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Soheila Pourmasumi1,2, Nicholas G. Kounis3, Monavar Naderi4, Robabe Hosseinisadat5, Arezoo Khoradmehr6, Niloofar Fagheirelahee7, Sophia N. Kouni8, Cesare de Gregorio9, Periklis Dousdampanis10, Virginia Mplani11, Marina A. Michalaki12, Panagiotis Plotas13, Stelios Assimakopoulos14, Christos Gogos15, Georgios Aidonidis16, Pavlos Roditis17, Nikos Matsas18, Dimitrios Velissaris19, Gianfranco Calogiuri20,21, Ming-Yow Hung22,23,24, Ioanna Koniari25
1Social Determinants of Health Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
2Clinical Research Development Unit, Ali-Ibn Abi-Talib Hospital, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
3Department of Internal Medicine, Division of Cardiology, University of Patras Medical School, Patras, Greece
4Knowledge and Information Science, Vice Chancellor for Science and Technology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
5Department of Obstetrics and Gynecology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
6The Persian Gulf Marine Biotechnology Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
7Department of Anatomy, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
8Speech Therapy Practice, Queen Olgas Square, Patras, Greece
9Department of Clinical and Experimental Medicine, University of Messina Medical School, Messina, Italy
10Department of Nephrology, Saint Andrews State General Hospital, Patras, Greece
11Intensive Care Unit, Patras University Hospital, Patras, Greece
12Department of Internal Medicine, Division of Endocrinology, Fculty of Health Sciences, University of Patras, Patras, Greece
13Department of Speech Therapy, University of Patras, Patras, Greece
14Department of Internal Medicine, Division of Infectious Diseases, University of Patras Medical School, Patras, Greece
15COVID-19 Unit, Papageorgiou General Hospital, Thessaloniki, Greece
16Interbalkan Medical Center, Thessaloniki, Greece
17Department of Cardiology, Mamatsio Kozanis General Hospital, Kozani, Greece
18Cardiology Private Practice, Agrinion, Greece
19Department of Internal Medicine, University of Patras, Patras, Greece
20Pneumonology Department, Civil Hospital “Ninetto Melli”, Pietro Vernoti, Brindisi, Italy
21Department of Internal Medicine, Immunology and Infectious Diseases, Section of Allergology and Clinical Immunology, University of Bari Medical School, Bari, Italy
22Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
23Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
24Taipei Heart Institute, Taipei Medical University, Taipei, Taiwan
25Departmentof Cardiology, Liverpool Heart and Chest Hospital, Liverpool, UK
DOI : 10.4274/balkanmedj.galenos.2023.2023-3-4
Pages : 153-164

Abstract

Several studies and research papers have been published to elucidate and understand the mechanism of the coronavirus disease 2019 (COVID-19) pandemic and its long-term effects on the human body. COVID-19 affects a number of organs, including the female reproductive system. However, less attention has been given to the effects of COVID-19 on the female reproductive system due to their low morbidity. The results of studies investigating the relationship between COVID-19 infection and ovarian function in women of reproductive age have shown the harmless involvement of COVID-19 infection. Several studies have reported the involvement of COVID-19 infection in oocyte quality, ovarian function, and dysfunctions in the uterine endometrium and the menstrual cycle. The findings of these studies indicate that COVID-19 infection negatively affects the follicular microenvironment and dysregulate ovarian function. Although the COVID-19 pandemic and female reproductive health have been studied in humans and animals, very few studies have examined how COVID-19 affects the female reproductive system. The objective of this review is to summarize the current literature and categorize the effects of COVID-19 on the female reproductive system, including the ovaries, uterus, and hormonal profiles. The effects on oocyte maturation, oxidative stress, which causes chromosomal instability and apoptosis in ovaries, in vitro fertilization cycle, high-quality embryos, premature ovarian insufficiency, ovarian vein thrombosis, hypercoagulable state, women’s menstrual cycle, the hypothalamus-pituitary-ovary axis, and sex hormones, including estrogen, progesterone, and the anti-Müllerian hormone, are discussed in particular.

INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic originated in China (Wuhan) in December 2019. Initially, the virus caused respiratory symptoms and pneumonia.1 The World Health Organization (WHO) officially announced COVID-19 as an acute respiratory virus syndrome and the most important disease in 2020.2 The COVID-19 pandemic resulted in several complex challenges for medical and public health systems worldwide. The extensive spread of COVID-19 from China to other countries became the main concern of governments and public health societies.3 In October 2022, the WHO reported that COVID-19 infection had caused approximately 6.5 million human deaths worldwide.4 Mortality rates remain high, especially in high-risk populations, including patients with heart disease, individuals with diabetes, and immunosuppressed patients with cancer.5

The COVID-19 pandemic has led to the undertaking of numerous studies and publications worldwide to elucidate the short- and long-term consequences of COVID-19 for the human body.6 COVID-19 mortality is strongly associated with gender. COVID-19 data have shown that male mortality rates are higher than female mortality rates.7,8 A meta-analysis revealed that although the numbers of men and women with confirmed COVID-19 infection are similar, the number of male patients admitted to intensive treatment units was three times greater than that of females.9 The percentage of mortality in females increases significantly after 55 years of age.8 Sex-related genetic factors, in combination with existing treatments, might represent an interesting mechanism and target for COVID-19 treatment.10 The female reproductive system is an organ system affected by COVID-19 that has received less attention due to the lack of related deaths.11 The angiotensin-converting enzyme (ACE2) receptor has been reported to be the main receptor involved in the penetration of coronaviruses into cells. Postcell invasion, COVID-19 disrupts the renin-angiotensin system (RAS) by down-regulating ACE2 expression in host cells, leading to an exacerbated proinflammatory response by angiotensin-II.12 This receptor is present in the female reproductive system, particularly in the ovaries and uterus, where it affects folliculogenesis, steroidogenesis, oocyte maturation, ovulation, and endometrial regeneration.13

Immunologic research has demonstrated that coronavirus infection triggers the induction of a cascade of ACE2 mediators. Under continuous infection conditions, other cascades are induced by transmembrane serine protease 2 (TMPRSS2) on infected cells, and elevated inflammatory responses and cytokine secretion are the main fatal factors in cases of COVID-19 infection.14,15 Following the elucidation of the immunological process, the vaccine production has become essential for disease prevention.16

Recent research has failed to provide strong clinical evidence supporting the presence of the COVID-19 virus in the female reproductive system, uterus, and vaginal secretions.17,18 However, according to some other reports, COVID-19 can disrupt fertility in women.19,20 Although no study has confirmed that oocytes can be directly affected by COVID-19 infection,21,22 the expression of ACE2 in the female reproductive system may affect steroidogenesis, folliculogenesis, oocyte maturation, and ovulation. Several reports have demonstrated a reduction in oocyte quality, impaired ovarian function, and disruptions in the uterus and menstrual cycles.20,23

In a previous review published in 2022, we assessed the effects of COVID-19 on the male reproductive system. The results of this review showed that COVID-19 and vaccination have no negative effects on sperm parameters and male fertility potential24 but can affect gametes or reproductive germ cells. Therefore, the COVID-19 pandemic can be considered to be a problem for natural pregnancy and artificial fertilization, including assisted reproductive technology (ART) and in vitro fertilization (IVF). Given that very few studies have been conducted on the relationship between COVID-19 and human/animal reproduction, investigations on the latest pathophysiological impact of the COVID-19 pandemic on the female reproductive system (ovaries, uterus, and sex hormones) and ART, the main fertility treatment procedure, are important.

The aim, therefore, of this study is to review the literature and categorize the effects of COVID-19 on the female reproductive system, including the ovaries, uterus, and hormonal profiles. Moreover, the effects of COVID-19 infection and vaccination on oocytes and embryos in the ART and IVF cycles were assessed.

SEARCH METHODS

For this review, an extensive literature search was performed on PubMed, Web of Science, and Scopus between 2019 and 2023. The following keywords, alone or in combination, were used for the search: COVID-19, COVID vaccine, SARS-CoV-2 vaccination, female reproductive system, fertility potential, ovary, uterus, menstrual cycle, sex hormones, ART, and IVF. Literature and articles published in English and available between 2019 and up to May 2023 were included. Studies without full text, marine experimental studies, and studies on factors of male infertility were excluded from assessment. The resulting articles were selected by screening their titles and reviewing their full text. Finally, only articles corresponding to the topics of interest were selected for this review. In addition, references from relevant reviews and ongoing studies were manually searched to locate other potentially eligible materials.

