Bowdoin Science Journal

Biology

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

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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.

The Anti-cancer and Antimicrobial Activity Associated with Sea Sponge Extracts

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Toxic Negombata magnifica sponge at Shaab el Erg reef (Red Sea, Egypt) (Alexander Vasenin, 2010)

With an ever-increasing demand for novel drug therapies, scientists are turning to marine organisms as a source of bioactive chemicals, whose properties can be harnessed for medical development. One such organism is a rather unlikely candidate: the sea sponge (phylum Porifera). Lacking a brain and a central nervous system, sea sponges rely upon specialized cells to perform their required functions. As result of their structural simplicity and sedentary existence, these ancient creatures have evolved to protect themselves against predation by means of toxic chemicals, which can prove similarly lethal to cancer cells and microbes in humans (El-Naggar et. al., 2022). A study published in Applied Sciences examined the properties of two sponge species, Negombata magnifica (finger sponge) and Callyspongia siphonella (tube sponge). This drew from the scientists’ previous study, which had indicated that all eight extracts of finger-sponge and tube-sponge studied promoted the death and inhibited the growth of cells associated with liver, breast, and colorectal cancer (El-Naggar et.al., 2022).

Whereas the earlier study had used four different solvents in the production of sponge extracts, this newerstudy examined only the methanolic extracts of Negombata magnifica (NmE) and Callyspongia siphonella (CsE). Sponge specimens were collected from the Dahab region on the Sinai Peninsula and soaked with methanol to obtain NmE and CsE. One microliter of each extract was examined for its contents of bioactive compounds via a Gas Chromatography–Mass Spectrometer (GC–MS analysis). Out of the 117 chemical compounds revealed by GC­–MS analysis, 37 were determined to be bioactive. These compounds were tested against cultured liver, breast, and colorectal cancer cell lines and ten test microorganisms representing filamentous fungi, yeasts, and Gram-positive and Gram-negative bacteria (El-Naggar et.al., 2022).

While CsE showed no antiproliferative action against the cancer cells, NmE dose-dependently impeded their growth: it induced cell cycle arrest in the liver cancer lines by inhibiting the cell division protein CDK6. It also halted mitotic progress in all three cell types by inhibiting D1 and E1 cyclins, which regulate progression through the cell cycle (Alao, 2007). Furthermore, NmE activated reactive oxygen species (ROS) production in liver cancer cells and induced apoptosis in all cell lines, via Bax (a pro-apoptotic regulatory protein) and caspase-3 (a death protease that cleaves cellular proteins) increase and BCL2 (an anti-apoptotic regulatory protein) decrease (Blanco and García-Sáez, 2018) (Ponder and Boise, 2019; Youle and Strasser, 2002). Regarding antimicrobial activity, CsE was shown to be a superior antimicrobial agent by acting against six microbial strains, whereas NmE reacted favorably to only two strains (El Naggar et. al., 2022).

Looking forward, the anti-cancer properties of NmE indicate its potential for development as an anti-cancer drug, while CsE is a promising source for antimicrobial drug discovery. Additionally, several of the compounds’ bioactivity is neither anti-cancer nor antimicrobial—for instance, both fenretinide and ethyl iso-allocholate have been attributed to anti-COVID-19 activity (Orienti, et. al., 2020; Poochi et. al., 2020). Ultimately, given that approximately eighty of the compounds have yet to be attributed to anti-cancer or anti-microbial mechanisms, the study emphasizes the importance of looking to Earth’s oceans as potential sources of bioactive compounds and harnessing the biological potential of marine organisms in the development of novel drug therapies.

References:

Alao, J.P. The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention. Mol Cancer 6, 24 (2007). https://doi.org/10.1186/1476-4598-6-24

El-Naggar, H. A., Bashar, M. A. E., Rady, I., El-Wetidy, M. S., Suleiman, W. B., Al-Otibi, F. O., Al-Rashed, S. A., et al. (2022). Two Red Sea Sponge Extracts (Negombata magnifica and Callyspongia siphonella) Induced Anticancer and Antimicrobial Activity. Applied Sciences, 12(3), 1400. MDPI AG. Retrieved from http://dx.doi.org/10.3390/app12031400

Orienti, I.; Gentilomi, G.A.; Farruggia, G. Pulmonary Delivery of Fenretinide: A Possible Adjuvant Treatment in COVID-19. Int. J. Mol. Sci. 2020, 21, 3812.

Peña-Blanco, A., & García-Sáez, A. J. (2018). Bax, Bak and beyond – mitochondrial performance in apoptosis. The FEBS journal, 285(3), 416–431. https://doi.org/10.1111/febs.14186

Ponder, K.G., Boise, L.H. (2019). The prodomain of caspase-3 regulates its own removal and caspase activation. Cell Death Discovery 5, 56. https://doi.org/10.1038/s41420-019-0142-1

Poochi, S.P.; Easwaran, M.; Balasubramanian, B.; Anbuselvam, M.; Meyyazhagan, A.; Park, S.; Bhotla, H.K.; Anbuselvam, J.; Arumugam, V.A.; Keshavarao, S.; et al. Employing bioactive compounds derived from Ipomoea obscura (L.) to evaluate potential inhibitor for SARS-CoV-2 main protease and ACE2 protein. Food Front. 2020, 1, 168–179.

