As of October 3rd, 2022, the COVID-19 pandemic has led to greater than 615 million circumstances of extreme acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), together with over 6.5 million deaths globally, in line with the World Well being Group (WHO). Chills, fever, shortness of breath, lack of scent, fatigue, diarrhea, nausea, and headache are some widespread COVID-19 signs. Moreover, quite a few case studies have documented the affect of SARS‑CoV‑2 infections on the human physique’s organs and methods. A number of questions have additionally been raised about its impact on girls’s reproductive well being, particularly being pregnant and fertility.
Varied research have reported menstrual cycle irregularity amongst girls following SARS‑CoV‑2 an infection, though menstruation is an understudied subject. Current research indicated about 16% of ladies reported menstrual disturbances following SARS‑CoV‑2 an infection. Moreover, a meta-analysis confirmed an affiliation of SARS‑CoV‑2 an infection with stillbirth, pre-term delivery, and decrease delivery weight.
Intercourse variations play an essential function in illness pathogenesis, prevalence, and modulation. Potential variations for such intercourse variations will be fluctuation of hormones throughout being pregnant and menstruation. Moreover, intercourse variations in immune responses have been noticed for a lot of viral respiratory infections. Though the affect of feminine intercourse hormones on the immune system is properly described, the reciprocal relationship shouldn’t be.
A brand new evaluate within the Biology of Replica journal analyzed the connection between the immune system and the feminine reproductive system whereas specializing in the consequences of COVID-19-associated immune responses on the reproductive system. The research searched PubMed to establish peer-reviewed literature in English as much as Might 2022 and eventually included 83 research.
Research: The affect of COVID-19 infection-associated immune response on the feminine reproductive system. Picture Credit score: eamesBot / Shutterstock
Immune responses in opposition to COVID-19
SARS-CoV-2, the causative agent of COVID-19 illness, is a positive-sense single-stranded RNA virus that may infect pulmonary epithelial cells by binding viral spike glycoprotein to the angiotensin-converting enzyme (ACE2) receptor. The pulmonary epithelial cells then provoke immune responses by secretion of interleukin 8 (IL-8) and attraction of neutrophils. The immune cells can then activate different pathways to set off the immune response, such because the Janus Kinase – Sign transducer and activator of the transcription pathway (JAK-STAT). The JAK-STAT pathway induces the transcription of nuclear issue kappa B (NF-κB) and different components that result in the manufacturing of pro-inflammatory cytokines. Analysis has proven excessive ranges of pro-inflammatory cytokines, together with IFN-g, IL-1B, IL-6, IL-2, and chemokines, enhance the severity of COVID-19 illness.
SARS-CoV-2, like different viral infections, impacts the hypothalamic-pituitary-adrenal (HPA) axis. Though the cytokines induce the hypothalamic corticotropin-releasing hormone (CRH) via the HPA axis to stimulate glucocorticoid launch, they will additionally instantly act on the adrenal and pituitary glands to launch glucocorticoids. Glucocorticoids are produced to cut back the impact of cytokine storms that can lead to the dying of COVID-19 sufferers. Nevertheless, glucocorticoids can have systemic signs and may result in anovulatory infertility.
Affect of progesterone and estrogen on immune cells
Earlier research have noticed that the hormonal fluctuation of progesterone and estrogen through the menstrual cycle can have an effect on the immune system in some ways. Progesterone receptors are discovered on pure killer (NK) cells, macrophages, dendritic cells, and CD4+ lymphocytes, whereas estrogen receptors are present in all immune cells.
The menstrual cycle includes 4 phases: the follicular, menstrual, luteal, and ovulation. Estrogen is dominant through the follicular part, whereas estrogen and progesterone ranges are excessive through the luteal part. Progesterone has anti-inflammatory results, whereas estrogen has pro-inflammatory results at low concentrations and anti inflammatory results at excessive concentrations.
Moreover, estrogen may inhibit the expression of IL-6, one of the vital COVID-19-related cytokines that trigger the cytokine storm via disruption of NF-κB transactivation. This implies that estrogen could be a protecting issue in opposition to a number of infections, together with SARS-CoV-2, and may additionally be accountable for a extra vital immune response of ladies to COVID-19 than males. Estrogen ranges are negatively correlated with inflammatory cytokines that may assist to guard girls from extreme cytokine storms and problems of COVID-19.
Position of immune cells within the endometrium
The endometrium includes a extremely energetic cytokine community that may assist in the recruitment or activation of leukocyte subtypes within the endometrium. Earlier research have additionally discovered up-regulation of macrophage-derived chemokine (MDC) and IL8 that may assist to set off an inflow of neutrophils within the endometrium earlier than menstruation.
Endometrial leukocytes encompass NK cells, macrophages, and neutrophils that may shield from microbial invasion through the secretory part of the menstrual cycle. B-lymphocytes have additionally elevated throughout this part, whereas there’s a lower in T-lymphocyte exercise. The exercise of T lymphocytes will increase through the early to mid-proliferative state and helps to filter residual endometrial particles following menstruation. Current research have indicated that endometrial immune cells dysregulation as a consequence of COVID-19 an infection could cause irregular uterine bleeding.