SUMMARY of EVIDENCE

Role of COVID-19 and Vaccination in the Female Reproductive System

Several pieces of evidence showed that after binding to target host cells, the coronavirus can create an immune response.19,23 ACE2 has been reported to be expressed in the female reproductive system. It plays an enzymatic role in RAS. Therefore, the connection between ACE2 and RAS is considered to be an important function in the physiology of the ovaries and uterus.12 Recent studies have demonstrated that COVID-19 can cause disruptions in female fertility potential.19,20 COVID-19 can infect granulosa cells and ovarian tissue, reduce oocyte quality and ovarian function, and lead to infertility or abortions.23,25 In addition, COVID-19 may harm endometrium epithelial cells and lead to premature implantation and early abortion.15 How COVID-19 affects fallopian tubes remains unknown, but COVID-19 may damage fallopian tubes indirectly.23 In 2020, Jing et al.26 evaluated the potential impact of COVID-19/ACE2 on the female reproductive system, demonstrating that ACE2 is widely expressed in the ovaries, uterus, vagina, and placenta. Moreover, angiotensin 1-7 and ACE-2 have been reported to control follicular growth and ovulation, degeneration, and angiogenesis in the yolk sac. In addition, several changes in the endometrial tissue can affect embryonic development.26 Wei et al.27 analyzed follicular fluid from ART treatment cases and demonstrated that the angiotensin 1-7 receptor  correlates positively with oocyte maturity and is an indicator of ovulation development.27 Another recent study illustrated that COVID-19 can affect oocyte maturation by increasing oxidative stress.23 Oxidative stress causes chromosomal instability and apoptosis in the reproductive system.28,29

Antivaccination sentiments and actions arose following the introduction of vaccination. Vaccines were implied to result in negative effects on the female reproductive system and consequently in infertility or abortion.30 Therefore, reviewing the studies and documents regarding the various effects of COVID-19 and vaccines on the female reproductive system is an important requirement. Orvieto et al.31 recently reported that they found no significant differences in implantation rates and high-quality embryos between cases with or without COVID-19 vaccination. They also showed that the implantation rate and embryo qualities in COVID-19-infected patients were significantly lower than those in healthy women.31 Bentov et al.21 reported that the quality of oocytes in COVID-19-vaccinated women was statistically similar to that in unvaccinated women. These clinical trials suggest that the COVID-19 vaccine has no negative effects on the human reproductive system.21,31

Ovaries

The symptoms of COVID-19 infection may vary from patient to patient. Although many studies have been conducted and reported on the respiratory,32 cardiac,33 eye,34 neurological,35 and urological36 symptoms related to COVID-19 infection, the ovarian outcomes in patients with COVID-19 infection have been less studied. Some studies have reported that COVID-19 has negative effects on ovarian function, whereas other works have reported favorable effects.37,38 A study conducted with the aim of investigating the relationship between COVID-19 infection and ovarian function in women of reproductive age demonstrated that COVID-19 leads to ovarian injury, including a reduction in ovarian reserves and reproductive endocrine responses.39 Herrero et al.37 investigated the effect of COVID-19 infection on ovarian function by comparing follicular fluid between the two control groups. They examined a group that had recovered from COVID-19 infection and the effect on follicular fluid in nonluteinized granulosa and human endothelial cell cultures. They concluded that COVID-19 infection adversely affected the follicular microenvironment and led to ovarian function dysregulation.37 However, most of the studies found no negative effect on the ovaries (Figure 1).

Bowman et al.40 evaluated the effect of BNT162b2 (Pfizer-BioNTech), mRNA-based COVID-19 vaccine, on 44 female rats. They prescribed a full human BNT162b2 dose of 30 μg mRNA/dose on days 14 and 21 before mating and on days 9 and 20 of pregnancy. They found that vaccination had no effect on ovarian or uterine parameters and female mating performance.40

A cohort autopsy study that investigated the systemic pathogenesis of COVID-19 in 26 autopsied cases41 did not find COVID-19 in the ovaries (n = 7). Another observational study conducted on 132 young women aged 18-40 years old before and after COVID-19 infection reported no visible effect on ovarian reserves.42

Patients with polycystic ovary syndrome (PCOS) are at risk of COVID-19 infection due to underlying diseases, such as diabetes, heart disease, and obesity.43,44 Women with PCOS suffer from COVID-19 infection at rates approximately 5-20% higher than men45 and are at a 28-50% higher risk for COVID-19 infection than women of the same age without PCOS.46 Women with PCOS who are infected with COVID-19 should receive appropriate emergency treatment because 80% of these females have hyperandrogenism, which inhibits immunity and controls TMPRSS2 and ACE2 that further facilitate the entry of virus into the cells.47 In these cases, the administration of antiendogens has a beneficial effect on the manifestations of COVID-19.46

