Potential Impact of COVID-19 on Female Reproductive Health

COVID-19 has emerged as the biggest pandemic of the world of all times. Its death toll is rising globally. COVID-19 mostly affects the lungs because the virus enters the host cells via the receptor for the ACE2 enzyme, which is also present in other organs of the human body. ACE2 plays the main role in the degradation of Ang II, resulting in the formation of angiotensin 1-7 (Ang 1-7) which maintains the level of Ang II. This communication gives an assessment of reproductive system functioning and its effects by the COVID-19 exposure. It is important to maintain the wellbeing for healthy nourishment of the fetus and safe delivery along with post health issues. ACE2 enzyme metabolism is expressed in the female reproductive system, and it may be potential target of COVID-19 exposure.


I N T R O D U C T I O N
Pneumonia cases of unknown etiology in the Wuhan city of China were reported in December, 2019 to the world health organization (WHO) and spread rapidly throughout the world (Wastnedge et al., 2021). Literature search shows that COVID-19 not only affects the female fertility but also damages the female reproductive functions (Jing et al., 2020;Li et al., 2020).
COVID-19 enters the target host cell by binding to the angiotensin converting enzyme II receptor, which is used as a primary receptor binding to the host cell (Matsuyama et al., 2010;Zhou et al., 2015), and the expression of angiotensin converting enzyme II is regulated in the host cells (Jing et al., 2020), as shown in the Figure 1. Angiotensin converting enzyme has been evaluated in the female reproductive system such as the ovaries, uterus, vagina and placenta and also in the other parts of the human body, including the respiratory tract, kidneys, heart and gastrointestinal system (Lippi et al., 2020). Notably, the angiotensin converting enzyme plays a regulatory role in reproduction (Fu et al., 2020) and may be disturbed by attacking ovarian tissue or destroying endometrial epithelial cells (Li et al., 2021). For COVID-19, Basigin is also considering as one of the most important receptors expressed in the uterus, in the stroma, and also in the ovary granulosa cells (Chen et al., 2010;Mahdian et al., 2020).

Female reproductive system
COVID-19 may affect the female reproductive system through invading the target cells, by binding to ACE2 (angiotensin-converting enzyme II). ACE2 usually maintains the levels of angiotensin II and angiotensin (1-7) to apply its special action, which is widely expressed in the vagina, uterus, ovaries and placenta. The reason of female fertility is the ovarian reserve, which could affect fecundity by decreasing egg quality when diminished (Steiner et al., 2017). Hence, the function of ovarian reserve for the impact of COVID-19 is the primary observation indicator on female fertility. Additionally, to explore heterogeneity we must include the type of fertility decline, age, the subgroup analyses and sensitivity studies are conducted. It is believed that fertility approximately starts at the age of thirteen and at the age of forty-nine the women begins to become infertile (Jensen et al., 2018). Female fertility declines naturally with ageing. At the age of thirty to thirty-five the decline in fertility is slow and steady. But, because of reduction in the ovarian reserve and oocyte quality, the decline increases after the age of thirty-five years (Ahmed et al., 2020).

ACE2 expressed in the ovary
In ovaries from both reproductive-age women and postmenopausal women, ACE2 mRNA transcripts were detected . From the Gene Cards, we analyzed the ACE2 data and came to know that ACE2 is extremely present in the ovary. Therefore, the ovary might be the potential target of COVID 19 (Jing et al., 2020).
The most common endocrinopathy that is polycystic ovary syndrome, mainly affects reproductive-aged women, with a frequency which may exceed 10 to 15%, according to the population studied and the criteria used for the diagnostic. COVID-19 has certain factors known to have direct associations with PCOS, including hyper-inflammation, ethnicity predisposition, hyperandrogenism, and very low vitamin-D levels. Furthermore, there is markedly high frequency of female patient populations with multiple cardio-metabolic conditions, including obesity, hypertension and type 2 diabetes, which may increase the risk of adverse COVID-19 consequences.

ACE2 expressed in uterus and vagina
In the uterus of both human (Vaz-Silva et al., 2009) and rats (Brosnihan et al., 2012), there is ACE2 mRNA, and the presence of ACE2 has been confirmed after analyzing the report from the Swedish based program and Human Genes database (Jing et al., 2020). In the regeneration of endometrium, vascular bed, menstruation initiation through spiral artery vasoconstriction, Angiotensin II plays a double role (Ahmed et al., 1995). Furthermore, Ang II enhances the endometrial fibrosis and also increases the stroma cells and proliferation of uterus epithelium (Shan et al., 2014;. In the endometrium, Angiotensin II functions for normal menarche, and sometimes alteration and dysfunctional uterine bleeding related with hyperplastic endometria (Li & Ahmed, 1996).

ACE2 expressed in pregnancy
All Angiotensin II, angiotensin (1-7) and ACE2 function mainly during pregnancy through regulating fetus formation and regulating blood pressure (Hering et al., 2010). Both ACE2 and angiotensin (1-7) act as a paracrine regulator in the early and late events of pregnancy (Neves et al., 2008). To control and balance the hydro-salinity and blood pressure of a pregnant women, ACE2 hydrolyzes angiotensin II into angiotensin (1-7), and angiotensin I hydrolyzes into angiotensin (1-9) and changes to angiotensin (1-7) (Pringle et al., 2011). To the pregnant women and fetuses, COVID-19 infection poses a high threat and causes fetal distress, premature birth and rupture of fetal membranes and caesarean section (Chen et al., 2020a;Zhu et al., 2020). Women brought to the labor ward should be checked according to the symptoms of COVID 19 and must be divided into separate ward based on the condition of their COVID report shown in the Figure 2.

C O N C L U S I O N
COVID-19 may infect the female reproductive system through the expression of ACE2 enzyme present in the different parts of the human body, which may cause fetal distress, menstrual disorder and infertility. Pregnant women should take the suitable measures and precautions during routine check-ups and visits to the hospital and labor ward.

C O N F L I C T O F I N T E R E S T
The authors have no conflict of interest to declare.