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Medicine

The Contraceptive Brain Drain: How Birth Control Alters Women’s Brains

April 2, 2023 by Divya Bhargava '26

There are millions of women taking steroids every day. But how is this possible? Are they just getting really buff? It feels like we always hear stories about how performance-enhancing drugs, namely steroids, are giving world-class athletes the boost they need to beat out their competition. But women across the globe are taking steroids every day as well, in the form of hormonal birth control. Despite their widespread use, side effects of hormonal contraceptives are largely unstudied, or have been until recently. In the last ten years, several studies have come out about the effect of taking a daily dose of steroids on women’s brains and mental health, which until now has been a severely neglected area where lack of knowledge affects millions of people worldwide. 

People take hormonal birth control, or hormonal contraceptives, for a myriad of reasons, from the obvious (preventing pregnancy) to the not-so-obvious (lessening iron deficiency) and everything in between. This type of medication simply refers to methods of pregnancy prevention that act on the endocrine system. The endocrine system controls growth, development, metabolism, and reproduction via signaling molecules called hormones. Two hormones in particular, estrogen and progesterone, control the menstrual cycle and are therefore the major components of hormonal birth control. Types of hormonal contraceptives come in many forms including the pill, the patch, the implant, injections, and hormonal intrauterine devices or IUDs, but despite the wide variety in the forms this medication takes, all of them contain one or both of these two hormones. As steroids, both estrogen and progesterone affect other body systems besides the reproductive system.

To study the impacts of taking a daily dose of steroids on other areas of the body, specifically the brain, Dr. Belinda Pletzer and her colleagues conducted a study in 2010. The brain is particularly susceptible to change due to an influx of synthetic hormones because it contains a very high quantity of hormone receptors. The brain needs to act as a “sponge” for these molecules since it plays an important role in creating the appropriate responses in the rest of the body. Pletzer’s study investigated how the sponginess of the brain would affect changes in its structure by comparing images of the brains of adult men, adult women during different stages of their menstrual cycle, and adult women taking hormonal contraceptives. To perform this comparison they used a technique called voxel-based morphology on MRIs of study participants (Pletzer et al., 2010). Voxel-based morphology measures differences in the concentration of tissue and the size and shape of different areas of the brain.

Overall, they found that women taking hormonal birth control had smaller areas of gray matter, or areas of the brain that have a high concentration of the cell bodies of nerve cells, when compared to “naturally cycling women” in both their follicular and luteal menstrual phases (Figure 1). Pletzer’s study also found interesting gendered differences in gray matter volume. While men had greater gray matter overall, the volume of gray matter in the prefrontal cortex, the pre-and postcentral gyri, and the supramarginal gyrus of both naturally cycling women and women taking hormonal contraceptives was higher than the volume of gray matter in these areas in men (Figure 2). These areas are involved in decision-making and problem-solving, controlling motor function, and emotional responses. However, the higher amount of gray matter in women in these areas was overshadowed by the larger volume of gray matter in men in the hippocampus, hypothalamus, parahippocampal and fusiform gyri, putamen, pallidum, amygdala, and temporal regions of the brain during the early follicular phase (A), mid-luteal phase (B), and in women taking hormonal birth control (C) (Figure 2). Many of these areas of reduced gray matter are ones of high importance for neurophysical ability and mental health.

Additionally, a study done by Rush University Medical Center showed an association between higher levels of gray matter and better cognitive function (“Everyday Activities Associated with More Gray Matter in Brains of Older Adults”). These findings suggest that taking birth control, and the associated decrease in gray matter, could be directly causing some of the symptoms women on hormonal contraceptives experience, such as brain fog, mood changes, and even anxiety and depression. For example, a smaller hypothalamus, one of the areas of decreased gray matter, is associated with heightened irritability and depression symptoms (“Study Finds Key Brain Region Smaller in Birth Control Pill Users”). Pletzer’s research and the work of others after her on the impact of birth control on structures of the brain represent important first steps in proving a causative relationship between birth control, symptoms associated with it, and structural changes in the brain.

Although this research has made some crucial preliminary steps into researching how taking a daily dose of steroids affects the brains of women taking hormonal contraceptives, the highly complex nature of the brain and its relationship with the regulation of the rest of the body means that further research is necessary. The sheer number of people that this issue affects means that it is essential to continue researching the impacts of this widely used drug. More importantly, knowing the potentially serious negative side effects enables millions of people to make more informed decisions concerning their health and their bodies.

