Research highlight: Investigating the metabolomics of menopause

Wang et al. Metabolic characterization of menopause: cross-sectional and longitudinal evidence. BMC Medicine 2018. DOI:https://doi.org/10.1186/s12916-018-1008-8

With the global population becoming older, there’s an increasing need to understand the complex biological mechanisms related to ageing. Whilst many studies have investigated the relationship between ageing-related diseases and chronological age, researchers are now using metabolic profiling to help them to identify the detailed metabolic changes that underpin biological ageing. Menopause is a particularly important subject for study as it represents a distinct age-related event that can provide us with valuable insights into age-related disease risk and health over life-course. For example, premature menopause has been linked to an increased risk of osteoporosis, cardiovascular disease, diabetes and premature mortality.(1) 

Previous studies have shown that post-menopausal women are at a higher cardiometabolic risk than those who are pre-menopausal, displaying adverse changes in metabolic health when measured. In order to determine if these changes are due to chronological ageing or ovarian ageing, Wang and colleagues explored both cross-sectional and longitudinal associations of reproductive status with 74 metabolic biomarkers (73 of which were measured using Nightingale’s NMR-based blood biomarker analysis). 

In the cross-sectional study, 3,312 midlife British women participating in the ALSPAC study were assessed by reproductive status and grouped into three groups based on STRAW criteria: Pre-menopausal (N= 2031 at baseline), Menopausal transition (N= 620 at baseline) and Post-menopausal (N= 661 at baseline).(2) After excluding women who had experienced a surgical menopause, used hormonal contraception or hormone replacement therapy (HRT), the remaining 1,492 women with completed information on STRAW data and metabolic profiles were followed-up for longitudinal analyses and classified into one of six mutually exclusive reproductive-status groups based on the STRAW criteria. 

Consistent results from the study showed that transition to menopause induces a wide variety of metabolic changes independent of chronological ageing. In the cross-sectional analyses, post-menopausal women had higher concentrations of intermediate density lipoprotein (IDL) and low-density lipoprotein (LDL) lipid measures compared to those who were pre-menopausal. In addition, their fatty acid concentrations as well as several non-lipid measures were increased. In contrast, merely minor metabolic differences were observed between women in the pre-menopausal transition and in pre-menopausal stage. 

In the longitudinal follow-up analyses, metabolic changes were observed to occur during the transition period from pre- to post- menopause, independent of underlying age trajectory. These metabolic alterations were found to include increased concentrations of very small very low-density lipoproteins (VLDLs), LDLs, apolipoprotein-B, remnant and LDL cholesterol, and reduced LDL particle size. These changes towards an atherogenic lipid profile were found to be broadly consistent with the associations patterns identified in the cross-sectional analyses, predisposing post-menopausal women to increased risk of cardiovascular diseases. Interestingly, post-menopausal women also exhibited a decreased proportion of saturated fatty acids, and higher concentrations of glutamine, valine, albumin, acetate and glycoprotein acetyls (GlycA), whereas C-reactive protein levels were not associated with reproductive status. GlycA is particularly notable as it is a biomarker of low-grade chronic inflammation and has been associated with increased risk of type 2 diabetes, cardiovascular diseases and all-cause mortality. Taken together, these results suggest that the observed metabolic changes were due to the effect of reproductive-status change over and above age-related changes.

In conclusion, these findings provide evidence that further supports our understanding of the metabolic characterization of menopause and suggest that these metabolic changes are independent of age and may, thus, reflect sex and gonadotropin hormonal changes relating to the menopausal transition. In addition, the results potentially underlie the relationship between menopause and cardiometabolic diseases. Detailed metabolic profiling will enable to distinguish those women with increased risk for developing cardiovascular disease during post-menopausal life. Understanding the molecular changes that occur during the menopausal transition may lead to applications of lifestyle interventions and therapeutic opportunities to diminish the adverse metabolic effects on these women. 

In this study, Nightingale’s blood biomarker analysis service was used to quantify 73 lipid and metabolite measures for 3,312 midlife women and a subgroup of 1,492 women at follow-up after 2.5 years. Nightingale’s NMR-based metabolomics platform has been successfully used in a wide range of research applications and has featured in over 150 peer-reviewed studies. 

Further reading

Access the full paper here and learn more about how metabolomics has been used to explore biological ageing in our interview with Professor Eline Slagboom here.

References: 

1. Muka et al. Association of Age at Onset of Menopause and Time Since Onset of Menopause With Cardiovascular Outcomes, Intermediate Vascular Traits, and All-Cause Mortality A Systematic Review and Meta-analysis. JAMA Cardiology 2016;1(7):767-776

2. Harlow et al. Executive summary of the stages of reproductive aging workshop + 10: addressing the unfinished agenda of staging reproductive aging. Journal of Clinical Endocrinology Metabolism 2012;97:1159–68. 

3. Wang et al. Metabolic characterization of menopause: cross-sectional and longitudinal evidence. BMC Medicine 2018 Doi: 10.1186/s12916-018-1008-8

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