Geburtshilfe Frauenheilkd 2021; 81(06): 612-636
DOI: 10.1055/a-1361-1948
GebFra Science
Guideline/Leitlinie

Perimenopause and Postmenopause – Diagnosis and Interventions. Guideline of the DGGG and OEGGG (S3-Level, AWMF Registry Number 015-062, September 2020)

Article in several languages: English | deutsch
Elisabeth C. Inwald
1   Klinik für Frauenheilkunde und Geburtshilfe, Lehrstuhl der Universität Regensburg, Caritas-Krankenhaus St. Josef, Regensburg, Germany; Leitlinienkoordinator(in)
,
Christian Albring
2   Frauenarzt, Präsident des Berufsverbandes der Frauenärzte e. V., Frauenärzte im Netz, Hannover, Germany
,
Erika Baum
3   Abteilung für Allgemeinmedizin, Präventive und Rehabilitative Medizin, Philipps Universität Marburg, Marburg, Germany
,
Maria Beckermann
4   Frauenärztin, delegiert von der Deutschen Gesellschaft für Psychosomatische Frauenheilkunde und Geburtshilfe (DGPFG) e. V., Köln, Germany
,
Kai J. Bühling
5   Leiter der Hormonsprechstunde, Klinik und Poliklinik für Gynäkologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
,
Günter Emons
6   Klinik für Gynäkologie und Geburtshilfe, Universitätsmedizin Göttingen, Göttingen, Germany
,
Thomas Gudermann
7   Walther-Straub-Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Ludwig-Maximilians-Universität München, München, Germany
,
Peyman Hadji
8   Frankfurter Hormon und Osteoporosezentrum, Frankfurt am Main; Phillips-Universität Marburg, Marburg, Germany
,
Bruno Imthurn
9   Universitätsspital Zürich, Klinik für Reproduktions-Endokrinologie, Zürich, Switzerland
,
Ludwig Kiesel
10   Universitätsklinikum Münster, Klinik für Frauenheilkunde und Geburtshilfe, Direktor, Münster, Germany
,
David Klemperer
11   Ostbayerische Technische Hochschule Regensburg, Fakultät Angewandte Sozial- und Gesundheitswissenschaften, Regensburg, Germany
,
Petra Klose
12   Kliniken Essen-Mitte, Knappschafts-Krankenhaus, Klinik für Naturheilkunde und Integrative Medizin, Essen, Germany
,
Klaus König
13   Stimmberechtigter Vertreter des Berufsverbandes der Frauenärzte, Eschborn, Germany
,
Stephanie Krüger
14   Department für seelische Gesundheit, Vivantes Klinikum Spandau, Berlin, Germany
,
Jost Langhorst
15   Stiftungslehrstuhl für Integrative Medizin der Universität Duisburg-Essen, Chefarzt, Klinik für Integrative Medizin und Naturheilkunde, Sozialstiftung Bamberg, Klinikum am Bruderwald, Bamberg, Germany
,
Michael Leitzmann
16   Universitätsklinikum Regensburg, Fakultät für Medizin, Institut für Epidemiologie und Präventivmedizin, Regensburg, Germany
,
Albert Ludolph
17   Universitätsklinikum Ulm, Klinik für Neurologie, Ulm, Germany
,
Diana Lüftner
18   Klinik für Hämatologie, Onkologie und Tumorimmunologie, Charité – Universitätsmedizin, Berlin, Germany
,
Dorothea Müller
19   Frauenselbsthilfe nach Krebs, Fulda, Germany
,
Joseph Neulen
20   Uniklinik RWTH Aachen, Klinik für Gynäkologische Endokrinologie und Reproduktionsmedizin, Aachen, Germany
,
Monika Nothacker
21   Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF), Berlin, Germany
,
Eckhard Petri †,
Horst Prautzsch
23   Überörtliche Gemeinschaftspraxis, Facharzt für Allgemeinmedizin, Akademische Lehrpraxis der Universität Tübingen, Tübingen, Germany
,
Vera Regitz-Zagrosek
24   Charité – Universitätsmedizin Berlin, Institut für Geschlechterforschung in der Medizin, Gender in Medicine (GiM), Berlin, Germany
,
Kathrin Schaudig
25   Hormone Hamburg, Praxis für gynäkologische Endokrinologie, Hamburg, Germany
,
Florian Schütz
26   Klinik für Gynäkologie und Geburtshilfe am Diakonissen-Stiftungskrankenhaus Speyer, Speyer, Germany
,
Anneliese Schwenkhagen
25   Hormone Hamburg, Praxis für gynäkologische Endokrinologie, Hamburg, Germany
,
Thomas Strowitzki
27   Abteilung für Gynäkologische Endokrinologie und Fertilitätsstörungen, Frauenklinik, Universitätsklinikum Heidelberg, Heidelberg, Germany
,
Petra Stute
28   Universitätsklinik für Frauenheilkunde, Inselspital Bern, Bern, Switzerland
,
Bettina-Maria Taute
29   Universitätsklinikum Halle, Schwerpunktbereich Angiologie der Klinik für Innere Medizin III, Halle, Germany
,
Clemens Tempfer
30   Frauenklinik der Ruhr Universität Bochum, Marienhospital Herne, Bochum/Herne, Germany
,
Christine v. Arnim
31   Abteilung und Lehrstuhl für Geriatrie, Universitätsmedizin Göttingen, Göttingen, Germany
,
Ludwig Wildt
32   Em Direktor der Universitätsklinik für Gynäkologische Endokrinologie und Reproduktionsmedizin, Vorsitzender der Ethikkommission, Medizinische Universität Innsbruck, Innsbruck, Austria
,
Eberhard Windler
33   Institut für Versorgungsforschung in der Dermatologie und bei Pflegeberufen (IVDP), Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
,
Olaf Ortmann
1   Klinik für Frauenheilkunde und Geburtshilfe, Lehrstuhl der Universität Regensburg, Caritas-Krankenhaus St. Josef, Regensburg, Germany; Leitlinienkoordinator(in)
› Author Affiliations
 

Abstract

Aim The aim of the interdisciplinary S3-guideline Perimenopause and Postmenopause – Diagnosis and Interventions is to provide help to physicians as they inform women about the physiological changes which occur at this stage of life and the treatment options. The guideline should serve as a basis for decisions taken during routine medical care. This short version lists the statements and recommendations given in the long version of the guideline together with the evidence levels, the level of recommendation, and the strength of consensus.

