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A recent Quick Take examined a review article that suggested hormonal contraceptives are neither mood nor physiologically neutral. Should we be telling women with mental health vulnerabilities not to use hormonal contraception?
Let’s look at one of the articles featured in that review. This article is by Johannes Hertel and colleagues in a publication from Nature, where she and her colleagues conclude “oral contraceptives may cause effects analogous to chronic psychological stressors.” Well, that sounds concerning, and although we cannot suddenly start recommending against oral contraceptive pills, we need to keep an ear on.
Remember, chronically elevated cortisol is a marker of psychological stress, and oral contraceptives chronically increase cortisol. So, Dr. Hertel and colleagues dug down to see if oral contraceptives activate the molecular pathways of stress within the hypothalamic-pituitary-adrenal axis. Is there a mechanism for the observed increase in cortisol that matches the stress pathway? If so, are there downstream effects on the hypothalamus like the volume reductions associated with chronic stress? The answer is that we can see changes with oral contraceptives––that are the same changes one sees in chronic stress––at the level of the molecular controls in the hypothalamus
Moreover, the hypothalamus shows similar volume reductions in women taking oral contraceptives compared to those not taking oral contraceptives––changes seen in chronic stress. I think this is alarming. However, this is just 1 study, and some of their results were not replicated in a second cohort of women, although the results were still significant when the cohorts were combined.
Dr. Hertel and colleagues were looking at oral contraceptives and a particular molecule called *FKBP5––*a **gene activated in women taking oral contraceptives in the same way that it is activated in people with chronic stress. These are RNA transcript changes relative to women who are not taking oral contraceptives. They also looked at the subject’s genotype for FKBP5 because there is a version that has a T instead of a C at one particular spot––which has been repeatedly associated with vulnerability to childhood trauma. Although Hertel et al.’s findings did not strongly implicate the T allele in the effects of oral contraceptives, it was impressive how far down they were drilling in this molecular physiology. On the other end, they were using structural MRI to look at hippocampal volumes to find a reduction in volume associated with oral contraceptive use.
In summary, there is a hint here that oral contraceptives might pose a risk for some women beyond a transitory worsening of mood, into something more concerning, like long-term hippocampal changes. Dr. Hertel and colleagues suggest that genotyping for a woman’s FKBP5 alleles might identify––especially if there is a history of childhood trauma––women who might be at risk of depression when given an oral contraceptive. To my knowledge, genotyping is not currently available to clinicians, but I can imagine that it will become part of the updated packages offered by the genotyping laboratories. For now, I think these results might hint toward an answer to a clinical finding that has always puzzled me, namely, why some women get worse on oral contraceptives in terms of mood, while others do not at all––perhaps, there is a difference in their FKBP5 genotype and the interaction with oral contraceptives.
For more information, I would recommend skimming a review about FKBP5 by Zannas et al. that I have linked full text here at Psychopharmacology Institute. I think you will be astounded at how much is known about this protein and its implications for understanding trauma and mood.
Abstract
Evidence for Stress-like Alterations in the HPA-Axis in Women Taking Oral Contraceptives
Johannes Hertel, Johanna König, Georg Homuth, Sandra Van der Auwera, Katharina Wittfeld, Maik Pietzner, Tim Kacprowski, Liliane Pfeiffer, Anja Kretschmer, Melanie Waldenberger, Gabi Kastenmüller, Anna Artati, Karsten Suhre, Jerzy Adamski, Sönke Langner, Uwe Völker, Henry Völzke, Matthias Nauck, Nele Friedrich, Hans Joergen Grabe
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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Reference
Hertel, J., König, J., Homuth, G., Van der Auwera, S., Wittfeld, K., Pietzner, M., Kacprowski, T., Pfeiffer, L., Kretschmer, A., Waldenberger, M., Kastenmüller, G., Artati, A., Suhre, K., Adamski, J., Langner, S., Völker, U., Völzke, H., Nauck, M., Friedrich, N., … Grabe, H. J. (2017). Evidence for stress-like alterations in the HPA-axis in women taking oral contraceptives. Scientific Reports, 7(1)
Related Reference
Zannas, A. S., Wiechmann, T., Gassen, N. C., & Binder, E. B. (2016). Gene–stress–epigenetic regulation of FKBP5: clinical and translational implications. Neuropsychopharmacology, 41(1), 261-274.