Premature ovarian insufficiency is another ovarian disease that occurs when the ovaries stop functioning before the age of 40. Here, the ovaries do not produce normal amounts of estrogen, and eggs are not released regularly, leading to infertility. This condition is also called premature ovarian failure.48

In July 2021, Wilkins and Al-Inizi49 presented the first report of premature ovarian insufficiency that developed in a woman who was infected with COVID-19. Two months before COVID-19 infection, the patient had normal regular periods; normal gonadotropin levels; and follicle stimulation hormone (FSH) and luteinizing hormone (LH) levels of 8 and 2 U/L, respectively. Seven months after the infection, her FSH and LH levels increased to 78 and 43 U/L, respectively. Two months later, when the test was repeated, her gonadotropin level remained high, indicating that she will need assisted reproductive methods to become pregnant.49

The reproductive tissue expresses the ACE2 receptor, which may be used by the COVID-19 virus to enter cells.26 Very few studies have shown the histological destruction of ovarian tissue following infection with COVID-19 and its treatment.49,50 The ACE2 receptor is speculated to be expressed at lower levels in ovarian tissue than in testicular tissue, further reducing the chance of viral invasion and glandular damage.49

COVID-19 infection is associated with a high risk of venous thromboembolism.51 Ovarian vein thrombosis (OVT) is a rare, serious, and uncommon condition and is mostly reported in the postpartum state.52 However, cases of OVT associated with COVID-19 have been reported. DeBoer et al.53 reported a case of OVT secondary to COVID-19 infection in a 56-year-old woman without a previous history of thromboembolism. The patient experienced abdominal pain that led to further evaluation through the computerized tomography of the abdomen and pelvis, and OVT was proven. The only risk factor in the patient was thrombosis induced by COVID-19 infection.53 The exact cause of OVT is unknown but is attributed to abnormal blood flow due to turbulence at vessel bifurcations and/or stenotic regions that can lead to blood stasis; abnormalities in the vessel wall due to endothelial damage and/or dysfunction; and abnormal blood constituents, namely, platelet and coagulation impairment leading to hypercoagulability.54 This triad, which is called Virchow’s triad, was described by Virchow over 150 years ago and revised in 2020.55 Pregnancy can lead to excessive coagulability, and the pregnant uterus can cause the compression of the right ovarian vein and inferior vena cava. Furthermore, uterine infection can lead to endothelial damage. In this review, the authors considered the most probable cause of OVT COVID-19 given the absence of other factors, such as a history of thromboembolic disorders, recent surgeries, and postpartum status.53

A number of studies have reported hypercoagulability in the form of venous and arterial thromboembolism with unknown pathogenesis in patients with COVID-19. Interestingly, changes in thrombotic factors, such as fibrinogen, factor VIII, Willebrand factor, and D-dimer, that can cause a hypercoagulable state have been reported in a number of other studies.56,57

Uterus

Several hormonal receptors, such as estrogen and progesterone receptors, are present in the uterus. Therefore, the uterine function is under hormonal control. These receptors are expressed in endometrial stromal cells. Hormone binding to receptors regulates endometrial growth, decidualization, cytokine secretion, and immune response activity.58

With the use of radioimmunoassay, angiotensin was detected in endometrial wash fluid at picomolar concentrations. Angiotensin is localized in the endometrium throughout the menstrual cycle and is more concentrated in the glandular epithelium during the mid- and late-secretory phases. This pattern corresponds to the pattern of ACE2 mRNA, which is more abundant in epithelial cells than in stromal cells (2-fold increase, p < 0.05) and in the secretory versus proliferative phase (6.6-fold increase, p < 0.01).59 The G-protein-coupled Mas receptor is similarly circulated between epithelial and stromal cells without any change during the menstrual cycle.59 The reduction in endometrial function has negative effects on fertility potential.60 RAS has been confirmed to be expressed at high levels in the uterus.26 Rare nonserious defects, including uterine pain, tension, and contraction, have been associated with COVID-19 infection and vaccination.61,62

Menstrual cycle

Women of reproductive age seek healthcare for abnormal uterine bleeding (AUB) more often than for any other condition, and AUB accounts for one-third of women’s outpatient visits to a gynecologist.63 Up to approximately 30% of the population is affected by AUB.64 This wide range may be explained by different ages and symptoms and, most importantly, underreporting. AUB has been studied mostly in relation to heavy menstrual bleeding, with little information available about other symptoms.65 Available evidence shows that as many as half of the affected women do not seek medical treatment for AUB despite having access to a healthcare provider.65,66 Although the menstrual cycle is poorly studied, evidence showed that infection with COVID-19 and vaccination with the BNT162b2 vaccine can affect the menstrual cycle.67,68

