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. 2017 Oct 26;7(1):14111.
doi: 10.1038/s41598-017-13927-7.

Evidence for Stress-like Alterations in the HPA-Axis in Women Taking Oral Contraceptives

Johannes Hertel  1   2 , Johanna König  3 , Georg Homuth  4 , Sandra Van der Auwera  3   5 , Katharina Wittfeld  5 , Maik Pietzner  6   7 , Tim Kacprowski  7   4 , Liliane Pfeiffer  8   9 , Anja Kretschmer  8   9 , Melanie Waldenberger  8   9 , Gabi Kastenmüller  10 , Anna Artati  11 , Karsten Suhre  10   12 , Jerzy Adamski  11   13   14 , Sönke Langner  15 , Uwe Völker  7   4 , Henry Völzke  7   16 , Matthias Nauck  6   7 , Nele Friedrich  6   7   17 , Hans Joergen Grabe  3   5
Affiliations

Evidence for Stress-like Alterations in the HPA-Axis in Women Taking Oral Contraceptives

Johannes Hertel et al. Sci Rep. .

Abstract

Using oral contraceptives has been implicated in the aetiology of stress-related disorders like depression. Here, we followed the hypothesis that oral contraceptives deregulate the HPA-axis by elevating circulating cortisol levels. We report for a sample of 233 pre-menopausal women increased circulating cortisol levels in those using oral contraceptives. For women taking oral contraceptives, we observed alterations in circulating phospholipid levels and elevated triglycerides and found evidence for increased glucocorticoid signalling as the transcript levels of the glucocorticoid-regulated genes DDIT4 and FKBP5 were increased in whole blood. The effects were statistically mediated by cortisol. The associations of oral contraceptives with higher FKBP5 mRNA and altered phospholipid levels were modified by rs1360780, a genetic variance implicated in psychiatric diseases. Accordingly, the methylation pattern of FKBP5 intron 7 was altered in women taking oral contraceptives depending on the rs1360780 genotype. Moreover, oral contraceptives modified the association of circulating cortisol with depressive symptoms, potentially explaining conflicting results in the literature. Finally, women taking oral contraceptives displayed smaller hippocampal volumes than non-using women. In conclusion, the integrative analyses of different types of physiological data provided converging evidence indicating that oral contraceptives may cause effects analogous to chronic psychological stressors regarding the regulation of the HPA axis.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Oral Contraceptives (OC) and metabolites (n = 230). (A) Relationship between Cortisol levels (Y-axis) and the time of blood sampling (X-axis) for OC users (red) and non OC users (blue) with non-linear regression line. (B) Box plots for circulating cortisol levels stratified for OC use and rs1360780 genotype. The main effect of OC intake (b = 0.92 95%-(CI): (0.75; 1.09), p = 6.734e-22) is not significantly modified by the rs1360780 genotype (b = 0.24, 95%-CI: (−0.18; 0.66), p = 0.259). (C) Scatter plot of the first two principle components (PCs) of the significantly associated phospholipids for OC users (red) and non OC users (blue) (D) Box plots for 2-Linoleoylglycerophosphocholine levels stratified for OC use and rs1360780 genotype. The main effect of OC intake (b = −0.24,95%-CI: (−0.39; −0.10), p = 0.001) is modified by the rs1360780 genotype (b = 0.63, 95%-CI:(0.26; 1.01), p = 0.001).
Figure 2
Figure 2
Oral Contraceptives (OC) and Glucocorticoid induced whole-blood transcript levels (n = 226). (A) DDIT4 transcript levels (quantile normalized residuals) against circulating cortisol levels for OC users (red) and no OC user (blue) (B) FKBP5 transcript levels (quantile normalized residuals) against circulating cortisol levels for OC users (red) and no OC user (blue) (C) FKBP5 transcript levels stratified for OC usage and rs1360780 genotype. An interaction between genotype and OC usage was observable (b = −0.34, 95%-CI: (−0.61; −0.08), p = 0.011). (D) DDIT4 transcript levels stratified for OC usage and rs1360780 genotype. No interaction between genotype and OC usage was observable (b = −0.01, 95%-CI: (−0.25; 0.23), p = 0.962).
Figure 3
Figure 3
OC intake and mean DNA methylation levels on five CpG sites in intron 7 of FKBP5. (A) Boxplots stratified for OC intake and the rs1360780 genotype. The effects of OC taking are modified by the rs1360780 genotype (OR = 1.23, 95%-CI: 1.00–1.53, p = 0 0.045). (B) Scatter plots CTQ score vs DNA methylation levels with corresponding regression lines stratified for OC intake and rs1360780 genotype (TT carrier red; GT/GG carrier blue). The regression lines in tendency do not have the same slope (OR = 1.03, 95%-CI: (1.00; 1.06), p = 0.074).
Figure 4
Figure 4
OC intake and clinical questionnaire scores (n = 230 for BDI-II, n = 200 for CTQ). (A) Scatter plot BDI-II scores (y-axis) vs. circulating cortisol levels (X-axis) with corresponding regression lines stratified for OC intake. The slopes of the regression lines were significantly different (b = 2.98, 95%-CI: (0.32; 5.64), p = 0.028). (B) Box plots for BDI-II scores stratified for OC intake and rs1360780 genotype with no interaction present between OC intake and the rs1360780 genotype (b = −0.05, 95%-CI: (−5.09; 4.98), p = 0.984). (C) Scatter plot CTQ scores (y-axis) vs. circulating cortisol levels (X-axis) with corresponding regression lines stratified for OC intake. The slopes of the regression lines were not significantly different (b = 1.01, 95%-CI: (−4.12; 6.14), p = 0.699). (D) Box plots for CTQ scores stratified for OC intake and rs1360780 genotype with no interaction present between OC intake and the rs1360780 genotype (b = 0.31, 95%-CI: (−7.06; 7.68), p = 0.934).
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References

    1. World Health Organization. 19th WHO Model List of Essential Medicines (2015).
    1. United Nations, Department of Economic and Social Affairs, Population Division. Trends in Contraceptive Use Worldwide 2015. (ST/ESA/SER.A/349) (2015).
    1. Oinonen KA, Mazmanian D. To what extent do oral contraceptives influence mood and affect? Journal of affective disorders. 2002;70:229–240. doi: 10.1016/S0165-0327(01)00356-1. - DOI - PubMed
    1. Young EA, et al. Influences of hormone-based contraception on depressive symptoms in premenopausal women with major depression. Psychoneuroendocrinology. 2007;32:843–853. doi: 10.1016/j.psyneuen.2007.05.013. - DOI - PMC - PubMed
    1. Zethraeus N, et al. A first-choice combined oral contraceptive influences general well-being in healthy women: a double-blind, randomized, placebo-controlled trial. Fertility and sterility. 2017;107:1238–1245. doi: 10.1016/j.fertnstert.2017.02.120. - DOI - PubMed

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