 

Works Cited

Rush University Medical Center. (2018, February 14). Everyday activities associated with more gray matter in brains of older adults: Study measured amount of lifestyle physical activity such as house work, dog walking and gardening. ScienceDaily. Retrieved March 11, 2023 from www.sciencedaily.com/releases/2018/02/180214093828.htm.

Lewis, C. A., Kimmig, A. C. S., Zsido, R. G., Jank, A., Derntl, B., & Sacher, J. (2019). Effects of hormonal contraceptives on mood: a focus on emotion recognition and reactivity, reward processing, and stress response. Current psychiatry reports, vol. 21, no.11, 2019, p 115. PubMed Central, https://doi.org/10.1007/s11920-019-1095-z.

Meyer, Craig H., Kinsley, Elizabeth A. “Women’s Brains on Steroids.” Scientific American, https://www.scientificamerican.com/article/womens-brains-on-steroids/. Accessed 7 Mar. 2023.

Nemoto, Kiyotaka. “[Understanding Voxel-Based Morphometry].” Brain and Nerve = Shinkei Kenkyu No Shinpo, vol. 69, no. 5, May 2017, pp. 505–11. PubMed, https://doi.org/10.11477/mf.1416200776.

Pletzer, Belinda, et al. “Menstrual Cycle and Hormonal Contraceptive Use Modulate Human Brain Structure.” Brain Research, vol. 1348, Aug. 2010, pp. 55–62. ScienceDirect, https://doi.org/10.1016/j.brainres.2010.06.019.

Sharma, Rupali, et al. “Use of the Birth Control Pill Affects Stress Reactivity and Brain Structure and Function.” Hormones and Behavior, vol. 124, Aug. 2020, p. 104783. ScienceDirect, https://doi.org/10.1016/j.yhbeh.2020.104783.

“Study Finds Key Brain Region Smaller in Birth Control Pill Users.” ScienceDaily, https://www.sciencedaily.com/releases/2019/12/191204090819.htm. Accessed 7 Mar. 2023.

Filed Under: Biology, Psychology and Neuroscience, Science Tagged With: Biology, Birth control, Medicine, Women's health

Teplizumab: A New Breakthrough in the Treatment of Type 1 Diabetes

April 2, 2023 by Blythe Thompson '26

     In Ancient Egypt, a diet of whole grains was prescribed to patients with frequent urination and emaciation (History of diabetes, 2020).  This condition, similarly documented by physicians in Ancient Greece, was likely first called “diabetes” by Apollonius of Memphis in the third century BCE. By the fifth century CE, type 1 diabetes had been differentiated from type 2, and in 1776, English physician Matthew Dobson confirmed the presence of excess glucose in the urine of diabetic patients. Canadian physician Frederick Banting and his colleagues successfully used insulin injections to treat a diabetic patient in 1922; this remains the predominant method of treatment today. Another milestone was reached this past November, when the drug Teplizumab (under the name Tzield) gained FDA approval. Teplizumab showed potential in delaying the onset of clinical type 1 diabetes in adults and pediatric patients 8 years and older who have not yet developed the condition (Commissioner of the FDA, 2022). 

     Type 1 diabetes, otherwise known as juvenile diabetes or insulin-dependent diabetes, is a form of diabetes mellitus in which a deficiency of insulin causes hyperglycemia (high blood sugar). It is referred to as “juvenile diabetes” because the symptoms of the condition typically appear in adolescence and is the result of an autoimmune disorder. The onset of type 1 diabetes depends on environmental factors that interact with predisposing genes to induce a long-term autoimmune attack against the pancreatic β cells, the insulin-producing cells of the pancreatic islets of Langerhans (de Beeck and Eizrik, 2018). 

