A prothrombin mutation, oral estrogens increase the risk of VTE [
      • Canonico M.
      • Plu-Bureau G.
      • Lowe G.D.O.
      • Scarabin P.-Y.
      Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis.
      ] [LE1]. Transdermal estradiol does not appear to increase this risk [
      • Straczek C.
      • Oger E.
      • Yon de Jonage-Canonico M.B.
      • Plu-Bureau G.
      • Conard J.
      • Meyer G.
      • Alhenc-Gelas M.
      • Lévesque H.
      • Trillot N.
      • Barrellier M.-T.
      • Wahl D.
      • Emmerich J.
      • Scarabin P.-Y.
      Estrogen and Thromboembolism Risk (ESTHER) Study Group, Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration.
      ] [LE3]. Current published data do not permit any definitive conclusion about the MHT-associated risk of VTE in women with a family history of VTE.
      To limit the venous thromboembolic risk attributable to oral estrogens, it is recommended that transdermal estradiol be preferred (grade B).
      In cases of a personal history of venous thromboembolic disease, obesity, or biological thrombophilia (factor V Leiden mutation, prothrombin G20210A mutation), it is recommended that oral estrogens not be used (grade A).
      In these situations, the use of transdermal estradiol may be proposed in combination with oral progesterone according to the individualized benefit-risk balance of menopause hormone therapy (grade C).

      4.6.3 Gynecological cancers [
      • Poudou C.
      • Baffet H.
      • Nadeau C.
      • Rolland A.-L.
      • Catteau-Jonard S.
      • Robin G.
      Benefit-risk balance of hormone replacement therapy: cancers and mortality. Postmenopausal women management - CNGOF and GEMVi clinical practice guidelines.
      ]