Methods The statements and recommendations are largely based on methodologically high-quality publications. The literature was evaluated by experts and mandate holders using evidence-based medicine (EbM) criteria. The search for evidence was carried out by the Essen Research Institute for Medical Management (EsFoMed). To some extent, this guideline also draws on an evaluation of the evidence used in the NICE guideline on Menopause and the S3-guidelines of the AWMF and has adapted parts of these guidelines.

Recommendations Recommendations are given for the following subjects: diagnosis and therapeutic interventions for perimenopausal and postmenopausal women, urogynecology, cardiovascular disease, osteoporosis, dementia, depression, mood swings, hormone therapy and cancer risk, as well as primary ovarian insufficiency.


#

I  Guideline Information

Guidelines program of the DGGG, OEGGG and SGGG

For information on the guidelines program, please refer to the end of this guideline.


#

Citation format

Perimenopause and Postmenopause – Diagnosis and Interventions. Guideline of the DGGG and OEGGG (S3-Level, AWMF Registry Number 015-062, September 2020). Geburtsh Frauenheilk 2021; 81: 612–636


#

Guideline documents

The complete long version of this guideline and the guideline report, which includes a list of the conflicts of interest of all of the authors, are available in German on the homepage of the AWMF: http://www.awmf.org/leitlinien/detail/ll/015-062.html


#

Guideline authors

See [Tables 1] to [4].

Table 1 Lead author and coordinating guideline author.

Author

AWMF professional society

Prof. Dr. Olaf Ortmann

DGGG

The professional societies/working groups/organizations/associations listed below have stated their interest in being involved in preparing the text of the guideline and participating in the consensus conference and appointed representatives to attend the consensus conference:

Table 2 Who are the guideline authors representing? Contributing target user groups.

DGGG working group/AWMF/non-AWMF professional society/
organization/association

Gynecological Oncology Working Group [Arbeitsgemeinschaft Gynäkologische Onkologie] (AGO)

Urogynecology and Pelvic Floor Reconstruction Study Group [Arbeitsgemeinschaft für Urogynäkologie und plastische Beckenbodenrekonstruktion] (AGUB)

Professional Association of Gynecologists [Berufsverband der Frauenärzte] (BVF)

German, Austrian and Swiss Society for the Prevention of Cardiovascular Disease [D·A·CH-Gesellschaft Prävention von Herz-Kreislauf-Erkrankungen e. V.]

German Society for General and Family Medicine [Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin] (DEGAM)

German Society for Angiology/Vascular Medicine [Deutsche Gesellschaft für Angiologie, Gesellschaft für Gefäßmedizin] (DGA)

German Society of Endocrinology [Deutsche Gesellschaft für Endokrinologie] (DGE)

German Society for Gynecological Endocrinology and Reproductive Medicine [Deutsche Gesellschaft für Gynäkologie, Endokrinologie und Fortpflanzungsmedizin] (DGGEF)

German Society of Gynecology and Obstetrics [Deutsche Gesellschaft für Gynäkologie und Geburtshilfe] (DGGG)

German Society for Hematology and Medical Oncology [Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie] (DGHO)

German Society for Internal Medicine [Deutsche Gesellschaft für Innere Medizin] (DGIM)

German Society for Cardiology, Heart and Circulation [Deutsche Gesellschaft für Kardiologie – Herz- und Kreislaufforschung] (DGK)

German Society of Neurology [Deutsche Gesellschaft für Neurologie] (DGN)

German Society of Pharmacology [Deutsche Gesellschaft für Pharmakologie] (DGP)

German Society for Psychosomatic Gynecology and Obstetrics [Deutsche Gesellschaft für psychosomatische Frauenheilkunde und Geburtshilfe] (DGPFG)

German Society for Psychiatry and Psychotherapy, Psychosomatics and Neurology [Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde] (DGPPN)

German Society for Senology [Deutsche Gesellschaft für Senologie] (DGS)

German Cancer Society [Deutsche Krebsgesellschaft] (DKG)

German Menopause Society [Deutsche Menopause Gesellschaft] (DMG)

German Osteology Association [Dachverband Osteologie] (DVO)

European Menopause and Andropause Society (EMAS)

Womenʼs Self-Help After Cancer Organization [Frauenselbsthilfe nach Krebs]

Society for Phytotherapy [Gesellschaft für Phytotherapie] (GPT)

International Menopause Society (IMS)

Austrian Society of Gynecology and Obstetrics [Österreichische Gesellschaft für Gynäkologie und Geburtshilfe] (OEGGG)

Swiss Society of Gynecology and Obstetrics [Schweizerische Gesellschaft für Gynäkologie und Geburtshilfe] (SGGG)

The SGGG has published two Expert Letters on the topic, which the respective specialists have declared to be still authoritative for Switzerland (the German- and French-speaking areas of Switzerland). For this reason and based on the advice of the AGER, the executive board of the SGGG has decided not to adopt the S3 guideline “Perimenopause and Postmenopause”.

This guideline was moderated by Dr. med. Monika Nothacker (AWMF-certified guideline moderator).

Table 3 Who are the guideline authors representing? Contributing target patient groups.

AWMF/non-AWMF professional society/organization/association

Womenʼs Self-Help After Cancer [Frauenselbsthilfe nach Krebs e. V.]