     When left untreated, juvenile diabetes poses serious health risks. The buildup of sorbitol—a sugar alcohol that is manufactured from glucose—within the eye can result in cataracts and blindness (CDC, 2022).  Excess sorbitol is also associated with blood vessel lesions and gangrene. Other significant health risks for individuals with juvenile diabetes include ketoacidosis, the buildup of acidic ketones that can cause diabetic comas and diminished brain function, and hypoglycemia, otherwise known as “insulin shock,” resulting from an overdose of insulin or the failure to eat and potentially causing nerve damage and death (CDC, 2022). Approximately 1.6 million Americans live with type 1 diabetes, including 200,000 youth. Furthermore, despite significant developments in the treatment of type 1 diabetes, desired glycemic targets are rarely achieved in patients, who continue to face a higher risk of complications and death because of their condition (Herold et. al., 2019). 

     In those who are genetically susceptible to type 1 diabetes, there are two asymptomatic stages prior to the development of overt hyperglycemia, the clinical disease which requires insulin treatment. Stage 1 is characterized by the appearance of autoantibodies targeting pancreatic cells and stage 2 involves dysglycemia, an abnormality in blood sugar stability (Herold et. al., 2019). In this case, metabolic responses to high levels of glucose could be impaired, but other metabolic indexes, such as the level of glycosylated hemoglobin, are normal. During these stages, insulin treatment is not required. The goal of Teplizumab is to delay the development of clinical (stage 3) diabetes in those currently in stages 1 and 2 (Herold et. al., 2019). 

     Teplizumab is an Fc receptor–nonbinding anti-CD3 monoclonal antibody that modifies CD8+ T lymphocytes, which are part of the body’s adaptive immune response and thought to be important effector cells that kill β cells in the pancreas (Herold et. al., 2019). Evidence indicates that type 1 diabetes is initiated by both CD4+ and CD8+ T cells (Li and Qin, 2014). Autoreactive T cells differentiate into effector (CD4+) cells by engaging β-cell antigens on local antigen-presenting cells; these effector CD4+ T cells stimulate other immune cells to target β cells, whereas the cytotoxic CD8+ T cells can directly kill β cells via cell-to-cell contact (Gearty et. al., 2022). The CD3 protein complex is involved in activating both the cytotoxic and helper T-cells (Yang et. al., 2005); thus, the anti-CD3 properties of Teplizumab can inhibit the T cell–mediated damage to β-cells. 

     In the Teplizumab trial, which was conducted over a 7-year period and led by Dr. Kevan Herold of Yale University, patients were randomly assigned to a single 14-day course of Teplizumab or placebo. Seventy-two percent of the participants were under the age of 18, and the majority had siblings with clinical type 1 diabetes, meaning they were at a high risk of developing the condition themselves (Herold et. al., 2019). Furthermore, of the 55 patients who were under 18, 47 had a confirmed dysglycemic oral glucose-tolerance test, one of the hallmarks of stage 2 type 1 diabetes, before undergoing randomization in the trial. Follow-up for progression to clinical type 1 diabetes was performed via oral glucose-tolerance tests every 6 months. The study indicated that a 2-week course of treatment with Teplizumab delayed the diagnosis of clinical type 1 diabetes in high-risk participants: following the completion of the trial, 57% of individuals in the Teplizumab trial group were diabetes-free compared to 28% in the placebo group, with a median delay in the diagnosis of clinical diabetes of 2 years (Figure 1). These results also reinforced prior findings that type 1 diabetes is a T-cell mediated condition and showed that immunomodulation before the onset of clinical type 1 diabetes is a promising development in the treatment of this disease (Herold et. al., 2019).

 

Figure 1. From the time of randomization until the clinical diagnosis of type 1 diabetes, the recipients of the Teplizumab infusion experienced a longer median time until diagnosis than those in the placebo group (adapted from K. C. Herold, et. al.). 

     Given the prevalence of patients with clinical type 1 diabetes, these results of this study are highly promising and a significant step forward in the mitigation of the harmful side effects of this condition. However, there are several areas which, in an effort to make the benefits of this trial widely applicable, require further research. Since the participants in the study were all relatives of patients with type 1 diabetes, it is currently unknown whether the findings can be applied to those who seem to be at risk for the type 1 diabetes and lack first-degree relatives with the condition (Evans-Molina and Oram, 2023). Furthermore, while patients can be carefully screened for the immunological or metabolic markers of preclinical type 1 diabetes in the research setting, a lack of infrastructure prevents a larger-scale screening of the general public and high-risk populations are typically the only groups surveyed for these symptoms (Evans-Molina and Oram, 2023). Finally, despite the promising results of the newly-approved drug, the current cost of treatment presents a significant barrier regarding access to care: one vial of Tzield costs $13,850, amounting to $193,000 over the 14-day infusion (Rodriguez, n.d.).  The exorbitant sum is not surprising, given the high cost of insulin medications and their widely-reported underuse (Herkert et. al., 2019). As a result, further efforts must be taken to ensure that those who are eligible for this new and potentially life-saving medication are able to access it. 

