Peri- and postmenopause—diagnosis and interventions interdisciplinary S3 guideline of the association of the scientific medical societies in Germany (AWMF 015/062): short version

This short version of the interdisciplinary S3 guideline “Peri- and Postmenopause—Diagnosis and Interventions” is intended as a decision-making instrument for physicians who counsel peri- and postmenopausal women. It is designed to assist daily practice. The present short version summarizes the full version of the guideline which contains detailed information on guideline methodology, particularly regarding the critical appraisal of the evidence and the assignment of evidence levels. The statements and recommendations of the full version of the guideline are quoted completely in the present short version including levels of evidence (LoE) and grades of recommendation. The classification system developed by the Centre for Evidence-based Medicine in Oxford was used in this guideline. Electronic supplementary material The online version of this article (10.1007/s00404-020-05682-4) contains supplementary material, which is available to authorized users.


Introduction
Peri-and postmenopausal women often seek medical assistance because of climacteric symptoms (e.g. vasomotoric symptoms). They want information (a) about the physiological changes during the menopausal transition period and (b) ways to alleviate their symptoms to improve their quality of life. During peri-and postmenopause, symptoms may change. Dysfunctions and diseases may develop that may or may not depend on the changes of sex hormones. Perimenopausal women often ask for information about how to prevent diseases that are typically associated with the perimenopausal transition and the postmenopause. The current S3 guideline, Peri-and Postmenopause-Diagnosis and Interventions' is based on the previous interdisciplinary S3 guideline, Hormone therapy in perimenopause and postmenopause' [1,Appendix]. The authors of the current S3 guideline intended to take a broader spectrum of issues of the peri-and postmenopause into account and provide evidence-based recommendations to counsel women in this period of life.
The different phases of the menopausal transition can be mainly diagnosed by clinical criteria. Hormone measurements are usually not necessary [1,2]. The following terms should be used for healthy women older than 45 years who have climacteric symptoms without laboratory tests: • Perimenopause-women with irregular menstrual cycles and possibly vasomotor symptoms. • Postmenopause-women without a menstrual bleeding for at least 1 year in the absence of interventions which may cause amenorrhea (e.g. oral contraceptives). • Peri-/postmenopause-women after hysterectomy with vasomotor symptoms. In women who are using hormone replacement therapy (HRT), it may be difficult to define the menopausal status.
In women older than 45 years, measurements of anti-Müllerian hormone, inhibin A, inhibin B, antral follicle count or ovarian volume should not be used to diagnose peri-or postmenopause. Follicle stimulating hormone (FSH) measurement may be used in women between 40 and 45 years with climacteric symptoms or irregular menstrual cycles and in women younger than 40 years with suspected premature ovarian insufficiency [1,2].

Symptoms
Vasomotor symptoms such as hot flushes and night sweats are the most common symptoms of the climacteric syndrome in peri-and postmenopausal women. Other symptoms such as sleep disturbances, mood swings, anxiety, and sexual impairment may also be associated with the peri-and postmenopause. In contrast to the vasomotoric symptoms, it is not clear whether the other symptoms are caused by hormonal changes. Loss of estradiol is the main cause of the climacteric syndrome, but the exact role of serum and tissue level changes of estradiol and other hormones such as androgens and gonadotropins is unclear.
Frequency and duration of all climacteric symptoms vary considerably and may be influenced by a number of factors such as general health and well-being, socioeconomic status, cultural influence, and other factors. The prevalence of hot flushes has been reported to be between 14 and 51% among premenopausal women, about 50% among perimenopausal women, and between 30 and 80% among postmenopausal women [3]. The median duration of hot flushes is 7.4 years. Longer durations typically occur when climacteric symptoms already develop in the premenopause [4].

Information
Peri-and postmenopausal women should be informed about the phases of peri-and postmenopause, the diagnosis, typical symptoms (vasomotor symptoms, sleep disorders, mood changes, urogenital symptoms, sexual impairment, changes in lifestyle and other measures which may affect health and well-being). In addition, they should be informed about the benefits and risks of different treatments strategies and the long-term effects of peri-and postmenopause on female health. Peri-and postmenopausal women should also be informed about different treatment options such as hormonal interventions, non-hormonal interventions and non-pharmacologic interventions.

