Hormone therapy in perimenopause and postmenopause (HT)

This short version of the interdisciplinary S3 guideline on hormone therapy in peri-and postmenopause (HT) is intended as a decision-making instrument for physicians and women considering HT. It is designed to assist daily practice. This short version summarises the long version that contains detailed information about the development of the guideline, particularly about establishing the evidence levels. The statements and recommendations, quoted completely, are marked with the relevant levels of evidence (LoE) and grades of recommendation. The classification system from the Centre for Evidence-based Medicine in Oxford was used in this guideline (see ''Attachment'').

# Introduction
Peri-and post-menopausal women often seek medical assistance because of climacteric symptoms (e.g. hot flushes and sweating), considering HT for the treatment of these symptoms. They hope for alleviation of these symptoms and possibly an improvement in their quality of life. While ageing, the symptoms may change, and there may be dysfunctions or diseases that also depend on sex hormones. This situation can influence the assessment of the risk-benefit ratio. The prevention of diseases that frequently develop in postmenopausal women is also often an issue when discussing HT.

## Compounds, forms of application, pharmacology
There are clinically relevant differences between the available estrogens, progestins and estrogen-progestin combinations as well as between the various forms of application of HT. These differences apply to the benefit as well as to some risks, and they should be taken into account when managing individual cases.

## Climacteric symptoms and their treatment
During the climacteric period, women often suffer from vasomotor complaints (hot flushes) and vaginal dryness. These symptoms were the most consistent findings observed in studies in this period of life. Other problems such as disturbed sleep, various physical symptoms, pain, urinary tract disorders, sexual problems and mood fluctuations have a less consistent association with the menopausal transition period. Estrogens are the most effective treatment for hot flushes and vaginal atrophy. The frequency of these complaints can be markedly reduced by HT, or the symptoms will even disappear completely. There are other complaints associated with the climacteric period which may be relieved with HT. If HT is indicated, an improvement of the woman's general well-being is possible.

# Statements
Hot flushes and vaginal dryness are associated with the transition from premenopause to postmenopause; the frequency of reports on these symptoms varies (LoE 2a).
Other complaints like disturbed sleep, various physical symptoms, urinary tract disorders, sexual problems, or mood fluctuations are inconsistently reported symptoms (LoE 2a).
Degree of consensus: strong consensus Estrogens are effective for the treatment of hot flushes (LoE 1a)
Conjugated equine estrogens, oral 17b-estradiol, and transdermal 17b-estradiol reduce hot flushes to a comparable degree (LoE 1a).
An additional treatment with progestins does not interfere with the effect of estrogens on vasomotor complaints (LoE 1a).
Tibolone is effective in the treatment of hot flushes (LoE 1a).
There is no difference in the effect of estrogen therapy on hot flushes between women with natural menopause and women after bilateral oophorectomy .
(see also the chapter on urogenital symptoms). Degree of consensus: strong consensus In women who were treated with various estrogens or estrogen-progestin combinations, positive as well as negative effects on the quality of life were found, but in some instances no effect was noted (LoE 1a).
Degree of consensus: consensus

## Recommendations
When assessing the risk-benefit ratio, one should bear in mind that the only two complaints most consistently reported by women during the menopausal transition are hot flushes and vaginal dryness (A). Degree of consensus: consensus Hot flushes can be treated with estrogens or, if applicable, estrogen-progestin combinations, or with tibolone (A).
When deciding on the indication, the risks and benefits presented in this guideline should be taken into account (A).
Degree of consensus: strong consensus The sole improvement of a woman's so-called general well-being or health-related quality of life is not an indication for HT (B HT is not indicated for the primary or secondary prevention of coronary heart disease in women at any age because there are other strategies with proven efficacy. However, numerous findings from observational studies suggest that HT may reduce the risk of myocardial infarction, when started early. In contrast to these findings, the WHI study, a randomized controlled trial, found a non-significant trend of risk reduction by ET in women aged 50-59 years, but not in older women. With combined estrogen-progestin therapy (EPT), the risk was increased at the beginning of treatment, but not after treatment duration of 5.6 years. Particularly, older women and women with a predisposition for cardiovascular disease had an increased risk at the beginning of treatment. Especially in older women ([60 years), systemic HT should only be initiated after careful assessment of risks and benefits, taking any pre-existing risk factors into consideration.

## Recommendation
HT is not indicated for the primary or secondary prevention of coronary heart disease (B).
There are other strategies with proven efficacy for primary or secondary prevention (A).
Degree of consensus: strong consensus

## Cerebrovascular disease
HT increases the risk for an ischaemic cerebrovascular event. This risk should always be considered in the assessment of risks and benefits, particularly in older women.

