The ageing ovary and uterus: new biological insights

Abstract

BACKGROUND Advanced maternal age is associated with reduced fertility and adverse pregnancy outcomes. This review details recent developments in our understanding of the biology and mechanisms underlying reproductive ageing in women and the implications for fertility and pregnancy. METHODS Sociological online libraries (IBSS, SocINDEX), PubMed and Google Scholar were searched for relevant demographic, epidemiological, clinical and biological studies, using key words and hierarchical MeSH terms. From this, we identified and focused on key topics where it was judged that there had been clinically relevant advances in the understanding of ovarian and uterine ageing with implications for improved diagnostics and novel interventions. RESULTS Mapping of the ovarian reserve, follicular dynamics and associated biomarkers, across the reproductive lifespan has recently been performed. This now allows an assessment of the effects of environmental, lifestyle and prenatal exposures on follicular dynamics and the identification of their impact during periods of germ cell vulnerability and may also facilitate early identification of individuals with shorter reproductive lifespans. If women choose to time their family based on their ovarian reserve this would redefine the meaning of family planning. Despite recent reports of the potential existence of stem cells which may be used to restore the primordial follicle and thereby the oocyte pool, therapeutic interventions in female reproductive ageing at present remain limited. Maternal ageing has detrimental effects on decidual and placental development, which may be related to repeated exposure to sex steroids and underlie the association of ageing with adverse perinatal outcomes. CONCLUSIONS Ageing has incontrovertible detrimental effects on the ovary and the uterus. Our enhanced understanding of ovarian ageing will facilitate early identification of individuals at greatest risk, and novel therapeutic interventions. Changes in both ovary and uterus are in addition to age-related co-morbidities, which together have synergistic effects on reducing the probability of a successful pregnancy outcome.

Figure 1

Maternal mortality rates by age group (years); UK: 2006–2008. Reproduced with permission from Cantwell et al. (2011).

Figure 2

Decline in primordial follicle pool with increasing age. The best model for the establishment of the NGF population after conception, and the subsequent decline until age at menopause as described by an asymmetric double Gaussian cumulative model with parameters = 5.56 (95% CI 5.38–5.74), =25.6 (95% CI 24.9–26.4), =52.7 (95% CI 51.1–54.2), =0.074 (95% CI 0.062–0.085) and =24.5 (95% CI 20.4–28.6). The figure shows the dataset (n = 325), the model, the 95% prediction limits of the model and the 95% CI for the model. The horizontal axis denotes age in months up to birth at age zero, and age in years from birth to 51 years. Reproduced with permission from Wallace and Kelsey (2010).

Figure 3

Mechanisms underlying activation of quiescent follicles. A summary of some of the components of the PI3K pathway that have been implicated in maintaining health of the primordial pool (black bar) and either suppressing (orange bar) or activating (green arrow) the initiation of growth. These details have been gathered through knockout mouse models (see Reddy et al., 2010 for review).

Figure 4

Comparison of serum AMH concentrations with NGF population and with NGF recruitment. The red line is the log-unadjusted validated AMH model (Kelsey et al., 2012), peaking at 24.5 years. The blue line denotes the decline in NGF population (Wallace and Kelsey, 2010), with peak population at 18–22 weeks gestation. The green line denotes the numbers of NGFs recruited towards maturation population (Wallace and Kelsey, 2010), with peak numbers lost at age 14.2 years on average. Each quantity has been normalized so that the peak occurs at 100%. Correlation coefficients (r) are given for AMH concentrations against the other two curves for birth to 24.5 years and for 24.5–51 years. Reproduced with permission from Kelsey et al. (2012).

Figure 5

Maternal age and the risk of Caesarean delivery, duration of spontaneous labour and operative vaginal delivery. Top panel: proportion of women delivered by emergency intrapartum Caesarean section in relation to the age (years) of the mother (n = 583 847). The bars are binomial 95% CIs. Middle panel: mean duration of spontaneous labour in relation to maternal age (n = 409,703). The bars are 95% CIs of the mean. Bottom panel: proportion of nulliparous women who required operative vaginal delivery in relation to maternal age among the 518 787 women delivered by a means other than emergency Caesarean section. The bars are binomial 95% CIs. Reproduced with permission from Smith et al. (2008).