Table 4 Guideline authors (in alphabetical order).

Author

Mandate holder

DGGG working group (AG)/
AWMF/non-AWMF professional society/organization/association

Dr. med. C. Albring

BVF, member of the Steering Committee

Prof. Dr. E. Baum

DEGAM

Dr. med. M. Beckermann

DGPFG

Prof. Dr. K. Bühling

D·A·CH

Prof. Dr. G. Emons

DGGG

Prof. Dr. T. Gudermann

DGP

Prof. Dr. P. Hadji

DVO

Prof. Dr. B. Imthurn

SGGG

PD Dr. med. E. C. Inwald

2nd coordinating guideline author

Prof. Dr. L. Kiesel

DMG, member of the Steering Committee

Prof. Dr. D. Klemperer

Expert, patient information

Dr. P. Klose

Mandate holder representing Prof. Langhorst, GPT

Dr. med. K. König

BVF

Prof. Dr. S. Krüger

DGPPN

Prof. Dr. J. Langhorst

GPT

Prof. Dr. M. Leitzmann

Expert, epidemiology

Prof. Dr. A. Ludolph

DGN

Prof. Dr. D. Lüftner

DGHO

Ms. D. Müller

Womenʼs Self-Help After Cancer

Prof. Dr. J. Neulen

DGGEF

Dr. med. M. Nothacker

AWMF

Prof. Dr. O. Ortmann

Coordinating guideline author, lead author, member of the Steering Committee

Prof. Dr. E. Petri

(died 21 September 2019)

AGUB

Dr. med. H. Prautzsch

DEGAM

Prof. Dr. F. Regitz-Zagrosek

DGK

Dr. med. K. Schaudig

Expert, gynecological endocrinology

Prof. Dr. F. Schütz

DGS

Dr. med. A. Schwenkhagen

Expert, gynecological endocrinology

Prof. Dr. T. Strowitzki

DGE

Prof. Dr. P. Stute

EMAS, member of the Steering Committee

Prof. Dr. B.-M. Taute

DGA

Prof. Dr. C. Tempfer

AGO

Prof. Dr. C. von Arnim

DGN

Prof. Dr. L. Wildt

OEGGG

Prof. Dr. E. Windler

DGIM, member of the Steering Committee


#
#

II  Guideline Application

Purpose and objectives

The guideline authors compiled consensual recommendations and statements on issues in the following areas:

  • diagnosis and therapeutic interventions for perimenopausal and postmenopausal women

  • urogynecology

  • cardiovascular disease

  • osteoporosis

  • dementia, depression, mood swings

  • HRT and cancer risk

  • primary ovarian insufficiency (POI)

  • other diseases


#

Targeted areas of patient care

  • Inpatient care

  • Outpatient care


#

Target user groups/target audience

The guideline is aimed at physicians who advise perimenopausal and postmenopausal women about the physiological changes, disorders and treatment options and treat them, for example:

  • gynecologists in private practice

  • hospital-based gynecologists

  • physicians who advise perimenopausal and postmenopausal women and treat their symptoms and disorders, e.g., general practitioners, specialists for internal medicine, psychiatrists, neurologists, etc.


#

Adoption and period of validity

The validity of this guideline was confirmed by the executive boards/heads of the participating medical professional societies, working groups, organizations and associations as well as by the boards of the DGGG, the DGGG guidelines commission, and the OEGGG in October and November of 2018 and was thus approved in its entirety. The guideline was published in January 2020 and was updated in September 2020 by the addition of an addendum. This guideline is valid from 1st January 2020 through to 31st December 2024. Because of the contents of this guideline, this period of validity is only an estimate.

Should changes become necessary before the guidelineʼs period of validity has expired, the Steering Committee will consult together on the issues and vote on proposed changes together with the guideline authors, using a structured consensus process.


#
#

III  Methodology

Basic principles

The method used to prepare this guideline was determined by the class to which this guideline was assigned. The AWMF Guidance Manual (version 1.0) has set out the respective rules and requirements for different classes of guidelines. Guidelines are differentiated into lowest (S1), intermediate (S2), and highest (S3) class. The lowest class is defined as consisting of a set of recommendations for action compiled by a non-representative group of experts. In 2004, the S2 class was divided into two subclasses: a systematic evidence-based subclass (S2e) and a structural consensus-based subclass (S2k). The highest S3 class combines both approaches.

This guideline has been classified as: S3


#

Grading of evidence

To evaluate the evidence (levels 1 – 5), this guideline uses the classification system of the Oxford Centre for Evidence-based Medicine in its most current version dating from 2009 ([Table 5]).

Table 5 Grading of evidence based on the Oxford classification system (from March 2009).

Level

Therapy/prevention, etiology/harm

Prognosis

Diagnosis

Differential diagnosis/symptom prevalence study

Economic and decision analyses

Source (contents, abbreviations, notes): http://www.cebm.net/?o=1025

1a

SYSTEMATIC REVIEWS (with homogeneity*) of RANDOMIZED CONTROLLED TRIALSs

SYSTEMATIC REVIEWS (with homogeneity*) of inception cohort studies; CLINICAL DECISION RULE" validated in different populations

SYSTEMATIC REVIEWS (with homogeneity*) of Level 1 diagnostic studies; CLINICAL DECISION RULE" with 1b studies from different clinical centers

SYSTEMATIC REVIEWS (with homogeneity*) of prospective cohort studies

SYSTEMATIC REVIEWS (with homogeneity*) of Level 1 economic studies

1b

Individual RANDOMIZED CONTROLLED TRIALS (with narrow confidence interval"¡)

Individual inception cohort study with > 80% follow-up; CLINICAL DECISION RULE" validated in a single population

Validating** cohort study with good" " " reference standards; or CLINICAL DECISION RULE" tested within one clinical center

Prospective cohort study with good follow-up****

Analysis based on clinically sensible costs or alternatives; systematic review(s) of the evidence; and including multi-way sensitivity analyses

