Assisted reproduction treatment during the Covid-19 pandemic: considerations based on ovarian physiology
The consequences of SARS-CoV-2 infection on pregnancy have generated a justified and considerable discussion, although pregnancy and neonatal outcomes so far appear encouraging. Recommendations for the management of pregnant women at risk of SARS-CoV-2 infection were recently published (1, 2), followed by guidelines of ESHRE and ASRM in the context of Assisted Reproduction, advising against the commencement of new treatment cycles, with the exception of urgent fertility preservation in oncology patients (3, 4).
However, apart from the undoubtedly important considerations of the effect of SARS-CoV-2 infection on pregnancy and the fetus, it is also important to also direct our attention to ovarian physiology and consider the theoretical risks that IVF treatment may pose on fertility patients, during the Covid-19 pandemic.
It was recently reported that angiotensin-converting enzyme 2 (ACE2) is used by SARS-CoV-2 for entry into human cells (5). ACE2 has wide distribution in several human organs, including the ovary (6), and is a member of the renin-angiotensin system (RAS), which has a central role in the female reproduction system.
There is currently limited published data on the effect of ACE2 on ovarian function and female fertility, and there is no evidence of ACE2 expression in human oocytes.
ACE2 expression has been identified in primordial, primary, secondary and antral follicles, stroma, and corpora lutea of human ovaries (6). In addition, ACE2 expression is upregulated during the course of follicle development, and further increases after gonadotrophin stimulation (7), and after hCG administration in rats (8). Ovarian RAS members, including ACE2, are known to be involved in ovarian physiology, regulatingfollicular development, steroidogenesis, ovulation and atresia. ACE2 was also shown to be indirectly implicated in oocyte maturation, as an Angiotensin(1-7)-forming enzyme (8).
Therefore, it is plausible to hypothesize that controlled ovarian stimulation may have several implications for women, in the context of a potential Covid-19 infection.
Potential higher risk of Covid-19 infection through higher ACE2 expression levels
The circulating levels of soluble ACE2 are low under normal conditions but may be up-regulated in certain clinical states (9). The presence of multiple large follicles in stimulated ovaries would equate with a considerable increase of ACE2 expression. A recent paper proposed a map of ACE2 expression levels over different cell types of different organs to identify the organs with high and low vulnerability according to ACE2 expression (10). Although, the ovary was not included in the organs under investigation in that study, it is possible that increased levels of ACE2 by multiple follicles of stimulated ovaries may be putting those patients at higher risk of Covid-19 infection.
Ovarian hyperstimuation syndrome (OHSS)
Fertility patients with excessive ovarian response are at high risk for developing OHSS. Severe OHSS is infrequent in the general IVF population (0.5%-5%), but its incidence is estimated at 11%-12% in high-risk patients (11, 12). The severe form of OHSS may be critical or even life-threatening, characterized by massive ovarian enlargement, ascites, pleural effusion, oliguria, haemoconcentration, adult respiratory distress syndrome and thromboembolic phenomena, and may require hospitalization in an intensive care unit (12). Clearly, this situation should be avoided under all circumstances, and even more so during the threat of Covid-19 infection, which would render the treatment and recovery of OHSS-patients infected with Covid-19 extremely difficult.
ACE2 downregulation and disruption of ovarian RAS after Covid-19 infection
The binding of SARS-CoV-2 spike protein causes down-regulation of ACE2 expression, which remains low with continued viral infection (13, 14). In the lung, this event leads to hyperactivation of RAS and contributes to lung failure pathology, which the most common symptom observed in Sars-Cov-2 infected patients (15). In the ovary, it may be hypothesized that a decrease in ACE2 expression following SARS-CoV-2 infection may disturb ovarian RAS. Disturbances in the ovarian RAS are associated with reproductive disorders, such as polycystic ovary syndrome, OHSS, ovarian tumors and ectopic pregnancy (16). In addition, it is unknown if RAS disturbance by SARS-CoV-2 infection may have an adverse impact on oocyte maturation and ovarian reserve.
Although the above considerations are speculative and currently not supported, nor refuted, by experimental data, it is important to retain a precautionary approach in the sector of assisted reproduction. Lessons from ovarian physiology may provide useful in raising awareness and directing new research on the effect of Covid-19 on IVF treatment and overall health of women undergoing ART. Importantly, more research is necessary on the ovarian ACE2 cascade following SARS-CoV-2 infection.
- American College of Obstetricians and Gynecologists. Practice Advisory: Novel Coronavirus 2019 (COVID-19). American College of Obstetricians and Gynaecologists. In. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/03/novel-coronavirus-2019, 2020.
- Royal College of Obstetricians and Gynaecologists. Coronavirus (COVID-19) Infection in Pregnancy. Information for healthcare professionals. Version 6. In. https://www.rcog.org.uk/globalassets/documents/guidelines/2020-04-03-coronavirus-covid-19-infection-in-pregnancy.pdf, 2020.
- ESHRE. Assisted reproduction and COVID-19. An updated statement from ESHRE. In. Vol. 2020, 2020.
- ASRM. PATIENT MANAGEMENT AND CLINICAL RECOMMENDATIONS DURING THE CORONAVIRUS (COVID-19) PANDEMIC. Update #1 (March 30, 2020 through April 13, 2020). In. https://www.asrm.org/globalassets/asrm/asrm-content/news-and-publications/covid-19/covidtaskforceupdate1.pdf, 2020.
- Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. 10.1016/j.cell.2020.02.052. Cell 2020.
- Reis FM, Bouissou DR, Pereira VM, Camargos AF, dos Reis AM, Santos RA. Angiotensin-(1-7), its receptor Mas, and the angiotensin-converting enzyme type 2 are expressed in the human ovary. Fertility and sterility 2011;95:176-81.
- Pereira VM, Reis FM, Santos RA, Cassali GD, Santos SH, Honorato-Sampaio K et al. Gonadotropin stimulation increases the expression of angiotensin-(1--7) and MAS receptor in the rat ovary. Reproductive sciences 2009;16:1165-74.
- Honorato-Sampaio K, Pereira VM, Santos RAS, Reis AM. Evidence that angiotensin-(1–7) is an intermediate of gonadotrophin-induced oocyte maturation in the rat preovulatory follicle. Experimental Physiology 2012;97:642-50.
- Serfozo P, Wysocki J, Gulua G, Schulze A, Ye M, Liu P et al. Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent. Hypertension 2020;75:173-82.
- Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. 10.1007/s11684-020-0754-0. Frontiers of Medicine 2020.
- Lainas G, Kolibianakis E, Sfontouris I, Zorzovilis I, Petsas G, Tarlatzi T et al. Outpatient management of severe early OHSS by administration of GnRH antagonist in the luteal phase: an observational cohort study. Reproductive Biology and Endocrinology 2012;10:69.
- Nastri CO, Teixeira DM, Moroni RM, Leitao VM, Martins WP. Ovarian hyperstimulation syndrome: pathophysiology, staging, prediction and prevention. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology 2015;45:377-93.
- Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005;11:875-9.
- Dijkman R, Jebbink MF, Deijs M, Milewska A, Pyrc K, Buelow E et al. Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63. J Gen Virol 2012;93:1924-9.
- Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005;436:112-6.
- Yoshimura Y. The ovarian renin-angiotensin system in reproductive physiology. 10.1006/frne.1997.0152. Frontiers in neuroendocrinology 1997;18:247-91.