Dear pill-takers, friends, partners, parents, and doctors of the pill-takers,

I am writing you this letter to inform you about some effects the hormonal contraceptive, also referred to as the pill, may have on you. These effects are complex and therefore may affect your brain plasticity as well as your behavior which then may affect the behavior of people around you. I know that you may be thinking that this is crazy to think about, but please bear with me until I get into some research that has been done on the effects of hormonal contraceptives on cognitive function amongst others. First, I will provide you with a brief background on the structure of the pill. Then I will get into the effects of the pill on (1) cognition and (2) psychopathology and finish with some notions you might want to consider.  

First of all, it is important to touch base on the chemical properties of hormonal contraceptives. Most of the pills are made up from a combination of the artificial estrogen (ethinyl estradiol) and progestin (artificial version of progesterone) (Berg, 2015). Although most pills use the same artificial estrogen which is synthesized from actual estrogen, there are about ten different versions of artificial progestin that are used in the pill (Sitruk-Ware, 2006).These various types of progestins are grouped into four generations based on the specific molecules they are derived from. Therefore, each generation will probably have slightly different effects on you and the way you feel. Keep in mind that these effects are also very individual, and therefore it is important to find the right pill with the right generation that works for you which may take some time. So, be patient with yourself and keep a journal handy which can help you better figure out how you feel when you are on a certain type of the pill.  

In terms of the effects of the hormonal contraceptive on cognition, I would like to highlight some findings on spatial skills and verbal memory. First, spatial skills have been consistently associated to oral contraceptive use such that oral contraceptive with androgenic progestins (mainly found in the first and second generation of progestins) facilitate 3D mental rotation performance (Beltz et al., 2020; Gurvich et al., 2020; Peragine et al., 2020). There is also emerging evidence suggesting that spatial skills continue into later life. For instance, Egan and Gleason (2012) examined women from 40 – 65 years of age on spatial skills including visual-spatial ability. They found that the women who used hormonal contraceptives at some point in their lives had better spatial skills compared to the women who never used hormonal contraceptives. This was especially true when the use of hormonal contraceptives was 15 years or longer. Although there is some evidence for the link between hormonal contraceptive and spatial skills, future research should go beyond the androgenicity of progestins and direct effects of cognition.

Similarly to findings on spatial skills, hormonal contraceptives seem to increase verbal memory skills (Mordecai et al., 2008; Peragine et al., 2020). For example, (Karim and colleagues (2016) explored the effects of hormonal contraceptives on cognitive function, including verbal memory in menopausal women by measuring executive function, verbal episodic memory, and global cognition. The results revealed that women who had a history of hormonal contraceptive use demonstrated better verbal memory compared to women who had no history of hormonal contraceptive use. The users of hormonal contraceptives also demonstrated better general cognition including spatial skills amongst others. Similarly to the findings on spatial skills, the effects were even stronger when hormonal contraceptives were used for 10 years or longer.

Although there is a decent amount of converging evidence of the hormonal contraceptive’s effects on cognition, including both spatial skills and verbal memory, not many neuroimagining studies exploring these effects have been conducted, therefore not allowing us to gain a further understanding of the neural circuits underlying these effects. Some review articles looking at MRI method suggest that (para)hippocampal along with other temporal regions including fusiform gyrus are regulated by the use of hormonal contraceptives (Brønnick et al., 2020; B. Pletzer et al., 2014; B. A. Pletzer & Kerschbaum, 2014). In addition to MRI studies, some studies on numerical cognition, which is a sub-discipline of the cognitive science, were conducted, which demonstrated that the brain activation patterns of oral contraceptive users are similar to men (Pletzer et al., 2014). Again, these findings need to be interpreted with caution as there is still need of conducting more research with larger samples to build upon previous studies. Taken together, the hormonal contraceptives do in fact alter cognition and therefore you should keep this in mind when thinking about getting on the pill.

Not only that hormonal contraceptives affect cognition, but they also affect psychopathology. The research in this subfield has mainly focused on depression (major depressive disorder and dysthymia) and anxiety (and its relation to stress, which I discussed in a previous blog post: https://psych-neuro.com/2023/01/16/chill-pill-the-link-between-oral-contraceptive-and-stress-response/) (Beltz, 2022). Before I get into the research, it is important to note that the effects of hormonal contraceptives on depression and anxiety are complex and that family history of mood disorders also plays a role.