# Statement
HT increases the risk for an ischaemic cerebrovascular event (LoE 1a). Degree of consensus: strong consensus

## Recommendation
The increased risk of stroke must always be considered in the assessment of risks and benefits of HT (A).

## Degree of consensus: strong consensus
Thromboembolic disease
HT increases the risk of venous thrombosis and pulmonary embolism, particularly in the first year of use and in the presence of risk factors such as congenital coagulation disorders. A meta-analysis of observational studies shows that the risk is lower with transdermal HT.

# Statement
Oral HT increases the risk of venous thrombosis and pulmonary embolism (VTE) (LoE 1a). Degree of consensus: strong consensus

## Recommendation
The increased risk of VTE must be considered while assessing the risks and benefits of HT. The risk is particularly high in the first year of HT use and further increases if there are additional predisposing risk factors for venous thrombosis (A).

## Degree of consensus: strong consensus

## Skin ageing
Available data are insufficient to make reliable statements on the effects of HT on the processes of skin ageing. Smaller comparative studies have, in part, shown a positive effect of estrogens on parameters of skin ageing. The limited number of randomized studies with small numbers of cases and significant methodological flaws, respectively have not yielded any reliable results.

# Statement
An alleviation of skin ageing processes by HT has not been proven (LoE 2b).

## Degree of consensus: strong consensus
Recommendation HT is not indicated for alleviating the processes of skin ageing (A). Degree of consensus: strong consensus

## Signs of skin androgenisation
There is only a small number of evaluable trials using HT with anti-androgenic progestins (cyproterone acetate [CPA], chlormadinone acetate [CMA], dienogest , and drospirenone [DRSP]) in the climacteric period. In particular, it is impossible to state if HT with anti-androgenic progestins can result in a significant improvement of androgenic skin changes, because there have been no specific trials addressing this question. However, if a combined estrogen-progestin therapy is indicated, women with cutaneous signs of androgenisation should primarily receive preparations with an anti-androgenic progestin compound instead of a preparation with a progestin deriving from the 19-nortestosterone group.

# Statement
Alleviation of the signs of skin androgenisation with HT has not been proven (LoE 5).

## Degree of consensus: strong consensus
Recommendation HT is not indicated to alleviate signs of skin androgenisation (A).

## Degree of consensus: strong consensus

## Diseases of the gall bladder and gall ducts
HT increases the risk of gall duct disease. This is mainly the effect of the estrogen compound. The risk is probably less profound with transdermal estrogen application.

# Statement
There is evidence that diseases of the gall bladder and gall ducts, particularly cholecystolithiasis, cholecystitis/ cholangitis as well as cholecystectomies, occur more frequently with HT (LoE Ib). Degree of consensus: strong consensus

## Recommendation
When assessing the risks and benefits of HT, the increased risk of cholecystitis/cholangitis, cholecystolithiasis and cholecystectomies must be taken into account (A).

## Degree of consensus: consensus

## Cognition
There is limited evidence from older clinical trials that ET has a short-term positive effect on cognition when used in premenopausal women after bilateral oophorectomy. The long-term effects of HT started during the menopausal transition or during the early postmenopausal period are unknown. Neither ET nor EPT were able to prevent the decline of cognitive functions in older postmenopausal women, either as short-or long-term treatment. The evidence is insufficient to assess if special forms of HT may confer any benefit. Observational studies have demonstrated a reduction of the risk for dementia, e.g. Alzheimer's disease, with the use of HT. However, these studies are heterogeneous and show a substantial bias. Therefore, based on the insufficient quality of the data, it is not possible to make recommendations on the basis of available evidence.

# Statement
In the Women's Health Initiative Memory Study (WHIMS), the relationship between HT and dementia in women over 65 years was investigated as part of the WHI. The endpoint ''mild cognitive impairment'' did not show any difference between HT and placebo, either with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA), or with CEE alone. With the endpoint ''possible dementia'', there was a significantly increased relative risk for the combination of CEE and MPA, but not for CEE alone, versus placebo.
In women with a diagnosis from mild to moderate Alzheimer's dementia, there was no significant difference between 1-year ET and placebo as to the overall appearance of the Alzheimer's dementia.