The increase in the prevalence of menstrual disorders before the start of vaccination is due to stress and sleep disorders. Moreover, in females, severe acute illness may alter the function of the hypothalamic-pituitary-gonadal (HPG) axis, decreasing the endogenous production of estrogen and progesterone.69

In a study in the USA between 2020 and 2022, women over 18 years of age who had received the COVID-19 vaccine were asked to report changes in their menstrual cycle. The most reported change was related to the increase in the duration of menses (83%). In this study, 67% of women mentioned an increase in menstrual symptoms, 4% reported bleeding after menopause, and 2.8% mentioned the resumption of bleeding in menopause.70 Another study found that COVID-19 infection and the BNT162b2 vaccine increased menstrual bleeding in the first and second cycles.65 In a study on 177 patients positive for COVID-19, 75% reported no change in bleeding volume, and 20% reported a reduction in bleeding volume. An increase in bleeding volume was found in only 9% of the cases. Although no difference in the volume of bleeding was found between patients with moderate and severe diseases, the duration of menstrual bleeding was longer in patients with severe disease.38

COVID-19 infection causes menstrual changes without long-term consequences. This effect is possible due to the interaction62 between the hypothalamic-pituitary-adrenal axis (HPA) and HPG. Research has shown that the effects of COVID-19 infection on the menstrual cycle are transient and may be caused by the response of the immune system to stress.71 Furthermore, the effect on the HPG axis causes changes in menstruation.72 An Italian study reported that menstrual disorders, such as delayed menstruation, menorrhagia, metrorrhagia, and menometrorrhagia, had a prevalence of 23-77% in the first 3 weeks after vaccination, especially after the second dose.62 In another study, Male68 demonstrated that mRNA and adenovirus-vectored COVID-19 vaccines do not cause menstrual changes, indicating that the immune response, rather than some specific vaccine component, may be responsible.68 A recent review stated that most women reported a prolonged cycle and decreased menstrual volume during COVID-19 infection and vaccination.73 However, infection severity did not affect the rate of cycle changes.67,74

Sex Hormones

The regulation of physiological hormonal responses in the female reproductive system stems from the hypothalamus. The hypothalamus controls the female reproductive cycle by regulating pituitary gland secretion. The hypothalamus receives internal and external stimulating factors and produces several hormones that regulate the function of the anterior pituitary gland.75 The direct effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on brain tissue is a possible hypothesis in the field of female fertility and COVID-19.76 The neurological symptoms experienced by patients with COVID-19 experience are evidence supporting the above hypothesis.77,78

ACE2 is known to be the entry gate of coronaviruses into human cells.79 ACE2 expression by the supporting cells of the olfactory epithelium may be the main gateway of viral entry into the brain tissue.80 However, the exact point of entry of the SARS-CoV-2 virus into the central nervous system remains unknown, but may occur via a blood-borne route or directly through the olfactory epithelium.81 Given that hypothalamic and pituitary tissues express high levels of ACE2, theoretically, these brain structures constitute targets for viral infections.82 In fact, evidence has revealed edema and apoptosis in hypothalamus nerve cells in patients with COVID-19. Moreover, the SARS-CoV-2 genome has been discovered in the brain.83

The Hypothalamus-Pituitary-Ovary axis (HPO) controls the human menstrual cycle through positive and negative feedback.69 A study reported serious endocrine disorders and a significant increase in the two pituitary hormones LH and prolactin in patients suffering from COVID-19.84 This study discovered the presence of the SARS-CoV-2 virus in the pituitary gland, suggesting that the SARS-CoV-2 virus can directly damage the nervous system and cause hormonal disorders.84 The increase in hormones may be partially due to a direct effect on brain tissue. Humans suffering from anxiety during the COVID-19 pandemic, especially women, can also suffer from endocrine disorders.85 Ding et al.86 reported that 48% of patients with COVID-19 infection had a psychological disorder, such as anxiety, depression, or insomnia, at the peak of the disease; this situation could lead to increased prolactin and dysfunction via the HPO axis. Changes in lifestyle due to extensive quarantines and the fear of contracting the virus have induced high levels of anxiety in women. Anxiety is reported in cases that have not been infected with COVID-19.85 Changes in the pattern of daily and sports activities during the pandemic can increase anxiety in people.87 In women, these lifestyle changes can increase LH levels; consequently, ovarian theca cells produce more testosterone and lead to secondary ovulation disruption.88 Hormonal defects may be more serious and challenging in women with PCOS or thyroid disorders who previously had endocrine problems.46 Several studies have demonstrated that the virus or immune responses following infection cause direct damage to ovarian follicles, infection, and inflammation. Abnormal sex hormone production and HPO axis disruption are the possible negative consequences of COVID-19 infection of the female reproductive system.89,90