Impact of SARS-CoV-2 an infection on the menstrual cycle
At present, research analyzing the affect of SARS-CoV-2 an infection on the menstrual cycle are scarce. A latest research indicated that 20% of SARS-CoV-2-positive girls confirmed a lower in menstrual quantity, 9% confirmed a rise in menstrual quantity, and 75% confirmed no change in menstrual quantity. One other research reported that about 16% of ladies skilled menstrual disturbances following SARS-CoV-2 an infection. Nevertheless, most research confirmed no vital intercourse hormone distinction between controls and COVID-19 sufferers, extreme and gentle sufferers, or sufferers with and with out menstrual adjustments. Subsequently, it’s assumed that immune response-mediated stress would possibly trigger momentary menstrual cycle adjustments as a consequence of interplay between the hypothalamic-pituitary-gonadal axis (HPG) and the HPA axis.
Interplay between the HPG and HPA axes
Glucocorticoids that are the end-products of the HPA axis activation have been reported to inhibit gonadotropin secretion, thereby suppressing the activation of the HPG axis. This course of will be modulated by feminine intercourse hormones, progesterone, and estrogen. Moreover, a number of research have reported larger cortisol ranges through the follicular part in comparison with the luteal part, which could additionally affect the activation of the HPA axis.
These contaminated through the follicular part have additionally been reported to have larger suppression of the HPG axis and the gonadotropin-releasing hormone (GnRH). Furthermore, CRH has been noticed to be concerned in suppressing the HPG axis unbiased of glucocorticoids. Cytokine storms ensuing as a consequence of SARS-CoV-2 infections can subsequently alter the HPA axis by rising glucocorticoids and CRH, which could result in menstrual disturbances, heavy menstrual bleeding, and anovulatory cycles.
Impact of COVID-19 vaccine on the menstrual cycle
At present, the menstrual disturbances caused by COVID-19 vaccinations are noticed to be momentary and resolve inside two cycles. Probably the most generally reported menstrual disturbances embody shorter inter-menstrual intervals and extended or heavier bleeding. Girls who skilled menstrual disturbances following the primary dose had been at a better danger of growing extra extreme signs following the second dose. The age of the ladies, historical past of being pregnant, second vaccine dose, and smoking historical past had been reported to be predictors of menstrual disturbances following SARS-CoV-2 an infection. Moreover, the menstrual disturbances had been comparable for all of the various kinds of COVID-19 vaccines.
Impact of SARS-CoV-2 on the placenta
The affect of SARS-CoV-2 an infection on the placenta continues to be poorly understood. For viral an infection and replication, the spike protein binds to the ACE-2 receptor of the goal cell. The virus and host cell membrane fusion happens by priming the spike protein with mobile trans-membrane serine protease 2 (TMPRSS2). Cells that co-express ACE-2 and TMPRSS2 are at a better danger of SARS-CoV-2 an infection. Nevertheless, just a few placental cells had been discovered to co-express ACE-2 and TMPRSS2.
The decidual immune response and expression of interferon-induced transmembrane (IFITM) antiviral transcripts can play a necessary function in defending SARS-CoV-2 an infection of the placenta. IFITM are proteins expressed in placental and epithelial cells and assist inhibit the replication of viruses. Nevertheless, ex vivo research have proven that SARS-CoV-2 can infect and propagate within the human placental cells, which is likely to be as a consequence of placental ischemia that happens as a consequence of maternal hypoxia or cytokine storm in grownup COVID-19 sufferers.
Impact of SARS-CoV-2 on being pregnant
A number of research have reported that SARS-CoV-2 infections are related to opposed being pregnant outcomes. These embody decrease delivery weight, pre-term delivery, stillbirth, and post-partum hemorrhage. These outcomes will be as a consequence of an elevated inflammatory state related to SARS-CoV-2 infections. As a result of cytokine storm generated by the SARS-CoV-2 an infection, corticosteroids are produced in better quantities, inflicting pre-term supply. Miscarriages will be caused by systemic irritation, unbalanced Th1/Th2 response, or elevated Th17/Treg ratio.
Impact of COVID-19 vaccine on being pregnant
The American Faculty of Obstetricians and Gynecologists (ACOG) and the Heart for Illness Management (CDC) suggest vaccinating pregnant and lactating girls in opposition to SARS-CoV-2. Current analysis has indicated that COVID-19 vaccines had been protected and efficient in being pregnant and weren’t related to any neonatal opposed occasions. Nevertheless, few non-serious signs, equivalent to uterine ache, uterine contraction, and uterine pressure, have been related to COVID-19 vaccines.
Impact of COVID-19 on fertility
The immune response in opposition to SARS-CoV-2 an infection was noticed to not have an effect on fertility for females. Nevertheless, SARS-CoV-2 an infection was discovered to affect the male reproductive system. A latest research highlighted a short-term discount in fertility in SARS-CoV-2 -positive males. Male sexual dysfunction ensuing from COVID-19 can last as long as 7 months following an infection. The cytokine storm as a consequence of SARS-CoV-2 an infection could cause injury to the blood-testes barrier in addition to trigger a rise in reactive oxygen species (ROS) manufacturing, which in flip impacts motility, spermatogenesis, and fertilization of mature sperms.
Conclusion
Cytokine storm as a consequence of SARS-CoV-2 an infection could cause short-term menstrual disturbances, pre-term supply, and miscarriages. It might additionally adversely affect the male reproductive system inflicting a discount in fertility and erectile dysfunction. Additional analysis must be finished to establish variations in signs between girls contaminated within the follicular part and people contaminated within the luteal part. Additionally, extra analysis is required to find out whether or not vaccine immunity or immune response differs on whether or not COVID-19 vaccine or SARS-CoV-2 an infection occurred through the follicular or luteal part.
