Potential Risk for Developing Severe COVID-19 Disease Among Anabolic Steroid Users Flavio Cadegiani,1,2 Erica M Lin,3 Andy Goren,4 Carlos G Wambier 3
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Case report BMJ Case Rep: first published as 10.1136/bcr-2021-241572 on 26 February 2021. Downloaded from Potential risk for developing severe COVID-19 disease among anabolic steroid users Flavio Cadegiani,1,2 Erica M Lin,3 Andy Goren,4 Carlos G Wambier 3 1Adrenal and Hypertension SUMMARY stage 1 but rapidly progressed to further stages. Unit, Division of Endocrinology A severe case of COVID-19 was observed in an otherwise His oxygen saturation was unusually low given and Metabolism, Department healthy 28-year -old man who had taken oxandrolone his lack of pre- existing disorders and the fact that of Medicine, Escola Paulista de 40 mg/day as an anabolic steroid. The patient had been he practised a variety of sports at the level of a Medicina, Universidade Federal taking oxandrolone for enhanced bodybuilding 30 days professional athlete. His blood oxygen saturation de São Paulo (EPM/UNIFESP), São Paulo, São Paulo, Brazil prior to presenting to an outpatient clinic with COVID-19 (SpO2) was 92%, C reactive protein (CRP) level 2Corpometria Institute, Brasilia, symptoms. The patient reported that his symptoms was 20.13 mg/L, erythrocyte sedimentation rate Distrito Federal, Brazil have rapidly worsened over the course of 4 days prior (ESR) was 10 mm/hour, ferritin was 299.4 ng/mL 3Department of Dermatology, to presenting at the clinic. As part of an experimental and creatine kinase-MB (CK- MB) was 7.95 ng/mL. The Warren Alpert Medical antiandrogen treatment for hyperandrogenic men The patient’s testosterone levels were 132.6 ng/dL School of Brown University, suffering from COVID-19, he was administered a single and his testosterone- to- estradiol ratio, a marker of Providence, Rhode Island, USA 600 mg dose of the novel antiandrogen proxalutamide. 4 metabolic and inflammatory disease when below Applied Biology Inc, Irvine, Twenty-four hours after administration of this dose, 13.3 validated in athletes, was 7.2.4–9 California, USA marked improvement of symptoms and markers of Based on the lack of androgenic alopecia (AGA) disease severity were observed. To our knowledge, this is clinically, the lower influence of length of AGA Correspondence to Dr Carlos G Wambier; the first case that potentially links anabolic steroid use to at his age, the lack of clinical signs of a genetic carlos_ wambier@ brown. edu COVID-19 disease severity. predisposition for severe COVID-19 based on angiotensin- converting enzyme 2 (ACE2) polymor- Accepted 15 February 2021 phisms since both of his parents did not require any BACKGROUND treatment; the fact that his father has grade 3- to-4 Men have been shown to be disproportionately AGA, obesity, hypertension and type 2 diabetes affected by COVID-19, an observation that may be mellitus, and his mother is an overweight, post- partially explained by androgen- mediated suscep- menopause smoker, and none of them developed tibility to the disease. Previous studies have found any symptom other than anosmia, ageusia and dry that sensitivity to androgens may be associated with cough (his father had the cough, his mother did severe symptoms, prompting investigations on the not), which makes it unlikely that he had unfavour- http://casereports.bmj.com/ use of antiandrogens as COVID-19 therapy. The able variants of ACE2. effects of antiandrogen therapy in patients with COVID-19 taking anabolic steroids have not been described previously. TREATMENT During the visit, the patient agreed to be treated CASE PRESENTATION with a single 600 mg dose of the antiandrogen An otherwise healthy 28- year-old man presented to proxalutamide followed by 200 mg daily proxalut- an outpatient clinic with shortness of breath, cough, amide for 7 days, after the physician administering rhinorrhea, muscle pain, arthralgia, fatigue, dizziness, the antiandrogen explained possible risks, and the diarrhoea and anosmia, and he was diagnosed with patient signed an informed consent for the use of on September 30, 2021 by guest. Protected copyright. COVID-19 confirmed by real- time reverse transcrip- proxalutamide for the treatment of his COVID-19 tion PCR test for SARS- CoV-2. The patient reported infection. rapidly worsening physical symptoms over the past 4 days. He did not suffer from any known preex- isting conditions. The patient reported being a body- OUTCOME AND FOLLOW-UP builder and had been using oxandrolone 40 mg/day Twenty- four hours after initially presenting to during the 30 days before this visit. He was taking the clinic, the patient returned to the clinic for nitazoxanide 500 mg two times a day and azithro- a follow-up examination. A substantial clinical mycin 500 mg/day since the beginning of symptoms, improvement of symptoms was observed, including with persistence and worsening of the symptoms in complete cessation of cough, fatigue and anosmia. the following 2 days. He denied using other medi- SpO2 