Medical Researchers Warn That Systemic Inflammation Triggered by COVID-19 Infections Affects Female Reproductive Health In A Variety Of Ways
: A review study conducted by researchers from the Department of Anatomy, Cell Biology and Physiological Sciences at the American University of Beirut-Lebanon and from the Department of Gynecology and Obstetrics at Johns Hopkins University, Baltimore-USA has found that systemic inflammation triggered by COVID-19 infections affects female reproductive health in a variety of ways.
The COVID-19 disease is a multi-system disease that has led to a pandemic with unprecedented ramifications. The pandemic has challenged scientists for the past 32 months and brought back previously abandoned research topics.
It has already been found that COVID-19 infection causes a myriad of symptoms ranging from mild flu-like symptoms to severe illness requiring hospitalization. Case reports showed multiple systemic effects of COVID-19 infection, including acute respiratory distress syndrome (ARDS), fibrosis, colitis, thyroiditis, demyelinating syndromes, and mania, indicating that COVID-19 can affect most human body systems.
A major concern for women all over the globe is whether a COVID-19 infection has any long-term effects on their menstrual cycle, fertility, or pregnancy.
Numerous published studies and COVID-19 News
coverages have suggested an effect on the reproductive health of women, and the study team hypothesizes that the reported reproductive adverse effects are due to the robust immune reaction against COVID-19 and the associated cytokine storm.
Although the SARS-CoV-2 receptor (angiotensin converting enzyme - ACE2) is expressed in the ovaries, uterus, vagina, and placenta, the study team hypothesizes that it plays a less important role in the adverse effects on the reproductive system.
The study team claims that cytokines and glucocorticoids act on the hypothalamo-pituitary gonadal (HPG) axis, arachidonic acid pathways, and the uterus which leads to menstrual disturbances and pregnancy-related adverse events such as preterm labor and miscarriages.
This hypothesis is further supported by the apparent lack of long-term effects on the reproductive health in females, indicating that when the cytokine storm and its effects are dampened, the reproductive health of women is no longer affected.
The review findings were published in the peer reviewed journal: Biology of Reproduction.
Numerous studies have reported menstrual cycle irregularity among women following SARS-CoV-2 infection, although menstruation is an understudied topic.
Most recent analysis have indicated that about 16% of women reported menstrual disturbances following SARS-CoV-2 infection. Additionally, a meta-analysis showed an association of SARS-CoV-2 infection with stillbirth, pre-term birth, and lower birth weight.
It has also been noted that sex differences play an important role in disease pathogenesis, prevalence, and modulation. Potential differences for such sex differences can be fluctuatio
n of hormones during pregnancy and menstruation.
Furthermore, sex differences in immune responses have been observed for many viral respiratory infections. Although the impact of female sex hormones on the immune system is well described, the reciprocal relationship is not.
The study team analyzed the relationship between the immune system and the female reproductive system while focusing on the effects of COVID-19-associated immune responses on the reproductive system. The study searched PubMed to identify peer-reviewed literature in English up to May 2022 and finally included 83 studies.
The SARS-CoV-2 virus, the causative agent of COVID-19 disease, is a positive-sense single-stranded RNA virus that can infect pulmonary epithelial cells by binding viral spike glycoprotein to the angiotensin-converting enzyme (ACE2) receptor.
Typically, the pulmonary epithelial cells then initiate immune responses by secretion of interleukin 8 (IL-8) and attraction of neutrophils. The immune cells can then activate other pathways to trigger the immune response, such as the Janus Kinase – Signal transducer and activator of the transcription pathway (JAK-STAT).
Importantly, the JAK-STAT pathway induces the transcription of nuclear factor kappa B (NF-κB) and other factors that lead to the production of pro-inflammatory cytokines.
Studies have shown that high levels of pro-inflammatory cytokines, including IFN-g, IL-1B, IL-6, IL-2, and chemokines, increase the severity of COVID-19 disease.
The SARS-CoV-2 infections, like other viral infections, affects the hypothalamic-pituitary-adrenal (HPA) axis. Although the cytokines induce the hypothalamic corticotropin-releasing hormone (CRH) through the HPA axis to stimulate glucocorticoid release, they can also directly act on the adrenal and pituitary glands to release glucocorticoids. Glucocorticoids are produced to reduce the effect of cytokine storms that can result in the death of COVID-19 patients. However, glucocorticoids can have systemic symptoms and can lead to anovulatory infertility.
Effects On The Endometrium
It has been found that the endometrium comprises a highly active cytokine network that can help in the recruitment or activation of leukocyte subtypes in the endometrium. Previous studies have also found up-regulation of macrophage-derived chemokine (MDC) and IL8 that can help to trigger an influx of neutrophils in the endometrium before menstruation.
