Abstracts from the NIHR INVOLVE Conference 2017

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Advanced Ovarian Ageing: Studies on Fertility and Vascular Health

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

Prenatal famine, birthweight, reproductive performance and age at menopause: the Dutch hunger winter families study

STUDY QUESTION: Is there an association between acute prenatal famine exposure or birthweight and subsequent reproductive performance and age at menopause? SUMMARY ANSWER: No association was found between intrauterine famine exposure and reproductive performance, but survival analysis showed that women exposed in utero were 24% more likely to experience menopause at any age. WHAT IS KNOWN ALREADY: Associations between prenatal famine and subsequent reproductive performance have been examined previously with inconsistent results. Evidence for the effects of famine exposure on age at natural menopause is limited to one study of post-natal exposure. STUDY DESIGN, SIZE, DURATION: This cohort study included men and women born around the time of the Dutch famine of 1944–1945. The study participants (n = 1070) underwent standardized interviews on reproductive parameters at a mean age of 59 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were grouped as men and women with prenatal famine exposure (n = 407), their same-sex siblings (family controls, n = 319) or other men and women born before or after the famine period (time controls, n = 344). Associations of famine exposure with reproductive performance and menopause were analysed using logistic regression and survival analysis with competing risk, after controlling for family clustering. MAIN RESULTS AND THE ROLE OF CHANCE: Gestational famine exposure was not associated with nulliparity, age at birth of first child, difficulties conceiving or pregnancy outcome (all P> 0.05) in men or women. At any given age, women were more likely to experience menopause after gestational exposure to famine (hazard ratio 1.24; 95% CI 1.03, 1.51). The association was not attenuated with an additional control for a woman's birthweight. In this study, there was no association between birthweight and age at menopause after adjustment for gestational famine exposure. LIMITATIONS, REASON FOR CAUTION: Age at menopause was self-reported and assessed retrospectively. The study power to examine associations with specific gestational periods of famine exposure and reproductive function was limited. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support previous results that prenatal famine exposure is not related to reproductive performance in adult life. However, natural menopause occurs earlier after prenatal famine exposure, suggesting that early life events can affect organ function even at the ovarian level. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the NHLBI/NIH (R01 HL-067914). TRIAL REGISTRATION NUMBER: Not applicable

Association between vascular health and ovarian ageing in type 1 diabetes mellitus

STUDY QUESTION: Is vascular health associated with ovarian reserve status using type 1 diabetes mellitus (DM-1) as a model for vascular compromise? SUMMARY ANSWER: No conclusive evidence for an association between vascular health and ovarian ageing was found in women with DM-1. WHAT IS KNOWN ALREADY: The mechanism behind advanced ovarian ageing has not yet been elucidated. We hypothesize that vascular impairment precedes ovarian ageing. DM-1 is hallmarked by premature vascular complications that may consequently play a role in the rate of primordial follicle decline. STUDY DESIGN, SIZE, DURATION: A cross-sectional, patient-control study was performed in 150 premenopausal, regular cycling women with DM-1, as well as a reference population of 177 healthy, fertile women. PARTICIPANTS/MATERIALS, SETTING, METHODS: In a single-study visit, an inventory of both ovarian reserve and vascular status was carried out in the DM-1 group. A transvaginal ultrasound to calculate the antral follicle count (AFC) and blood sampling for anti-Müllerian hormone (AMH), lipids, C-reactive protein and HbA1c measurements were performed. Furthermore, vascular screening including measurements of blood pressure, flow-mediated dilation, peripheral arterial tonometry, pulse wave velocity, pulse wave analysis and intima-media thickness was carried out. The relative decrease in serum AMH levels in women with DM-1 compared with healthy references was investigated. MAIN RESULTS AND THE ROLE OF CHANCE: Systolic blood pressure was negatively correlated with both serum AMH (P= 0.006) and AFC (P= 0.004) in the DM-1 group. A non-linear relationship between HDL-cholesterol and serum AMH was found (P= 0.0001). No associations were detected between other vascular risk factors or vascular function tests and serum AMH or AFC in women with DM-1. With regard to the comparison of AMH levels between women with and without DM-1, mean AMH levels were 2.5 ± 1.9 ng/ml and 3.0 ± 2.8 ng/ml, respectively. After adjustment for confounders the difference in AMH levels between both groups appeared non-significant (fold change: 0.92, 95% confidence interval: 0.68-1.23). LIMITATIONS, REASON FOR CAUTION: The use of different AMH assays and the cross-sectional design may limit the interpretation of this study. WIDER IMPLICATIONS OF THE FINDINGS: The lack of evident association between vascular health and ovarian ageing may be the result of an insufficient vascular compromise in the relatively young, DM-1 group. STUDY FUNDING/COMPETING INTERESTS: No external funding was received for conducting or publishing this study. F.Y., W.S., A.F., F.L.J.V., M.J.C.E. and H.W.d.V. have nothing to disclose. F.J.M.B. has received fees and grant support from the following companies: Ferring, Gedeon Richter, Merck Serono, Medical Specialties Distributors and Roche. TRIAL REGISTRATION NUMBER: Not applicable

