Diabetes as a potential compounding factor in COVID-19-mediated male subfertility

Abstract

Recent work indicates that male fertility is compromised by SARS-CoV-2 infection. Direct effects derive from the presence of viral entry receptors (ACE2 and/or CD147) on the surface of testicular cells, such as spermatocytes, Sertoli cells, and Leydig cells. Indirect effects on testis and concentrations of male reproductive hormones derive from (1) virus-stimulated inflammation; (2) viral-induced diabetes, and (3) an interaction between diabetes and inflammation that exacerbates the deleterious effect of each perturbation. Reproductive hormones affected include testosterone, luteinizing hormone, and follicle-stimulating hormone. Reduction of male fertility is also observed with other viral infections, but the global pandemic of COVID-19 makes demographic and public health implications of reduced male fertility of major concern, especially if it occurs in the absence of serious symptoms that would otherwise encourage vaccination. Clinical documentation of COVID-19-associated male subfertility is now warranted to obtain quantitative relationships between infection severity and subfertility; mechanistic studies using animal models may reveal ways to mitigate the problem. In the meantime, the possibility of subfertility due to COVID-19 should enter considerations of vaccine hesitancy by reproductive-age males.

The influence of SARS‐CoV‐2 on male reproduction and men's health

“…Additionally persistent fever during viral infection might contribute to oxidative stress by reducing the levels of heat shock proteins (HSP). This could exacerbate the impact of ROS on spermatogenesis 26,43 . In a prolonged state of inflammation, there is a rise in the production of inflammatory signalling molecules like interleukins (IL‐1, IL‐6, IL‐8, IL‐10, IL‐17), TNF‐α and NF‐kβ.…”

“…This could exacerbate the impact of ROS on spermatogenesis. 26,43 In a prolonged state of inflammation, there is a rise in the production of inflammatory signalling molecules like interleukins (IL-1, IL-6, IL-8, IL-10, IL-17), TNF-α and NF-kβ. This results in an escalation of reactive oxygen species (ROS) production, accompanied by an increase in polymorphonuclear leukocytes and granulocytes.…”

Diabetes-induced male infertility: potential mechanisms and treatment options

“…Under the condition of diabetes, hyperglycemia is involved in the production of systemic inflammation. Chronic inflammation can cause testicular endocrine disorder and lead to male reproductive dysfunction by releasing inflammatory cytokines or directly and independently affecting the HPG axis and/or testicular cells (Jiang et al 2022 ). For example, IL-1β and CCL2 inhibit androgen synthesis by inhibiting the activity of steroid-producing enzymes and ultimately induce apoptosis in Leydig cells (Jiang et al 2020 ).…”

“…The study found that the interaction between inflammation and diabetes further aggravates the impact of both on the male reproductive system. The related mechanisms mainly include excessive accumulation of ROS, excessive release of cortisol, decreased level of triiodothyronine, and misalignment of activin/statin/follistatin axis (Jiang et al 2022 ). In addition, hyperglycemia induces inflammation of the male reproductive system, leading to sperm damage and male infertility, and may also be associated with the repolarization of tissue macrophages from the anti-inflammatory M2-like subtype to the pro-inflammatory M1-like subtype (Tavares et al 2017 ).…”

Testicular pathological alterations associated with SARS-CoV-2 infection

“…Among men who had confirmed COVID-19 infection, a higher proportion of individuals had pre-existing conditions such as diabetes mellitus, hyperlipidemia, hypertension, and hypogonadism ( 30 ). Additionally, diabetes and obesity are associated with lowered testosterone levels, testicular dysfunction, and inflammation, which can compromise the MRT ( 31 ). Studies have found diabetic patients with severe COVID-19 are more susceptible in developing orchiepididymitis; of these cases, testicular pain leading to necrosis in the seminiferous tubule and significant calcification in the testicular artery was found during diagnosis ( 32 ), which may suggest that COVID-19 could trigger systemic vasculitis ( 33 ).…”