Long-COVID cognitive impairments and reproductive hormone deficits in menmay stem from GnRH neuronal death
Creators: name: Florent Sauve
name: Sreekala Nampoothiri
name: Sophie A. Clarke
name: Daniela Fernandois
name: Caio Fernando Ferreira Coêlho
name: Julie Dewisme
name: Edouard G. Mills
name: Gaetan Ternier
name: Gaetan Ternier
name: Ludovica Cotellessa
name: Cristina Iglesias-Garcia
name: Helge Mueller-Fielitz
name: Thibaud Lebouvier
name: Romain Perbet
name: Vincent Florent
name: Marc Baroncini
name: Ariane Sharif,
name: June Ereño-Orbea
name: Maria Mercado-Gómez
name: Asis Palazon
name: Virginie Mattot
name: Florence Pasquier
name: Sophie Catteau-Jonard
name: Maria Martinez-Chantar
name: Erik Hrabovszky
name: Mercé Jourdain
name: Dominique Deplanque
name: AnnamariaMorelli,
name: Giulia Guarnieri
name: Laurent Storme
name: Cyril Robil,
name: François Trottein
name: Ruben Nogueiras
name: Markus Schwaninger
name: Pascal Pigny
name: Julien Poissy
name: Konstantina Chachlaki
name: Claude-Alain Maurage
name: Paolo Giacobini
name: Waljit Dhillo
name: S. Rasika
name: Vincent Prevot
Publisher: name: Zenodo
Year: 2023

description: Summary
Background We have recently demonstrated a causal link between loss of gonadotropin-releasing hormone (GnRH),
the master molecule regulating reproduction, and cognitive deficits during pathological aging, including Down
syndrome and Alzheimer's disease. Olfactory and cognitive alterations, which persist in some COVID-19 patients,
and long-term hypotestosteronaemia in SARS-CoV-2-infected men are also reminiscent of the consequences of
deficient GnRH, suggesting that GnRH system neuroinvasion could underlie certain post-COVID symptoms and
thus lead to accelerated or exacerbated cognitive decline.
Methods We explored the hormonal profile of COVID-19 patients and targets of SARS-CoV-2 infection in postmortem
patient brains and human fetal tissue.
Findings We found that persistent hypotestosteronaemia in some men could indeed be of hypothalamic origin,
favouring post-COVID cognitive or neurological symptoms, and that changes in testosterone levels and body weight
over time were inversely correlated. Infection of olfactory sensory neurons and multifunctional hypothalamic glia
called tanycytes highlighted at least two viable neuroinvasion routes. Furthermore, GnRH neurons themselves
were dying in all patient brains studied, dramatically reducing GnRH expression. Human fetal olfactory and
vomeronasal epithelia, from which GnRH neurons arise, and fetal GnRH neurons also appeared susceptible to
infection.
Interpretation Putative GnRH neuron and tanycyte dysfunction following SARS-CoV-2 neuroinvasion could be
responsible for serious reproductive, metabolic, and mental health consequences in long-COVID and lead to an
increased risk of neurodevelopmental and neurodegenerative pathologies over time in all age groups.
Funding European Research Council (ERC) grant agreements No 810331, No 725149, No 804236, the European
Union Horizon 2020 research and innovation program No 847941, the Fondation pour la Recherche Médicale (FRM)
and the Agence Nationale de la Recherche en Santé (ANRS) No ECTZ200878 Long Covid 2021 ANRS0167 SIGNAL,
Agence Nationale de la recherche (ANR) grant agreements No ANR-19-CE16-0021-02, No ANR-11-LABEX-0009, No.
ANR-10-LABEX-0046, No. ANR-16-IDEX-0004, Inserm Cross-Cutting Scientific Program HuDeCA, the CHU Lille
Bonus H, the UK Medical Research Council (MRC) and National Institute of Health and care Research (NIHR).
Copyright © 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: COVID-19; GnRH; Neurodevelopment; Cognition; Infertility; Hypothalamus