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 [
[1]
].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 [
2
, 3
, 4
, 5
, 6
, 7
, 8
, 9
, 10
, 11
, 12
, 13
, 14
, 15
, 16
, 17
] 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 [
[2]
].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 [
1
, 18
]. 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 [19
, 20
].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 [
21
, 22
].4.1.2 In women using hormonal contraception
Neither hormone assays [
22
, 23
, 24
] 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 [
25
, 26
, 27
] (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) [
28
, 29
, - 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.
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.
30
, 31
, 32
]. Radiation therapy also increases primordial follicle atresia; its toxicity is modulated by age, dose, and the radiation field [[33]
].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 [
34
, 35
]. 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 [
[36]
]. 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 [
[37]
] (expert opinion).- 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.
In women treated with GnRH agonists or tamoxifen, no additional evaluation (hormone assays or ultrasound) [
38
, - 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.
PLoS One. 2013; 8e66616https://doi.org/10.1371/journal.pone.0066616
39
] 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 [
3
, 4
] 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% [
[40]
]. At the age of 50, the lifetime risk of dying from CVD is about 45% [[41]
].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 [
42
, 43
, 44
, 45
] and the decrease in BMD [46
, - 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.
47
] [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 [48,49,50] [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] [49,51,52].
- -Dual X-ray absorptiometry (DXA) is the gold standard for measuring BMD [[46]]. 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.
- 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.42,53].
Table 1Clinical risk factors for fracture.
| Nonmodifiable risk factors | Modifiable risk factors |
|---|---|
|
|
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 [
46
, - 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.
47
]. BMD measurement by DXA in early postmenopausal women is predictive of the 10-year—and even up to 20-year—risk of osteoporotic fractures [53
, 54
, 55
, 56
, 57
, 58
] [LE2]. Its sensitivity is about of 60% and its specificity of 70% [- 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).
Bone. 2020; 140115543https://doi.org/10.1016/j.bone.2020.115543
[57]
].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 [
46
, - 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.
59
, - 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).
60
, - 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.
61
]. 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 [
6
, 62
, 63
, 64
] [LE2].- 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.
Table 2Clinical risk factors for cardiovascular disease.
(Adapted from the French society for arterial hypertension
[65]
.)| CVD risk level | Risk factors |
|---|---|
| High to very high |
|
| Moderate ≥2 major risk factors | Standard risk factors
|
| Low to moderate |
|
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).
4.3 Lifestyle and menopause
At menopause, improving lifestyle which includes healthy nutrition [
[3]
] and the promotion of physical activity [[4]
] 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 [
[66]
]. 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 [67
, 68
].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 [
[3]
].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 [
69
, 70
].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 [
71
, 72
].- 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.
Cochrane Database Syst. Rev. 2011; CD000333https://doi.org/10.1002/14651858.CD000333.pub2
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 [
73
, 74
] [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 [72
, - 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.
Cochrane Database Syst. Rev. 2011; CD000333https://doi.org/10.1002/14651858.CD000333.pub2
74
] [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 [[75]
] [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 [
[73]
] [LE2].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 [
[76]
].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 [
[77]
] [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 [
20
, 78
, 79
, 80
]. They last on average 5 to 7 years but can persist more than 15 years [20
, 81
].4.4.1 Menopause hormone treatment (MHT): general principles
Prescription of MHT (specific substance, route of administration, regimen) [
[7]
] 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 [
[82]
].- 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] [
83
, 84
, 85
, 86
, 87
, - 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.
88
, 89
, 90
, 91
].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 [
92
, 93
] [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].
4.4.3 Nonhormonal alternatives to MHT
Nonhormonal alternatives have been evaluated mainly in the management of VMS [
[8]
]. 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% [94
, 95
, 96
] (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.
- •Beta-alanine: data are insufficient to evaluate its efficacy in the treatment of VMS and therefore it cannot be recommended [[97]].
- •Among selective serotonin reuptake inhibitors (SSRIs), paroxetine, citalopram, and escitalopram are effective in reducing the frequency and severity of VMS [LE2]. Studies of fluoxetine and sertraline are inconclusive [98,99,100] [LE2]. It should be noted that fluoxetine, paroxetine, and to a lesser degree, sertraline, citalopram, and escitalopram are competitive inhibitors of CYP 450 2D6, which is involved in tamoxifen metabolism [101,
- Kelly C.M.
- Juurlink D.N.
- Gomes T.
- Duong-Hua M.
- Pritchard K.I.
- Austin P.C.
- Paszat L.F.
Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study.BMJ. 2010; 340c693https://doi.org/10.1136/bmj.c693102]. - •Among serotonin norepinephrine reuptake inhibitors (SNRIs), venlafaxine at low doses is effective in decreasing the frequency and severity of VMS [[103]] [LE1]. Desvenlafaxine, the active metabolite of venlafaxine, is effective in decreasing the frequency and severity of hot flushes [[104]] [LE1].
- •Gabapentin [[105]], pregabalin [[106]], oxybutinin [107,108] and clonidine [109,110] are effective in decreasing the frequency and severity of VMS [LE2].