Serum AMH levels in women with a history of preeclampsia suggest a role for vascular factors in ovarian aging

Context: The association between early menopause and vascular disease as a possible causative factor has recently received attention. Preeclampsia (PE) is associated with future cardiovascular risk factors, and this premature vascular aging potentially modifies the ovarian aging process. OBJECTIVE: The purpose of this study was to assess whether women with a history of PE have lower anti-Mullerian hormone (AMH) levels than women with normotensive pregnancies. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted in a tertiary referral center. PATIENTS: Clinical data and blood samples of participants in the Preeclampsia Risk EValuation in FEMales study were used (336 women with a history of PE and 329 women after a normotensive pregnancy). Interventions: There were no interventions. MAIN OUTCOME MEASURES: The relative decrease in AMH levels was assessed after a median follow-up of 10.5 years. RESULTS: The mean AMH level was 2.00 +/- 1.87 mug/L in the PE group compared with 2.26 +/- 2.56 mug/L in the reference group. Linear regression analysis with censoring for undetectable AMH levels, adjusted for age, smoking, and hormonal contraceptive use, showed a relative reduction in AMH levels of 20.9% at any age (fold change 0.79, 95% confidence interval, 0.67-0.94). CONCLUSIONS: We demonstrate that women with a history of PE have significantly lower AMH levels than women with normotensive pregnancies. Calculations based on a reference population indicate advancement of reproductive age of approximately 1.5 years. Because PE is considered a manifestation of impaired vascular health, these results support the hypothesis that compromised vascular health could act as a causative mechanism in early ovarian aging

Age at menopause in women with type 1 diabetes mellitus : the OVADIA study

STUDY QUESTION: Is type 1 diabetes a determinant of advanced ovarian ageing, resulting in an early age at natural menopause? SUMMARY ANSWER: No clear evidence was provided that type 1 diabetes is a determinant of accelerated ovarian ageing resulting in an early menopause. WHAT IS KNOWN ALREADY: The association between type 1 diabetes and early menopause has been examined previously with inconsistent results. STUDY DESIGN, SIZE, DURATION: A cross-sectional study was performed in 140 post-menopausal women with, and 5426 postmenopausal women without, diabetes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Both women with and without diabetes had experienced natural menopause. Study participants filled out a standardized questionnaire including report of their age at last menstrual period. Differences in menopausal age were analysed using linear regression analyses, with adjustment for possible confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Mean age at natural menopause was 49.8 +/- 4.7 years in women with type 1 diabetes and 49.8 +/- 4.1 in women without diabetes. Linear regression analyses showed that type 1 diabetes was not associated with an earlier menopause compared with the reference group without diabetes, after adjustment for age, smoking history and parity (difference in age at menopause between women with type 1 diabetes and reference group 0.34 years, 95% confidence interval -0.34, 1.01). LIMITATIONS, REASON FOR CAUTION: Age at menopause was self-reported and assessed retrospectively. We had no information regarding microvascular complications therefore a possible association between vascular health and menopausal age could not be investigated. WIDER IMPLICATIONS OF THE FINDINGS: It has been hypothesized that the possible mechanism behind an accelerated ovarian ageing process in type 1 diabetes is prolonged poor glycaemic control and subsequent effects on vascular health. The improved glycaemic control during the last decades may have prevented vascular damage from occurring to an extent that would affect organ function. Nevertheless, the present findings are reassuring for reproductive health prospects in women with type 1 diabetes