madman
Super Moderator
Abstract
Coronavirus disease 2019 (COVID-19), which resulted from the pandemic outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a massive inflammatory cytokine storm leading to multi-organ damage including that of the brain and testes. While the lungs, heart, and brain are identified as the main targets of SARS-CoV-2-mediated pathogenesis, reports on its testicular infections have been a subject of debate. The brain and testes are physiologically synchronized by the action of gonadotropins and sex steroid hormones. Though the evidence for the presence of the viral particles in the testicular biopsies and semen samples from COVID-19 patients is highly limited, the occurrence of testicular pathology due to abrupt inflammatory responses and hyperthermia has increasingly been evident. The reduced level of testosterone production in COVID19 is associated with altered secretion of gonadotropins. Moreover, hypothalamic pathology which results from SARS-CoV-2 infection of the brain is also evident in COVID-19 cases. This article revisits and supports the key reports on testicular abnormalities and pathological signatures in the hypothalamus of COVID-19 patients and emphasizes that testicular pathology resulting from inflammation and oxidative stress might lead to infertility in a significant portion of COVID-19 survivors. Further investigations are required to monitor the reproductive health parameters and HPG axis abnormalities related to secondary pathological complications in COVID-19 patients and survivors.
Introduction
In the current uncertain life-changing scenario, the entire world has been negatively impacted by the pandemic outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1, 2]. Presently, persistent fever, chillness, cough, pneumonia, and loss of smell and taste have been considered as the emerging clinical symptoms of the SARS-CoV-2 infection-mediated coronavirus disease 2019 (COVID-19) [3–5]. While a significant percentage of people with SARS-CoV-2 infection are asymptomatic, clinical signs and pathogenesis of COVID-19 appear to vary among infected individuals depending upon the lifestyle, age, respiratory, metabolic, renal, and cardiovascular conditions [6–8]. SARS-CoV-2 causes several life-threatening clinical complications including acute respiratory distress syndrome (ARDS), cardiovascular failure, nervous system damage, gastrointestinal disorders, and renal dysfunctions in a considerable number of COVID19 patients worldwide [9–13]. However, SARS-CoV-2- induced clinical outcome and pathogenic events during and post-recovery stages of COVID-19 are yet to be fully determined [8]. In general, the surface spike (S) viral proteins of SARS-CoV-2 have an affinity towards angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), through which it invades the host [14, 15]. Notably, ACE2 and TMPRSS2 are expressed by various tissues and organs which have the potential risk of SARS-CoV-2 infection leading to various pathological consequences [15–17]. While the lungs have been initially identified as the primary pathogenic targets of SARS-CoV-2, an increasing number of scientific evidence indicates comorbid clinical symptoms and multi-organ defects including the pathology of the testes and brain in COVID-19 patients [8, 18–21]. Notably, COVID-19 has been characterized by many neuropathological signatures due to the neuroinvasive attribute of SARS-CoV-2 [8, 12, 19, 22–25]. It has been reported that SARS-CoV-2 can cross the blood-brain barrier (BBB) and infect the ACE2 expressing neurons and glial cells, thereby leading to neuroinflammation and neuropathogenesis in the brain regions including the hypothalamus that controls various physiological functions like maintenance of the body temperature and hormonal balance [8, 12, 17, 25, 26]. Dysregulation of endocrine functions is an important clinical issue as it is related to different disorders including hypothyroidism, hypogonadism, anxiety, stress, and depression that are clearly evident in COVID-19 cases [27–30]. While the possible impact of COVID-19 on the abnormal hypothalamic-pituitary-adrenal (HPA) axis has been speculated [31], SARS-CoV-2- mediated dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis remains obscure. The brain and testes are endocrinologically linked by gonadotropins and testosterone through the regulation of the HPG feedback loop [30, 32]. While testes-derived circulating levels of sex steroid hormones are important for the regulation of the HPG axis and reproductive functions, COVID-19-associated testicular dysfunction, declined levels of testosterone and infertility require an intense scientific focus.