- Pandya K.J.
- Raubertas R.F.
- Flynn P.J.
- Hynes H.E.
- Rosenbluth R.J.
- Kirshner J.J.
- Pierce H.I.
- Dragalin V.
- Morrow G.R.
Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. - •Homeopathy (tested mainly in women with a history of breast cancer) [[111]], vitamin E [
- Kassab S.
- Cummings M.
- Berkovitz S.
- van Haselen R.
- Fisher P.
Homeopathic medicines for adverse effects of cancer treatments.Cochrane Database Syst. Rev. 2009; CD004845https://doi.org/10.1002/14651858.CD004845.pub2112,113], and omega 3 [[114]] have not been shown to be effective in managing VMS.- Mohammady M.
- Janani L.
- Jahanfar S.
- Mousavi M.S.
Effect of omega-3 supplements on vasomotor symptoms in menopausal women: a systematic review and meta-analysis.Eur. J. Obstet. Gynecol. Reprod. Biol. 2018; 228: 295-302https://doi.org/10.1016/j.ejogrb.2018.07.008
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 [
115
, - Lethaby A.
- Marjoribanks J.
- Kronenberg F.
- Roberts H.
- Eden J.
- Brown J.
Phytoestrogens for menopausal vasomotor symptoms.
Cochrane Database Syst. Rev. 2013; CD001395https://doi.org/10.1002/14651858.CD001395.pub4
116
] [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 [
[117]
].Placebo-controlled studies show no significant difference in the frequency and severity of VMS in women taking red clover [
[116]
], black cohosh (or Cimicifuga racemosa) [[118]
], or Chinese herbs [- Leach M.J.
- Moore V.
Black cohosh (Cimicifuga spp.) for menopausal symptoms.
Cochrane Database Syst. Rev. 2012; CD007244https://doi.org/10.1002/14651858.CD007244.pub2
[119]
] [LE2].- Zhu X.
- Liew Y.
- Liu Z.L.
Chinese herbal medicine for menopausal symptoms.
Cochrane Database Syst. Rev. 2016; 3CD009023https://doi.org/10.1002/14651858.CD009023.pub2
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 [
[120]
] [LE3].Neither primrose oil [
[121]
] nor ginseng appears to be effective in reducing the frequency of VMS or improving the quality of life score in postmenopausal women [[122]
] [LE2].- 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.
Medicine (Baltimore). 2016; 95e4914https://doi.org/10.1097/MD.0000000000004914
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 [
123
, - Dodin S.
- Blanchet C.
- Marc I.
- Ernst E.
- Wu T.
- Vaillancourt C.
- Paquette J.
- Maunsell E.
Acupuncture for menopausal hot flushes.
Cochrane Database Syst. Rev. 2013; CD007410https://doi.org/10.1002/14651858.CD007410.pub2
124
] (LE3).Cognitive-behavioral therapy (CBT) [
125
, 126
] [LE2], hypnosis [116
, 117
, 118
] [LE2] and yoga [- Leach M.J.
- Moore V.
Black cohosh (Cimicifuga spp.) for menopausal symptoms.
Cochrane Database Syst. Rev. 2012; CD007244https://doi.org/10.1002/14651858.CD007244.pub2
[119]
] [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 [- Zhu X.
- Liew Y.
- Liu Z.L.
Chinese herbal medicine for menopausal symptoms.
Cochrane Database Syst. Rev. 2016; 3CD009023https://doi.org/10.1002/14651858.CD009023.pub2
[127]
] [LE2].Neither physical exercise nor relaxation had any significant effect on the frequency of VMS [
128
, - Saensak S.
- Vutyavanich T.
- Somboonporn W.
- Srisurapanont M.
Relaxation for perimenopausal and postmenopausal symptoms.
Cochrane Database Syst. Rev. 2014; CD008582https://doi.org/10.1002/14651858.CD008582.pub2
129
, - Daley A.
- Stokes-Lampard H.
- Macarthur C.
Exercise for vasomotor menopausal symptoms.
Cochrane Database Syst. Rev. 2011; CD006108https://doi.org/10.1002/14651858.CD006108.pub3
130
] [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 [[10]]
The term genitourinary syndrome of menopause (GSM) has replaced the term vulvovaginal atrophy [
[131]
]. Its prevalence varies according to studies from 27% to 70% [132
, 133
, 134
].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 [
131
, 135
, 136
]. 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 [
[137]
]. Complementary examinations (pH, mucosal biopsy, microbiota assessment, etc.) are not useful in the diagnosis of GSM (LE2).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 [
[135]
] [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 [
138
, 139
] [LE1]. All low-dose vaginal estrogens, including estradiol and estriol, have been shown to improve GSM symptoms [[140]
] [LE2].The combination of estriol and lactobacilli appears to have synergistic effects [
[141]
] [LE2]. Pharmacological data are not available for promestriene. Prasterone (DHEA) is effective against GSM symptoms [[142]
] [LE2]. Herbal therapy has not been shown to be effective in managing this syndrome [[143]
] [LE3].Low-dose vaginal estrogens for durations of treatment of less than 2 years have not shown any effect on the endometrium [
[144]
] [LE1]. Current data do not show an increased risk of breast cancer in women without a history of breast cancer [144
, 145
], but the safety of using this type of local treatment in women with a history of breast cancer is uncertain [[146]
] [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 [[11]]
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 [
147
, - 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.