Prior to 2016, there was mixed evidence on the links between depression and hormonal contraceptives. In fact, Keyes et al. (2013) reported that use of hormonal contraceptives can protect against depression. However, a remarkable study conducted in Denmark disproved these findings. Skovlund and others (2016) compared hormonal contraceptives’ users to never users and found that women who used hormonal contraceptives were three times more likely to receive a depression diagnosis or antidepressant prescription. Specifically, the results suggested that women who used non-oral and progestin only hormonal contraceptives were at increased risk. Furthermore, women who initiated the use of hormonal contraceptives during adolescence (15-19 years of age), especially those who used IUD were also at an increased risk for depression. However, it is necessary to note that the risk for depression peaked within 6 months and then declined as much that the hormonal contraceptive users had reduced risk for depression compared to non-users after around 4 years. These findings are also consistent with Lundin and colleagues (2022) who also found that women using non-oral hormonal contraceptives, including IUDs, were at greater risk of developing depression. This was slightly more prevalent in adolescents. Two years later, Skovlund and others (2018) conducted a follow-up study which examined the associations of hormonal contraceptive with suicide attempts and suicides. The hormonal contraceptive users in the study initiated the use in adolescence. The results demonstrated that women using hormonal contraceptives were twice as likely to attempt suicide and triple as likely to commit a successful suicide compared to non-users. Congruent with Skovlund et al. (2016), non-oral users and adolescents (15-19 year-olds) were at the biggest risk. More recent studies also suggest that adolescent use of hormonal contraceptives prior to 19 years of age increases the prevalence of depression risk among women compared to non-users or users who initiated hormonal contraceptive use after 19 years of age (Anderl et al., 2020, 2022). One possible explanation for this link is due to adolescence being a period of increased neural sensitivity to sex hormones which may impact brain circuits that are associated with depression. These impacts may last into adulthood.

Luckily there are more neuroimaging studies of the effects of hormonal contraceptives on psychopathology than there is on cognition as mentioned above. Generally speaking, brain regions that are involved in emotion processing like amygdala, insula, and anterior cingulate cortex are altered by the exogenous ovarian hormones presented in hormonal contraceptives which affect the activation and deactivation of these brain regions and association with depression and anxiety development (Beltz, 2022).

Figure 1. Hormonal contraceptives (HC) influences on linear continua of cognition and psychopathology in the context of relative gender differences in those domains. Based on abstractions from the extant literature, red shows relative means for naturally cycling (NC) women, blue shows relative means for men, and yellow shading shows the range of potential means for HC users; there is a range because findings depend on HC formulations or administrations and on individual differences in effects across users. Dark yellow dots show hypothetical points of individual HC users, highlighting the variability and multidimensionality of effects. Based on previous research, men outpeform NC women in mental rotations, but HC women are better at mental rotations than NC women (first line). Women are better at verbal memory than men, but HC women tend to outperform NC women in verbal memory (second line). In terms of depression likelihood, HC users are between men and NC women which is evident in some past research on depression (third line). Taken from Beltz, 2022.

In conclusion, my intention of writing this letter is NOT to tell you to not use hormonal contraceptives, rather my intention is to provide you with some information on the effects of hormonal contraceptives on cognition and psychopathology that you may experience. Although hormonal contraceptives may increase your spatial skills and verbal memory, they may also increase the likelihood of you developing mood disorders like depression. On the other hand, keep in mind that every woman is different, including you and so there is a chance that none of these effects of hormonal contraceptives apply to you. So please take the information you learned from this letter and keep it in mind when you are making the decision of using hormonal contraceptives or switching from one type to another. 🙂

KJ

References

Anderl, C., Li, G., & Chen, F. S. (2020). Oral contraceptive use in adolescence predicts lasting vulnerability to depression in adulthood. Journal of Child Psychology and Psychiatry, 61(2), 148–156. https://doi.org/10.1111/jcpp.13115

Anderl, C., Wit, A. E., Giltay, E. J., Oldehinkel, A. J., & Chen, F. S. (2022). Association between adolescent oral contraceptive use and future major depressive disorder: A prospective cohort study. Journal of Child Psychology and Psychiatry, 63(3), 333–341. https://doi.org/10.1111/jcpp.13476

Beltz, A. M. (2022). Hormonal contraceptive influences on cognition and psychopathology: Past methods, present inferences, and future directions. Frontiers in Neuroendocrinology, 67, 101037. https://doi.org/10.1016/j.yfrne.2022.101037

Beltz, A. M., Kelly, D. P., & Berenbaum, S. A. (2020). Sex differences in brain and behavioral development. In Neural Circuit and Cognitive Development (pp. 585–638). Elsevier. https://doi.org/10.1016/B978-0-12-814411-4.00027-5