 

Sources: 

CDC. (2022, November 3). Prevent diabetes complications. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/managing/problems.html 

Commissioner, O. of the. (2022, November 18). FDA approves first drug that can delay onset of type 1 diabetes. FDA. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-can-delay-onset-type-1-diabetes 

de Beeck, A. O., & Eizirik, D. L. (2016). Viral infections in type 1 diabetes mellitus—Why the β cells? Nature Reviews. Endocrinology, 12(5), 263–273. https://doi.org/10.1038/nrendo.2016.30 

Dolgin, E. (2023). How a pioneering diabetes drug offers hope for preventing autoimmune disorders. Nature, 614(7948), 404–406. https://doi.org/10.1038/d41586-023-00400-x 

Evans-Molina, C., & Oram, R. A. (2023). Teplizumab approval for type 1 diabetes in the USA. The Lancet Diabetes & Endocrinology, 11(2), 76–77. https://doi.org/10.1016/S2213-8587(22)00390-4 

Gearty, S. V., Dündar, F., Zumbo, P., Espinosa-Carrasco, G., Shakiba, M., Sanchez-Rivera, F. J., Socci, N. D., Trivedi, P., Lowe, S. W., Lauer, P., Mohibullah, N., Viale, A., DiLorenzo, T. P., Betel, D., & Schietinger, A. (2022). An autoimmune stem-like CD8 T cell population drives type 1 diabetes. Nature, 602(7895), 156–161.  https://doi.org/10.1038/s41586-021-04248-x 

Herkert, D., Vijayakumar, P., Luo, J., Schwartz, J. I., Rabin, T. L., DeFilippo, E., & Lipska, K. J. (2019). Cost-related insulin underuse among patients with diabetes. JAMA Internal Medicine, 179(1), 112–114. https://doi.org/10.1001/jamainternmed.2018.5008 

Herold, K. C., Bundy, B. N., Long, S. A., Bluestone, J. A., DiMeglio, L. A., Dufort, M. J., Gitelman, S. E., Gottlieb, P. A., Krischer, J. P., Linsley, P. S., Marks, J. B., Moore, W., Moran, A., Rodriguez, H., Russell, W. E., Schatz, D., Skyler, J. S., Tsalikian, E., Wherrett, D. K., … Greenbaum, C. J. (2019). An anti-cd3 antibody, teplizumab, in relatives at risk for type 1 diabetes. New England Journal of Medicine, 381(7), 603–613. https://doi.org/10.1056/NEJMoa1902226 

History of diabetes: Early science, early treatment, insulin. (2020, June 17). https://www.medicalnewstoday.com/articles/317484 

Li, M., Song, L.-J., & Qin, X.-Y. (2014). Advances in the cellular immunological pathogenesis of type 1 diabetes. Journal of Cellular and Molecular Medicine, 18(5), 749–758. https://doi.org/10.1111/jcmm.12270 

Masharani, U. B., & Becker, J. (2010). Teplizumab therapy for type 1 diabetes. Expert Opinion on Biological Therapy, 10(3), 459–465. https://doi.org/10.1517/14712591003598843 

Rodriguez, A. (n.d.). FDA approves first treatment that delays Type 1 diabetes. Why it could be “game changing.” USA TODAY. Retrieved April 2, 2023, from https://www.usatoday.com/story/news/health/2022/11/18/fda-approves-teplizumab-delays-onset-diabetes/10721707002/ 

Yang, H., Parkhouse, R. M. E., & Wileman, T. (2005). Monoclonal antibodies that identify the CD3 molecules expressed specifically at the surface of porcine γδ-T cells. Immunology, 115(2), 189–196. https://doi.org/10.1111/j.1365-2567.2005.02137.x 



Filed Under: Biology Tagged With: Diabetes, Immunology, Immunotherapy, Medicine

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