Therapeutical interventions
Evidence-based recommendation

Vasomotoric symptoms
Estradiol is the most efficient means of therapy of climacteric symptoms. Therefore, HRT should be offered all women with moderate to severe climacteric symptoms with significant impairment of their quality of life. For women with an intact uterus, EPT is the most efficient treatment of vasomotoric symptoms. Hysterectomized women should only receive ET. The progestin component of EPT can be applied cyclically or continuously. Potent progestins such as synthetic progestins should be used for at least 10-12 days per month. Shorter treatment periods, or the use of natural progesterone and dydrogesterone instead of synthetic progestins may increase the risk of endometrial hyperplasia and endometrial cancer. One must consider that different HRT preparations or routes of application have different risk profiles. Transdermal application may have a better risk-benefit ratio and should be preferred over oral preparations. Women who desire phytotherapy should be informed that numerous preparations exist, and that the safety of these preparations is often unclear. In addition, combinations of different phytotherapy compounds may have different effects and may interact with concurrent medications [1,2].

Starting and stopping HRT
After starting HRT, women should consult their gynaecologist regularly (initially after 3 months) to monitor treatment effectiveness and tolerability of the therapy. Women should be advised to consult their gynaecologist in case of atypical bleeding. Modification of HRT has to be considered for several reasons during different phases of peri-and postmenopause. When treatment is well tolerated and no pathological symptoms occur, yearly gynecologic consultations are appropriate. Vaginal ultrasound examinations and endometrial thickness measurements should not be used routinely during HRT [5].
If it is determined that HRT should be stopped, two options can be offered: gradually reducing HRT or ceasing immediately. Gradually reducing may limit recurrence of symptoms in the short term. Whichever method is chosen, it has no influence on the recurrence rate of symptoms in the longer term. Randomised controlled trials have shown that in women with urinary incontinence, vaginal ET leads to significant improvements compared to placebo. However, a significantly higher prevalence of incontinence was documented when ET was applied systemically. Specifically, prevalence of urinary incontinence was doubled compared to placebo. EPT also leads to increases of urinary incontinence. However, the effect was smaller than in ET users [6,11].

Overactive bladder
Evidence-based statement

Cardiovascular disease
Evidence-based recommendation

Level of Evidence 2b Grade of recommendation B
Degree of consensus + + The risk for cardiovascular disease in peri-and postmenopausal women varies depending on their risk profile. These risk factors should be controlled optimally to exclude contraindications for HRT. Therefore, cardiovascular risk factors have to be identified and treated before HRT is initiated Because of the various limitations of the trials, mainly the WHI, statements and recommendations on the effects of HRT on cardiovascular diseases are based on a moderate level of evidence. Large randomized intervention trials have shown no general protection against cardiovascular diseases by HRT but indicate a neutral or even negative effect of HRT in postmenopausal women [17]. The analyses of data including recent studies indicate the need for caution, but individualized treatment may have little risk or even cardiovascular 1 3 benefit. The transdermal application has advantages over the oral form [18]. In any case, the prerequisite seems to be the control of the conventional risk factors for cardiovascular events such as heart attack and stroke. Regardless of the study results, previous vascular events may be contraindications for HRT [1,2].

Thromboembolism
Evidence-based recommendation

Level of Evidence 2a Grade of recommendation A
Degree of consensus + + Women should be informed that risk of thromboembolism is higher during oral compared to transdermal ET and EPT The highest vascular risks of oral HRT are venous thrombosis and thromboembolism [1,2,19,21]. ET and EPT double the risk by about two cases per 1000 women per year [22,25]. Estrogens and progestogens have thrombogenic effects that are dose dependent and substance specific, which are more pronounced in the initial phase of therapy and increase with age, weight and genetic predisposition [20,21]. With low-dose transdermal therapy, there was no evidence of an increased risk of thromboembolism probably due to the lack of a first-pass effect in the liver [19,21].

