Effects of 5‐alpha reductase inhibitors on lung function: A reason for discontinuation during COVID‐19 pandemic?

Dear Editor,

Goren and colleagues have written an informative article on how androgens may be implicated in coronavirus disease 2019 (COVID‐19) severity. ¹ They detailed that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) cell entry depends on priming of a viral spike surface protein by transmembrane protease serine 2 (TMPRSS2) that is present in the host. In type II pneumocytes, TMPRSS2 expression is associated with an increase in androgen receptor (AR) expression due to AR‐regulated TMPRSS2 gene. ² Furthermore, angiotensin‐converting enzyme 2 (ACE2) is the attachment molecule to the viral spike surface protein, and an androgen decrease has been associated with reduced ACE2 activity. ³ Based on the abovementioned observations, the authors suggested that AR antagonists including antiandrogens such as 5‐alpha reductase inhibitors (5‐ARIs; ie, finasteride and dutasteride), androgen synthesis inhibitors, and antigonadotropins be studied in COVID‐19 as there could be a therapeutic benefit from these agents.

Finasteride is approved by the US Food and Drug Administration for androgenetic alopecia and benign prostate hypertrophy, and dutasteride for androgenetic alopecia in South Korea and Japan. ⁴ 5‐ARIs have been shown to reduce AR activity in many tissues. ¹ , ⁴ However, caution should be exercised when attempting to draw conclusions about the safety of medications such as 5‐ARIs that have variable effects on multiple tissues. Finasteride and less selective dutasteride block 5‐AR isoform 3, which is expressed in the respiratory epithelium and fibroblasts. ⁵ Interstitial pneumonia is the main cause of respiratory failure, the leading cause of death among COVID‐19 patients. Studies have shown that androgen metabolism is involved in the proper functioning of the respiratory epithelium. Restoration of surfactant layer may be controlled by the metabolism of androgens, where 5‐AR plays a definitive role. ⁶ 5‐AR minimizes androgen potential in the lungs, thus helping maintain and restore the surfactant layer. ⁷

Furthermore, alveolar repair after inflammatory lung disease requires close contact between fibroblasts and lung epithelial cells, ⁸ and androgens have been reported to disrupt such communication. ⁹ It is thought that disruption of communication between fibroblasts and alveolar type II cells occurs via transforming growth factor beta and epidermal growth factor receptor signaling pathways. ¹⁰ As the respiratory epithelium regeneration mechanisms are activated during inflammatory states such as pneumonia, 5‐ARIs may hamper such regeneration by disrupting androgen metabolism. ⁶ Therefore, inhibition of 5‐AR may result in impairment of regeneration capacity of the respiratory epithelium and prolonged or complicated recovery that can be associated with increased mortality.

Based on the aforementioned observations, finasteride and dutasteride may disrupt androgen metabolism in the lungs, which could aggravate respiratory disease in COVID‐19 and thus have a negative impact in the course of the disease. ⁶ It would be worth performing a review of records of male COVID‐19 patients for 5‐ARI use including those that developed severe COVID‐19‐related respiratory disease and deceased patients. Such study could allow clarifying whether 5‐ARI use may be associated with worse respiratory disease. Healthcare providers may consider discontinuing 5‐ARIs such as finasteride during the COVID‐19 pandemic at least in those individuals tested positive for SARS‐CoV‐2 and those at high risk for the disease.

CONFLICT OF INTEREST

The author declares no conflict of interest.

Kroumpouzos G. Effects of 5‐alpha reductase inhibitors on lung function: A reason for discontinuation during COVID‐19 pandemic? Dermatologic Therapy. 2020;33:e13535. 10.1111/dth.13535