1c

All-or-none§

All-or-none case series

Absolute SPins and SNouts" "

All-or-none case series

Absolute better-value or worse-value analyses" " " "

2a

SYSTEMATIC REVIEWS (with homogeneity*) of cohort studies

SYSTEMATIC REVIEWS (with homogeneity*) of either retrospective cohort studies or untreated control groups in RANDOMIZED CONTROLLED TRIALSs

SYSTEMATIC REVIEWS (with homogeneity*) of level > 2 diagnostic studies

SYSTEMATIC REVIEWS (with homogeneity*) of 2b and better studies

SYSTEMATIC REVIEWS (with homogeneity*) of level > 2 economic studies

2b

Individual cohort study (including low quality RANDOMIZED CONTROLLED TRIALS; e.g., < 80% follow-up)

Retrospective cohort study or follow-up of untreated control patients in RANDOMIZED CONTROLLED TRIALS; Derivation of CLINICAL DECISION RULE" or validated on split-sample§§§ only

Exploratory** cohort study with good" " " reference standards; CLINICAL DECISION RULE" after derivation, or validated only on split-sample§§§ or databases

Retrospective cohort study, or poor follow-up

Analysis based on clinically sensible costs or alternatives; limited review(s) of the evidence, or single studies; and including multi-way sensitivity analyses

2c

“Outcomes” Research; Ecological studies

“Outcomes” Research

Ecological studies

Audit or outcomes research

3a

SYSTEMATIC REVIEWS (with homogeneity*) of case-control studies

SYSTEMATIC REVIEWS (with homogeneity*) of 3b and better studies

3b

Individual case-control study

Non-consecutive study; or without consistently applied reference standards

Non-consecutive cohort study, or very limited population

Analysis based on limited alternatives or costs, poor quality estimates of data, but including sensitivity analyses incorporating clinically sensible variations.

4

Case series (and poor-quality cohort and case-control studies§§)

Case series (and poor-quality prognostic cohort studies***)

Case-control study, poor or non-independent reference standard

Case series or superseded reference standards

Analysis with no sensitivity analysis

5

Expert opinion without explicit critical appraisal, or based on physiology, bench research or “first principles”

Expert opinion without explicit critical appraisal, or based on economic theory or “first principles”


#

Grading of recommendations

While grading the quality of the evidence (strength of evidence) should be an indication of the resilience of published data and thus of the level of certainty/uncertainty associated with the data, the level of recommendation reflects the result of weighing up desired and unwanted consequences of alternative approaches.

The level of obligation indicates the medical importance of complying with a guideline recommendation when the recommendation is based on the current state of scientific knowledge. When this is not the case, it is possible or even imperative to deviate from the recommendation given this guideline. The body publishing this guideline is not creating legally binding obligations, because it has no legal powers to pass laws, directives, or ordinances (within the meaning of German laws on ordinances and directives). This approach has been confirmed by the German Federal High Court of Justice (Decision of the Federal High Court of Justice VI ZR 382/12).

Grading the evidence in S2e/S3-level guidelines using the Oxford classification permits gradations of recommendations to be made for this type of guideline. Symbols are used to indicate the level of obligation to comply with the recommendation, with the three different levels of obligation reflected by the different strengths of the linguistic terminology. This type of grading is currently generally used, not just by the AWMF but also by the German Medical Association and its National Healthcare Guidelines [Nationale Versorgungsleitlinien (NVL)] ([Table 6]).

Table 6 Grading of recommendations (in English, according to Lomotan et al. Qual Saf Health Care 2010).

Symbols

Description of binding character

Expression

A

Strong recommendation with highly binding character

must/must not

B

Regular recommendation with moderately binding character

should/should not

0

Open recommendation with limited binding character

may/may not

In addition to evaluating the evidence, the above listed classification of recommendations also reflects the clinical relevance of underlying studies and measures/factors which were not included in the grading of the evidence, such as the choice of patient population, intention-to-treat or per-protocol-outcome analyses, medical or ethical behavior toward the patient, country-specific applicability, etc. Thus, there may be linear correlation between a strong, moderate or weak level of evidence leading to a strong, ordinary or open recommendation. Upgrading to a Grade A recommendation or downgrading to a Grade 0 recommendation is only possible for moderate levels of evidence. In exceptional circumstances, additional background information will have to be provided if the highest level of evidence only leads to a weak/open recommendation or vice versa.

  • Strong level of evidence → Grade A or Grade B recommendation

  • Moderate level of evidence → Grade A or Grade B or Grade 0 recommendation

  • Weak level of evidence → Grade B or Grade 0 recommendation


#

Statements

Expositions or explanations of specific facts, circumstances or problems without any direct recommendations for action included in this guideline are referred to as “Statements”. It is not possible to provide any information about the grading of evidence for these Statements.


#

Achieving consensus and level of consensus

At structured consensus-based conferences (S2k/S3 level), authorized participants attending the session vote on draft statements and recommendations. This may lead to significant amendments to formulations, etc. Finally, the extent of consensus is determined based on the number of participants. ([Table 7]).

Table 7 Classification of strength of consensus.

Symbol

Level of consensus

Extent of agreement in percent

+++

Strong consensus

> 95% participants agree

++

Consensus

> 75 – 95% participants agree

+

Majority agreement

> 50 – 75% participants agree

No consensus

< 51% participants agree


#

Expert consensus

As the name already implies, this refers to consensus decisions taken specifically with regard to recommendations/statements made without a prior systematic search of the literature (S2k) or for which evidence is lacking (S2e/S3). The term “expert consensus” (EC) used here is synonymous with terminology used in other guidelines such as “good clinical practice” (GCP) or “clinical consensus point” (CCP). The strength of the recommendation is graded as previously described in the chapter on the grading of recommendations but without the use of symbols; it is only expressed semantically (“must”/“must not” or “should”/“should not” or “may”/“may not”).


