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

Key words

perimenopause - postmenopause - hormone (replacement) therapy - diagnosis - therapy - cancer risk - guideline

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

Therapeutic interventions

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

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

Urogenital atrophy

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

Overactive bladder

Recurrent urinary tract infections

3  Cardiovascular disease

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

Cerebrovascular events

Coronary heart disease

4  Osteoporosis

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

6  HRT and the risk of cancer

HRT and the risk of breast cancer

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

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

HRT after endometrial cancer

Vaginal ET after endometrial cancer

HRT and the risk of ovarian cancer

HRT after ovarian cancer

HRT and the risk of colorectal cancer

7  Primary ovarian insufficiency (POI)

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