Letter to the Editor re: Baldassarri et al., 2021 “Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males”

We would like to thank Baldassarri et al. for presenting their findings that short androgen receptor (AR) polyQ alleles confer protection against life-threatening COVID-19 infection among European males [[1]Baldassarri M et al.Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.EBioMedicine. 2021; 103246Summary Full Text Full Text PDF Scopus (38) Google Scholar]. Data previously presented by McCoy et al. suggests that longer AR CAG repeats are associated with more severe COVID-19 disease. In skeletal muscle, for example, long AR CAG repeats confer increased transcriptional activity in response to testosterone. In prostate cancer, short CAG repeats have been associated with a poor prognosis. This difference in skeletal muscle and prostate tissue could be explained by the tissue-dependent expression of co-factors that aid in activation of the androgen response element (ARE) [[2]McCoy J 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. 2021; 35: e15-e17Crossref PubMed Scopus (23) Google Scholar]. Baldassarri et al. suggested to initiate clinical trials of testosterone therapy in men expressing defective androgen signaling and having serologic evidence of hypoandrogenism [[1]Baldassarri M et al.Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males.EBioMedicine. 2021; 103246Summary Full Text Full Text PDF Scopus (38) Google Scholar]. There is evidence that th lower AR activity caused by the longer CAG repeats is biologically compensated by increased testosterone levels. The response to testosterone therapy may be increased in patients with shorter CAG repeats, who have enhanced AR activity [[3]Tirabassi G Cignarelli A Perrini S et al.Influence of CAG repeat polymorphism on the targets of testosterone action.Int J Endocrinol. 2015; : 1-12Crossref Scopus (56) Google Scholar]. We suggest a more robust discussion in light of already published randomized clinical trials addressing the role of antiandrogen therapy in reducing disease severity by reducing expression of TMPRSS2. Randomized control trials with 5-alpha-reductase inhibitors and antiandrogens have shown accelerated viral clearance at 7 days and improvement in inflammatory markers in males infected with SARS-CoV-2 compared to males treated with a placebo as well as a reduction in COVID-19 symptoms and hospitalization rates among males [[4]Cadegiani FA McCoy J Gustavo Wambier C Goren A Early Antiandrogen Therapy With Dutasteride Reduces Viral Shedding, Inflammatory Responses, and Time-to-Remission in Males With COVID-19: A Randomized, Double-Blind, Placebo-Controlled Interventional Trial (EAT-DUTA AndroCoV Trial –Biochemical).Cureus. 2021; https://doi.org/10.7759/cureus.13047Crossref Google Scholar]. A single case report gives much information about how external androgens seem to exacerbate COVID-19 symptoms, and how blocking the androgen receptor with a strong antiandrogen such as proxalutamide, seems to resolve COVID-19 symptoms within the first 24 hours of therapy [[5]Cadegiani F Lin EM Goren A Wambier CG. Potential risk for developing severe COVID-19 disease among anabolic steroid users.BMJ Case Report. 2021; 14e241572Crossref PubMed Scopus (12) Google Scholar]. We expect the publication of the results of the NCT04728802 (Proxalutamide Treatment for Hospitalized COVID-19 Patients) soon, which may strongly discourage clinical trials with androgens in hospitalized COVID-19 patients. We are thankful to the authors for their contribution to current literature, and we look forward to more studies investigating genetic and hormonal predictors of COVID-19 disease severity, as well as results of ongoing studies of antiandrogen therapy for COVID-19 by other groups. None Declared None