#
#

IV  Guideline

1  Diagnosis and therapeutic interventions in perimenopausal and postmenopausal women

Diagnosis

Evidence-based recommendation 1.E1

Level of evidence LLA

Level of recommendation A

Level of consensus ++

A diagnosis of perimenopause and postmenopause in women over the age of 45 must be based on clinical parameters.

Evidence-based recommendation 1.E2

Level of evidence LLA

Level of recommendation A

Level of consensus ++

Using FSH levels to diagnose perimenopause and postmenopause must only be done in women between the ages of 40 and 45 years with menopausal symptoms (e.g., hot flushes, changes in their menopausal cycle) and in women below the age of 40 if there are indications of primary ovarian insufficiency.


#

Therapeutic interventions

Evidence-based recommendation 1.E3

Level of evidence 1a

Level of recommendation A

Level of consensus ++

Women with vasomotor symptoms must be offered HRT after they have been informed about the short-term (up to 5 years) and long-term benefits and risks of treatment. EPT with an appropriate progestogen dose should be considered for non-hysterectomized women while hysterectomized Frauen should receive ET.

Before starting hormone treatment, women should be informed that the vasomotor symptoms may return again when they terminate HRT.

Evidence-based recommendation 1.E4

Level of evidence 3

Level of recommendation A

Level of consensus ++

Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), clonidine and gabapentin must not be routinely prescribed as first-choice drugs for vasomotor symptoms.

Evidence-based recommendation 1.E5

Level of evidence 1b

Level of recommendation 0

Level of consensus ++

Cognitive behavioral therapy (CBT), isoflavones and black cohosh products may be used to treat vasomotor symptoms.

For the dissenting opinion of the Society for Phytotherapy, see the “Vote of the Society for Phytotherapy (GPT)” in the long version of this guideline.


#

Efficacy and safety of interventions

[Tables 8] and [9].

Table 8 Efficacy and risks of different interventions for hot flushes.

Verified benefit

Possible benefit

Unlikely to be beneficial

Low risk of harm or of discontinuing treatment

Expectant management or placebo, CBT (mindfulness, cognitive und behavioral therapy)

Black cohosh 5 – 6.5 mg/d (herbal preparation), isoflavones 30 – 80 mg/d, incl. phytoestrogen-rich diet, red clover, S-equol, genistein 30 – 60 mg/d, rheum rhaponticum, acupuncture, St. Johnʼs wort 300 mg/d

Sports (3 – 6 months), deep relaxation (4 – 12 weeks), vitamin E

Moderate risk of harm or of discontinuing treatment

estrogens, tibolone

SSRI, SNRI, gabapentin, clonidine

DHEA (dehydroepiandrosterone)

Raloxifene

Risk of harm not sufficiently investigated

Chinese herbal remedies used in TCM, melatonin

Table 9 Efficacy (= reduced frequency of hot flushes) of different interventions and probability that the patient will discontinue treatment compared to placebo in non-hysterectomized women who present with vasomotor perimenopausal and postmenopausal symptoms.

Intervention

MR (mean ratio)

Efficacy

OR (odds ratio)

Treatment discontinued*

* An OR of less than 1 signifies treatment compliance; an OR of more than 1 indicates the risk of treatment being discontinued.

Non-oral estrogen plus progestogens

0.23 (0.09 – 0.7)

Black cohosh

0.4 (0.17 – 0.9)

Oral estrogen plus progestogens

0.52 (0.25 – 1.06)

0.61 (0.73 – 0.99)

Tibolone

0.55 (0.24 – 1.29)

5.65 (0.94 – 172.9)

Acupuncture

0.58 (0.23 – 1.36)

Isoflavones

0.62 (0.44 – 0.87)

0.95 (0.51 – 1.76)

Herbal remedies

0.71 (0.24 – 2.07)

0.5 (0.07 – 4.3)

Sham acupuncture

0.75 (0.19 – 1.9)

SSRI/SNRIs

0.84 (0.54 – 1.31)

1.66 (1.07 – 2.61)

Chinese herbal remedies

0.95 (0.46 – 1.9)

1.58 (0.42 – 6.66)

Raloxifene

1.65 (0.61 – 4.51)

CEE + bazedoxifene

0.31 (0.1 – 1.0)

Gabapentin

0.88 (0.63 – 1.23)

Valerian root

0.4 (0.01 – 5.4)


#

Changes in sexual functioning

Evidence-based recommendation 1.E6

Level of evidence 1b

Level of recommendation 0

Level of consensus ++

Testosterone therapy may be considered after psychosexual exploration for women who experience a loss of libido in perimenopause and postmenopause if HRT is not effective. The patient must be informed that this is an off-label use.


#

Urogenital atrophy

Evidence-based recommendation 1.E7

Level of evidence 1b

Level of recommendation A

Level of consensus +++

Women with symptomatic urogenital atrophy must be offered the use of moisturizers and lubricants either as a stand-alone treatment or together with vaginal ET. Treatment may be continued for as long as necessary.

Estriol-based preparations should be preferred for vaginal estrogen applications. Routine vaginal sonography to measure endometrial thickness must not be carried out when the patient is being treated with topical ET (cf. S3-guideline Endometrial Cancer, AWMF registry number 032-034).


#
#

2  Urogynecology

Stress incontinence

Evidence-based statement 2.S1

Level of evidence 1a

Level of consensus ++

Vaginal ET may improve urinary incontinence in postmenopausal women.

Evidence-based recommendation 2.E8

Level of evidence 1a

Level of recommendation A

Level of consensus ++

Patients must be informed prior to starting systemic ET/EPT that this treatment may lead to urinary incontinence or result in a worsening of urinary incontinence.

Evidence-based recommendation 2.E9

Level of evidence 1a

Level of recommendation A

Level of consensus ++

Postmenopausal patients with urinary incontinence must be offered pelvic floor training and vaginal ET.