# Statements
HT does not show any benefit on the signs of dementia in women with Alzheimer's disease (LoE 1a).
Degree of consensus: strong consensus Continuous combined HT increases the risk of dementia in women aged over 65 years (LoE 2a).
Degree of consensus: strong consensus

## Recommendation
HT should not be recommended to decrease the risk of dementia (A).

## Degree of consensus: strong consensus
Breast cancer
The use of HT increases the risk of breast cancer. The increased risk was seen after duration of use of 5 or more years. Meta-analyses incorporating both observational studies and randomized controlled trials have also shown an increased risk of breast cancer with ET alone. The effect was weaker than with EPT. In addition, the increase of risk by ET, compared with EPT, was only seen after a longer duration of use. The WHI did not show any increased risk after a mean duration of ET use of 7.1 years. After HT is discontinued, the risk decreases. After a few years, the risk does not differ from the risk of women who never used HT.

# Statements
EPT increases the risk of breast cancer (LoE 1b).
ET increases the risk of breast cancer to a lesser degree than EPT (LoE 2a).
Degree of consensus: strong consensus/consensus

## Recommendation
The increased risk of breast cancer must be considered while assessing the benefits and risks of HT (A).

## Degree of consensus: strong consensus

## Ht in cancer patients
According to a recent randomized trial, HT use after breast cancer leads to a markedly increased risk of recurrence.
Assessing the risk of HT after endometrial, ovarian or colorectal cancer is difficult because only few observational studies are available. These did not demonstrate an increased risk of recurrence when HT was used. Yet, the number of cases is too low to draw reliable conclusions about the safety of HT after treatment of the cancer entities mentioned earlier.

# Statements
HT increases the risk of recurrence when used after breast cancer (LoE 2b).
The risk of HT use after treated endometrial, ovarian or colorectal cancer has not been studied sufficiently (LoE 2b).
Since lack of data, no statement is possible regarding other types of tumours (LoE 5).
Degree of consensus: strong consensus/consensus
Recommendation HT is contraindicated after breast cancer treatment (A).

## Degree of consensus: strong consensus

## Premature menopause
Women with premature menopause (\40 years of age) are a heterogeneous group. The available studies have mostly investigated women with surgical oophorectomy. From a clinical point of view, it seems to make sense to use HT in women with premature menopause, at least until the average age of natural menopause (about 50 years).

# Statements
It is unclear whether the benefits and risks of HT in women with premature menopause differ from those in women with natural menopause aged around 50 years (LoE 2a).
HT is appropriate for the treatment of hot flushes and vaginal atrophy in symptomatic women with premature menopause (LoE 2a).
Degree of consensus: strong consensus/consensus

## Recommendation
In women with premature menopause, HT can be used until the average age of natural menopause (0).

## Degree of consensus: consensus

## Alternative therapies
Currently, there is no evidence that herbal remedies have a reliable effect on vasomotor complaints. Isoflavones or Cimicifuga racemosa can be considered in cases of mild hot flushes or sweating, since a decrease of climacteric complaints is possible in few cases. It is not possible to predict if this treatment will be effective in the individual case. In cases of severe vasomotor complaints, a sufficient therapeutic effect cannot be expected. If there are contraindications against hormonal therapies, and the woman expresses an urgent desire for treatment, selective serotonin re-uptake inhibitors (SSRI) and gabapentin may be considered as an individual experimental treatment. It should be noted that neither medication is currently approved for this indication. Therefore, a medical justification based on the risk-benefit assessment is needed, and the patient must be thoroughly informed about the situation (''off label use''). For all alternative therapies, there is a lack of data on long-term safety.

# Statements
Isoflavone containing supplements made from soybeans or red clover, or a nutrition rich in phytoestrogens, do not reduce hot flushes, or only marginally, if at all (LoE 1a). Currently, the possible risks of alternative therapies cannot be assessed with sufficient reliability (LoE 1a).
Degree of consensus: strong consensus

## Recommendation
Phytoestrogens and other herbal or non-hormonal therapies cannot be recommended as an alternative to HT (0).