Youle, R., Strasser, A. (2008). The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9, 47–59. https://doi.org/10.1038/nrm2308

 

From Crystal Balls to Blue Flies: Death Prediction in the Modern Scientific World

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To most people, the phrase “death prediction” conjures distant images of glowing crystal balls, vibrant tarot cards, or the mystical fortune tellers in popular movies like Big and Ghost. Despite the terrifying implications of a finite and predictable death, a societal obsession with it pervades our media, culture, and everyday life. Though death prediction has historically been confined to fiction and spirituality, scientific advances are transforming it into an imminent next step.

Until the early 2010s, death prediction in the scientific sphere was limited to chronological age. The basic understanding that humans are more likely to die as they reach the end of their average life span was, and still is in many ways, the foundation to any scientific attempts to predict mortality (Gaille et al.). However, more recently, researchers have discovered observable markers of “physiological age”, or traits independent of chronological age that indicate when an individual organism is near the end of its life. In a 2012 experiment, scientists Rera et al. found a reliable predictor in the model organism Drosophila melanogaster, otherwise known as the common fruit fly. According to the study, the flies enter an identifiable “pre-death stage” marked by an increase in intestinal permeability, which can accurately predict when they are near the end of their life. Increases in intestinal permeability were tracked by injecting the drosophila flies with a non-digestible blue dye and observing if their intestinal walls allowed the dye to pass through, causing them to externally turn blue (in drosophila with normal levels of intestinal permeability the dye remained confined to the digestive tract). The high intestinal permeability associated with the blue flies and pre-death stage was appropriately dubbed the “Smurf phenotype”.

Drosophila with the Smurf phenotype were observed to have significantly lower remaining life spans than their age-matched non-Smurf counterparts. While the link between intestinal dysfunction and approaching death is still not fully understood, recent data point to changes in immunity-related gene expression and the aging fly’s microbiome as potential causes. These changes can be caused by old age or other afflictions; in the Smurf flies who were significantly below the average lifespan of the species, other morbidities were often observed, such as mitochondrial dysfunction, increased internal bacterial load, and insulin resistance syndrome. Evidently, the flies’ transition to their “pre-death stage”, or the Smurf phenotype, is a more accurate and comprehensive predictor of death than chronological age (Rera et al.). This biological phenomenon was later observed in other animals too, notably zebrafish and nematodes (Gaille et al.). The prevalence of this observable transition in multiple organisms coupled with its accuracy is slowly but surely turning mortality prediction into a reality.

Surprisingly, death prediction in humans is not far off from the developments seen in Drosophila and other model organisms. In a 2019 UCLA clinical trial, scientists tentatively proved that intestinal permeability is linked to approaching mortality in humans. While the trial was small and needs to be replicated, it provided significant evidence that the efficacy of intestinal permeability decline in death prediction has significant potential for human mortality prediction (Angarita et al.).

Outside of intestinal permeability, scientists have discovered alternative ways to predict a pre-death stage in humans. In a 2014 study, Pinto et al. theorized that olfaction could serve as another indicator as it relies heavily on peripheral and central cell regeneration, which tend to degrade near the end of an individual’s life due to old age or other morbidities. In the study, roughly 3,000 adults in the age range of 57-85 were asked to identify five different common odorants via forced choice. After 5 years, scientists collected data on which subjects were still alive, and analyzed the connection between their olfactory capability and mortality within the 5 year span. The findings were startling: the mortality rate was four times higher for adults with complete loss of smell than adults with fully intact senses of smell (Pinto et al.).

  A: Olfactory dysfunction versus 5 year mortality separated by age group

B: Progression of errors in scent identification versus 5 year mortality (Pinto et al.)

While other methods of death prediction such as biomarkers, genetic screenings, and
demographic studies exist, the discovery of pre-death indicators like intestinal permeability and olfactory decline grant us a unique and improved perspective on mortality. As research continues to grow on this subject, we must question the implications these developments have on our society: how will we reckon with the seemingly impossible ability to predict the future? Is it possible to enjoy life with an exact knowledge of its end? How will both health and wealth inequalities affect the commercialization of testing for death prediction? The moral and ethical dilemmas arising from this development are boundless.

Though these questions do not have finite answers, they must remain present in our discussions of death prediction. While scientific innovations like mortality predictors hold great promise in advancing society, they also have the capacity to exacerbate inequity and other social ills. As rapid development continues to occur in the scientific world, we must maintain both an open mind and an understanding of the complex challenges change poses to our world.

Works Cited

Angarita, Stephanie A. K., et al. “Quantitative Measure of Intestinal Permeability Using Blue Food Coloring.” Journal of Surgical Research, vol. 233, Jan. 2019, pp. 20–25. DOI.org (Crossref), https://doi.org/10.1016/j.jss.2018.07.005.

Gaille, Marie, et al. “Ethical and Social Implications of Approaching Death Prediction in Humans – When the Biology of Ageing Meets Existential Issues.” BMC Medical Ethics, vol. 21, no. 1, Dec. 2020, p. 64. DOI.org (Crossref), https://doi.org/10.1186/s12910-020-00502-5.

Pinto, Jayant M., et al. “Olfactory Dysfunction Predicts 5-Year Mortality in Older Adults.” PLoS ONE, edited by Thomas Hummel, vol. 9, no. 10, Oct. 2014, p. e107541. DOI.org (Crossref), https://doi.org/10.1371/journal.pone.0107541.

Rera, Michael, et al. “Intestinal Barrier Dysfunction Links Metabolic and Inflammatory Markers of Aging to Death in Drosophila.” Proceedings of the National Academy of Sciences, vol. 109, no. 52, Dec. 2012, pp. 21528–33. DOI.org (Crossref), https://doi.org/10.1073/pnas.1215849110.

Cover Image Credit: https://www.npr.org/2019/07/26/745361267/hello-brave-new-world