Advanced Ovarian Ageing: Studies on Fertility and Vascular Health

Abstract

This thesis aims to identify patient characteristics and ovarian reserve markers that forecast pregnancy in women with advanced ovarian ageing and to investigate whether unfavourable cardiovascular health is associated with advanced ovarian ageing. Female reproductive ageing comprises the gradual decline in both oocyte quantity and quality will lead to four reproductive milestones, i.e. subfertility, sterility, menopausal transition and menopause. Female age has been identified as an important modulator of the reproductive ageing process, although the large inter-individual variation in normal ovarian ageing varies considerably, suggesting other factors may play a role. Women with a poor response in IVF or with elevated basal FSH levels, expressions of limited oocyte quantity, are suggested to have poor pregnancy prospects (an expression of poor oocyte quality), although reasonable pregnancy prospects have been published. The possible inconsistency between the quantity and quality of the primordial follicle pool as observed in women with advanced ovarian ageing evokes the question whether Anti-Mullerian Hormone (AMH) or patient characteristics can identify those women who still have acceptable pregnancy prospects. The large variation in normal ovarian ageing is also expressed by a considerable variation in age at normal menopause, covering a range from 40 to 60 years of age. Early menopause is associated with an increased risk of cardiovascular disease. However, recently it has been suggested that vascular health may act as cause instead of a consequence of menopause.

This thesis investigates whether markers of vascular ageing are associated with advanced ovarian ageing. Elucidation of these associations will create more understanding about the variation of the reproduction ageing process. The studies presented in this thesis focus on pregnancy forecasting based on information regarding quantitative ovarian reserve status, as well as the role of vascular health and unfavourable conditions during intra-uterine life in female reproductive ageing patterns. We studied these issues in several clinical cohorts, that serve as an extreme phenotype for compromised ovarian reserve, vascular health status or foetal environment.

In this thesis it was confirmed that there is a complex interplay between ovarian reserve quantity and quality. Female age plays an important role in the modulation of this interaction. Women with advanced ovarian ageing, as expressed by a poor response in IVF or elevated basal FSH levels, appear to be a heterogeneous group in which ovarian reserve tests, next to female age, may identify those women with reasonable pregnancy prospects. Future research will help us unravel the mechanisms behind the individual variation of ovarian ageing.

Furthermore, no conclusive evidence was found for an association between vascular health and the ovarian ageing process, using women with a history of preeclampsia, women with type 1 diabetes and women with exposure to prenatal famine as a model of compromised vascular health. To elucidate whether vascular compromise accelerates ovarian ageing, future studies would benefit from animal studies with an interventional design.