ACADEMIA Letters Dehydroepiandrosterone (DHEA) and COVID-19. Friend or Foe? Stephen Cherniske COVID-19 disease severity and death are significantly greater in men. When there is a gender difference in the incidence or severity of a disease, it is common for researchers to jump to the hormone hypothesis. The idea that androgens are immunosuppressive (known as the immunocompetence handicap hypothesis, or ICHH) is often cited as a biological principle, when in fact, it is a hotly debated issue.[1] In the COVID literature, however, the ICHH is taken as gospel, leading some (with no evidence) to suggest treating men with anti-androgens. Multiple authors have proposed supplementing at-risk males (first responders, doctors, other essential workers) with estrogen and progesterone as a way to diminish COVID-19 incidence, mortality, and morbidity. [2],[3] Now comes Jonathan Nyce, suggesting that supplementation with DHEA will also increase one’s risk for COVID-19 disease.[4] He uses the ICHH argument and also points to the US, where DHEA is classified as a nutritional supplement and is used by an unknown number of men and women as part of an anti-aging strategy. According to Nyce, the struggles that Americans have had getting this pandemic under control may be due in part to their use of DHEA, even though many countries where DHEA is not available are faring worse than the US, including Belgium, Spain, Italy, UK, Argentina, Mexico, and Brazil.[5] An opposing point of view DHEA is considered to be a weak androgen because of its reduced ability (compared to testosterone and DHT) to bind to androgen receptors. But it is important to note that DHEA acts as a prohormone, supplying both androgens and estrogens in tissues throughout the body and Academia Letters, July 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Stephen Cherniske, stephencherniske108@gmail.com Citation: Cherniske, S. (2021). Dehydroepiandrosterone (DHEA) and COVID-19. Friend or Foe? Academia Letters, Article 1787. https://doi.org/10.20935/AL1787. 1 brain.[6] Importantly, DHEA has a myriad of functions independent from its conversion to sex steroids, and as the body’s most widely circulating steroid, has been called the most comprehensive repair molecule in human physiology.[7] In fact, there is abundant evidence to suggest that DHEA may be protective against COVID-19 disease. 1. High levels of DHEA are associated with competent and balanced immunity.[8],[9] 2. Low levels of DHEA are associated with increased risk for ischemic heart disease, cardiovascular mortality, atherosclerosis, osteoporosis, all forms of dementia and all inflammatory diseases.[10] 3. Animal studies and one human clinical trial have shown DHEA to be an effective vaccine adjuvant. [11],[12] 4. Far from being immunosuppressive, research clearly shows that DHEA is an effective immune modulator, potentiating immunity against a variety of pathogens, maintaining immune competence in aging, and restoring immune balance in autoimmune disorders such as SLE and RA.[13] 5. NK cell deficits, both in number and cytotoxicity, have been shown to correlate strongly with COVID-19 disease severity and deaths.[14] DHEA administration has been shown in animal and human studies to augment both NK cell number and anti-viral activity. [15] In one clinical trial with men (mean age of 63 years) DHEA administration resulted in a 22-37% increase in NK cell numbers with a concomitant 45% increase in cytotoxicity.[16] 6. COVID-19 disease frequently results in cognitive impairment and other adverse effects in the central nervous system. DHEA is synthesized in the brain, has neuroprotective and neuro-regenerative effects,[17],[18] and even modest (25 mg/d) supplementation with DHEA has produced significant improvement in cognition and activities of daily living in elderly women with mild to moderate cognitive impairment.[19] The Bottom Line To determine the validity of either of these opposing hypotheses would be easy and inexpensive. All hospitals have stored blood samples from COVID-19 patients, as well as records regarding treatments and outcomes. Comparing the level of serum DHEA sulfate (DHEAS) to the severity of the disease and the outcome would reveal any meaningful association. If Academia Letters, July 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Stephen Cherniske, stephencherniske108@gmail.com Citation: Cherniske, S. (2021). Dehydroepiandrosterone (DHEA) and COVID-19. Friend or Foe? Academia Letters, Article 1787. https://doi.org/10.20935/AL1787. 2 Nyce’s hypothesis is correct, elevated levels DHEAS would be associated with more severe disease, but I strongly suspect that we would find the opposite; that low levels of DHEAS would be associated with disease severity, just as has been found with cardiovascular disease, diabetes, asthma, obesity, dementia, autoimmunity, and multiple inflammatory disorders. An excellent example of this type of research was recently published in EClinicalMedicine. An international team of researchers looked at serum DHEAS and lung function in 3,770 women. In findings that are certainly relevant to this discussion, the authors report: Women with low DHEA-S had lower FEV1 and FVC, and were at a greater risk of having airflow limitation and restrictive pattern on spirometry than women with higher DHEA-S levels. In longitudinal analyses, low DHEA-S at baseline was associated with a greater incidence of airflow limitation after an 11-years follow-up.