#

Overactive bladder

Evidence-based statement 2.S2

Level of evidence 1b

Level of consensus +++

Systemic HRT may worsen existing urinary incontinence. Vaginal ET may be offered to women with overactive bladder (OAB).

Evidence-based recommendation 2.E10

Level of evidence 1b

Level of recommendation 0

Level of consensus ++

Once urological disease has been ruled out as the cause of urge symptoms, the patient may be offered topical ET. This may reduce the frequency of urination and urge symptoms.


#

Recurrent urinary tract infections

Evidence-based statement 2.S3

Level of evidence 2b

Level of consensus ++

Changes to the vaginal pH and microbiome in postmenopausal women predispose them to urinary tract infections. There is a positive correlation with older age.

Evidence-based recommendation 2.E11

Level of evidence 2a

Level of recommendation B

Level of consensus ++

When postmenopausal women have recurrent cystitis, vaginal ET should be carried out before starting long-term antibiotic prophylaxis.


#
#

3  Cardiovascular disease

Evidence-based recommendation 3.E12

Level of evidence 2b

Level of recommendation B

Level of consensus ++

The basic cardiovascular risk of perimenopausal and postmenopausal women varies greatly, depending on the individual risk factors. Risk factors should be optimally controlled to ensure that they do not constitute a contraindication for HRT. Vascular risk factors should therefore be investigated and treated before starting HRT ([Table 10]).

Table 10 Effects of oral HRT on cardiovascular disease in the Womenʼs Health Initiative.

EPT

ET

Verum

Control

HR

95% Cl

p

Verum

Control

HR

95% Cl

p

Abbreviations: Verum: 0.625 mg conjugated estrogens plus continuous 2.5 mg medroxyprogesterone acetate, HR: hazard ratio, 95% CI: 95% confidence interval, p: significance.

Deep vein thrombosis

122

61

1.87

1.37, 2.54

< 0.001

85

59

1.48

1.06, 2.07

0.02

Stroke

159

109

1.37

1.07, 1.76

0.01

169

130

1.35

1.07, 1.70

0.01

Coronary heart disease

196

159

1.18

0.95, 1.45

0.13

204

222

0.94

0.78, 1.14

0.53

Cardiovascular mortality

79

70

1.05

0.76, 1.45

0.77

109

112

1.00

0.77, 1.31

0.98

Overall mortality

250

238

0.97

0.81, 1.16

0.76

301

299

1.03

0.88, 1.21

0.68

Thromboembolism

Evidence-based recommendation 3.E13

Level of evidence 2a

Level of recommendation A

Level of consensus ++

Women must be informed that their risk of thromboembolism will be higher if they take oral ET or EPT and that the risk of thromboembolism associated with oral estrogen intake is higher than for transdermal applications.


#

Cerebrovascular events

Evidence-based recommendation 3.E14

Level of evidence 2b

Level of recommendation A

Level of consensus ++

Women must be informed that oral EPT might increase the risk of ischemic cerebrovascular events but that transdermal ET does not. The absolute risk of stroke in younger women is very low.


#

Coronary heart disease

Evidence-based recommendation 3.E15

Level of evidence 2b

Level of recommendation A

Level of consensus ++

Women must be informed that EPT does not increase cardiovascular risk or only minimally increases the risk and that ET neither increases nor decreases cardiovascular risk. When this evidence is considered alongside the risk of thromboembolism and ischemic stroke, it is clear that HRT is not suitable for the prevention of coronary heart disease but should be used to treat menopausal symptoms before the age of 60.


#
#

4  Osteoporosis

Evidence-based statement 4.S4

Level of evidence 1a

Level of consensus +++

HRT significantly reduces the risk of osteoporosis-associated fractures.

Evidence-based statement 4.S5

Level of evidence 2a

Level of consensus ++

The fracture-reducing effect of HRT was detectable irrespective of the duration of hormone intake (i.e., already after a short intake period of < 1 year) or age at the start of therapy. Moreover, the fracture-reducing effect appears to persist to a lesser degree after terminating HRT ([Tables 11] and [12]).

Table 11 Risk factors for osteoporosis.

Medical specialty

Risk factor

General risk factors/General medicine

  • Age (2 × to 4 × higher per decade from the age of 50)

  • Gender (women/men: 2 to 1)

  • Prevalence of vertebral body fractures (2 × to 10 × higher)

  • Low-trauma peripheral fracture

  • Paternal or maternal proximal femur fracture

  • Multiple falls

  • Immobility

  • Smoking

  • Underweight (BMI < 20)

  • Cortisone therapy > 3 months > 2.5 mg

Endocrinology

  • Cushingʼs syndrome

  • Primary hyperparathyroidism

  • Growth hormone deficiency due to pituitary insufficiency

  • Hyperthyroidism

  • Type 1 or type 2 diabetes mellitus

  • Glitazone therapy

Gastroenterology

  • B II gastric resection or gastrectomy

  • Celiac disease

  • Proton pump inhibitors

Geriatric medicine

  • Sedatives

  • Antipsychotics

  • Benzodiazepines

Gynecology

  • Aromatase inhibitors

  • Hypogonadism

Cardiology

  • Congestive heart failure

Neurology

  • Epilepsy and anti-epileptic drugs

  • Depression and antidepressants

Pneumology

  • COPD

Rheumatology/Orthopedics

  • Rheumatoid arthritis

  • Ankylosing spondylitis

Table 12 Current treatment options for osteoporosis in postmenopausal women.