Estrogen

SARS-CoV-2 replication and maturation have been shown to be influenced by the estrogen hormone.91 Inflammatory responses to pathogens and infections are well known to be mediated by estrogen, and estrogen receptors (ERα/β) have been implicated in the suppression of viral gene transcription.92 Zafari Zangeneh and Sarmast Shoushtari93 reported that in a hepatitis C model, the selective estrogen receptor degrader fulvestran can block the effect of 17-estradiol in vitro.  Numerous studies have confirmed estradiol’s modulatory function in systemic and pulmonary inflammatory responses.94 Estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and ERα/β are expressed in most immune cells. This expression pattern confirms the prominent role of ERs in innate/adaptive immune function responses.92 For example, the important influence of estrogen and its receptors on B-cell and dendritic cell functions are well recognized in lupus. As in arthritis models, ERα has a multifactorial immune-protective effect in lupus. ERα agonists act to facilitate this immune-protective effect. Therefore, the modulatory function of ERα can be an important therapeutic target for autoimmunity.95 ER2 influences the expression of human ACE2 protein (as the host cell receptor), which can have an important role in coronavirus uptake.96 In women, the regulation of proinflammatory immune processes against COVID-19 appears to be associated with increased anti-inflammatory regulation and antiviral defens97(Figure 1).

Costeira et al.98 investigated the relationship between estrogen and COVID-19 severity. Their results showed that in premenopausal women, a high level of estrogen had a protective effect against COVID-19 infection.98

Progesterone

Progesterone is a steroid sex hormone with a main role in the menstrual cycle, pregnancy, and human embryonic development. This hormone has an anti-inflammatory role. Before menstruation, the level of progesterone decreases rapidly, and inflammatory cells attack the endometrium, leading to an inflammatory response.99 In addition to its known role in reproduction, progesterone can change the balance of cytokines in immune responses and may cause a high level of regulatory T-cells with a cluster of differentiation 4 and CD8 marker expansion.100 Moreover, progesterone causes immune adaptation and tolerance that facilitates and maintains pregnancy.101

Evidence showed that the severity of symptoms and mortality rate of COVID-19 are higher in men than in women.7,102 Researchers have suggested that sex steroids may have a protective role against COVID-19.7,8 Estrogen and progesterone, which are both female sex steroids, and their metabolite allopregnanolone have an anti-inflammatory role that can change immune cell responses.8 These changes may facilitate the proliferation and repair of respiratory epithelial cells and protect cells against COVID-19 infection.8 Several studies were designed on the basis of this theory to assess the effect of progesterone and estrogen treatment on COVID-19 infection.103,104 In 2020, Gordon et al.105 reported that progesterone is an antiviral hormone that can protect the human body against COVID-19 infection. However, the potential of progesterone to reduce COVID-19 symptoms in men remains ambiguous.

Anti-Müllerin Hormone

Anti-Müllerin hormone (AMH) is secreted by small antral follicles; it is an important index for evaluating ovarian reserves that is not influenced by the menstrual cycle, exogenous sex hormones, or pregnancy.106 Li et al.38 evaluated the level of AMH in COVID-19-infected women to assess the effects of COVID-19 on AMH. They reported that the level of AMH in patients with COVID-19 was not different from that in the control group. In consideration of the reversible menstrual changes and the absence of reductions in estradiol and progesterone levels in women with COVID-19 infection, SARS-CoV-2 infection is assumed to have a small effect on ovarian reserves. However, long-term studies are suggested.38

Soysal and Yılmaz107 performed a prospective cross-sectional study on 60 female patients aged 25-30 years old to evaluate the effect of mRNA COVID-19 vaccines on ovarian reserves. They examined AMH levels in patients 1-5 days before vaccination and 60-90 days after vaccination and compared them with those in the control group that did not receive the vaccine. Postvaccine AMH values in the study group were similar to those in the control group, and no significant difference was found between prevaccine and postvaccine AMH values in the study group. These researchers stated that people who intend to get pregnant should know that the vaccine, which is the most important tool for fighting against COVID-19 infections, has no effect on ovarian reserves.107

