Potential risk for developing severe COVID-19 disease among anabolic steroid users.

A severe case of COVID-19 was observed in an otherwise healthy 28-year-old man who had taken oxandrolone 40 mg/day as an anabolic steroid. The patient had been taking oxandrolone for enhanced bodybuilding 30 days prior to presenting to an outpatient clinic with COVID-19 symptoms. The patient reported that his symptoms have rapidly worsened over the course of 4 days prior to presenting at the clinic. As part of an experimental antiandrogen treatment for hyperandrogenic men suffering from COVID-19, he was administered a single 600 mg dose of the novel antiandrogen proxalutamide. Twenty-four hours after administration of this dose, marked improvement of symptoms and markers of disease severity were observed. To our knowledge, this is the first case that potentially links anabolic steroid use to COVID-19 disease severity. © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Background

Men have been shown to be disproportionately affected by COVID-19, an observation that may be partially explained by androgen-mediated susceptibility to the disease. Previous studies have found that sensitivity to androgens may be associated with severe symptoms, prompting investigations on the use of antiandrogens as COVID-19 therapy. The effects of antiandrogen therapy in patients with COVID-19 taking anabolic steroids have not been described previously.

Case presentation

An otherwise healthy 28-year-old man presented to an outpatient clinic with shortness of breath, cough, rhinorrhea, muscle pain, arthralgia, fatigue, dizziness, diarrhoea and anosmia, and he was diagnosed with COVID-19 confirmed by real-time reverse transcription PCR test for SARS-CoV-2. The patient reported rapidly worsening physical symptoms over the past 4 days. He did not suffer from any known preexisting conditions. The patient reported being a bodybuilder and had been using oxandrolone 40 mg/day during the 30 days before this visit. He was taking nitazoxanide 500 mg two times a day and azithromycin 500 mg/day since the beginning of symptoms, with persistence and worsening of the symptoms in the following 2 days. He denied using other medications or other hormones (such as testosterone or growth hormone). The patient weighed 79 kg had a body mass index of 26.1 kg/m2 and did not present with acne or the ‘Gabrin’ sign.1–3

Investigations

The patient was at stage 2 of the WHO Clinical Outcome Scale and also Brescia respiratory stage 1 but rapidly progressed to further stages. His oxygen saturation was unusually low given his lack of pre-existing disorders and the fact that he practised a variety of sports at the level of a professional athlete. His blood oxygen saturation (SpO2) was 92%, C reactive protein (CRP) level was 20.13 mg/L, erythrocyte sedimentation rate (ESR) was 10 mm/hour, ferritin was 299.4 ng/mL and creatine kinase-MB (CK-MB) was 7.95 ng/mL. The patient’s testosterone levels were 132.6 ng/dL and his testosterone-to-estradiol ratio, a marker of metabolic and inflammatory disease when below 13.3 validated in athletes, was 7.2.4–9

Based on the lack of androgenic alopecia (AGA) clinically, the lower influence of length of AGA at his age, the lack of clinical signs of a genetic predisposition for severe COVID-19 based on angiotensin-converting enzyme 2 (ACE2) polymorphisms since both of his parents did not require any treatment; the fact that his father has grade 3-to-4 AGA, obesity, hypertension and type 2 diabetes mellitus, and his mother is an overweight, postmenopause smoker, and none of them developed any symptom other than anosmia, ageusia and dry cough (his father had the cough, his mother did not), which makes it unlikely that he had unfavourable variants of ACE2.

Treatment

During the visit, the patient agreed to be treated with a single 600 mg dose of the antiandrogen proxalutamide followed by 200 mg daily proxalutamide for 7 days, after the physician administering the antiandrogen explained possible risks, and the patient signed an informed consent for the use of proxalutamide for the treatment of his COVID-19 infection.

Outcome and follow-up

Twenty-four hours after initially presenting to the clinic, the patient returned to the clinic for a follow-up examination. A substantial clinical improvement of symptoms was observed, including complete cessation of cough, fatigue and anosmia. SpO2 improved to 98%, CRP level dropped to 0.45 mg/L, ESR lowered to 2 mm/hour, ferritin decreased to 125.7 ng/mL and CK-MB fell to 5.46 ng/mL.

During a follow-up period of 4 weeks, the patient remained asymptomatic and presented with no treatment side effects. Since this patient was followed in an outpatient setting, and we followed up with him closely, no CT scan was necessary. No additional medications were given due to his rapid improvement.

