The field of Reproductive Medicine saw many plans put on hold in the wake of Covid-19. Not much was known about the impact of the disease on the reproductive system, fertility and assisted reproductive medicine. However, with an intensification into researching the effects of the virus on reproductive health, insights are slowly emerging to help in the management of Reproductive Medicine during this crisis and beyond.

Research has shown that the SARS-CoV-2 infection employs the angiotensin-converting enzyme 2 (ACE2) receptor in the renin-angiotensin system (RAS) for viral entry in cells (Sriram et al., 2020). This same ACE2 receptor is present in the reproductive system and, unsurprisingly, numerous reports have been made regarding the influence of Covid-19 on the reproductive system of both men and women. (Li Y., et al., 2020). 

Although ACE2 is found throughout the female reproductive system, it is mostly present in the ovaries, making them potential targets for damage by SARS-CoV-2 (Yan et al., 2020). The downregulation of ACE2 by SARS-CoV-2 may cause alterations in normal ovarian physiology, such as follicular development and oocyte maturation, impacting oocyte quality and fertility. Oxidative stress is also increased by angiotensin-2 (Ang II), as it exerts pro-inflammatory effects, possibly detrimental to reproductive ability (Pan et al., 2013). The RAS complex is also significantly present in the uterus, mostly confined to the epithelial and stromal cells of the endometrium. Therefore, if COVID-19 damages endometrial epithelial cells, it may affect early embryo implantation (Li R. et al., 2020). 

A normal level of Ang II expression is also crucial for maintaining regular menstrual cycles and endometrial activity, as it facilitates regeneration of blood vessels and the endometrium and initiates menstruation. Endometrial and myometrial activities including endometrial regeneration, proliferation, fibrosis, and stromal proliferation are regulated by the intricate balance of Ang II and Ang-(1-7) in the uterus - stimulated by Ang II and inhibited by Ang-(1-7). SARS-CoV-2 Infection of the uterus may severely disrupt such balance. In fact, disruption of Ang II levels has been found to be related to dysfunctional uterine bleeding associated with hyperplastic endometrium (Yan et al., 2020). In the fallopian tubes, Ang II has been found in the endothelium and stroma (Herr et al., 2013). The function of Ang II in these tissues remains unclear, but one study reported that it stimulates the ciliary beat frequency in epithelial cells (Vinson et al., 1997, Yan et al., 2020).

Although studies regarding vertical transmission are controversial, and there is insufficient evidence to confirm transplacental COVID-19 infection, concerns exist about possible detrimental effects of SARS-CoV-2 infection on pregnancy. Expression of ACE2 is higher in the placenta than in the lungs, further substantiating the risk of placental SARS-CoV-2 infection. Low placental ACE2 and Ang-(1-7) have been reported to be associated with intrauterine growth restriction, an outcome that has also been observed in pregnant women with COVID-19. These findings suggest that placental COVID-19 infection may have severe implications for pregnancy outcomes (Yan et al., 2020).

Therefore, considering evidence obtained so far, although COVID-19 has not yet been reported to damage female fertility, its potential detrimental effects cannot be ignored. If patients who recover from COVID-19 undergo ART, it is unknown whether their oocyte quality, quantity, and other parameters will be affected, nor is the duration of abnormality. Further research will most certainly be needed to assess these parameters.

In the male reproductive system, some parts of the testis have been found to contain ACE2 (the spermatogonia, Leydig cells, and Sertoli cells), rendering them potential SARS-CoV-2 targets. The Leydig cells, Sertoli cells, and seminiferous tubules also contain Ang-(1-7) receptor. Infertile men with severely impaired spermatogenesis have lower ACE2 and Ang-(1-7) receptor levels compared with fertile men. As Leydig cells are responsible for steroidogenesis and secretion, particularly testosterone, ACE2 and Ang-(1-7) expression in Leydig cells strongly suggests their potential roles in the regulation of steroidogenesis and secretion, spermatogenesis, and hence their influence on male fertility (Pan et al., 2013, Younis et l., 2020).

Multiple studies have also reported a high risk of male patients with COVID-19 developing orchitis-like symptoms, suggesting viral orchitis. A histological study of 12 testes of deceased patients with COVID-19 revealed characteristics of viral orchitis, lymphocytic infiltration, seminiferous tubular injury, reduced numbers of Leydig cells, vascular congestion and extensive germ cell destruction (Singh et al., 2020). As COVID-19 is associated with coagulopathy, the orchitis could have resulted from vasculitis (Corona et al., 2020). Furthermore, the possibility of orchitis leading to infertility as a complication of infection with coronaviruses, such as SARS-CoV-1, is widely accepted (Xu et al., 2006, Sefars et al., 2020). Importantly, Inflammatory infiltration may disrupt spermatogenesis, impede steroidogenesis, and destroy cells in seminiferous tubules (Paoli et al., 2020). In fact, much evidence has been presented that highlights hormonal changes in patients with COVID-19. 

Studies have revealed significant increases in serum luteinising hormone (LH) and prolactin levels among male patients with COVID-19. A significant decrease in testosterone to LH ratio and follicle-stimulating hormone to LH ratio were also reported. The hypothesis has been presented that the LH increase in COVID-19 resulted from the early stage of impaired testosterone production and was caused by reduction of Leydig cells (Illiano et al., 2020). Therefore, considering the risk of clinical hypogonadism as the disease progresses, it is important to perform follow-up with post-recovery patients for at least 3 to 6 months, with serum LH and testosterone-to- LH ratio serving as clinical indicators of primary hypogonadism (Verma et al., 2020).

As well as focussing on women who have SARS-CoV-2 infection, or who have recently recovered from it, the implications on the outcomes of ART on men must also be seriously taken into consideration. 

Infection and viral-mediated immune response to SARS-CoV-2 may disrupt steroidogenesis, spermatogenesis and destroy cells of the seminiferous tubules (Paoli et al., 2020, Younis et l., 2020). Semen samples of patients with moderate SARS-CoV-2 infection were shown to have significantly lower sperm concentration, lower total number of sperm per ejaculation, lower total number of motile sperm, and lower total number of progressively motile sperm than normal patients (Khalili et al., 2020). In combination with the risk of sexual transmission, the consideration of deferring conception in recovered patients until more evidence is available should be taken seriously. Most recent recommendations advise that sperm donation/cryopreservation of active/recovered COVID-19 patients should be avoided, as many viruses remain viable and infectious when cryopreserved (Yakass and Woodward 2020). 

According to most recent guidelines, specific protocols should be implemented regarding screening and management of patients, both women and men, undertaking ART during the COVID-19 pandemic (ESHRE guidelines 2020). A risk assessment for all patients accessing ART is also recommended. For example, there is an increased risk of lung and kidney complications if patients with COVID-19 develop ovarian hyperstimulation syndrome during ovarian stimulation (La Marca et al., 2020). As a general recommendation, a shared decision between doctors and patients should be made concerning fertility care in this period. Patients are allowed to decide autonomously whether to resume or postpone ART treatment, but it is the doctors’ responsibility to counsel them on all the risks and benefits involved. Individualisation of patients’ ART treatment is the key to safe practice during this ongoing COVID-19 pandemic (Lee et al., 2021).