In another study, AMH levels were evaluated before and 3 months after two mRNA SARS-CoV-2 vaccinations. Analyses were performed in different age groups, and no significant changes were observed. Anti-COVID 19 antibody levels increased in all vaccinated women in 3 months, and the correlation between antibody and AMH levels was not reported. COVID-19 vaccination was concluded to be unassociated with a reduction in ovarian reserves at 3 months.108

Role of COVID-19 in Assisted Reproductive Technology

At the start of the COVID-19 pandemic, hospitals were overwhelmed by sick patients, resulting in a shortage of intensive care unit beds and personal protective equipment for medical workers. The main medical societies in the field of reproductive medicine, including the European Society of Human Reproduction and Embryology, American Society for Reproductive Medicine (ASRM), International Federation of Fertility Societies, and Red Latinoamericana de Reproducción Asistida, recommended patients with infertility to consider deferring pregnancy.109 Many infertility clinics temporarily halted their practice between March and April 2020 to reduce SARS-CoV-2 transmission and conserve medical resources.110 Fertility societies worldwide also suggested the suspension of ovulation induction, intrauterine insemination, IVF, sperm and oocyte cryopreservation, fresh/frozen embryo transfers, and other reproductive treatments.111

These extraordinary measures were taken for the following reasons:

1) Medical emergencies were kept at bay by avoiding complications associated with assisted reproduction and pregnancy. Concerns about horizontal transmission to the fetus and potential complications related to the virus during pregnancy in patients positive for COVID-19 were raised.

2) SARS-CoV-2 infection and mortality rates led specialty professional organizations to create task forces to regulate measures to reduce COVID-19 transmission to health care workers and patients.

3) Worldwide, fertility clinic staff worked hard throughout the COVID-19 pandemic to maintain effective fertility services.112

The guidelines released by ASRM on March 17, 2020, stated that new treatment cycles should be suspended and ongoing cycles paused while embryos were transferred and cryopreserved. As a result of the suspension, only nonelective fertility preservation (for example, storing eggs or sperm before chemotherapy) was permitted.110 Whether the infection of the reproductive system by COVID-19 can affect gametes or reproductive germ cells must be assessed. The COVID-19 pandemic can be considered as a crisis for ART and natural pregnancy.113 Annually, ART is used worldwide with millions of treatment cycles for infertile patients. During the acute phase of the COVID-19 pandemic, fertility treatments were postponed despite the rarity of the data on the infection of the female reproductive system. Therefore, assessing the risk of viral transmission by sexual fluids and gametes is necessary to transfer embryos and ensure laboratory safety during ART.114

Oocytes and Embryos in IVF Cycles

Considering the known mechanisms of SARS-CoV-2 penetration into cells (i.e., the need for the expression of the ACE2 and TMPRSS2 receptors), the assessment and screening of oocytes and embryos in ART are necessary to determine whether or not SARS-CoV-2 can infect oocytes and embryos.115

ACE2 mRNA expression in human ovarian tissue has been determined on the basis of an RNA sequencing database. Ovarian tissue is susceptible to COVID-19.49 During oocyte retrieval in ART, mature follicles and oocyte-cumulus complexes (COCs) are aspirated. In this procedure, the female gamete (oocyte) is naturally out of reach.116 Kong et al.117 reported that in COCs, ACE2 is highly expressed, whereas TMPRSS2 is not expressed or expressed at low levels; moreover, cumulus cells have the potential to be infected because they are possible targets of SARS-CoV-2 for cell entry. Therefore, COCs may not act as a barrier to the entry of viruses into oocytes. A similar study reported on the expression of ACE2 and TMPRSS2 in oocytes.118 The researchers showed that ACE2 and TMPRSS2 expression levels increase in relation to oocyte maturation.118 Mature oocytes may be exposed to the risk of infection and viral transmission. The oocyte retrieval process is an alternative route for oocyte infection. Vaginal oocyte retrieval is an invasive procedure, and preventing the contamination of follicular fluid samples by blood or vaginal fluid is difficult.119 Indeed, coronaviruses have been found to be present in the blood samples of infected patients.120