      4.6.3.1 Breast cancer

      The lifetime risk of breast cancer for a woman aged 50 years is estimated at 9%. In France, the incidence of breast cancer increased from 2010 to 2018 (+0.6% per year on average), after having stabilized between 2003 and 2010, particularly in women aged 55 to 69 years. In contrast, mortality has fallen steadily between 1990 and 2018 (−1.3% per year) [
      • Sancho-Garnier H.
      • Colonna M.
      Breast cancer epidemiology.
      ].
      The meta-analysis of the Collaborative Group on Hormonal Factors in Breast Cancer published in 1997 [
      Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer.
      ] had quantified the absolute excess risk of breast cancer associated with MHT as about 2 additional cases per 1000 women treated for 5 years and 6 additional cases per 1000 women treated for 10 years.
      The WHI trial was the first randomized trial to confirm the increased risk of breast cancer with the combination of CEE and MPA after 5 years of treatment [LE1] [
      • Chlebowski R.T.
      • Hendrix S.L.
      • Langer R.D.
      • Stefanick M.L.
      • Gass M.
      • Lane D.
      • Rodabough R.J.
      • Gilligan M.A.
      • Cyr M.G.
      • Thomson C.A.
      • Khandekar J.
      • Petrovitch H.
      • McTiernan A.
      • Investigators W.H.I.
      Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial.
      ]. On the other hand, CEE alone was associated with a decreased risk of breast cancer after almost 7 years of treatment [LE1] [
      • Anderson G.L.
      • Limacher M.
      • Assaf A.R.
      • Bassford T.
      • Beresford S.A.A.
      • Black H.
      • Bonds D.
      • Brunner R.
      • Brzyski R.
      • Caan B.
      • Chlebowski R.
      • Curb D.
      • Gass M.
      • Hays J.
      • Heiss G.
      • Hendrix S.
      • Howard B.V.
      • Hsia J.
      • Hubbell A.
      • Jackson R.
      • Johnson K.C.
      • Judd H.
      • Kotchen J.M.
      • Kuller L.
      • LaCroix A.Z.
      • Lane D.
      • Langer R.D.
      • Lasser N.
      • Lewis C.E.
      • Manson J.
      • Margolis K.
      • Ockene J.
      • O’Sullivan M.J.
      • Phillips L.
      • Prentice R.L.
      • Ritenbaugh C.
      • Robbins J.
      • Rossouw J.E.
      • Sarto G.
      • Stefanick M.L.
      • Van Horn L.
      • Wactawski-Wende J.
      • Wallace R.
      • Wassertheil-Smoller S.
      Women's Health Initiative Steering Committee, Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.
      ]. The relative risk of breast cancer attributable to CEE and MPA was 1.26 (IC 95% 1.01–1.59) and that of CEE alone was 0.77 (IC 95% 0.59–1.01).
      European and French observational studies (E3N, EPIC, CECILE, Finnish and British studies) show that the risk of breast cancer attributable to MHT is higher with estrogen-progestogen combinations than with estrogens alone [LE1] and depends on the specific progestins used [
      • Lyytinen H.
      • Pukkala E.
      • Ylikorkala O.
      Breast cancer risk in postmenopausal women using estrogen-only therapy.
      ,
      • Fournier A.
      • Berrino F.
      • Clavel-Chapelon F.
      Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study.
      ,
      • Bakken K.
      • Fournier A.
      • Lund E.
      • Waaseth M.
      • Dumeaux V.
      • Clavel-Chapelon F.
      • Fabre A.
      • Hémon B.
      • Rinaldi S.
      • Chajes V.
      • Slimani N.
      • Allen N.E.
      • Reeves G.K.
      • Bingham S.
      • Khaw K.-T.
      • Olsen A.
      • Tjønneland A.
      • Rodriguez L.
      • Sánchez M.-J.
      • Etxezarreta P.A.
      • Ardanaz E.
      • Tormo M.-J.
      • Peeters P.H.
      • van Gils C.H.
      • Steffen A.
      • Schulz M.
      • Chang-Claude J.
      • Kaaks R.
      • Tumino R.
      • Gallo V.
      • Norat T.
      • Riboli E.
      • Panico S.
      • Masala G.
      • González C.A.
      • Berrino F.
      Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Prospective Investigation into Cancer and Nutrition.
      ,
      • Cordina-Duverger E.
      • Truong T.
      • Anger A.
      • Sanchez M.
      • Arveux P.
      • Kerbrat P.
      • Guénel P.
      Risk of breast cancer by type of menopausal hormone therapy: a case-control study among post-menopausal women in France.
      ,
      • Vinogradova Y.
      • Coupland C.
      • Hippisley-Cox J.
      Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases.
      ] [LE2]. Combinations of estradiol with micronized progesterone or dydrogesterone do not significantly increase the risk of breast cancer for treatment durations less than 5 years [
      • Olié V.
      • Plu-Bureau G.
      • Conard J.
      • Horellou M.-H.
      • Canonico M.
      • Scarabin P.-Y.
      Hormone therapy and recurrence of venous thromboembolism among postmenopausal women.
      ,
      • Curb J.D.
      • Prentice R.L.
      • Bray P.F.
      • Langer R.D.
      • Van Horn L.
      • Barnabei V.M.
      • Bloch M.J.
      • Cyr M.G.
      • Gass M.
      • Lepine L.
      • Rodabough R.J.
      • Sidney S.
      • Uwaifo G.I.
      • Rosendaal F.R.
      Venous thrombosis and conjugated equine estrogen in women without a uterus.
      ,
      • Cushman M.
      • Kuller L.H.
      • Prentice R.
      • Rodabough R.J.
      • Psaty B.M.
      • Stafford R.S.
      • Sidney S.
      • Rosendaal F.R.
      Women's Health Initiative Investigators
      Estrogen plus progestin and risk of venous thrombosis.
      ,
      • Sweetland S.
      • Beral V.
      • Balkwill A.
      • Liu B.
      • Benson V.S.
      • Canonico M.
      • Green J.
      • Reeves G.K.
      Million Women Study Collaborators
      Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study.
      ,
      • Canonico M.
      • Oger E.
      • Conard J.
      • Meyer G.
      • Lévesque H.
      • Trillot N.
      • Barrellier M.T.
      • Wahl D.
      • Emmerich J.
      • Scarabin P.Y.
      EStrogen and THromboEmbolism Risk (ESTHER) Study Group
      Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study.
      ] [LE2]. However, for longer durations, there is a slight increase in the relative risk of breast cancer [LE3].
      There are no data about the excess risk of breast cancer and the dose of estrogens, nor does the risk appear to differ by the route of their administration—oral or transdermal [LE2]. Combined regimens are associated with a higher risk of breast cancer than sequential regimens [
      • Beral V.
      Million women study collaborators, breast cancer and hormone-replacement therapy in the million women study.
      ,
      • Olsson H.L.
      • Ingvar C.
      • Bladström A.
      Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden.
      ,
      • Stahlberg C.
      • Pedersen A.T.
      • Lynge E.
      • Andersen Z.J.
      • Keiding N.
      • Hundrup Y.A.
      • Obel E.B.
      • Ottesen B.
      Increased risk of breast cancer following different regimens of hormone replacement therapy frequently used in Europe.