Initially, the testes were thought to be the target of SARS-CoV-2 due to the expression of the ACE2 in different cellular compartments of the testes [21, 33–36]. However, evidence for the presence of the viral particles in the testicular biopsies and semen samples from COVID-19 patients is highly limited [37, 38]. Despite the unavailability of clear scientific proof for the presence of SARS-CoV-2 in the testes and semen samples, degeneration of seminiferous tubule, reduced number of Leydig cells and impaired spermatogenesis have been evident in a significant number of COVID-19-positive cases [37–39]. Besides, male subjects with COVID-19 have been reported to exhibit a decreased level of testosterone and altered secretion of the hypothalamus-mediated secretion of gonadotropins such as luteinizing hormone (LH) and follicle-stimulating hormone(FSH) in the pituitary [37, 40–42]. This article revisits the key reports on testicular abnormalities as well as pathological signatures in the hypothalamus of COVID-19 patients. Further, the article supports the notion that COVID19 patients and survivors might be at risk of infertility due to testicular atrophy, hypothalamic pathology, pituitary abnormalities, and disruption of sex hormone profile. Further investigations are required to monitor the reproductive health parameters and HPG axis abnormalities related to secondary pathological complications in the positive cases during and after the recovery from COVID-19.
*Testicular Dysfunction in COVID-19
*Altered Levels of Gonadotropins in COVID-19
*Testicular Pathology: a Key Determinant of Infertility and Dysfunction of HPG Axis in COVID-19
Conclusion
Although the presence of SARS-CoV-2 in the testes remains controversial, hypogonadism resulting from the inflammation in the testes is increasingly evident [105, 106]. Thus, a defect in the steroidogenesis in the testes reflected by the reduced level of testosterone may be the underlying basis for the abnormal levels of FSH and LH in patients with COVID-19. In turn, low testosterone levels could lead to defects in spermatogenesis, erectile dysfunction, and infertility in COVID-19 [30, 107]. Therefore, understanding the impact of COVID-19 on testicular pathology has become an important clinical responsibility. FSH and LH have also been known to play roles in non-reproductive functions, while increased levels of FSH and LH have been reported to be the biomarkers for testicular damage and some secondary pathological consequences [108, 109]. The dysregulation of the HPG axis has been associated with diseases like chronic kidney disease and liver cirrhosis [110–113]. Also, the incidence of disorders of the HPG axis ranging from hypothyroidism to neurodegenerative senescence could be a likely consequence [102, 114, 115]. Therefore, a detailed study of the endocrinological and reproductive parameters of COVID-19 patients has become inevitable.
Coronavirus disease 2019 (COVID-19), which resulted from the pandemic outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a massive inflammatory cytokine storm leading to multi-organ damage including that of the brain and testes. While the lungs, heart, and brain are identified as the main targets of SARS-CoV-2-mediated pathogenesis, reports on its testicular infections have been a subject of debate. The brain and testes are physiologically synchronized by the action of gonadotropins and sex steroid hormones. Though the evidence for the presence of the viral particles in the testicular biopsies and semen samples from COVID-19 patients is highly limited, the occurrence of testicular pathology due to abrupt inflammatory responses and hyperthermia has increasingly been evident. The reduced level of testosterone production in COVID19 is associated with altered secretion of gonadotropins. Moreover, hypothalamic pathology which results from SARS-CoV-2 infection of the brain is also evident in COVID-19 cases. This article revisits and supports the key reports on testicular abnormalities and pathological signatures in the hypothalamus of COVID-19 patients and emphasizes that testicular pathology resulting from inflammation and oxidative stress might lead to infertility in a significant portion of COVID-19 survivors. Further investigations are required to monitor the reproductive health parameters and HPG axis abnormalities related to secondary pathological complications in COVID-19 patients and survivors.