148
, 149
] [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 [[5]]
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 [
150
, - 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.
151
] [LE1].Estrogens have a dose-effect relation [LE1], but with great interindividual variability in the densitometric response to MHT [
152
, 153
, 154
]. Neither the route of estrogen administration [155
, 156
] nor the type of treatment regimen (with or without progesterone or a synthetic progestin) [157
, 158
] influences the bone response to MHT [LE1].- 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.
Eur. J. Obstet. Gynecol. Reprod. Biol. 2001; 99: 261-265https://doi.org/10.1016/s0301-2115(01)00382-7
MHT significantly decreases the risk of fracture at all bone sites in postmenopausal women, including women at low risk of fracture [
159
, 160
, 161
, - 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.
162
, 163
] [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 [
164
, - 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?.
165
].- Gosset A.
- Pouillès J.-M.
- Trémollieres F.
Menopausal hormone therapy for the management of osteoporosis.
Best Pract Res Clin Endocrinol Metab. 2021; 35101551https://doi.org/10.1016/j.beem.2021.101551
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 [[6]]
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) [
[166]
], in particular the Women's Health Initiative (WHI) [[167]
], have largely called into question the expected benefit of MHT on the CVD risk [- 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.
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women'’s health initiative randomized controlled trial.
JAMA. 2002; 288: 321-333
[168]
]. 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).- 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.
Cochrane Database Syst Rev. 2015; CD002229https://doi.org/10.1002/14651858.CD002229.pub4
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 [
[168]
] [LE1]. Nevertheless, the risk of a first coronary event has been reported to rise the first year 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.
Cochrane Database Syst Rev. 2015; CD002229https://doi.org/10.1002/14651858.CD002229.pub4
166
, 167
] [LE2].- 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.
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women'’s health initiative randomized controlled trial.
JAMA. 2002; 288: 321-333
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 [
168
, - 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.
Cochrane Database Syst Rev. 2015; CD002229https://doi.org/10.1002/14651858.CD002229.pub4
169
] [LE1].The risk of MI does not differ by type of estrogen [LE2], route of estrogen administration (LE3), or type of progestin [
[170]
] [LE3].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 [
167
, - 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.
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women'’s health initiative randomized controlled trial.
JAMA. 2002; 288: 321-333
171
] [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 [
172
, - 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.
BMJ. 2010; 340c2519https://doi.org/10.1136/bmj.c2519
173
] [LE3].4.6.2.3 Venous thromboembolic risk [[11]]
Venous thromboembolic disease (VTE) includes deep vein thrombosis and pulmonary embolism. The incidence of VTE increases with age [
[174]
].Oral estrogens (CEE and estradiol) multiply the risk of VTE in the general population by a factor of 1.7 compared with placebo [
[175]
] [LE1]. The risk appears to be greater with CEE than with estradiol [LE2] and to be modulated by the type of progestin [[176]
] [LE2].- 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.
BMJ. 2019; 364k4810https://doi.org/10.1136/bmj.k4810
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 [
171
, 175
, 176
, - 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.
BMJ. 2019; 364k4810https://doi.org/10.1136/bmj.k4810
177
, - 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.
Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study.
178
] [LE3].In women with a personal history of VTE (deep vein thrombosis or pulmonary embolism), oral estrogen therapy increases the risk of VTE recurrence [
[179]
] [LE1]. Transdermal estradiol does not further increase the risk of VTE recurrence [[180]
] [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 [
181
, 182
, 183
] [LE1]. Transdermal estradiol does not appear to be associated with an increased risk of VTE regardless of BMI [176
, - 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.
BMJ. 2019; 364k4810https://doi.org/10.1136/bmj.k4810
184
] [LE2].- 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.
Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study.
In women with a factor V Leiden mutation or a G20210A prothrombin mutation, oral estrogens increase the risk of VTE [
[185]
] [LE1]. Transdermal estradiol does not appear to increase this risk [[186]
] [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.- 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.
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 [[12]]
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) [
[187]
].The meta-analysis of the Collaborative Group on Hormonal Factors in Breast Cancer published in 1997 [
[188]
] 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] [
[189]
]. On the other hand, CEE alone was associated with a decreased risk of breast cancer after almost 7 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.
[190]
]. 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).- 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.
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 [
145
, 191
, 192
, - 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.
193
, - 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.
PLoS ONE. 2013; 8e78016https://doi.org/10.1371/journal.pone.0078016
194
] [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 [- 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.
BMJ. 2020; 371m3873https://doi.org/10.1136/bmj.m3873
180
, 181
, 182
, 183
, 184
] [LE2]. However, for longer durations, there is a slight increase in the relative risk of breast cancer [LE3].- 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.
Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study.
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 [
83
, 84
, 85
- 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.