Abstract

Various dermatologic diseases came into notice worldwide after the COVID-19 pandemic. The stress and the anxiety associated with the COVID-19 pandemic have been seen as the causal factor behind many psychosocial dermatologic diseases, such as psoriasis, chronic urticaria, and alopecia areata. It has been seen that there is increasing likelihood in the occurrence of alopecia area after the COVID-19 outbreak which is usually observed after months of contracting the illness. Alopecia areata is described as a non scarring type of autoimmune hair loss ,recurrent in nature. As emotional stress burden increases, the incidence of alopecia increases, and after the occurrence of alopecia , psychiatric disorders are often triggered. Given the importance of psychiatric disorders in alopecia, after the COVID-19 pandemic, there are numerous stress factors like travel ban, social distancing, gathering, and conveyance restrictions starting to take place. Henceforth this is clearly suggesting that there is a vicious circle between alopecia and psychiatric disorders. There is a high need to study deeply in order to derive any conclusion establishing the relationship between the Alopecia and COVID-19 pandemic. The transcription of transmembrane protease serine 2 (TMPRSS2) regulated by the AR. This protease is important to cleave SARSCoV-2 spike glycoprotein, this cleavage, also termed “priming,” is essential for the spike protein of virus to bind to human angiotensinconverting enzyme 2 (ACE2), needed for the cellular entry for infection. Targeting the TMPRSS2,whether directly or indirectly through.

• 1.   Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708-1720. https://doi.org/10.1056/ nejmoa2002032.
• 2.   McCoy J, Wambier CG, Vano-Galvan S, et al. Racial variations in COVID-19 deaths may be due to androgen receptor genetic variants associated with prostate cancer and androgenetic alopecia. Are antiandrogens a potential treatment for COVID-19? J Cosmet Dermatol. 2020;19:1542-1543. https:// doi. org/10.1111/jocd.13455.
• 3.   Wambier CG, Vaño-Galván S, McCoy J, Pai S, Dhurat R, Goren A. Androgenetic alopecia in COVID-19: compared to age-matched epidemiologic studies and hospital outcomes with or without the Gabrin sign. J Am Acad Dermatol. 2020;83:e453-e454. https://doi. org/10.1016/j.jaad.2020.07.099.
• 4.   Channappanavar R, Fett C, Mack M, Ten Eyck PP, Meyerholz DK, Perlman S. Sex-based differences in susceptibility to severe acute FIGURE 2 TMPR2SS2 might be the bullseye to control the SARSCoV- 2 infection. SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TMPR2SS2, transmembrane protease serine 2 respiratory syndrome coronavirus infection. J Immunol. 2017; 198(10):4046-4053. https://doi.org/10.4049 jimmunol.1601896.
• 5.   Goren A, McCoy J, Wambier CG, et al. What does androgenetic alopecia have to do with COVID-19? An insight into a potential new therapy. Dermatol Ther. 2020;33:e13365. https://doi.org/10.1111/ dth.13365.
• 6.   Wambier CG, Goren A, Vaño-Galván S, et al. Androgen sensitivity gateway to COVID-19 disease severity. Drug Dev Res. 2020;81: 771-776. https:// doi.org/10.1002/ddr.21688.
• 7.   Wambier CG, Goren A. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is likely to be androgen mediated. J Am Acad Dermatol. 2020;83:308-309. https://doi.org/10. 1016/ j.jaad.2020.04.032.
• 8.   Ramos PM, Ianhez M, Miot HA. Alopecia and gray hair are associated with COVID-19 severity. Exp Dermatol. 2020;29:1250-1252. https://doi.org/ 10.1111/exd.14220.
• 9.   Wambier CG, Vaño-Galván S, McCoy J, Pai S, Dhurat R, Goren A. Androgenetic alopecia in COVID-19: compared to age-matched epidemiologic studies and hospital outcomes with or without the Gabrin sign. J Am Acad Dermatol. 2020;83:e453- e454. https://doi. org/10.1016/j.jaad.2020.07.099.
• 10.   Montopoli M, Zumerle S, Vettor R, et al. Androgendeprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (N = 4532). Ann Oncol. 2020;31:1040-1045. https:/ /doi.org/10.1016/j. annonc.2020.04.479.
• 11.   Wambier CG, Goren A, Vaño-Galván S, et al. Androgen sensitivity gateway to COVID-19 disease severity. Drug Dev Res. 2020;81: 771-776. https:// doi.org/10.1002/ddr.21688.
• 12.   Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pohlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2014; 88(2):1293-1307. https://doi. org/10.1128/JVI.02202-13.
• 13.   Heinlein CA, Chang C. Androgen receptor (AR) coregulators: an overview. Endocr Rev. 2002;23:175- 200. https://doi.org/10.1210/ edrv.23.2.0460.