Antiresorptive medication

Evidence of fewer vertebral body fractures

Fewer peripheral fractures

Fewer proximal femur fractures

Aledronate

A

A

A

Ibadronate

A

B

Risedronate

A

A

A

Zoledronic acid

A

A

A

Denosumab

A

A

A

Bazedoxifene

A

B

Raloxifene

A

B

Estrogens

A

A

A


#

5  Dementia, depression, mood swings

Evidence-based recommendation 5.E16

Level of evidence LLA

Level of recommendation A

Level of consensus +++

Perimenopausal and postmenopausal women must be advised that it is not clear whether having HRT prior to the 65th year of life affects the risk of dementia.

Evidence-based recommendation 5.E17

Level of evidence LLA

Level of recommendation A

Level of consensus ++

The indications for a pharmacological treatment of depression during perimenopause must comply with general treatment guidelines (there are no direct specific studies on its efficacy in perimenopause).

There are currently no clear indications that there are any differences in the effectiveness of antidepressants based on menopausal status.

There is insufficient evidence to recommend HRT or psychotherapy to treat perimenopausal depression.


#

6  HRT and the risk of cancer

HRT and the risk of breast cancer

Evidence-based recommendation 6.E18

Level of evidence 1a

Level of recommendation A

Level of consensus ++

Women who are considering HRT must be informed that HRT (EPT/ET) may lead to a slight or even no increase in their risk of breast cancer. The potential increase in the level of risk depends on the composition of the specific HRT and the duration of HR intake and decreases after HRT is discontinued ([Table 13]).

Table 13 Absolute risk of breast cancer for different forms of HRT: differences in breast cancer incidence per 1000 postmenopausal women over a period of 7.5 years (95% CI).

HRT type

Study type

Current use

ET

RCT

4 less (− 11 to + 8)

Observational study

6 more (1 to 12)

EPT

RCT

5 more (− 4 to 36)

Observational study

17 more (14 to 20)


#

HRT after breast cancer

Evidence-based statement 6.S6

Level of evidence 2b

Level of consensus +++

HRT may increase the risk of recurrence in women previously treated for breast cancer.

Evidence-based recommendation 6.E19

Level of evidence 2b

Level of recommendation A

Level of consensus +++

HRT must not be carried out in women who have had breast cancer. HRT may be considered in individual cases when non-hormonal therapies have failed and the patient is experiencing a significant reduction in her quality of life.

Addendum

The S3-guideline “Perimenopause and Postmenopause – Diagnosis and Interventions” was published in January 2020 (Oncology Guidelines Program, 2020). The comprehensive meta-analysis of prospective and retrospective data from observational studies and randomized studies on the association between perimenopausal and postmenopausal hormone therapy (HT) and the risk of breast cancer by the Collaborative Group on Hormonal Factors in Breast Cancer published in August 2019 was not yet included in the S3-guideline at the time of publication. Because of the relevance of the data, the authors of the S3-guideline “Perimenopause and Postmenopause – Diagnosis and Interventions”, represented by the guidelineʼs Steering Committee, updated the S3-guideline by adding an addendum which states their position regarding the meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer (Collaborative Group on Hormonal Factors in Breast Cancer, 2020).

The authors of the S3-guideline “Perimenopause and Postmenopause – Diagnosis and Interventions” are of the opinion that the figures given in [Table 14] are suitable when informing patients with menopausal symptoms seeking advice. After taking sequential combined HT for 5 years from the age of 50, it is expected that there will 14 additional cases of breast cancer per 1000 women during the next 20 years. If treatment consists of continuous-combined HT, the number of additional women developing breast cancer is expected to be 20, while estrogen therapy is considered to lead to an additional 5 cases with breast cancer. These risk figures are consistent with previously known data and should be used to advise patients prior to planning HT. Changes to the statements and recommendations published in the S3-guideline “Perimenopause and Postmenopause – Diagnosis and Interventions” (Oncology Guidelines Program, 2020) because of the results of the meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer (Collaborative Group on Hormonal Factors in Breast Cancer, 2020) are not necessary. As regards the advice given to patients concerning the duration of planned HT, physicians should refer to [Table 15]. Based on the results of the meta-analysis by the Collaborative Group on Hormonal Factors in Breast Cancer (Collaborative Group on Hormonal Factors in Breast Cancer, 2020), there is no increased risk of breast cancer in the 9 years after ending estrogen therapy if estrogen therapy only lasted for a maximum of 4 years (relative risk [RR] 1.07; 95% confidence interval [CI] 0.96 – 1.20). After ending up to 4 years of combined EPT treatment (sequential combined HT or continuous-combined HT), there is also no increased risk of breast cancer during the following 9 years (RR 1.06; 95% CI 0.98 – 1.15) ([Table 15]). However, the data of the Collaborative Group on Hormonal Factors in Breast Cancer point to an increased risk of being diagnosed with breast cancer during the time the patient is taking ET or EPT, starting already in the first year of therapy ([Table 15]). The epidemiological data do not make it clear whether this is a biological effect or whether it merely reflects an increased probability of detection.

Table 14 Risk of breast cancer associated with a specific type of hormone treatment in perimenopause and postmenopause.

Type of HT

Additional cases of breast cancer over 20 years per 1000 women after 5 years of HT from the age of 50

Additional cases of breast cancer over 20 years per 1000 women after 10 years of HT from the age of 50

HT: hormone treatment, EPT: estrogen-progestogen therapy, ET: estrogen therapy

Data from: Collaborative Group on Hormonal Factors in Breast Cancer

Sequential EPT

+ 14

+ 29

Continuous-combined EPT

+ 20

+ 40

ET

+ 5

+ 11

Table 15 Risk of breast cancer during hormone therapy in perimenopause and postmenopause and over the next 9 years after terminating hormone therapy in perimenopause and postmenopause.