Cerebrovascular events
Evidence-based recommendation Level of Evidence 2b Grade of recommendation A Degree of consensus + + Women should be informed that oral EPT, but not transdermal ET may increase the risk for ischemic cerebrovascular events. Absolute risk for cerebral stroke is very low in younger women Ischemic strokes are the second most common and because of possible persistent disabilities very serious risk of oral HRT [2,18,19,26]. In absolute numbers, the risk increases by 1 case per 1000 women per year during oral ET or EPT intake [22,27,28]. An increase in the risk of stroke may be avoidable using transdermal HRT up to a dose of 50 µg [1,2].

Coronary heart disease
Evidence-based recommendation

Level of Evidence 2b Grade of recommendation A
Degree of consensus + + Women should be informed that EPT does not increase their cardiovascular risk or has only a minor effect. ET does not increase cardiovascular risk or may even reduce it. HRT is not appropriate for the primary or secondary prevention of coronary heart disease. HRT should be started before the age of 60 years for the treatment of climacteric symptoms Neither ET nor EPT have significant influences on the risks for coronary heart disease in primary and secondary prevention [17,22,23,25]. However, HRT initiated within the first 10 years after menopause appears to be associated with a lower coronary event rate, while starting 20 years or more after menopause significantly increases the risk [1,2,19,25].

Osteoporosis
Evidence-based statement The reduction of osteoporotic fracture risk by HRT is independent of treatment duration (even treatment duration of less than 1 year leads to reduction of the risk of osteoporotic fractures) and age at initiation of HRT. In addition, risk reduction seems to persist after stopping HRT

Prevention
Excessive weight reduction leads to an increased risk for atraumatic fractures. A body mass index below 20 should be avoided. Consequently, weight gain is associated with reduced risk of atraumatic fractures. Weight gain above a body mass index of 35 should be avoided. Exercise and sufficient intake of calcium and vitamin D is recommended [1,2,29,32].

Treatment
A number of therapies are licensed for the treatment of osteoporosis: estrogen (in combination with progestin in non-hysterectomised women), bisphosphonates, selective estrogen receptor modulators (SERMs), and a human monoclonal antibody against the RANK ligand (Denosumab) and parathyroid hormone (teriparatid). The efficiency of EPT or ET for primary prevention of osteoporotic factors has been demonstrated in observational studies and randomized controlled trials. The current version of the S3 Guideline of the German Association of Osteology (DVO) recommends that prevention or treatment of osteoporosis by HRT is feasible when women have concurrent climacteric symptoms or do not tolerate or have contraindications against licensed treatments for the prevention or treatment of osteoporosis [1,2,29,32]. The reduction of fractures by HRT is independent of the duration of HRT and the age at treatment initiation. In addition, the risk reducing effect of HRT seems to persist at a lower level after its termination. Since osteoporosis is a chronic disease, treatment is usually performed for longer durations depending on the assumed baseline risk for fractures. The mean duration is 3-4 years. In accordance to the results of the WHI, the following risk reducing effects can be expected: − 23 fractures per 1000 HRT users (confidence interval [CI] 10-33), − 20 non-vertebral fractures per 1000 HRT users (CI 6-30), − 8 vertebral fractures per 1000 HRT users (CI − 18 to + 9), − 0 hip fractures per 1000 HRT users (CI − 10 to + 4), − 36 wrist fractures per 1000 HRT users (CI 19-43) [1,2]. In women with premature ovarian insufficiency, HRT or oral contraceptives should be used until the age of natural menopause to prevent osteoporosis and osteoporotic fractures.

Dementia, depression and mood changes
Evidence-based recommendation Level of Evidence LLA Grade of recommendation A Degree of consensus +++ Peri-and postmenopausal women should be informed that it is unclear whether HRT before the age of 65 has an influence on the risk of dementia.Peri-and postmenopausal women should be informed that it is unclear whether HRT before the age of 65 has an influence on the risk of dementia There are no data with strong evidence for an increase for the risk or a beneficial effect on dementia in women using HRT before the age of 65 years [2]. In the WHI, it was demonstrated that HRT when initiated after the age of 65 years increased the risk for dementia significantly [22]. HRT may be considered for mood changes which develop or worsen during the menopausal transition. There is no evidence for an effect of selective serotonin reuptake inhibitors (SSRI) or selective noradrenalin reuptake inhibitors (SNRI) on menopausal mood changes [2].
There is no convincing data for the efficacy of HRT in prevention or treatment for depression in peri-und postmenopausal women. Women with depression should be treated according to current treatment guidelines [33,34].

