INDEX
SUMMARY………6
1.INTRODUCTION………...8
1.1. Ovarian reserve, ovarian ageing and menopause………..8
1.2. Premature ovarian insufficiency ……….17
1.2.1. Definition and prevalence……….17
1.2.2. Physiopathologic mechanisms………18
1.2.3. Etiology………20
1.2.4. Genetic causes………22
1.2.4.1. The X Chromosome……….22
1.2.4.2. Autosomes………31
1.2.5. Reproductive implications……….42
2.OBJECTIVES………48
2.1. Identification of new genes involved in the development of POI 2.2. Characterisation of the different options of assisted reproduction technologies (ART) in patients with genetic risk of developing POI 3.METHODS AND MATERIALS………..48
4.RESULTS AND DISCUSSION……….50
4.1. Genetic factors implicated in the development of idiopathic POI………50
4.1.1. Cohort of POI patients and controls at the Hôpital Erasme………..50
4.1.2. Candidate genes: DNA sequencing results and discussion……….50
-‐ FSHR………..51
-‐ GDF9……….52
-‐ AMHR2……….53
-‐ BMP15 (Paper 1: Variants of the BMP15 gene in a cohort of patients with premature ovarian failure)………55
-‐ AMH (Paper 2: AMH mutations with reduced in vitro bioactivity are related to POI)……….57
4.2. Reproductive outcome in patients with a known genetic factor associated with POI……59
4.2.1. Pregnancy outcome after oocyte donation in patients with genetic POI:
Patients with Turner syndrome and partial X monosomy (Paper 3: Pregnancy outcome after oocyte donation in patients with Turner’s syndrome and partial X monosomy)……….59
4.2.2. Fertility preservation in patients with genetic risk of premature ovarian insufficiency: characteristics of the first requests at the Hôpital Erasme………..60 4.2.3. Discussion……….61
5.CONCLUSIONS AND PERSPECTIVES………..65
6.SUPPLEMENTARY DATA………74
7.BIBLIOGRAPHY………78