Type of HT

Relative risk of breast cancer during HT

Relative risk of breast cancer up to 9 years after the end of HT

HT: hormone therapy, ET: estrogen therapy, EPT: estrogen-progestogen therapy, RR: relative risk, CI: confidence interval

Data from: Collaborative Group on Hormonal Factors in Breast Cancer

ET with 1 – 4 years of treatment

RR 1.17; 95% CI 1.10 – 1.26

RR 1.07; 95% CI 0.96 – 1.20

EPT (continuous-combined or sequential combined) with 1 – 4 years of treatment

RR 1.60; 95% CI 1.52 – 1.69

RR 1.06; 95% CI 0.98 – 1.15

A total of 17 of the 25 mandate holders entitled to vote voted on and agreed to the addendum. There were no dissenting votes. Eight mandate holders did not vote (abstained). Of the 17 mandate holders who were entitled to vote and voted, 4 had a conflict of interest.

The results of the vote on the addendum showed a strong consensus.


#
#

HRT and the risk of endometrial cancer

Evidence-based statement 6.S7

Level of evidence 2

Level of consensus +++

In non-hysterectomized women, HRT consisting only of an estrogen without the protection afforded by progestogens is a risk factor for developing endometrial cancer. The effect depends on the duration of hormone therapy.

Evidence-based statement 6.S8

Level of evidence 2

Level of consensus ++

A reduction in the risk of endometrial cancer was observed for patients who took continuous-combined HRT with conjugated equine estrogens and medroxyprogesterone acetate as the progestogen, with an average duration of intake of 5.6 years.

Evidence-based statement 6.S9

Level of evidence 2

Level of consensus +++

Continuous-combined HRT for < 5 years may be considered safe with regard to the risk of endometrial cancer.

Evidence-based statement 6.S10

Level of evidence 3

Level of consensus ++

Long-term continuous-combined HRT for > 6 years or > 10 years may lead to an increased risk of endometrial cancer.

Evidence-based statement 6.S11

Level of evidence 4

Level of consensus +

The use of progesterone or dydrogesterone in the context of continuous-combined HRT may increase the risk of developing endometrial cancer.

Evidence-based statement 6.S12

Level of evidence 3

Level of consensus ++

Sequential combined HRT may increase the risk of developing endometrial cancer. The effect depends on the duration, type, and dose of the progestogen.

Evidence-based statement 6.S13

Level of evidence 3

Level of consensus +++

Sequential combined HRT taken for less than 5 years and using a synthetic progestogen may be considered safe with regard to the risk of endometrial cancer.

Evidence-based recommendation 6.E20

Level of evidence LLA

Level of recommendation A

Level of consensus ++

ET must only be taken by hysterectomized women. Combined EPT for non-hysterectomized women must include 10 days, or better 14 days, of a progestogen per treatment month.


#

HRT after endometrial cancer

Evidence-based statement 6.S14

Level of evidence 2b

Level of consensus +++

Whether taking HRT after prior treatment for endometrial cancer constitutes a risk has not yet been sufficiently investigated.

Evidence-based recommendation 6.E21

Level of evidence 2b

Level of recommendation EK

Level of consensus ++

HRT may be considered for patients previously treated for endometrial cancer if the patientsʼ menopausal symptoms significantly compromise their quality of life and non-hormonal alternatives have failed.


#

Vaginal ET after endometrial cancer

Evidence-based recommendation 6.E22

Level of evidence 4

Level of recommendation A

Level of consensus ++

Symptoms of atrophic vaginitis in patients who were previously treated for endometrial cancer must be treated primarily using inert lubricating gels or creams.

Consensus-based recommendation 6.E1

Expert consensus

Level of consensus ++

Topical ET after primary therapy of endometrial cancer may be considered if the effect of treatment with inert lubricating gels or creams is not satisfactory.


#

HRT and the risk of ovarian cancer

Evidence-based recommendation 6.E23

Level of evidence 2a

Level of recommendation A

Level of consensus ++

Women who are considering HRT must be informed that ET or EPT may increase the risk of ovarian cancer. The effect may already appear when HRT is taken for less than 5 years and decreases again after hormone treatment is discontinued.


#

HRT after ovarian cancer

Evidence-based statement 6.S15

Level of evidence 2b

Level of consensus ++

It is not possible to make any statements about the safety of taking HRT after treatment for ovarian cancer.

Evidence-based recommendation 6.E24

Level of evidence 2b

Level of recommendation 0

Level of consensus +++

HRT may be used to treat women previously treated for ovarian cancer after they have been properly informed about the risks.


#

HRT and the risk of colorectal cancer

Evidence-based recommendation 6.E25

Level of evidence 2a

Level of recommendation A

Level of consensus +++

Women must be informed that HRT may reduce the risk of colorectal cancer. This must not be construed as an indication for the preventative use of HRT.


#
#

7  Primary ovarian insufficiency (POI)

Evidence-based recommendation 7.E26

Level of evidence 2b

Level of recommendation B

Level of consensus ++

Women with POI should be informed about the importance of taking hormones, either in the form of HRT or in the form of combined oral contraceptives (COCs), at least until the women reach the natural age of menopause and as long as taking HRT or COCs is not contraindicated for them.

Evidence-based statement 7.S16

Level of evidence 2b

Level of consensus ++

There is no clear-cut evidence that there is any difference in the efficacy of treatment with HRT compared to the efficacy of combined oral contraceptives.

The literature is listed in the long German-language version of this guideline.


#
#
#

Conflict of Interest/Interessenkonflikt

The conflicts of interest of the authors are listed in the long German-language version of this guideline./Die Interessenkonflikte der Autoren sind in der deutschen Langfassung der Leitlinie aufgelistet.

Correspondence/Korrespondenzadresse

Prof. Dr. med. Olaf Ortmann
Ärztlicher Direktor
Direktor der Klinik für Frauenheilkunde und Geburtshilfe
Lehrstuhl der Universität Regensburg
Caritas-Krankenhaus St. Josef
Landshuter Straße 65
93053 Regensburg
Germany   

Publication History

Received: 15 January 2021
Received: 02 December 2020

Accepted: 18 January 2021

Publication Date:
02 June 2021 (online)

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany