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New Avenues to Reduce Long-Term Complications in Preterm Infants

Some GnRH neurons (green) express NOS1 (red) during their migration from the nose to the brain during fetal life. The GnRH + NOS1 double-labeled cells appear in yellow. © Vincent Prévot/Inserm

Children born prematurely have a higher risk of not just cognitive and sensory disorders, but also infertility in adulthood. In a new study, a team of researchers from Inserm, University Hospital Lille and Université de Lille at the Lille Neuroscience and Cognition laboratory has opened up interesting avenues for improving their prognosis. By conducting research into a rare disease known as congenital hypogonadotropic hypogonadism, the scientists have discovered the key role of an enzyme and the therapeutic potential of the neurotransmitter that it synthesizes – nitric oxide – in reducing the risk of long-term complications in the event of prematurity. Their findings are described in Science Translational Medicine.

Congenital hypogonadotropic hypogonadism is a rare disease characterized by delayed puberty or the complete absence of puberty in adolescence, leading to infertility. Some forms of the disease are caused by a lack of production of GnRH, a hormone produced in the brain that remotely controls the development and functioning of male and female gonads through various intermediaries.

The team of Vincent Prévot, Inserm Research Director, specializes in the dialogues between the brain and the rest of the body.

Here the scientists looked at nitric oxide, a neurotransmitter that regulates the activity of GnRH neurons, and more specifically NOS1, the enzyme that synthesizes it.

“Nitric oxide suppresses the electrical activity of the GnRH neurons and modulates the release of this hormone, so NOS1 dysfunction was not ruled out as being the cause of congenital hypogonadotropic hypogonadism,” explains Prévot, the principal coordinator of the study.

To go further, his team collaborated with a laboratory in Lausanne (Switzerland) which has a cohort of 341 patients with this disease. Using DNA samples, they looked for the presence of rare mutations on the gene encoding the NOS1 enzyme and found five different mutations that could explain the disease. Some of the individuals concerned had, in addition to fertility problems, sensory and cognitive disorders (intellectual disability or loss of hearing or smell).

An application in the context of preterm birth?

The next stage of the study consisted of developing a NOS1-deficient mouse model[1] in order to better understand the role of this enzyme. The researchers encountered puberty problems, as well as sensory and neurological alterations, as observed in humans with congenital hypogonadotropic hypogonadism. They also saw an exacerbation of minipuberty in these animals. Minipuberty occurs in all mammals just after birth (between one and three months of age in humans) and triggers an initial brain activation of the axis controlling reproduction prior to the “real” puberty in adolescence.

Here the researchers observed that the peak of the sex hormone associated with this minipuberty was twice as high in NOS1-deficient mice.

“This caught our attention because premature infants also tend to present a more intense minipuberty than usual. And the greater the prematurity, the greater the risk of neurosensory and mental complications in adulthood,” reiterates Konstantina Chachlaki, Inserm researcher and first author of the study.

Based on these observations, the researchers tested the administration of nitric oxide in NOS1-deficient mice just after their birth, during the minipuberty period. What they saw was the reversal of all the symptoms they had developed: the puberty problems and sensory and neurological disorders disappeared, and this was over the long term, for the remainder of their lives.

An ongoing clinical trial

These promising findings could help to improve the care of preterm infants. Nitric oxide is also given to some children born prematurely, to facilitate the opening of the bronchi in the event of breathing difficulties.

“In light of this consistency of observations and practices, we decided to set up a clinical trial to test the effect of nitric oxide in preterm infants by studying reproductive and neurosensory parameters,” explain Prévot and Chachlaki, who are coordinating a European project dedicated to…“Administering nitric oxide at birth could reduce the risk of reproductive, sensory and intellectual complications in children born prematurely. This is what we are going to try to verify in the wake of these astonishing discoveries in mice,” they continue.

The miniNO trial was launched at University Hospital Lille in partnership with a hospital in Athens (Greece). The objective is to verify whether children receiving this treatment go on to experience normal minipuberty and puberty, and whether they develop fewer sensory and neurological complications compared to premature infants who were not administered nitric oxide at birth.


[1] In which the gene encoding the NOS1 enzyme was disactivated.

Researcher Contact

Vincent Prévot

Directeur de recherche Inserm
Responsable de l’équipe Développement et plasticité du cerveau neuroendocrine
Unité U1172 – Lille Neuroscience & Cognition – Lille

E-mail : rf.mresni@toverp.tnecniv
Téléphone sur demande

Press Contact



NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits: reversal with NO therapy in infantile mice

Konstantina Chachlaki 1,2,3,4,5 *, Andrea Messina 3,4 *, Virginia Delli1,2 Y, Valerie Leysen 1,2 Y, Csilla Maurnyi 6, Chieko Huber 7, Gaëtan Ternier1, 2, Katalin Skrapits 6, Georgios Papadakis 3,4, Sonal Shruti 1,2, Maria Kapanidou 8, Xu Cheng 3,4, James Acierno 3,4, Jesse Rademaker 3,4, S Rasika 1,2, Richard Quinton 9, Marek Niedziela 10, Dagmar L’Allemand 11, Duarte Pignatelli 12, Mirjam Dirlewander 13, Mariarosaria Lang-Muritano 14, Patrick Kempf 15, Sophie Catteau-Jonard 1,2,16, Nicolas J. Niederländer 3,4, Philippe Ciofi 17, Manuel Tena-Sempere 18-20, John Garthwaite 23, Laurent Storme 2,21, Paul Avan 22, Erik Hrabovszky 6, Alan Carleton 7, Federico Santoni 3,4, Paolo Giacobini 1, 2, Nelly Pitteloud 3,4 ©*, Vincent Prevot 1, 2 ©*

1 Univ. Lille, CHU Lille, Inserm, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience and Cognition, UMR-S 1172, F-59000 Lille, France

2 FHU 1,000 days for Health, School of Medicine, F-59000 Lille, France

3 Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, 1011 Lausanne, Switzerland

4 Faculty of Biology and Medicine, University of Lausanne, Lausanne 1005, Switzerland

5 University Research Institute of Child Health and Precision Medicine, National and Kapodistrian University of Athens, “Aghia Sophia” Children’s Hospital, Athens, Greece

6 Laboratory of Reproductive Neurobiology, Institute of Experimental Medicine, 43 Szigony St., Budapest 1083 Hungary

7 Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva, Switzerland

8 Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK

9 Translational & Clinical Research Institute and the Royal Victoria Infirmary, University of Newcastle-upon-Tyne NE1 3BZ, UK10 Department of Paediatric Endocrinology and Rheumatology, Poznan University of Medical Sciences,Poznan, Poland.

11 Department of Endocrinology, Children’s Hospital of Eastern Switzerland, St. Gallen, Switzerland

12 Department of Endocrinology, Hospital S João; Department of Biomedicine, Faculty of Medicine of the University of Porto; IPATIMUP Research Institute, Porto, Portugal

13 Pediatric Endocrine and Diabetes Unit, Children’s Hospital, University Hospitals and Faculty of Medicine, Geneva, CH1205, Switzerland

14 Division of Pediatric Endocrinology and Diabetology and Children’s Research Centre, University Children’s Hospital, Zurich, Switzerland

15 Department of Diabetes, Endocrinology, Clinical Nutrition & Metabolism, Inselspital, Bern University Hospital, University of Bern, Switzerland

16 Department of Gynaecology and Obstretic, Jeanne de Flandres Hospital, Centre Hospitalier Universitaire de Lille, F-59000 Lille, France

17 Inserm, U1215, Neurocentre Magendie, Université de Bordeaux, F-33077 Bordeaux, France

18 Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain.

19 Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC/HURS), Cordoba, Spain.

20 CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain.

21 Department of Neonatology, Hôpital Jeanne de Flandre, CHU of Lille, F-59000, France

22 Université de Clerremont-Ferrand, Clermont-Ferrand, France

23 The Wolfson Institute for Biomedical Research, University College London, London, UK

Y These authors contributed equally

Science Translational Medicine, le 5 octobre 2022

DOI : 10.1126/scitranslmed.abh2369