Furthermore, endometrial leukocytes consist of NK cells, macrophages, and neutrophils that can protect from microbial invasion during the secretory phase of the menstrual cycle. B-lymphocytes have also increased during this phase, while there is a decrease in T-lymphocyte activity. The activity of T lymphocytes increases during the early to mid-proliferative state and helps to clear out residual endometrial debris following menstruation.
Numerous studies have recently indicated that endometrial immune cells dysregulation due to COVID-19 infection can cause abnormal uterine bleeding.
Effects On The Menstrual Cycle
Research analyzing the impact of SARS-CoV-2 infection on the menstrual cycle are scarce. A past study indicated that 20% of SARS-CoV-2-positive women showed a decrease in menstrual volume, 9% showed an increase in menstrual volume, and 75% showed no change in menstrual volume.
Yet another study reported that about 16% of women experienced menstrual disturbances following SARS-CoV-2 infection.
Most studies however showed no significant sex hormone difference between controls and COVID-19 patients, severe and mild patients, or patients with and without menstrual changes. Therefore, it is assumed that immune response-mediated stress might cause temporary menstrual cycle changes due to interaction between the hypothalamic-pituitary-gonadal axis (HPG) and the HPA axis.
The HPG And HPA Axes
Glucocorticoids which are the end-products of the HPA axis activation have been reported to inhibit gonadotropin secretion, thereby suppressing the activation of the HPG axis.
Importantly, this process can be modulated by female sex hormones, progesterone, and estrogen. Additionally, several studies have reported higher cortisol levels during the follicular phase compared to the luteal phase, which might also influence the activation of the HPA axis.
Women infected during the follicular phase have also been reported to have higher suppression of the HPG axis and the gonadotropin-releasing hormone (GnRH). Moreover, CRH has been observed to be involved in suppressing the HPG axis independent of glucocorticoids. Cytokine storms resulting due to SARS-CoV-2 infections can therefore alter the HPA axis by increasing glucocorticoids and CRH, which might lead to menstrual disturbances, heavy menstrual bleeding, and anovulatory cycles.
Effects On The Placenta
To date, the impact of SARS-CoV-2 infection on the placenta is still poorly understood. For viral infection and replication, the spike protein binds to the ACE-2 receptor of the target cell. The virus and host cell membrane fusion occurs by priming the spike protein with cellular trans-membrane serine protease 2 (TMPRSS2). Cells that co-express ACE-2 and TMPRSS2 are at a higher risk of SARS-CoV-2 infection. However, only a few placental cells were found to co-express ACE-2 and TMPRSS2.
However, the decidual immune reaction and expression of interferon-induced transmembrane (IFITM) antiviral transcripts can play an essential role in protecting SARS-CoV-2 infection of the placenta. IFITM are proteins expressed in placental and epithelial cells and help inhibit the replication of viruses.
Ex vivo studies however have shown that SARS-CoV-2 can infect and propagate in the human placental cells, which might be due to placental ischemia that occurs due to maternal hypoxia or cytokine storm in adult COVID-19 patients.
Effects On Pregnancy
Numerous studies have reported that SARS-CoV-2 infections are associated with adverse pregnancy outcomes. These include lower birth weight, pre-term birth, stillbirth, and post-partum hemorrhage. These outcomes can be due to an increased inflammatory state associated with SARS-CoV-2 infections. Due to the cytokine storm generated by the SARS-CoV-2 infection, corticosteroids are produced in greater amounts, causing pre-term delivery. Miscarriages can be brought about by systemic inflammation, unbalanced Th1/Th2 response, or increased Th17/Treg ratio.
Effect On Fertility
Interestingly, the immune response against SARS-CoV-2 infection was observed not to affect fertility for females.
However, SARS-CoV-2 infection was found to impact the male reproductive system. A recent study highlighted a short-term reduction in fertility in SARS-CoV-2 -positive males. Male sexual dysfunction resulting from COVID-19 can last up to 7 months following infection. The cytokine storm due to SARS-CoV-2 infection can cause damage to the blood-testes barrier as well as cause an increase in reactive oxygen species (ROS) production, which in turn affects motility, spermatogenesis, and fertilization of mature sperms.
Hence women trying to conceive with a male partner who was previously infected might have problems.
The study review found that cytokine storm due to SARS-CoV-2 infection can cause short-term menstrual disturbances, pre-term delivery, and miscarriages. It can also adversely impact the male reproductive system causing a reduction in fertility and erectile dysfunction. Further research needs to be done to identify differences in symptoms between women infected in the follicular phase and those infected in the luteal phase. Also, more studies are warranted to determine whether immune response differs on whether SARS-CoV-2 infection occurred during the follicular or luteal phase.
In a totally unrelated development, Thailand Medical News
would like to warn that the prevalence of breast cancers and cervix cancers has risen over the last 30 months along with a lot of anomalous aggressive cancers. We strongly recommend that all women undergo frequent health screenings and health check-ups.
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