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Hypotestosteronemia in COVID-19 or post COVID syndrome could be of hypothalamic origin

A significant proportion of male COVID-19 patients have low testosterone levels, which can persist for months after recovery from infection. It is uncertain whether gonadotropin-releasing hormone (GnRH) neurons or their functions are affected in individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The research group from France, the United Kingdom, Spain, Germany, Hungary, and Italy examined the hormone profile of male COVID-19 patients at various times after infection. They also used the postmortem brain tissue of patients who died of COVID-19 to investigate possible SARS-CoV-2 infection of GnRH neurons and olfactory epithelia. The results have shown that persistent hypotestosteronemia in COVID-19 or long COVID syndrome could be of hypothalamic origin due to impaired GnRH function, or hypogonadotropic hypogonadism.

SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA virus. Its genome encodes four structural proteins, namely the spike (S), envelope (E), nucleocapsid (N), and membrane (M) protein. Two host-cell factors are important for SARS-CoV-2 viral entry into many cell types: angiotensin-converting enzyme 2 (ACE2), which is bound by S-protein, and transmembrane protease, serine 2 (TMPRSS2), which cleaves S-protein, allowing this binding to take place.

Neurons secreting GnRH are located in the infundibular nucleus of the tuberal region of the hypothalamus. Their terminals contact fenestrated vessels of the pituitary portal system to secrete the hormone. The absence of the blood-brain barrier in the median eminence- an adaptation that is essential for peptide neurohormones such as GnRH to reach their target cells in the pituitary gland and for circulating peripheral signals to enter the brain — may represent a gap in the brain’s defense mechanisms against pathogens.

A specialized population of hypothalamic glia, the tanycytes, controls this process. Tanycytic endfeets are in contact with fenestrated capillaries at the external pial surface of the median eminence, and dynamically interact with GnRH axon terminals, thereby regulating the periodic release of GnRH. This process may be disturbed in infected patients, contributing to the hypothalamic-pituitary-gonadal (HPG) axis dysregulation.

When the HPG axis is functioning correctly, GnRH triggers the release of gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which then act on the gonads to stimulate the production of steroid hormones and gametogenesis. The feedback from gonadal steroids influences the release of GnRH and gonadotropins. A decrease in gonadal steroid levels leads to a compensatory increase in LH and FSH levels, and vice versa.

During embryogenesis, the GnRH neurons migrate from the olfactory placode into the brain but remain in contact with the olfactory bulb via long dendrites. Therefore, GnRH neurons may be exposed to SARS-CoV-2 via two distinct neuroinvasive pathways, the olfactory and the hematogenic pathways at the median eminence level. The role of the hypothalamic circuits in the SARS-CoV-2 infection of the central nervous system (CNS), and their possible involvement in the neurological manifestations of COVID-19, has been discussed in previous theoretical papers.  https://discovermednews.com/the-involvement-of-hypothalamic-circuits-in-sars-cov-2-infection-of-the-central-nervous-system/

About the study

The study included 60 male patients, aged 35–82 years, positive for SARS-CoV-2. COVID-19 diagnosis was confirmed with positive reverse transcription polymerase chain reaction (rt-PCR) of nasopharyngeal swabs for SARS-CoV-2 or a positive serum SARS-CoV-2 IgG antibody test, chest radiograph, or computed tomography scan. The controls were 50 patients aged 28–87 years, not infected with SARS-CoV-2. The study also included 47 patients with the post-COVID syndrome, older than 18 years, at least three months after COVID-19 diagnosis. Those taking steroids after recovery from COVID-19 were excluded.

Blood samples were taken at the first week following admission, and at two and four weeks if the patient was still hospitalized. At the second follow-up over a year after COVID-19, serum T, LH, and FSH levels were determined again in 22 participants.

The researchers also investigated the potential SARS-CoV-2 infection of GnRH neurons and olfactory epithelia in the brains of four patients who died of COVID-19 in the ICU, including one who had a viremia at the time of death. The control brain samples were from five age-matched patients who died before the pandemic or who did not test positive for COVID-19. The olfactory epithelia of 7-, 11- and 14-week-old human fetuses (from voluntarily terminated pregnancies) were also examined.

Results

Testosterone levels were either moderately or severely decreased in 57 of 60 COVID-19 patients. Three patients had normal or near-normal testosterone levels and intermediate concentrations of LH during the first week in the ICU. 

Out of 57 patients with low testosterone levels only six had the compensatory LH increase expected with the normal function of the HPG axis, 38 had intermediate LH concentrations, whereas 13 had very low LH concentrations, indicating a dysfunction of the HPG axis. The FSH levels followed a similar pattern to those of LH.

Seven individuals with abnormal HPG axis function at the first follow-up had normal testosterone levels at the second follow-up visit more than a year after COVID-19. However, at the second follow-up, two individuals had extremely low total testosterone levels without a compensatory increase in LH levels, confirming that hypogonadism in these individuals could be of hypothalamic origin. 

A comparable analysis in 47 male patients diagnosed with long COVID syndrome, three months or more after acute COVID-19, demonstrated that eleven of them had low total testosterone levels, and none of them had an increase in LH, indicating a persistent dysfunction of the HPG axis. FSH levels were mostly normal.

These data observed at the second follow-up, as well as in the group of individuals suffering from long COVID syndrome, show that COVID-19 can result in persistent or delayed hypogonadotropic hypogonadism one year after the infection.

The postmortem examination of the brain tissue of four patients who died of COVID-19 in the ICU demonstrated that the hypothalamus of three COVID-19 patients, including one with viremia, had detectable SARS-CoV-2 N proteins. Multifunctional hypothalamic glia, referred to as tanycytes were infected with SARS-CoV-2. Immunofluorescence demonstrated abundant N protein and double-stranded RNA (dsRNA) in the median eminence/infundibular nucleus, indicating robust SARS-CoV-2 entry and replication. In control patients, such labeling was absent.

The S protein was found in vessels, some neuron-like cells, and cells of the ependymal wall. The immunolabelling for the S protein was extremely high in tanycytic endfeets that coexpress ACE2-and TMPRSS2. Abundant S proteins, ACE2 and TMPRSS2 were also detected in the olfactory nerve layer, where axons from sensory neurons of the olfactory epithelium enter the olfactory bulb. Viral dsRNA was found in numerous olfactory bulb cells bordering the olfactory nerve layer.

A third of GnRH neurons from the brain tissue of four patients who died of COVID-19 displayed a bloated or abnormal morphology. The uninfected controls had a negligible number of abnormal GnRH neurons. Some GnRH neurons were immunoreactive for cleaved caspase-3, an apoptosis marker.

Olfactory sensory neurons of 7-, 11- and 14-week-old human fetuses also abundantly expressed ACE2 and TMPRSS2. The authors pointed out the possibility that at least some GnRH neurons in human fetuses could be infected with SARS-CoV-2 via the olfactory pathway during embryonic development.

Conclusion

This study has shown that hypothalamic cells can be infected by SARS-CoV-2 via at least two distinct neuroinvasive pathways, the olfactory and the hematogenic pathways at the median eminence level, bypassing the blood-brain barrier. The impaired function of GnRH may lead to low testosterone levels, or hypogonadotropic hypogonadism in patients suffering from COVID-19 or long COVID syndrome.

This article was published in eBioMedicine.

Journal Reference

Suave F, Nampoothiri S, Clarke SA et al. Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death. EbioMedicine 2023; 96: 104784.  https://doi.org/10.1016/j.ebiom.2023.104784

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