3.2.1 Endothelial dysfunction

Endothelial function has clearly been described as having a crucial role in maintaining erectile function. The corpora cavernosa requires dynamic, responsive, and healthy vasculature for the erectile process. After initiation, nitric oxide, prostaglandin E1 and acetylcholine are released which signal the smooth muscles of the penile arterioles to relax. This vasodilatation increases blood flow to the corporal body sinusoids which fill with blood and compress the sub-tunical venous plexus between the tunica albuginea and the peripheral sinusoids, thus reducing venous outflow. The stretching of the tunica occludes emissary veins to further decrease venous outflow to a minimum to allow for corporal engorgement and the complete erection [10].

SARS-CoV-2 has extensive evidence for its deleterious effects on blood vessels. In the wake of the disease, scientists have now found that that the virus affects the vascular system as much as it does the respiratory system. Most well-known are the endothelial dysfunction that leads to deep vein thrombosis and subsequent life-threatening pulmonary emboli. The corporal bodies require patent and healthy blood vessels for the dynamic erectile process as described. It has been uncovered that endothelial cells in the corpus cavernosa contain the protein angiotensin-converting enzyme 2 (ACE2) receptor. This receptor is also found in the lungs and is key to the pathological mechanism of COVID-19 causing respiratory distress [11]. SARS-CoV-2 uses the ACE2 receptor to facilitate entry into these target endothelial cells. This is mediated by transmembrane serine protease 2 and cathepsin L which helps cleave the viral particle permitting engagement with the receptor. Studies examining vascular beds of respiratory tissue in COVID-19 patients reveals widespread endothelial activation and associated microangiopathy and thrombosis with angiogenesis. Comparing these findings with lung samples of influenza virus which are absent of these vascular changes confirms this process to be specifically a SARS-CoV-2 sequalae and not merely a viral effect [12, 13].

The endothelium possesses an extremely intricate and complex set of properties to sustain an immaculate homeostasis. Unlike other tissues, endothelium has the unique quality of maintaining blood in the liquid form and prevents the formation of clotting and coagulation cascades to sustain life. These endothelial cells are lined with heparin sulfate proteoglycans, thrombomodulin and prostacyclins promoting anticoagulant properties at the lumen wall. In conjunction with these factors, the endothelial cells also produce tissue-type plasminogen activator and uro-kinase plasminogen activator forming pro-fibrinolytic properties to inhibit clot formation and platelet aggregation [14]. Other essential components required for erection are dynamic vasodilation for crucial corpus cavernosa filling. This is facilitated by nitric oxide, endothelial-derived hyperpolarizing factor and prostacyclin.

SARS-CoV-2 effectively counteracts many of these protective mechanisms. The virus acts directly on these endothelial cells by binding and entering triggering widespread cytopathic effects by reducing VE-Cadherin, degrading basement membranes resulting in endothelial sloughing and death. It also acts indirectly on the cells by triggering a pro-inflammatory cytokine storm which leads to excessive production of the ligands interleukin (IL)-1α, IL-6 and tumour necrosis factor (TNF)-α [15]. Tissue factor, thromboxane, cluster of differentiation (CD)40 ligand are all expressed in response to these stressors triggering pathological pro-coagulant pathways leading to microthrombi of the vessels [16]. There is evidence these microthrombi can infarct capillary beds and end arterioles leading to resistance in blood flow to the corpora. Much like the heart in pro-inflammatory, pro-coagulant conditions; blood supply to the end organ is restricted resulting in ED. The vasodilatory mechanisms are also affected as the inflammatory cytokines and cellular damage causes a shift in the arachidonic acid pathway, decreasing prostacyclin production and increasing production of thromboxane A2 [14]. The high circulating levels of thromboxane have strong vasoconstrictive properties which lead to insufficient filling of the corporal bodies to impede formation of a full erection.