EPT
EPT may increase breast cancer risk. This was shown in a number of meta-analyses that included observational studies as well as randomized controlled trials (RCTs). In the randomized Women´s Health Initiative (WHI) trial, EPT led to an increased relative risk of breast cancer of 1.26 with 8 additional cases per 10,000 women per year [22,35]. Cohort studies have shown that continuous combined EPT leads to higher increases in breast cancer risk than sequential EPT.
RCTs and observational studies demonstrated that current users of EPT have an increased breast cancer risk. However, this risk is reduced after stopping HRT. When HRT was initiated at or around the age of menopause, breast cancer risk increases were higher than in women who initiated HRT more than 5 years after menopause. EPT-containing progesterone leads to smaller increases of breast cancer risk compared to EPT-containing synthetic progestins [36]. However, progesterone has a smaller anti-proliferative effect on the endometrium than synthetic progestins. In the WHI, study breast cancer mortality was increased in HRT users in the short term, but not after 18 years of follow-up [1,2,37].

ET
In contrast to a large number of observational studies, the WHI trial demonstrated a significant risk reduction for breast cancer in ET versus placebo users [38]. The mean duration of ET was 7 years. Three smaller RCTs did not find significant differences in breast cancer risk of women using ET compared to placebo [39,41]. Observational studies have shown a small increase in breast cancer risk in women using ET. The duration of ET treatment leading to an elevated breast cancer risks is controversial. Breast cancer-specific mortality was reduced in ET uses in the 18-years follow-up in the WHI trial [37]. However, this calculation is based on a small number of breast cancer cases.
In summary, HRT may be associated with increased breast cancer risk. The elevation is relatively small and has to be included in the individual risk-benefit calculation before initiating HRT for climacteric symptoms.

Vaginal ET and breast cancer risk
Vaginal ET may lead to increases of systematic estrogen levels. It is not known whether it may also lead to increases of breast cancer risk. Ultra-low doses of vaginal ET (e.g. 0.03 mg estriol, 2-3 applications per week) lead to good clinical effects on vaginal symptoms. It is unlikely that such an ultra-low-dose vaginal ET has a causal influence on breast cancer risk even when the therapy is used chronically [42]. Meta-analyses including observational studies and RCTs could not demonstrate an increased risk of relapse of breast cancer after using HRT [43,46]. However, these studies have considerable methodological limitations such as low numbers of cases and short follow-up. The HABITS trial, an RCT, demonstrated an increase of breast cancer relapse in breast cancer survivors using HRT [44,45]. However, the number of only 442 women in this study was small. The Stockholm randomized trial with 378 breast cancer survivors found no increased risk of relapse in the HRT arm. Therefore, it is not possible to make reliable conclusions on the oncological safety of HRT among breast cancer survivors.

HRT after breast cancer
In the randomised controlled LIBERATE trial 3000 women with vasomotoric symptoms after breast cancer were treated with tibolone or placebo. Tibolone led to increased risk of breast cancer (hazard ratio [HR] 1.40) after a median followup of 3.1 years [47].

