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. 2016 Oct;45(5):1445-1457.
doi: 10.1093/ije/dyw147. Epub 2016 Aug 18.

Effects of Hormonal Contraception on Systemic Metabolism: Cross-Sectional and Longitudinal Evidence

Free PMC article

Effects of Hormonal Contraception on Systemic Metabolism: Cross-Sectional and Longitudinal Evidence

Qin Wang et al. Int J Epidemiol. .
Free PMC article


Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood.

Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24-49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception.

Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery.

Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation.

Keywords: amino acids; combined oral contraceptive pills; cytokines; fatty acids; hormonal contraception; hormones; inflammation; lipoproteins; metabolomics; progestin-only contraceptives; risk factors.


Figure 1.
Figure 1.
Cross-sectional associations of the use of combined oral contraceptive pills (COCPs) and progestin-only contraceptives (POCs) with 75 molecular measures. Non-users of any hormonal contraception were used as the reference group, so the association magnitudes denote the difference in each measure between hormonal contraceptive users and non-users. Association magnitudes are reported in standard deviation-units to ease the comparison across multiple measures. Associations were adjusted for age and meta-analysed for three independent population-based cohorts. In total, 1157 women using COCPs and 535 using POCs were compared with 4149 non-users of hormonal contraception. VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; C, cholesterol; FA, fatty acids; PUFA, polyunsaturated fatty acids; MUFA, monounsaturated fatty acids; SHBG, sex hormone-binding globulin. Open and closed symbols indicate P ≥ 0.0004 and P < 0.0004, respectively.
Figure 2.
Figure 2.
Longitudinal changes in molecular concentrations in response to starting, stopping and persistent use of combined oral contraceptive pills (COCPs). The 6-year metabolic changes for starting (n = 52), stopping (n = 94) and persistently using (n = 89) COCPs were compared with those of persistent non-users (n = 392) in the Young Finns Study (YFS) cohort. A null result for persistent users indicates metabolic changes consistent with those for the persistent non-users (i.e. changes that would occur with age or any secular event over the 6-years of follow-up) that is no further worsening effects were detected due to persistent use of COCPs. The marked changes for starters and stoppers, and their opposite directions, suggest that the metabolic effects were produced by starting to use COCPs and normalized by stopping the use. The longitudinal associations were adjusted for baseline age. Open and closed diamonds indicate P ≥ 0.0004 and P < 0.0004, respectively. Abbreviations are as for Figure 1.
Figure 3.
Figure 3.
Correlation between cross-sectional and longitudinal metabolic associations with the use of combined oral contraceptive pills (COCPs). The correspondence of cross-sectional associations with starting and stopping the use of COCPs is shown on the left and right panels, respectively. Each point represents a single metabolic measure. Horizontal and vertical grey lines denote 95% confidence intervals for the cross-sectional and longitudinal associations, respectively. The grey shaded areas serve to guide the eye for the slope. A linear fit of the overall correspondence summarize the match between cross-sectional and longitudinal associations, with R2 denoting the goodness of fit. A slope of ±1 and R2 = 1 would strongly support the causal effects of COCP use on the metabolic measures. Abbreviations are as for Figure 1.

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