The influences of sex differences on disease have been severely understudied until recent scientific history. Most of the knowledge about every aspect of disease comes from a basis of research using male participants. Although the accumulated bank of medical knowledge mainly comes from male physiology, it gets generalized as a standard. Only after researchers began including female participants did differences in disease presentation between sexes catch the attention of the medical research community. Even when female participants are included, the influence of sex is not a main point of result analysis. Today, there is still nowhere near a full understanding of how aspects of sex play a role as modifiers of disease across the board.
The effects of sex hormones on the brain and their role in neurodegenerative disease have been explored by Nguyen et al. Progesterone, an ovarian hormone important for regulating pregnancy and the menstrual cycle, is a known neuroprotectant that could be a possible stroke treatment. It is known that brain-derived neurotrophic factor (BDNF) release mediates progesterone’s protective functions, which itself is mediated by the Pgrmc1 progesterone receptor. Nguyen et al. set out to investigate how the microRNA (miRNA) let-7i regulates progesterone’s protective functions during ischemia in a mouse model. In this study, let-7i, which has been found to increase during strokes, was shown to negatively regulate the expression of Pgrmc1 and BDNF, which is connected to more severe stroke pathophysiology. Let-7i was also found to prevent progesterone from protecting the neurons from oxygen-glucose deprivation (OGD) during a stroke, which in turn increases expression of let-7i. Then when they inhibited the miRNA let-7i, they found an increase in progesterone’s neuroprotective effects and a facilitation of functional recovery following stroke. While progesterone treatment alone was unable to decrease the size of the ischemic lesion, a combined treatment of progesterone with let-7i enhanced mature BDNF expression from glia, reduced ischemic injury, and promoted better functional recovery. The work of Nguyen et al. highlights the significance of a prominent sex hormone in the severity of injury following a form of neurological damage, as well as the ability to recover and restore function.
Dr. Meharvan Singh, one of the lead researchers in the Nguyen et al. study, gave a research talk at Loyola University Chicago highlighting this study as well as other prominent findings from his research studying the effects of hormones on neurodegenerative disease. He discussed sex hormones and their role in observed sex differences in the risk for age-associated diseases like Alzheimer’s. He described how estrogen plays a significant role in memory and Alzheimer’s disease. He then made a striking point: women are three times more likely to develop Alzheimer’s than men, women also have an also undetectable amount of estrogen in their bodies post-menopause. People do not generally develop Alzheimer’s disease until they are at the age that menopause has generally already occurred in women. This shows a glaring disparity in prior understanding, diagnosis, and treatment of a leading cause of death in the United States.
Mauvais-Jarvis et al. compiled a review that explores the role of sex and gender as modifiers of the most common causes of death and morbidity (Mauvais-Jarvis et al., 2020). They aimed to emphasize sex and gender differences as a significant aspect of chronic disease that needs to be considered by clinicians and researchers at every step. It is noted that researching sex differences regarding disease is usually deemed a specialized research interest, but Mauvais-Jarvis et al. push for its centralization in medical research as it deems great significance throughout all medicine. Sex differences among different diseases are discussed, from heart disease to pneumonia to diabetes. When discussing stroke, the loss of female sex hormones in menopause Is cited as a main reason for an increased ischemic stroke risk in middle-aged women, and menopausal hormone therapy has shown to reduce that risk. An overall statistic is given, showing that while men are more likely to have a stroke, women have poorer outcomes and are more likely to die from a stroke. When discussing the influence of sex differences on Alzheimer’s disease, it is noted that early menopause and late initiation of menopausal hormone therapy increases women’s’ risk of Alzheimer’s disease, when two-thirds of individuals in the U.S. with this disease are female. This research and statistics, along with similar findings for many other ailments, support the argument proposed by Mauvais-Jarvis et al. calling to make the influences of sex differences much more central in the field of medical research.
The Nguyen et al. study and Dr. Singh's research talk at Loyola University Chicago showed how vital research investigating the influence of sex differences like hormones on neurodegenerative disease is for the future of medicine. The Mauvais-Jarvis et al. review article use similar research to build their case for centralizing research of sex differences across the medical research field. This area of research is incredibly important to provide researchers and clinicians with the best knowledge to better the understanding, diagnosis, and treatment of so many different diseases. There must be a much larger emphasis on these differences in future research to ensure the best care and treatment for all individuals, both male and female.
References:
Nguyen, Trinh, et al. “Let-7i Inhibition Enhances Progesterone-Induced Functional Recovery in a Mouse Model of Ischemia.” Proceedings of the National Academy of Sciences, vol. 115, no. 41, 2018, https://doi.org/10.1073/pnas.1803384115.
Mauvais-Jarvis , F., Merz , N. B., Barnes, P. J., Brinton, R. D., Carrero, J.-J., & DeMeo, D. L. (2020). Sex and gender: modifiers of health, disease, and medicine. The Lancet, 396(10252). https://doi.org/https://doi.org/10.1016/S0140-6736(20)31561-0
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