• 14.   Culig Z, Bartsch G, Hobisch A. Interleukin-6 regulates androgen receptor activity and prostate cancer cell growth. Mol Cell Endocrinol. 2002;197:231-238. https://doi.org/10.1016/S0303- 7207(02)00263-0.
• 15.   Okitsu K, Kanda T, Imazeki F, et al. Involvement of interleukin-6 and androgen receptor signaling in pancreatic cancer. Genes Cancer. 2010;1:859-867. https://doi.org/10.1177/1947601910383417.
• 16.   Kim HS, Moreira DM, Jayachandran J, et al. Prostate biopsies from black men express higher levels of aggressive disease biomarkers than prostate biopsies from white men. Prostate Cancer Prostatic Dis. 2011;14:262-265. https://doi.org/10.1038/ pcan.2011.18.
• 17.   Tirabassi G, Cignarelli A, Perrini S, et al. Influence of CAG repeat polymorphism on the targets of testosterone action. Int J Endocrinol. 2015;2015:1-12. https://doi.org/10.1155/2015/298107.
• 18.   Bennett CL, Price DK, Kim S, et al. Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status. J Clin Oncol. 2002;20: 3599- 3604. https://doi.org/10.1200/JCO.2002.11.085.
• 19.   Ellis JA, Scurrah KJ, Cobb JE, Zaloumis SG, Duncan AE, Harrap SB. Baldness and the androgen receptor: the AR polyglycine repeat polymorphism does not confer susceptibility to androgenetic alopecia. Hum Genet. 2007;121:451-457. https://doi.org/10.1007/ s00439-006-0317-8.
• 20.   Haring R, Ernst F, Schurmann C, et al. The androgen receptor CAG repeat polymorphism as a risk factor of low serum testosterone and its cardiometabolic effects in men. Int J Androl. 2012;35:511-520. https:/ /doi.org/10.1111/j.1365-2605.2011.01220.x.
• 21.   Kim JW, Bae YD, Ahn ST, Kim JW, Kim JJ, Moon DG. Androgen receptor CAG repeat length as a risk factor of late-onset hypogonadism in a Korean male population. Sex Med. 2018;6: 203-209. https:// doi. org/10.1016/j.esxm.2018.04.002.
• 22.   Goren A, Vaño-Galván S, Wambier CG, et al. A preliminary observation: male pattern hair loss among hospitalized COVID-19 patients in Spain—a potential clue to the role of androgens in COVID-19 severity. J Cosmet Dermatol. 2020;19(7):1545-1547. https://doi.org/10.1111/jocd.13443.
• 23.   Sheppard RL, Spangenburg EE, Chin ER, Roth SM. Androgen receptor polyglutamine repeat length affects receptor activity and C2C12 cell development. Physiol Genomics. 2011;43:1135-1143. https:// doi. org/10.1152/physiolgenomics.00049.2011.
• 24.   Trigunaite A, Dimo J, Jørgensen TN. Suppressive effects of androgens on the immune system. Cell Immunol. 2015;294:87-94. https:// doi.org/10.1016/ j.cellimm.2015.02.004.
• 25.   Kim JW, Bae YD, Ahn ST, Kim JW, Kim JJ, Moon DG. Positive correlation between androgen receptor CAG repeat length and metabolic syndrome in a Korean male population. World J Mens Health. 2018;36:73. https://doi.org/10.5534/wjmh.17029.
• 26.   Huhtaniemi IT, Pye SR, Limer KL, et al. Increased estrogen rather than decreased androgen action is associated with longer androgen receptor CAG repeats. J Clin Endocrinol Metab. 2009;94:277-284. https://doi.org/10.1210/jc.2008-0848.
• 27.   Scaramuzzino C, Casci I, Parodi S, et al. Protein arginine methyltransferase 6 enhances polyglutamine-expanded androgen receptor function and toxicity in spinal and bulbar muscular atrophy. Neuron. 2015;85:88-100. https://doi org/10.1016/ j.neuron.2014.12.031.
• 28.   He X, Li T, Kang N, et al. The protective effect of PRMT6 overexpression on cigarette smoke extractinduced murine emphysema model. Int J COPD.2017;12:3245-3254. https://doi.org/10.2147/ COPD.S144881.
• 29.   Goren A, Cadegiani FA, Wambier CG, et al. Androgenetic alopecia may be associated with weaker COVID-19 T-cell immune response: An insight into a potential COVID-19 vaccine booster. Med Hypotheses. 2020:110439. https://doi.org/ 10.1016/j.mehy.2020. 110439.
• 30.   Wambier CG, Vaño-Galván S, McCoy J, et al. Androgenetic alopecia present in the majority of patients hospitalized with COVID-19: the “Gabrin sign”. J Am Acad Dermatol. 2020;83:680-682. https:/ /doi. org/10.1016/j.jaad.2020.05.079.