Beltz, A. M., Loviska, A. M., Kelly, D. P., & Nielson, M. G. (2022). The Link Between Masculinity and Spatial Skills Is Moderated by the Estrogenic and Progestational Activity of Oral Contraceptives. Frontiers in Behavioral Neuroscience, 15, 777911. https://doi.org/10.3389/fnbeh.2021.777911

Brønnick, M. K., Økland, I., Graugaard, C., & Brønnick, K. K. (2020). The Effects of Hormonal Contraceptives on the Brain: A Systematic Review of Neuroimaging Studies. Frontiers in Psychology, 11, 556577. https://doi.org/10.3389/fpsyg.2020.556577

Egan, K. R., & Gleason, C. E. (2012). Longer Duration of Hormonal Contraceptive Use Predicts Better Cognitive Outcomes Later in Life. Journal of Women’s Health, 21(12), 1259–1266. https://doi.org/10.1089/jwh.2012.3522

Gebel Berg, E. (2015). The Chemistry of the Pill. ACS Central Science, 1(1), 5–7. https://doi.org/10.1021/acscentsci.5b00066

Gurvich, C., Warren, A. M., Worsley, R., Hudaib, A.-R., Thomas, N., & Kulkarni, J. (2020). Effects of Oral Contraceptive Androgenicity on Visuospatial and Social-Emotional Cognition: A Prospective Observational Trial. Brain Sciences, 10(4), 194. https://doi.org/10.3390/brainsci10040194

Karim, R., Dang, H., Henderson, V. W., Hodis, H. N., St. John, J., Brinton, R. D., & Mack, W. J. (2016). Effect of Reproductive History and Exogenous Hormone Use on Cognitive Function in Mid- and Late Life. Journal of the American Geriatrics Society, 64(12), 2448–2456. https://doi.org/10.1111/jgs.14658

Keyes, K. M., Cheslack-Postava, K., Westhoff, C., Heim, C. M., Haloossim, M., Walsh, K., & Koenen, K. (2013). Association of Hormonal Contraceptive Use With Reduced Levels of Depressive Symptoms: A National Study of Sexually Active Women in the United States. American Journal of Epidemiology, 178(9), 1378–1388. https://doi.org/10.1093/aje/kwt188

Lundin, C., Wikman, A., Lampa, E., Bixo, M., Gemzell‐Danielsson, K., Wikman, P., Ljung, R., & Sundström Poromaa, I. (2022). There is no association between combined oral hormonal contraceptives and depression: A Swedish register‐based cohort study. BJOG: An International Journal of Obstetrics & Gynaecology, 129(6), 917–925. https://doi.org/10.1111/1471-0528.17028

Mordecai, K. L., Rubin, L. H., & Maki, P. M. (2008). Effects of menstrual cycle phase and oral contraceptive use on verbal memory. Hormones and Behavior, 54(2), 286–293. https://doi.org/10.1016/j.yhbeh.2008.03.006

Peragine, D., Simeon-Spezzaferro, C., Brown, A., Gervais, N. J., Hampson, E., & Einstein, G. (2020). Sex difference or hormonal difference in mental rotation? The influence of ovarian milieu. Psychoneuroendocrinology, 115, 104488. https://doi.org/10.1016/j.psyneuen.2019.104488

Pletzer, B. A., & Kerschbaum, H. H. (2014). 50 years of hormonal contraception—time to find out, what it does to our brain. Frontiers in Neuroscience, 8. https://doi.org/10.3389/fnins.2014.00256

Pletzer, B., Kronbichler, M., Nuerk, H.-C., & Kerschbaum, H. (2014). Hormonal contraceptives masculinize brain activation patterns in the absence of behavioral changes in two numerical tasks. Brain Research, 1543, 128–142. https://doi.org/10.1016/j.brainres.2013.11.007

Sitruk-Ware, R. (2006). New progestagens for contraceptive use. Human Reproduction Update, 12(2), 169–178. https://doi.org/10.1093/humupd/dmi046

Skovlund, C. W., Mørch, L. S., Kessing, L. V., Lange, T., & Lidegaard, Ø. (2018). Association of Hormonal Contraception With Suicide Attempts and Suicides. American Journal of Psychiatry, 175(4), 336–342. https://doi.org/10.1176/appi.ajp.2017.17060616

Skovlund, C. W., Mørch, L. S., Kessing, L. V., & Lidegaard, Ø. (2016). Association of Hormonal Contraception With Depression. JAMA Psychiatry, 73(11), 1154. https://doi.org/10.1001/jamapsychiatry.2016.2387