Vaginal ET after breast cancer
Women who have been or are being treated for breast cancer may complain about vaginal symptoms such as dryness, dyspareunia, and pain. They use vaginal ET six times more often than systemic HRT. Vaginal ET may lead to increases in serum estrogen levels. Vaginal ETs are different in type, dosage, and frequency of application. In Germany, estriol is frequently used for vaginal ET. Ultra-low-dose estriol in combination with lactobacillus acidophilus was tested in a small study on its safety and efficacy. In this study, vaginal atrophy was significantly improved and serum levels of estriol were only increased during the initial period of ET. After 4 weeks of treatment, levels of estriol were slightly elevated in 50% of users while not at all in the remaining 50%. It can be concluded that ultra-low-dose vaginal estriol therapy (0.03 mg, 3 applications per week) may be used in breast cancer survivors if non-hormonal alternatives had insufficient results [48]. ET may lead to an increased risk of endometrial cancer in postmenopausal, non-hysterectomized women. This effect is dependent on duration and dose of ET [5]. Standard doses (e.g. 2 mg estradiol, 0.625 mg conjugated equine estrogen) increase the relative risk of endometrial cancer after more than 3 years of use up to five times and after 10 years of use up to ten times. This effect persists for several years after stopping ET. Therefore, HRT should include at least 1 mg norethisterone or 2 mg medroxyprogesterone acetate or an equivalent progestin in combined continuous HRT users or at least 5 mg medroxyprogesterone acetate or an equivalent progestin in sequential HRT users with a sufficient duration of progestin treatment (10-15 days per treatment month) [49,52]. EPT is performed in a sequential or continuous combined form. Sequential EPT containing at least 10 days of progestin treatment (for up to 5 years) did not increase the risk of endometrial cancer [53]. Longer sequential EPT may increase endometrial cancer risk. The reduction of progestin use for less than 10 days per month significantly increases endometrial cancer risk (RR 3.0-4.4) [51,54]. The progestin component of EPT was shown to influence the risk of endometrial cancer in the prospective E3N cohort study. In this study, long-term application of progesterone or dydrogesterone increased endometrial cancer risk (progesterone HR 2.66 after more than 5 years of treatment; dydrogesterone HR 1.69 after more than 5 years of treatment) [55]. Continuous combined EPT with conjugated equine estrogen and medroxyprogesterone acetate led to reduced risk for endometrial cancer [56]. In observational studies such as the Million Women Study and the EPIC study, a significantly reduced endometrial cancer risk was found in continuous combined HRT users [52,53]. Other studies, however, documented significant risk increases [51,54].

Vaginal ET and endometrial cancer risk
Clinical studies did not show increased rates of endometrial hyperplasia after vaginal ET. Therefore, it is not recommended to add a progestin to vaginal ET. However, there are no data on endometrial safety of vaginal ET when used for more than 1 year [5]. A recent meta-analysis has included only one randomized trial and five observational studies assessing the safety of HRT in women who have been treated for endometrial cancer. Of note, the risk of endometrial cancer relapse was reduced in HRT users. However, most studies included in this meta-analysis were retrospective observational studies. Therefore, the evidence regarding the oncological safety of HRT among endometrial cancer survivors is limited. It can only be concluded that HRT after early stage endometrial cancer may not lead to a relevant increase of the risk of relapse [5,57,59].  [60]. Ph-stabilizing preparations with a pH between 4 and 4.5 have been shown to be efficient in this indication [61]. Local ET may alleviate the symptoms of vaginal atrophy after radiotherapy of the vagina [62]. Retrospective observational studies did not show increased rates of relapse after vaginal ET [63]. However, the evidence is limited and does not prove oncological safety [5].

HRT and ovarian cancer risk
Evidence-based recommendation

Level of Evidence 2a Grade of recommendation A
Degree of consensus + + Women considering HRT should be informed that ET and EPT may increase ovarian cancer risk. This effect has been observed after treatment durations of less than 5 years and is reduced after stopping treatment The Collaborative Group on Epidemiological Studies of Ovarian Cancer performed a meta-analysis of 52 studies. This included data from 21 488 postmenopausal women with ovarian cancer. Data from prospective trials showed that HRT users had increased risk for ovarian cancer after HRT durations of less than 5 years (RR 1.43). The absolute increase of risk is 1 in 1000 after 5 years and 1 in 1600 women using HRT [64].