• 31.   Birch MP, Messenger AG Genetic factors predispose to balding and non-balding in men. Eur J Dermatology. 2001.
• 32.   Norwood OT. Male pattern baldness: classification and incidence. South Med J. 1975;68(11):1359-1365. https://doi.org/10.1097/ 00007611-197511000- 00009.
• 33.   Lee J, Yousaf A, Fang W, Kolodney M. Male balding is a major risk factor for severe COVID-19. J Am Acad Dermatol. 2020;83: e353-e354. https://doi. org/ 10.1016/j.jaad.2020.07.062.
• 34.   Wambier CG, McCoy J, Goren A. Male balding as a major risk factor for severe COVID-19: a possible role for targeting androgens and transmembrane protease serine 2 to protect vulnerable individuals. J Am Acad Dermatol. 2020;83:e401-e402. https://doi. org/ 10.1016/j. jaad.2020.09.015.
• 35.   Cadegiani FA, Lim RK, Goren A, et al. Clinical symptoms of hyperandrogenic women diagnosed with COVID-19. J Eur Acad Dermatology Venereol. 2020:jdv.17004. https://doi.org/10.1111/jdv.17004.
• 36.   Goren A, Wambier CG, Herrera S, et al. Antiandrogens may protect against severe COVID-19 outcomes: results from a prospective cohort study of 77 hospitalized men. J Eur Acad Dermatol Venereol. 2020:jdv.16953. https://doi. org/10.1111/jdv.16953.
• 37.   McCoy J, Cadegiani FA, Wambier CG, et al. 5-alphareductase inhibitors are associated with reduced frequency of COVID-19 symptoms inmales with androgenetic alopecia. J Eur Acad Dermatology Venereol. 2020:jdv.17021. https:// doi.org/10.1111/ jdv. 17021.
• 38.   Cadegiani Flavio A, Wambier, Carlos G, Goren A. Spironolactone: an anti-androgenic and antihypertensive drug that may provide protection against the novel coronavirus (SARS-CoV-2) induced acute respiratory distress syndrome (ARDS) in COVID-19. Front Med. 2020;7, https:// doi.org/ 10.3389/fmed.2020.00453.
• 39.   Vicenzi M, Ruscica M, Iodice S, et al. The efficacy of the mineralcorticoid receptor antagonist canrenone in COVID-19 patients. J Clin Med. 2020;9(9):2943. https://doi.org/10.3390/jcm9092943.
• 40.   McCoy J, Wambier CG, Herrera S, et al. Androgen receptor genetic variant predicts COVID-19 disease severity: a prospective longitudinal study of hospitalized COVID-19 male patients. J Eur Acad Dermatol Venereol. 2020:jdv.16956. https://doi. org/ 10.1111/jdv. 16956.
• 41.   Baldassarri M, Picchiotti N, Fava F, et al. Shorter androgen receptor polyQ alleles protect against lifethreatening COVID-19 disease in males. medRxiv. 2020. https://doi.org/10.1101/2020.11.04. 20225680.
• 42.   Cadegiani FA, McCoy J, Wambier CG, Goren A. Dutasteride reduces viral shedding, inflammatory responses and accelerates remission in COVID-19: biochemical findings of a randomized double blind placebo controlled interventional trial (the DUTA AndroCoV-trialbiochemical). ResearchGate. https:/ /www.researchgate.net/ publication/346487081. Accessed November 28, 2020.
• 43.   WambierCarlosG, Mccoy J, Goren A. Male balding as a major risk factor for severe COVID-19: a possible role for targeting androgens and transmembrane protease serine 2 to protect vulnerable individuals. J Am Acad Dermatol. 2020;83:e401-e402. https:// doi.org/10.1016/j.jaad.2020.09.015.
• 44.   Ansarin K, Tolouian R, Ardalan M, et al. Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: a randomized clinical trial. Bioimpacts. 2020;10(4):209-215. https://doi.org/10. 34172/bi.2020.27.
• 45.   Li T, Sun L, Zhang W, et al. Bromhexine hydrochloride tablets for the treatment of moderate COVID-19: an open-label randomized controlled pilot study. Clin Transl Sci. 2020;13:1096-1102. cts.12881 https://doi.org/10.1111/cts.12881.
• 46.   Olaleye OA, Kaur M, Onyenaka CC. Ambroxol hydrochloride inhibits the interaction between severe acute respiratory syndrome coronavirus 2 spike protein's receptor binding domain and recombinant human ACE2. bio Rxiv Prepr Serv Biol. 2020. https://doi. org/10.1101/2020.09.13.295691.

Data Sharing Statement

Funding