Discussion

Anabolic androgen steroids (AAS) and performance-enhancing drugs have been previously reported to trigger severe viral pneumonia with acute respiratory distress syndrome in young patients.10 11 Oxandrolone at 40 mg/day is not considered to be a very high dose of this synthetic, nonaromatisable androgen that is regarded as a dihydrotestosterone (DHT) analogue.12 DHT is known to promote the expression of transmembrane serine protease 2 (TMPRSS2), and androgen signalling regulates SARS-CoV-2 infectivity.13 TMPRSS2 plays a crucial role in COVID-19 infectivity and pathogenesis since COVID-19 employs it for spike protein priming before it is internalised in an ACE2-facilitated fashion.14 DHT significantly increases ACE2 levels and internalisation of recombinant SARS-CoV-2 spike protein, and antiandrogens reduced SARS-CoV-2 infection in human embryonic cell-derived lung organoids.13 The relationship between androgens and COVID-19 is supported by the epidemiological corroboration that prepubertal children are rarely affected by clinically severe COVID-19.15 Additionally, COVID-19 is unproportionally more severe among men compared with women, among AGA men compared with non-AGA men, hyperandrogenic women compared with nonhyperandrogenic women and androgen deprivation therapy-driven suppressed men compared with nonsuppressed men affected by prostate cancer.16–18 A recently published study also found that the antiandrogen enzalutamide suppressed SARS-CoV-2 entry into human lung cells.19 Furthermore, dutasteride, a 5-alpha-reductase inhibitor commonly used to treat benign prostate hyperplasia and androgenetic alopecia by suppressing DHT production, has been previously observed to reduce symptoms and severity of COVID-19.20 21 Findings from the NCT04729491 trial, a double-blinded, placebo-controlled randomised clinical trial, found that early antiandrogen therapy with dutasteride has been shown to reduce COVID-19 viral shedding, inflammatory responses and time-to-remission.22 A cohort of 32 men with median age of 52 undergoing testosterone replacement therapy diagnosed with COVID-19 showed a very high hospitalisation (62.5%) and fatality rate (9.4%).23

A previously reported series of 11 young women and 2 young men taking oxandrolone or tranexamic acid for hereditary angioedema-reported COVID-19 symptom frequency of anosmia/dysgeusia of 77% and dyspnoea of 31%.24 In a communication with the authors, at their hereditary angioedema clinic, oxandrolone is prescribed at lower dosages (4–5 mg/day) for angioedema prophylaxis, and the only woman who required hospitalisation was not using oxandrolone. We raise the possibility that DHT-derived AAS may lead to increased disease severity in a dose-dependent manner.

This case describes concerning, evident progression of COVID-19 in an otherwise healthy man; such progression is unlikely to be due to other risk factors other than the misuse of AAS. The speed of disease progression could have led to more severe states that could require hospitalisation and intensive care admission for mechanical ventilation. The rationale for the choice of high-dose proxalutamide was based on the level of androgenic toxicosis caused by the unsafe usage of the DHT-derived steroid, oxandrolone, which required a plausible specific therapeutic option with biological rationale. Proxalutamide is reportedly the strongest antiandrogen agent, with an established safety profile in previous phase II studies for castrate resistant prostate cancer and an accumulated dose of 24 g in 8 weeks.25 In addition, proxalutamide is under investigation for early antiandrogenic therapy for COVID-19, with positive interim results when used at a dose of 200 mg/day until full recovery of symptoms, in a randomised, double-blinded, placebo-controlled trial, with 0% hospitalisation rate compared with the 27% hospitalisation rate with standard-of-care therapy.26

To the best of our knowledge, this is the first case report of a young, otherwise healthy patient taking anabolic steroids with severe COVID-19 symptoms that were successfully treated using antiandrogen therapy.

When asked to describe his experience, the patient reported that ‘before I started the treatment for COVID-19, I was taking oxandrolone. I noticed a great improvement with suspension of oxandrolone and the start of the treatment prescribed. From 1 day to the next, I already felt much better. This was a great improvement’.

Anabolic steroids may increase risk of COVID-19 disease severity.

Early administration of a potent antiandrogen markedly improved symptoms and laboratory markers of disease severity.

Early antiandrogen therapy in patients with increased androgen activity (such as those taking anabolic steroids or with the Gabrin sign) may contribute to reduction of symptoms and severity of COVID-19.