LIST OF TABLES………18

TABLE OF CONTENTS

REMERCIEMENTS (Acknowledgments in French)………8

LIST OF ABBREVIATIONS.………..14

LIST OF TABLES………18

LIST OF FIGURES………..18

RESUME (French abstract)………..19

ABSTRACT………..20

OUTLINE OF THE THESIS………21

Part 1. INTRODUCTION……….22

1.A. Breast cancer incidence and mortality rates………..22

1.B. Breast cancer risk and protective factors (this part is submitted as two review articles)..23

1.B.1. Lifestyle-related breast cancer risk and protective factors………27

Overweight and obesity………..33

Weight changes………37

Hyperinsulinemia………39

Hyperglycemia……….39

High circulating levels of insulin growth factor-1………39

Diabetes………40

Tobacco………41

Alcohol……….42

Menopausal hormone therapy………...43

Oral contraception………..43

Night shift work………...44

Breastfeeding………...45

Parity………46

Age at first birth………..46

Physical activity………...46

Dietary factors……….47

Diagnostic radiation………50

Medications………..51

1.B.2. Unchangeable breast cancer risk and protective factors………...57

Age………61

Gender………..61

Race / Ethnicity………...61

Height………...62

Endogenous sex hormones……….62

Age at menarche………..63

Age at menopause………...64

Exposure to ionizing radiation………...64

Mammographic density………..65

Benign breast diseases………67

In situ breast carcinoma……….67

Personal history of invasive breast cancer………68

Family history of invasive breast cancer………...69

Gene mutations………69

Bone mineral density………..71

Others………...71

1.B.3. Conclusions on breast cancer risk and protective factors……….73

1.C. Menopausal hormone therapy: Historical perspective, definition and indications...75

1.C.1. History of menopausal hormone therapy………...75

1.C.2. Definition of menopausal hormone therapy………...77

1.C.3. Current indications for menopausal hormone therapy………..78

Menopausal symptoms………...78

Genito-urinary syndrome of menopause………..78

Bone loss………...79

Others………...80

1.C.4. Actual guidelines on menopausal hormone therapy use………81

1.D. Menopausal hormone therapy and breast cancer risk………...88

1.D.1. Women Health Initiative studies………88

1.D.2. The “Million Women Study”………..91

1.D.3. The E3N study………93

1.D.4. Other studies………..96

1.D.5. Tibolone…….………..…100

1.D.6. Comments and summary on the risk of breast cancer associated with menopausal hormone therapy and tibolone use………..102

1.E. Non-hormonal therapies for menopausal symptoms………..………….115

1.E.1. Vasomotor symptoms………115

Non-hormonal drugs……….115

Complementary alternative medicine……….118

Other alternatives……….121

1.E.2. Genito-urinary syndrome of menopause………..122

Vaginal moisturizers and lubricants………...122

Fractional CO

vaginal laser and low-energy dynamic quadripolar radiofrequency…122

1.E.3. Conclusions on non-hormonal therapies for menopausal symptoms………...123

Part 2. OWN RESEARCH………..124

2. A. Objectives of the research………..124

2.B. Published articles……….125

2.B.1. Published articles on the analysis of the changes in BC incidence and MHT sales…125 Study 1: Evolution of breast cancer incidence in relation to hormone replacement therapy use in Belgium……….125

Study 2: Update of the evolution of breast cancer incidence in relation to hormone replacement therapy use in Belgium………...126

Study 3: Systematic review about breast cancer incidence in relation to hormone replacement therapy use………...127

Study 4: Menopausal hormone therapy use in 17 European countries during the last decade……….128

Study 5: Menopausal hormone therapy use in relation to breast cancer incidence in 11 European countries………...129

2.B.2. Published article on the impact of menopausal hormone therapy on breast cancer prognostic factors………...130

Study 6: Influence of HRT on prognostic factors for breast cancer: a systematic review after the Women's Health Initiative trial………130

2.B.3. Published articles on the medical support for climacteric symptoms in breast cancer patients………131

Study 7: Safety of hormone therapy after breast cancer: a qualitative systematic review……….131

Study 8: Safety of alternative treatments for menopausal symptoms after breast cancer:

a qualitative systematic review………132

Study 9: A survey among breast cancer survivors: treatment of the climacteric after

breast cancer………..………133

Study 10: Treatment of climacteric symptoms in breast cancer patients: a retrospective

study from a medication databank………..………134

Part 3. GENERAL DISCUSSION………..135

3.A. The influence of menopausal hormone therapy on breast cancer………...135

3.A.1. Trends in breast cancer incidence and menopausal hormone therapy sales………...135

3.A.2. The influence of menopausal hormone therapy on breast cancer characteristics and

mortality………..142

Menopausal hormone therapy use and breast cancer characteristics……….142

Menopausal hormone therapy use and breast cancer mortality………..149

3.B. The safety and prevalence of use of menopausal treatments in breast cancer patients...153

Part 4. CONCLUSIONS……….165

Part 5. REFERENCES………168