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Fertility hormone may benefit people with Down syndrome

Substance associated with fertility had a positive impact on functions such as memory and reasoning. (Photo: Reproduction)

A hormone associated with fertility and reproduction improved cognition in mouse models of Down syndrome. According to a French study published in the journal Science, genetic structures that regulate the production of the substance, which was also tested in seven males, are dysfunctional in these patients, impacting a number of neurons. Currently, there are no specific treatments for the cognitive deficit related to the so-called trisomy of chromosome 21.

Researchers at the University of Lille and the University Hospital of Lausanne, both in France, tested the effectiveness of gonadotropin-releasing hormone (GnRH) injection therapy to boost cognition skills, first in animals and then in a study. -pilot involving human patients. According to the scientists, the results were promising: the treatment led to better cognitive function and brain connectivity.

Down syndrome affects about one in 800 births and results in a variety of clinical manifestations, including a decline in cognitive ability. With age, 77% of people with the condition experience symptoms similar to those of Alzheimer’s disease. The gradual loss of smell, typical of neurodegenerative disorders, is also commonly diagnosed from the prepubertal period onwards, with potential deficits in sexual maturation occurring in men.

Mechanism

Recent findings have suggested that neurons that express GnRH – a hormone known to regulate reproduction via the hypothalamus – could also act in other regions of the brain, with a potential role in other functions, such as cognitive. With this idea in mind, the team from the Laboratory of Neuroscience and Cognition in Lille, led by Vincent Prévot, also director of the National Institute of Health and Medical Research (Inserm) in France, studied the mechanism that regulates GnRH in mouse models. with Down syndrome.

The laboratory demonstrated that five strands of microRNA that regulate the production of this hormone – which are found on chromosome 21 – are dysfunctional. This leads to abnormalities in neurons that secrete GnRH. The findings were confirmed at both the genetic and cellular levels. Inserm scientists were able to demonstrate that the progressive cognitive and olfactory deficiencies observed in mice were closely linked to the altered secretion of the substance.

The Inserm researchers were then able to demonstrate that restoring the physiological function of the GnRH system restores cognitive and olfactory abilities in trisomic mice. These findings were discussed with Nelly Pitteloud, professor at the Faculty of Biology and Medicine at the University of Lausanne and head of the Department of Endocrinology, Diabetology and Metabolism at the Centro Hospitalar Universitario Vaudois (CHUV).

The scientist’s research focuses on congenital deficiency of GnRH, a rare disease, which is manifested by the absence of spontaneous puberty. These patients receive pulsatile GnRH therapy to reproduce the natural rhythm of GnRH secretion in order to induce puberty.

injections

The researchers therefore decided to test the effectiveness of pulsatile GnRH therapy on cognition and smell deficits in trisomic mice, following a protocol identical to that used in humans. After 15 days, the team was able to demonstrate restoration of olfactory and cognitive functions in mice.

The next step for scientists and clinicians involved a pilot clinical trial in patients to assess the effects of this treatment. Seven men with Down syndrome, aged between 20 and 50, received a subcutaneous dose of GnRH every two hours for six months, via a pump placed in their arm. Cognitive and olfactory tests, as well as MRI scans, were performed before and after the experimental therapy.

From a clinical point of view, cognitive performance increased in six of the seven patients, with improvements in three-dimensional representation, understanding of instructions, reasoning, attention and episodic memory. However, the treatment had no impact on olfactory ability. Measures to enhance cognitive functions were confirmed by brain scans performed by CHUV’s Department of Clinical Neuroscience, which revealed a significant increase in functional connectivity.

The data suggest that the treatment works in the brain by strengthening communication between certain regions of the cortex. “Maintenance of the GnRH system appears to play a key role in brain maturation and cognitive functions,” explains Prévot. “In Down syndrome, pulsatile GnRH therapy looks promising, especially as it is an existing treatment with no significant side effects,” adds Pitteloud. According to the authors, the findings now justify the launch of a larger study – including women – to confirm the effectiveness of the treatment in people with trisomy 21, but also for neurodegenerative diseases such as Alzheimer’s.

In a commentary also published in Science, Hanne M. Hoffmann, a researcher at Michigan State University in the United States, said that the treatment appears to be promising. “Pulsatile administration of GnRH appears to be a promising approach, with few side effects, to improve cognitive function in a wide range of cognitive decline conditions,” wrote Hoffmann, who was not part of the study.