improved to 98%, CRP level dropped to © BMJ Publishing Group 0.45 mg/L, ESR lowered to 2 mm/hour, ferritin Limited 2021. No commercial cations or other hormones (such as testosterone or re-use . See rights and growth hormone). The patient weighed 79 kg had a decreased to 125.7 ng/mL and CK-MB fell to permissions. Published by BMJ. body mass index of 26.1 kg/m2 and did not present 5.46 ng/mL. 1–3 During a follow-up period of 4 weeks, the To cite: Cadegiani F, Lin EM, with acne or the ‘Gabrin’ sign. Goren A, et al. BMJ Case patient remained asymptomatic and presented Rep 2021;14:e241572. INVESTIGATIONS with no treatment side effects. Since this patient doi:10.1136/bcr-2021- The patient was at stage 2 of the WHO Clin- was followed in an outpatient setting, and we 241572 ical Outcome Scale and also Brescia respiratory followed up with him closely, no CT scan was Cadegiani F, et al. BMJ Case Rep 2021;14:e241572. doi:10.1136/bcr-2021-241572 1 Case report BMJ Case Rep: first published as 10.1136/bcr-2021-241572 on 26 February 2021. Downloaded from necessary. No additional medications were given due to his castrate resistant prostate cancer and an accumulated dose of rapid improvement. 24 g in 8 weeks.25 In addition, proxalutamide is under inves- tigation for early antiandrogenic therapy for COVID-19, with positive interim results when used at a dose of 200 mg/ DISCUSSION day until full recovery of symptoms, in a randomised, double- Anabolic androgen steroids (AAS) and performance-enhancing blinded, placebo-controlled trial, with 0% hospitalisation rate drugs have been previously reported to trigger severe viral compared with the 27% hospitalisation rate with standard- of- pneumonia with acute respiratory distress syndrome in young care therapy.26 10 11 patients. Oxandrolone at 40 mg/day is not considered to be To the best of our knowledge, this is the first case report of a a very high dose of this synthetic, nonaromatisable androgen young, otherwise healthy patient taking anabolic steroids with 12 that is regarded as a dihydrotestosterone (DHT) analogue. severe COVID-19 symptoms that were successfully treated using DHT is known to promote the expression of transmembrane antiandrogen therapy. serine protease 2 (TMPRSS2), and androgen signalling regu- 13 lates SARS- CoV-2 infectivity. TMPRSS2 plays a crucial role Patient’s perspective in COVID-19 infectivity and pathogenesis since COVID-19 employs it for spike protein priming before it is internalised 14 When asked to describe his experience, the patient reported in an ACE2-faci litated fashion. DHT significantly increases that ‘before I started the treatment for COVID-19, I was taking ACE2 levels and internalisation of recombinant SARS-CoV -2 oxandrolone. I noticed a great improvement with suspension spike protein, and antiandrogens reduced SARS- CoV-2 infec- 13 of oxandrolone and the start of the treatment prescribed. From tion in human embryonic cell-derived lung organoids. The 1 day to the next, I already felt much better. This was a great relationship between androgens and COVID-19 is supported improvement’. by the epidemiological corroboration that prepubertal children are rarely affected by clinically severe COVID-19.15 Addition- ally, COVID-19 is unproportionally more severe among men Learning points compared with women, among AGA men compared with non- AGA men, hyperandrogenic women compared with nonhyper- ► Anabolic steroids may increase risk of COVID-19 disease androgenic women and androgen deprivation therapy- driven severity. suppressed men compared with nonsuppressed men affected ► Early administration of a potent antiandrogen markedly by prostate cancer.16–18 A recently published study also found improved symptoms and laboratory markers of disease that the antiandrogen enzalutamide suppressed SARS- CoV-2 severity. entry into human lung cells.19 Furthermore, dutasteride, a ► Early antiandrogen therapy in patients with increased 5- alpha- reductase inhibitor commonly used to treat benign pros- androgen activity (such as those taking anabolic steroids tate hyperplasia and androgenetic alopecia by suppressing DHT or with the Gabrin sign) may contribute to reduction of production, has been previously observed to reduce symptoms symptoms and severity of COVID-19. 20 21 and severity of COVID-19. Findings from the NCT04729491 http://casereports.bmj.com/ trial, a double- blinded, placebo-controlled randomised clinical Contributors FC, AG and CGW were involved in the conception and design of trial, found that early antiandrogen therapy with dutasteride has the work. FC acquired data and provided care to the case. FC, EML, AG, CGW were been shown to reduce COVID-19 viral shedding, inflammatory involved in data analysis and interpretation, drafting the work, revising it critically for responses and time- to- remission.22 A cohort of 32 men with important intellectual content, and final approval of the published version. FC, EML, median age of 52 undergoing testosterone replacement therapy AG and CGW agree to be accountable for all aspects of the work.