Introduction
In the current uncertain life-changing scenario, the entire world has been negatively impacted by the pandemic outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1, 2]. Presently, persistent fever, chillness, cough, pneumonia, and loss of smell and taste have been considered as the emerging clinical symptoms of the SARS-CoV-2 infection-mediated coronavirus disease 2019 (COVID-19) [3–5]. While a significant percentage of people with SARS-CoV-2 infection are asymptomatic, clinical signs and pathogenesis of COVID-19 appear to vary among infected individuals depending upon the lifestyle, age, respiratory, metabolic, renal, and cardiovascular conditions [6–8]. SARS-CoV-2 causes several life-threatening clinical complications including acute respiratory distress syndrome (ARDS), cardiovascular failure, nervous system damage, gastrointestinal disorders, and renal dysfunctions in a considerable number of COVID19 patients worldwide [9–13]. However, SARS-CoV-2- induced clinical outcome and pathogenic events during and post-recovery stages of COVID-19 are yet to be fully determined [8]. In general, the surface spike (S) viral proteins of SARS-CoV-2 have an affinity towards angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), through which it invades the host [14, 15]. Notably, ACE2 and TMPRSS2 are expressed by various tissues and organs which have the potential risk of SARS-CoV-2 infection leading to various pathological consequences [15–17]. While the lungs have been initially identified as the primary pathogenic targets of SARS-CoV-2, an increasing number of scientific evidence indicates comorbid clinical symptoms and multi-organ defects including the pathology of the testes and brain in COVID-19 patients [8, 18–21]. Notably, COVID-19 has been characterized by many neuropathological signatures due to the neuroinvasive attribute of SARS-CoV-2 [8, 12, 19, 22–25]. It has been reported that SARS-CoV-2 can cross the blood-brain barrier (BBB) and infect the ACE2 expressing neurons and glial cells, thereby leading to neuroinflammation and neuropathogenesis in the brain regions including the hypothalamus that controls various physiological functions like maintenance of the body temperature and hormonal balance [8, 12, 17, 25, 26]. Dysregulation of endocrine functions is an important clinical issue as it is related to different disorders including hypothyroidism, hypogonadism, anxiety, stress, and depression that are clearly evident in COVID-19 cases [27–30]. While the possible impact of COVID-19 on the abnormal hypothalamic-pituitary-adrenal (HPA) axis has been speculated [31], SARS-CoV-2- mediated dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis remains obscure. The brain and testes are endocrinologically linked by gonadotropins and testosterone through the regulation of the HPG feedback loop [30, 32]. While testes-derived circulating levels of sex steroid hormones are important for the regulation of the HPG axis and reproductive functions, COVID-19-associated testicular dysfunction, declined levels of testosterone and infertility require an intense scientific focus.
Initially, the testes were thought to be the target of SARS-CoV-2 due to the expression of the ACE2 in different cellular compartments of the testes [21, 33–36]. However, evidence for the presence of the viral particles in the testicular biopsies and semen samples from COVID-19 patients is highly limited [37, 38]. Despite the unavailability of clear scientific proof for the presence of SARS-CoV-2 in the testes and semen samples, degeneration of seminiferous tubule, reduced number of Leydig cells and impaired spermatogenesis have been evident in a significant number of COVID-19-positive cases [37–39]. Besides, male subjects with COVID-19 have been reported to exhibit a decreased level of testosterone and altered secretion of the hypothalamus-mediated secretion of gonadotropins such as luteinizing hormone (LH) and follicle-stimulating hormone(FSH) in the pituitary [37, 40–42]. This article revisits the key reports on testicular abnormalities as well as pathological signatures in the hypothalamus of COVID-19 patients. Further, the article supports the notion that COVID19 patients and survivors might be at risk of infertility due to testicular atrophy, hypothalamic pathology, pituitary abnormalities, and disruption of sex hormone profile. Further investigations are required to monitor the reproductive health parameters and HPG axis abnormalities related to secondary pathological complications in the positive cases during and after the recovery from COVID-19.
*Testicular Dysfunction in COVID-19
*Altered Levels of Gonadotropins in COVID-19
*Testicular Pathology: a Key Determinant of Infertility and Dysfunction of HPG Axis in COVID-19
Conclusion
Although the presence of SARS-CoV-2 in the testes remains controversial, hypogonadism resulting from the inflammation in the testes is increasingly evident [105, 106]. Thus, a defect in the steroidogenesis in the testes reflected by the reduced level of testosterone may be the underlying basis for the abnormal levels of FSH and LH in patients with COVID-19. In turn, low testosterone levels could lead to defects in spermatogenesis, erectile dysfunction, and infertility in COVID-19 [30, 107]. Therefore, understanding the impact of COVID-19 on testicular pathology has become an important clinical responsibility. FSH and LH have also been known to play roles in non-reproductive functions, while increased levels of FSH and LH have been reported to be the biomarkers for testicular damage and some secondary pathological consequences [108, 109]. The dysregulation of the HPG axis has been associated with diseases like chronic kidney disease and liver cirrhosis [110–113]. Also, the incidence of disorders of the HPG axis ranging from hypothyroidism to neurodegenerative senescence could be a likely consequence [102, 114, 115]. Therefore, a detailed study of the endocrinological and reproductive parameters of COVID-19 patients has become inevitable.