These mechanisms which have been studied extensively in other areas of the body are likely how SARS-CoV-2 causes ED. This local effect on blood vessels however is likely not the sole organic mechanism through which the virus affects erectile function.

3.2.2 COVID-19 related Hypogonadism

Growing evidence supports an endocrine dysfunction model as a secondary causative agent for ED in COVID-19 infection. Studies have emerged showing an acquired hypogonadism is present in up to 90% in males admitted to hospital with COVID-19 [17]. The ACE2 receptor is demonstrated to be readily expressed on cells of the testes including spermatogonia, Sertoli cells and Leydig cells which are crucial in testosterone production [18, 19, 20]. The ACE2 gene is essential in steroidogenesis as ACE2 knockout mice studies exhibit spermatogenesis and hormonal dysregulation [20]. The proposed mechanism COVID-19 related hypogonadism results from destruction and damage of Leydig cells via direct and indirect viral mechanisms. Leydig cells are the major site for testosterone production. The release of luteinizing hormone (LH) from the pituitary gland stimulated G protein-coupled receptors causing increases in cyclic adenosine 3′, 5′-cyclic monophosphate (cAMP) formation which leads to cholesterol conversion to testosterone which releases the steroid hormone to circulate. Damage and destruction to these cells causes reduced synthesis of testosterone.

The effects of testosterone on erectile function are broad and likely act in a multitude of processes. Firstly, central effects of testosterone are important in initiating the erectile process. Several areas in the brain including the hypothalamus, medial preoptic area and most importantly the amygdala all express androgen receptors. These areas facilitate sexual behaviours in presence of appropriate stimuli. This is demonstrated clinically in studies of patients with low testosterone correlating with significant reductions in sexual desire and libido [21]. Conversely, testosterone therapy can significantly improve ED [22]. In fact, self-defined unfaithful men were found to have significantly higher androgen levels than their faithful counterparts [23].

Low testosterone is also closely linked with metabolic syndrome as well. This syndrome constitutes a combination of known ED risk factors including dyslipidaemia, hypertension, hyperglycaemia and obesity. All these conditions are risk factors for developing ED. Lastly, although considered modest, testosterone also has a positive impact on the enzymatic steps necessary for the initiation of the erectile process. Testosterone is shown to have positive effects on nitric oxide which is essential for vasodilation of arterioles and filling of the corporal bodies [24]. Immunohistochemical analyses have revealed reduced nitric oxide expression in the corpora cavernosum of COVID-19 infected men compared to non-infected men [25]. Testosterone is also important for mediating inhibition of RhoA-Rho-kinase located in the corporal bodies which leads to vasodilatation of arterioles further facilitating erectile function. Low testosterone levels are associated with significantly raised levels of RhoA and Rho-kinase in the corpora cavernosa. These increased levels prevent the relaxation of penile smooth muscle and vasodilatation to initiate a complete erection [26].

3.2.3 Other factors

The influence of COVID-19 on erectile function should not solely be put down to its biological effects on the erectile process. As many are aware, the pandemic has led to a multitude of psychosocial factors that indirectly influence not only erectile function but sexual activities. In the wake of a natural disaster such as earthquake and flooding, there is well documented evidence that sexual function in males and females drops markedly [27, 28]. COVID-19 is no different as we see anxiety related to the pandemic and certain lifestyle and financial stressors plays a large role on sexual function. Isolating at home also changes the relationship dynamics where intimacy can be affected with the “over-exposure” to each other. Other factors to consider are deterioration in general health and wellbeing from the virus impacting cardiovascular health and thus erectile function. Furthermore, mental health deterioration also heavily contributes to the reduction in erectile function and sexual activities in the population.

Future research should create large scale prospective trials to assist with further correlating the link between COVID-19 and ED. Moreover, further studies utilising electron microscopy to characterize the SARS-CoV-2 replication cycle and pathological mechanisms within penile tissues would be beneficial in uncovering more about pathogenesis behind COVID-19 related ED.