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COVID-19 is the clinical disease caused by the SARS-CoV-2 virus which was originated in Wuhan, China. SARS-CoV-2 virus was known to evolve from the bat coronavirus and possess 96% of its genome with the bat coronavirus BatCoV RaTg13
COVID-19 is the clinical disease caused by the SARS-CoV-2 virus which was originated in Wuhan, China. SARS-CoV-2 virus was known to evolve from the bat coronavirus and possess 96% of its genome with the bat coronavirus BatCoV RaTg13. It is associated with massive cytokine storm which results in multiple organ systems damage. Clinically, COVID-19 symptoms are persistent fever, cough, pneumonia, and loss of smell and taste. The interaction of the SARS-CoV-2 viral Spike protein and ACE2 on cells co-expressing ACE2 and the cellular transmembrane protease serine 2 (TMPRSS2) has been identified as the mechanism of cellular entry for the SARS-CoV-2 virus. Hence, the testes also express ACE2 receptors, there are some investigations done to check the possible impact of COVID-19 on male fertility.1
COVID-19 and the hypothalamic-pituitary-gonadal axis1
The hypothalamic-pituitary-gonadal axis (HPG) endocrinologically links the brain and testis through the production of gonadotropins and testosterone as well as the HPG feedback loop. This axis regulation is important for sex hormone production and fertility. Abnormal levels of gonadotropins have been identified in COVID-19 patients. Hence, evaluation is required whether there is any involvement of COVID-19 on HPG.
Many studies showed that COVID-19 can impact testicular hormone production. One study by Ma et al. found high luteinizing hormone (LH) levels and lower testosterone to LH ratios in SARS-CoV-2 patients. These abnormalities could indicate a disruption in sex hormone secretion associated with COVID-19 disease. One more study showed that the COVID-19 patients were found to have significantly lower testosterone, higher LH, and prolactin. SARS-CoV-2 has been shown to cross the blood-brain barrier. Once past the barrier, it infects ACE2 expressing cells, leading to neuro-inflammation which can disrupt normal physiologic functions such as temperature regulation and hormone balance. It has been reported that fever of > 39-degree Celsius for over three days can lead to a significant reduction in semen concentration and motility. One more study suggested that hypothalamic lesions and enlarged pituitary gland in COVID-19 patients could alter the regulation of gonadotropin release leading to a subsequent reduction in testosterone level.
The use of glucocorticoids for the management of COVID-19 can also impact fertility. Exogenous glucocorticoid use can disrupt the HPG axis, which is well known to lead to temporary effects on fertility. Hence, a balanced concentration of glucocorticoids is required to maintain gonadal function. Dexamethasone is one of the only medications used to reduce mortality in COVID-19 patients and is routinely administered.
Hypogonadism after SARS-CoV-2 infection2
ACE2 & TMPRSS2 are critical factors of virus transmission. ACE is mainly expressed in many organs, including, lung, cardiovascular system, kidney, intestine, liver, and testes. The expression of ACE2 is highest in testes, predominantly in spermatogonia, Leydig, and Sertoli cells. TMPRSS2 is mainly expressed in spermatogonia and spermatids. Male patients had developed testosterone deficiency as an acute complication.
Hypogonadism after SARS-CoV-2 infection was explained with several mechanisms, including:
(1) direct invasion of COVID-19 via binding to testicular ACE2 receptors,
(2) cytokine activated damage to the seminiferous epithelium,
(3) inhibition of the production of steroids and testosterone by the leucocyte infiltration and interferon secretion in the testicular interstitium, and
(4) increase in prolactin levels due to stress.
Expression of Interleukin6 (IL-6) and its receptors are detected in testes, and IL-6 mediated immune response is blamed on testicular injury via IL-6 related leukocyte infiltration.
In one study, it was observed that there was a high rate of hypogonadism, especially secondary hypogonadism, and about half of the patients had hypogonadism in the sixth months’ follow-up. 2
COVID-19 infection & Sperm DNA fragmentation3
The sperm DNA fragmentation index (DFI) is a measure of DNA damage that has emerged as an important tool in the evaluation of male fertility potential. High levels of sperm DNA damage have been associated with spontaneous pregnancy loss and poor assisted reproductive technology outcomes. SARS-CoV-2 may cause damage to the male reproductive system via both direct and indirect mechanisms, or a combination of both. Oxidative stress is a common cause of male infertility and likely represents one of the mechanisms by which COVID-19 elevates sperm DFI. There is very little published data on sperm DFI and COVID-19.Ma, et al. examined a group of males (age ranging from 20 to 49 years) who endured mild to moderate COVID-19 infection. In this study, DNA fragmentation was measured with the sperm chromatin dispersion assay and found that one-third of patients demonstrated high DFI (mean 20.05 ± 3.80 %), as well as low sperm motility (defined as progressive and non progressive <40%). The authors concluded that impaired sperm quality, reflected by a high sperm DFI, may represent a complication of COVID-19 in certain men.
The acute and chronic effects of COVID-19 on semen quality and spermatogenesis are still largely unknown, however, COVID-19 may be detrimental to men who want natural or assisted conception.
|Dr Narmada Hadigal MBBS (OMC), DGO (GMC), DNB, MNAMS, DPHA.
Laparoscopy & Hysteroscopy Surgeon, Fertility Specialist.
Director for NARMADA FERTILITY & ENDOSCOPY CENTER, Secunderabad.