Pulsatile GnRH therapy boosted brain connectivity in pilot study

Regular doses of gonadotropin-releasing hormone (GnRH) boosted cognitive skills in people with Down syndrome (trisomy 21), a pilot clinical trial showed.

Cognitive performance increased in all but one of seven adult men with Down syndrome treated with pulsatile GnRH therapy, a treatment currently used in Kallmann syndrome, according to Vincent Prevot, PhD, of University de Lille in France, and colleagues.

Moreover, interventions that restored GnRH functions reversed olfactory and cognitive defects in Down syndrome mice and in a mouse model of Alzheimer’s disease, Prevot and co-authors reported in Science.

The findings suggest GnRH, a hormone associated with fertility and reproduction, may play a role in olfaction and cognition.

“This is the first study to propose a promising efficient and safe therapy to improve cognition in trisomy 21, though our data have to be validated by a larger-scale randomized clinical trial,” Prevot told MedPage Today.

“The study demonstrates that the GnRH neurons and GnRH could be used by the brain to measure the fitness of the organism and, conversely, that decline in the rhythmic release of GnRH could play a role in the pathophysiology of neurodevelopment disorders and potentially in neurodegenerative diseases in which the loss of olfaction is usually an early sign of the onset of dementia,” Prevot added.

The mouse study data “suggest a similar treatment could be used in patients with Alzheimer’s disease to mobilize their cognitive reserve and improve their well-being,” he said.

Down syndrome, the most common genetic cause of intellectual disability, is caused by having three copies of chromosome 21 instead of the usual two. Many adult Down syndrome patients have symptoms similar to early-onset Alzheimer’s disease and gradual loss of olfaction.

“The loss of olfaction in Down syndrome is frequently associated with deficits in fertility, both of which start around puberty,” observed Hanne Hoffmann, PhD, of Michigan State University in East Lansing, in an accompanying editorial.

Most GnRH-positive neurons project from the hypothalamus to the median eminence and release GnRH in a pulsatile pattern to promote gonadal function and fertility, Hoffmann noted. A subset of GnRH neurons project to the hippocampus and cortex where pulsatile GnRH promotes cognitive function.

“The physiological role of this population of GnRH neurons has remained poorly understood, but now [Prevot and colleagues] have found that they are associated with memory and cognition,” she wrote.

In the pilot study, small minipumps that administered pulsatile GnRH therapy were placed under the skin of seven adult men with Down syndrome. The pumps released GnRH at a rate of 75 ng per kg of body weight per pulse at 2-hour intervals for 6 months. Six age-matched healthy male controls were also recruited to compare baseline parameters.

Pulsatile GnRH improved working memory, attention, and verbal comprehension in the Down syndrome patients. It also increased neuronal connectivity in the hippocampus and cortex.

“However, GnRH treatment did not improve olfaction nor did it change the profile of reproductive hormones, except for a reduction in follicle stimulating hormone, which was close to levels observed in controls after treatment ended,” Hoffmann noted.

“The unexpected findings of the cognition-boosting effect of GnRH have broad potential,” she added. Memory and brain fog problems that emerge during menopause, for example, might be prevented by normalizing the pulsatile release of GnRH with implantable minipumps, she suggested.

“To fully establish the value of pulsatile GnRH to enhance cognitive function, a randomized controlled study including both sexes will be required,” Hoffmann pointed out. “If GnRH neurons that project to cognitive centers in the brain lose their capacity to release GnRH at the required level in older adults, pulsatile GnRH might provide unanticipated benefits to slow down cognitive decline.”