Evidence showing that the RAS system plays an important role in reproductive processes, such as folliculogenesis, steroidogenesis, oocyte maturation, and ovulation, exists.20 Jing et al.26 reported that the angiotensin 1-7 receptor ACE2 is present at all stages of follicle maturation in the human ovaries. ACE2 is expressed in the endometrium and in epithelial and stromal cells. In addition, the expression of this gene changes with the menstrual cycle and is higher in the secretory phase than in the proliferative phase. This state can be related to angiotensin-II homeostasis and can regulate endometrial regeneration.59 Previous studies have demonstrated that ACE2 is expressed in rat and bovine ovarian granulosa cells.37,121 Orvieto et al.31 investigated the effect of infection with COVID-19 on subsequent IVF cycles, revealing that although COVID-19 has no effect on the patient’s ovarian reserves, the number of high-quality embryos decreased. They suggested postponing IVF treatment for at least 3 months after recovery to achieve better effects and to choose healthy gametes that have not been exposed to infection.31 In another observational study, researchers attempted to evaluate the effect of the COVID-19 vaccine on subsequent IVF cycles and reported that the COVID-19 vaccine has no effect on the function and ovarian reserves of patients in their immediate subsequent IVF cycles.122 In a cohort study, Bentov et al.21 investigated the effect of COVID-19 infection and the BNT162b2 mRNA vaccine on ovarian follicles and their function. This study included 32 consecutive patients undergoing oocyte retrieval who were divided into three groups, namely, the nonvaccinated, uninfected control (n = 14), vaccinated (n = 9), and recovering from COVID-19 (n = 9) groups. Bentov et al.21 analyzed anti-COVID-19 immunglobulin (Ig)G, progesterone, estrogen, and heparin sulfate levels in serum and follicular fluid samples and the number and maturity of aspirated oocytes. Their results showed that although the coronavirus and BNT162b2 mRNA vaccine led to the rapid formation of anti-COVID-19 IgG in the serum and follicular fluid, infection, vaccination, and immune response did not exert a measurable harmful effect on ovarian function.21

The answer to the question of whether embryos can be infected by SARS-CoV-2 remains unclear. The available evidence shows that blastocysts may have viral receptors. During development, human embryos could be susceptible to coronavirus entry. Moreover, blastocysts can express the genes for proteins involved in viral endocytosis and duplication.123 Other researchers have investigated the risks of COVID-19 transmission through embryos.124 Oguejiofor et al.125 investigated viral transmission in bovines infected by flaviviruses through IVF. Although viruses were found in follicular fluid and COCs after in vitro maturation, no virus was detected in the embryos after 7 days.125

In conclusion, information about COVID-19 and its effects; the methods of COVID-19 transmission; and the mortality rates of pregnant women, fetuses, and infants remains inadequate. Currently, the available information on pregnant women with COVID-19 and the transmission of COVID-19 to embryos remains limited but can still be used to provide recommendations to infertile cases undergoing IVF cycles and pregnant women.

The strength of the present study is that it considered parts of the female reproductive system (organs and hormonal axis), allowing the review and summarization of important points about the pathophysiology of COVID-19 and vaccination in the female reproductive system. The present study is a narrative review and did not assess female fertility, COVID-19, and COVID-19 vaccination systematically. Therefore, some aspects of these topics may not have been investigated. A systematic review and meta-analysis of the above topics, based on the findings presented here, could be more beneficial.

Recent studies on the female reproductive system during COVID-19 infection and vaccination showed that in women, the reproductive system may be harmlessly involved in COVID-19 infection. Although low ovarian reserves and menstrual cycle and hormonal defects were reported in cases of COVID-19 infection, scientific evidence showing that COVID-19 vaccination has negative effects on the female reproductive system does not exist. Current studies support the view that vaccination against COVID-19 infection is not harmful to the female reproductive system. However, future studies are needed to support and investigate this assumption. Moreover, studies monitoring people who have received COVID-19 vaccination during pregnancy have not identified any pregnancy-specific safety concerns. Additional information on non-mRNA vaccines, vaccination early in pregnancy, and the longer-term outcomes of infants is also needed. Preventive methods should be taken as long as the pathogenesis and complications of COVID-19 in pregnant women, oocytes, and embryos remain unclear. Awareness of the updated information related to the COVID-19 is necessary.

Author Contributions: Concept- S.K.; Writing- S.P., N.G.K., M.N., R.H., A.K., N.F., S.N.K., C.G., P.D., V.M., M.A.M., P.P., S.A., C.d.G., G.A., P.R., N.M., D.V., G.C., M-Y.H., I.K.

Conflict of Interest: No conflict of interest was declared by the authors.

Funding: The authors declared that this study received no financial support.

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