HRT after ovarian cancer
Evidence-based statement Level of Evidence 2b Degree of consensus + + The safety of HRT after treatment of ovarian cancer is unclear

Evidence-based recommendation
Level of Evidence 2b Grade of recommendation 0 Degree of consensus +++ HRT may be used after treatment of ovarian cancer and appropriate consultation with the patient After treatment, ovarian cancer patients may experience natural or therapy-induced menopause. These patients may suffer from climacteric symptoms. Younger women may develop estrogen-associated diseases such as coronary heart disease and osteoporosis [65,70]. There are only few studies that examined the safety of HRT after ovarian cancer [71]. Three observational studies could not demonstrate increased risk of relapse [66,68,69]. However, there are a number of methodological limitations. A randomized study with 150 patients showed improved survival in the group of women treated with HRT after a median follow-up of 19.1 years (HR 0.63; 95% CI 0.44-0.90). The authors conclude that HRT after ovarian cancer is safe. However, this study has a number of limitations and the safety of HRT after ovarian cancer remains unclear [67].
Since none of the studies showed an increased, but rather a risk reduction, HRT may be considered when women complain of severe climacteric symptoms. Especially in younger women with iatrogenic menopause after ovarian cancer treatment, the risk of mortality due to coronary heart disease is increased. In these women ET should be considered. Reproductive factors may influence the risk of colorectal cancer. Studies have shown that HRT has no effect or reduces the risk for colorectal cancer [72,73]. In the WHI trial, the risk of colon cancer was reduced by 37% in EPT users. ET did not have any effect on colorectal cancer risk [74]. Observational studies had conflicting results. The majority of these studies showed a risk reduction after HRT use. A meta-analysis including data from RCTs and observational studies showed that EPT as well as ET significantly reduced the risk of colorectal cancer (RR 0.74; 95% CI 0.68-0.81 and RR 0.79; 95% CI 0.69-0.91, respectively). A recent publication of data from five Danish cancer registries including 1.1 million women also demonstrated that ET and EPT reduced the risk of colorectal cancer with a minimal effect of EPT on rectal cancer [73].

Premature ovarian insufficiency (POI)
Evidence-based recommendation All types of menstrual disturbances and various climacteric symptoms can be found. Women with POI/POF have a higher risk for estrogen-dependent diseases. However, there is no prospective study which shows lower mortality by hormonal substitution. It might make sense to continue hormonal treatment in women with POF until the average age of menopause.
There seems to be no difference between a hormonal substitution with HRT or contraceptive pills, although two studies reported a small difference in blood pressure in favour of HRT compared to contraceptive pills [76,77]. Both treatment options can be discussed with POI/POF patients. In women > 40 years, HRT should be preferred.
Women with POI/POF should be informed about the following facts: • HRT might have a positive effect on blood pressure compared to contraceptive pills. • HRT and contraceptive pills have a positive effect on bone health. • HRT does not offer protection from pregnancies. • Women with POI and contraindications for HRT should be advised about cardiovascular risks, bone health and alternative treatments of climacteric symptoms. • Women with POI should be generously transferred to specialized centres.

Informing women about HRT
Women should be informed about risks and benefits of medical interventions. The communication should include the probabilities of expected benefits and possible risks of harm with the patient and possibly with an accompanying person. For an individual assessment and evaluation of the probability of benefit and the risk of harm of HRT individual factors such as the woman´s general state of health, age at menopause, previous HRT, duration and use, doses and type of HRT and diseases while using HRT should be taken into consideration. To give adequate information about the risks to the woman seeking advice, the doctor must be familiar with the principles of risk calculation. He or she should also be able to communicate the probabilities in such a way that the patient can make her own individual decision for or against the initiation of HT. The figures necessary for this communication can be found in the long version and in Table 1 [1]. The GPT does not support the undifferentiated recommendation on the use of cimicifuga, the level of evidence and grade of recommendation. In contrast to other cimicifuga products (e.g. food supplements), cimicifuga medical products with marketing authorizations have proven their usefulness. Only these should be recommended.
Grade of recommendation: A (isopropanolic Cimicifuga medicinal products). B (ethanolic Cimicifuga medicinal products) Level of evidence: 1b (isopropanolic Cimicifuga medicinal products). 2b (ethanolic Cimicifuga medicinal products) For the full text on the position of the GPT see electronic supplementary material.