## Degree of consensus: strong consensus

## Risk communication
Risk communication is defined as communication about the probabilities of expected benefits and the possible risks of harm by HT, 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, individual factors such as the woman's general state of health, age, age at menopause, previous HT, duration of use, dosage and type of HT, and diseases while using HT should be taken into consideration. In order 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 the balance sheet (see ''attachments''). Notes: Users can add a minus-sign ''-'' to denote the level of that fails to provide a conclusive answer because: either a single result with a wide confidence interval or a systematic review with troublesome heterogeneity. Such evidence is inconclusive, and therefore can only generate Grade D recommendations * By homogeneity we mean a systematic review that is free of worrisome variations (heterogeneity) in the directions and degrees of results between individual studies. Not all systematic reviews with statistically significant heterogeneity need be worrisome, and not all worrisome heterogeneity need be statistically significant. As noted above, studies displaying worrisome heterogeneity should be tagged with a ''-'' at the end of their designated level Clinical Decision Rule. (These are algorithms or scoring systems that lead to a prognostic estimation or a diagnostic category.) a See note above for advice on how to understand, rate and use trials or other studies with wide confidence intervals  Met when all patients died before the Rx became available, but some now survive on it; or when some patients died before the Rx became available, but none now die on it   By poor quality cohort study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both exposed and non-exposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a sufficiently long and complete follow-up of patients. By poor quality case-control study we mean one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded), objective way in both cases and controls and/or failed to identify or appropriately control known confounders    Split-sample validation is achieved by collecting all the information in a single tranche, then artificially dividing this into ''derivation'' and ''validation'' samples An ''Absolute SpPin'' is a diagnostic finding whose specificity is so high that a positive result rules-in the diagnosis. An ''Absolute SnNout'' is a diagnostic finding whose sensitivity is so high that a negative result rules-out the diagnosis aa Good, better, bad and worse refer to the comparisons between treatments in terms of their clinical risks and benefits Good reference standards are independent of the test, and applied blindly or objectively to applied to all patients. Poor reference standards are haphazardly applied, but still independent of the test. Use of a non-independent reference standard (where the 'test' is included in the 'reference', or where the 'testing' affects the 'reference') implies a level 4 study Better-value treatments are clearly as good but cheaper, or better at the same or reduced cost. Worse-value treatments are as good and more expensive, or worse and the equally or more expensive ** Validating studies test the quality of a specific diagnostic test, based on prior evidence. An exploratory study collects information and trawls the data (e.g. using a regression analysis) to find which factors are 'significant' *** By poor quality prognostic cohort study we mean one in which sampling was biased in favour of patients who already had the target outcome, or the measurement of outcomes was accomplished in \80% of study patients, or outcomes were determined in an unblinded, nonobjective way, or there was no correction for confounding factors **** Good follow-up in a differential diagnosis study is[80%, with adequate time for alternative diagnoses to emerge (for example 1-6 months acute, 1-5 years chronic) Arch Gynecol Obstet (2011) The balance sheet listed above is intended for demonstration of the risk of HT with respect to different endpoints.

## Attachment

## Levels of evidence
There are different indices available to quantify the effect of interventions:
Absolute risk reduction (ARR) describes the absolute difference in the rate of undesirable events in the experimental group (E) compared with the control group (C) if the experimental treatment is effective (ARR = C -E). The reciprocal value of the ARR is the number needed to treat (1/ARR = NNT). NNT is a clinically intuitive measure for endpoints to describe the effects of a certain treatment. It represents the number of patients who must be treated to prevent one additional undesirable event.
The absolute risk increase (ARI) describes the absolute difference in the rate of undesirable events in the experimental group in comparison with the control group if the experimental treatment is worse (ARI = |C -E|).
The reciprocal value of the ARI is the number needed to harm (NNH). NNH is a clinically intuitive measure for endpoints to describe the unwanted effects of a certain treatment. It represents the number of patients who must be treated to cause one additional undesirable event.
The relative risk reduction (RRR) describes the relative decrease in the rate of undesirable events in the experimental study group as compared with the control group (RRR = |C -E|/C).
Example: Phlebothrombosis If the yearly rate of phlebothrombosis in postmenopausal users of oral ET is 22 in 10,000 women, and the rate in non-users is 11 in 10,000 women, the RR is RR 14 22 10; 000=year A 11 10; 000=year 14 2
This means a doubled risk of phlebothrombosis when using ET for 1 year. An RR of more than 1.0 indicates an increased risk. An RR of 1.2 signifies a risk increase by 20%. An RR of less than 1.0 indicates a decrease of risk. An RR of 0.5, for example, would mean a risk decrease by 50%-the probability of an event when using ET would then be only half as high as with non-use.
For the evaluation of risks, it is often more useful to state the absolute risk (AR). The AR describes the risk difference by calculating the difference in the incidence between exposed and non-exposed populations. In the example used above (phlebothrombosis in ET users) the AR is AR 14 22 10; 000=year A 11 10; 000=year 14 11 10; 000=year This means that there will be 11 additional phlebothromboses per year for every 10,000 women using oral ET. Changes in the AR are, however, significantly influenced by the pre-existing risk found in the exposed persons.

## Report on guidelines and methods
The long version, the list of references and the detailed report on guidelines and methods are published in German on the DGGG homepage (http://www.dggg.de, area ''Leitlinien'').
This guideline was developed under the aegis of the DGGG and approved by the following institutions:
Medical associations