Effects of Coronavirus Disease 2019 (COVID-19), Including Its Prevention and Treatment, on the Male Reproductive System

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Effects of Coronavirus Disease 2019 (COVID-19), Including Its Prevention and Treatment, on the Male Reproductive System

The COVID-19 pandemic has raised significant concerns about its multisystemic effects, including potential impacts on the male reproductive system. The virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), binds to angiotensin-converting enzyme 2 (ACE2) receptors to enter host cells. ACE2 is abundantly expressed in the testis, with mRNA levels exceeding those in the lungs or kidneys. This distribution suggests the testis is a potential target for viral invasion, raising questions about SARS-CoV-2’s direct and indirect effects on male fertility, hormonal regulation, and reproductive health.

ACE2 Expression and Testicular Vulnerability

ACE2 plays a dual role in COVID-19 pathogenesis and male reproductive physiology. In the renin-angiotensin-aldosterone system (RAAS), ACE2 hydrolyzes angiotensin II (AngII) to generate angiotensin-(1–7) [Ang-(1–7)], which binds to Mas receptors to exert vasodilatory, anti-inflammatory, and antifibrotic effects. In the testis, ACE2 and Mas receptors are localized in seminiferous tubules and interstitial cells. Studies indicate that the ACE2-Ang-(1–7)-Mas axis regulates spermatogenesis, sperm motility, and testosterone synthesis. For instance, Mas agonists improve sperm motility in men with asthenospermia by activating the phosphoinositide 3-kinase/AKT pathway. Conversely, Mas knockout mice exhibit reduced testicular weight, abnormal spermatogenesis, and altered steroidogenic gene expression, underscoring the axis’s importance in reproductive function.

SARS-CoV-2’s high binding affinity for ACE2 may disrupt this balance. Elevated AngII levels observed in COVID-19 patients correlate with disease severity and viral load. Excess AngII promotes hypertension, which damages penile vasculature and endothelial cells, contributing to erectile dysfunction. Hypertension-induced vasoconstriction mediated by endothelin-1 further reduces penile blood flow, exacerbating sexual dysfunction.

Viral Presence in Semen and Gonadal Dysfunction

A pivotal study by Li et al. detected SARS-CoV-2 RNA in semen from 15.8% (4/25) of acute-phase patients and 8.7% (2/23) of recovering patients. This finding suggests potential testicular or epididymal infection, though viral viability and transmission risks remain unclear. Additionally, hormonal profiling revealed elevated luteinizing hormone (LH) and a reduced testosterone-to-LH ratio in infected men, indicating possible Leydig cell dysfunction. This gonadotropin elevation implies compensatory mechanisms to maintain testosterone production, but prolonged hormonal imbalance could impair spermatogenesis and fertility.

Pharmacological Impacts on Male Reproduction

COVID-19 treatments, including antivirals and immunomodulators, may exert reproductive toxicity:

  1. Ribavirin: Animal studies show reversible reductions in testosterone, spermatogenesis inhibition, and sperm DNA damage. Seminal ribavirin concentrations exceed serum levels by twofold, necessitating contraception during and for ≥8 months post-treatment.
  2. Lopinavir/Ritonavir: Rat models demonstrate oxidative testicular damage, abnormal sperm morphology, and reduced epididymal sperm counts.
  3. Chloroquine Phosphate: Disrupts spermatogenesis and epididymal function in preclinical studies.
  4. Glucocorticoids: High doses compromise the blood-testis barrier, allowing toxins to enter seminiferous tubules and induce germ cell apoptosis. Short-term, low-dose regimens pose minimal risk.

Disinfectants and Reproductive Toxicity

Chemical disinfectants widely used during the pandemic, such as chlorine compounds, peracetic acid, and phenolic agents, raise concerns about reproductive safety:

  • Chlorine-Based Disinfectants: Mice exposed to hypochlorite developed increased sperm head deformities.
  • Peracetic Acid: Linked to embryonic defects and spontaneous abortions in animal models.
  • Phenolic Compounds: Associated with developmental abnormalities in offspring.
    While 75% ethanol and diluted chlorine solutions are considered safe, improper use or excessive concentrations may harm sperm quality and embryonic development.

Psychological Stress and Semen Quality

The pandemic’s psychological toll—marked by anxiety, depression, and post-traumatic stress—adversely affects male fertility. Chronic stress activates the hypothalamic-pituitary-adrenal axis, suppressing gonadotropin-releasing hormone and downstream testosterone production. Clinical studies correlate stress with reduced semen volume (mean decrease: 0.5 mL), lower sperm concentration (12% reduction), and increased sperm DNA fragmentation (15–20% elevation). Stress-induced oxidative stress further exacerbates sperm mitochondrial dysfunction and motility impairment.

Clinical Implications and Recommendations

  1. Monitoring Gonadal Function: COVID-19 patients, particularly those with severe disease, should undergo hormonal profiling (testosterone, LH, follicle-stimulating hormone) and semen analysis post-recovery.
  2. Antiviral Therapy Precautions: Men receiving ribavirin or protease inhibitors require counseling on contraception and long-term fertility preservation.
  3. Safe Disinfection Practices: Adherence to recommended disinfectant concentrations (e.g., 0.1% sodium hypochlorite) minimizes reproductive risks.
  4. Mental Health Support: Interventions to alleviate pandemic-related stress may mitigate its negative impact on semen parameters.

Conclusion

SARS-CoV-2’s interaction with ACE2 receptors in the testis, combined with treatment-related toxicity and environmental stressors, poses multifaceted risks to male reproductive health. While direct viral invasion of the testis remains incompletely understood, pharmacological agents, disinfectants, and psychological stress demonstrably impair spermatogenesis, hormonal balance, and sexual function. Comprehensive strategies encompassing viral containment, judicious drug use, and psychological support are essential to safeguarding male fertility during and beyond the pandemic.

doi.org/10.1097/CM9.0000000000001375

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