[20] As the oldest scientist in the US supplementing with DHEA for over 30 years, my money is on DHEA as a friend. Now, who will take up the challenge and review the COVID patient data? References [1] Sci Rep. 2018; 8: 7392. No evidence for the immunocompetence handicap hypothesis in male humans. Judyta Nowak, Bogusław Pawłowski, Barbara Borkowska, Daria Augustyniak, and Zuzanna Drulis-Kawa. doi: 10.1038/s41598-018-25694-0. PMCID: PMC5943526. PMID: 29743556 [2] Asian Pac J Trop Med. 2021; 14(1): 5–9. doi: 10.4103/1995-7645.304293. Gender disparity in COVID-19: Role of sex steroid hormones. Anuja Lipsa and Jyothi S Prabhu. [3] Aging Dis. 2021 Apr 1;12(2):671-683. doi: 10.14336/AD.2020.1211. Global Sex Disparity of COVID-19: A Descriptive Review of Sex Hormones and Consideration for the Potential Therapeutic Use of Hormone Replacement Therapy in Older Adults. Samuel C Okpechi, et al. [4] Endocr Relat Cancer. 2021 Feb;28(2):R47-R53. doi: 10.1530/ERC-20-0439. Alert to US physicians: DHEA, widely used as an OTC androgen supplement, may exacerbate COVID-19. Jonathan Nyce [5] https://www.movehub.com/blog/best-and-worst-covid-responses/ Accessed 05/09/21 [6] Front Neuroendocrinol. 2001 Jul;22(3):185-212. doi: 10.1006/frne.2001.0216. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinolAcademia Letters, July 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Stephen Cherniske, stephencherniske108@gmail.com Citation: Cherniske, S. (2021). Dehydroepiandrosterone (DHEA) and COVID-19. Friend or Foe? Academia Letters, Article 1787. https://doi.org/10.20935/AL1787. 3 ogy. F Labrie , V Luu-The, C Labrie, J Simard. [7] Regelson W, Kalimi M. Dehydroepiandrosterone (DHEA): a pleiotropic steroid. How can one steroid do so much? Adv Anti-Aging Med.1996;1:287-317. [8] Vitamins and Hormones. Volume 108, 2018, Pages 125-144. DHEA Modulates Immune Function: A Review of Evidence. Sean P.Prall, Michael P.Muehlenbein. [9] Applied Physiology, Nutrition, and Metabolism. 8 April 2008. Impact of DHEA(S) and cortisol on immune function in aging: a brief review. Thomas W. Buford and Darryn S. Willoughby. https://doi.org/10.1139/H08-013 [10] Front Neuroendocrinol. 2009 Jan;30(1):65-91. doi: 10.1016/j.yfrne.2008.11.002. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Nicole Maninger , Owen M Wolkowitz, Victor I Reus, Elissa S Epel, Synthia H Mellon. [11] Ann N Y Acad Sci. 1994 Aug 15;730:144-61. doi: 10.1111/j.1749-6632.1994.tb44246.x. The development of effective vaccine adjuvants employing natural regulators of T-cell lymphokine production in vivo. R A Daynes , B A Araneo. [12] Ann N Y Acad Sci. 1995 Dec 29;774:232-48. doi: 10.1111/j.1749-6632.1995.tb17384.xi1. DHEAS as an effective vaccine adjuvant in elderly humans. Proof-of-principle studies. B Araneo 1, T Dowell, M L Woods, R Daynes, M Judd, T Evans [13] J Steroid Biochem Mol Biol. 2010 May 31;120(2-3):127-36. doi: 10.1016/j.jsbmb.2009.12.016. Dehydroepiandrosterone as a regulator of immune cell function. Jon Hazeldine , Wiebke Arlt, Janet M Lord [14] Experimental Hematology & Oncology volume 10, Article number: 5 (2021). Natural killer cells associated with SARS-CoV-2 viral RNA shedding, antibody response and mortality in COVID-19 patients. Changqian Bao, et al. [15] . J Clin Endocrinol Metab. 1999 Sep;84(9):3260-7. Dehydroepiandrosterone sulfate enhances natural killer cell cytotoxicity in humans via locally generated immunoreactive insulin-like growth factor I. Solerte SB, Fioravanti M, Vignati G, Giustina A, Cravello L, Ferrari E. [16] J Gerontol A Biol Sci Med Sci. 1997 Jan;52(1):M1-7. doi: 10.1093/gerona/52a.1.m1. Activation of Immune Function by Dehydroepiandrosterone (DHEA) in Age-Advanced Academia Letters, July 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Stephen Cherniske, stephencherniske108@gmail.com Citation: Cherniske, S. (2021). Dehydroepiandrosterone (DHEA) and COVID-19. Friend or Foe? Academia Letters, Article 1787. https://doi.org/10.20935/AL1787. 4 Men. O Khorram , L Vu, S S Yen [17] Front Neuroendocrinol. 2009 Jan;30(1):65-91. doi: 10.1016/j.yfrne.2008.11.002. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Nicole Maninger , Owen M Wolkowitz, Victor I Reus, Elissa S Epel, Synthia H Mellon [18] Vitam Horm. 2018;108:175-203. doi: 10.1016/bs.vh.2018.01.004. Astrocyte Neuroprotection and Dehydroepiandrosterone. Bruno D Arbo , Felipe S Ribeiro , Maria F Ribeiro [19] Geriatr Gerontol Int. 2010 Oct;10(4):280-7. doi: 10.1111/j.1447-0594.2010.00625.x. Effects of dehydroepiandrosterone supplementation on cognitive function and activities of daily living in older women with mild to moderate cognitive impairment. Shizuru Yamada, et al. [20] EClinicalMedicine Volume 23, June 2020. Low serum DHEA-S is associated with impaired lung function in women. Giancarlo Pescea, Kai Triebner, et al. https://www. thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30133-4/fulltext Academia Letters, July 2021 ©2021 by the author — Open Access — Distributed under CC BY 4.0 Corresponding Author: Stephen Cherniske, stephencherniske108@gmail.com Citation: Cherniske, S. (2021). Dehydroepiandrosterone (DHEA) and COVID-19. Friend or Foe? Academia Letters, Article 1787. https://doi.org/10.20935/AL1787. 5