Q&A Report: New Horizons: Gonadotropin-Releasing Hormone and Cognition
The answers to these questions have been transcribed and edited from the webinar with:
Vincent Prevot, PhD
Research Director and Laboratory Head
Development and Plasticity of the Neuroendocrine Brain
Lille Neuroscience & Cognition, Inserm
How long does the treatment with pulsatile GnRH last after the infusion cessation? If you stop treatment, do the cognitive, structural, and functional effects reverse?
This is indeed a crucial question we are currently addressing. Patients receive the pump for six months, and then the pump is removed. Afterward, we conduct the same tests in patients six months after stopping the pump. Interestingly, some patients appear to maintain their cognitive performance, while others experience a decline.
So in this small clinical trial, a fraction maintained their improved cognitive performances and a fraction dropped off 6 months after cessation of infusion. Nelly Pitteloud, MD is currently analyzing the corresponding changes in functional connectivity using resting state fMRI and the results should be available soon.
In mice, this has unfortunately not been done but is something that could be done in the future.
Could we also intervene earlier in life? In childhood for example? Wouldn’t that be even more efficient?
We cannot intervene before puberty onset as we may do more bad than good by interfering with this important process. The idea here is to intervene after puberty; that is to say around the age of 15, perhaps.
We are also currently exploring this in the mouse model, and we found that the origin of the alteration of GnRH production was at mini puberty; this period is between the 1st week of life and 6 months of life in humans.
In Down syndrome mice, the GnRH system appears to be more active.
Mini puberty is a window in which we could intervene to decrease the amplitude of mini puberty or if mini puberty is not present, here we could give the GnRH treatment to mimic a “normal” mini puberty window.
What are the underlying mechanisms for the effect of GnRH on cognition?
In mice, the data from the hippocampus and in vivo electrophysiological data point towards an effect on myelination; specifically, the myelination of some circuits which were somehow unmyelinated or demyelinated. In human patients, there was a tendency to increase myelination in some areas but no statistical significance as there were only 7 patients.
It is also possible that functional connectivity was improved in some default networks which were known to be “asleep” in down syndrome patients. Other default neural networks are seemingly altered in down syndrome patients (such as between the hippocampus and the amygdala) that increase anxiety. Thus, it is possible that individuals with Down syndrome learn differently because they are anxious.
GnRH treatment also affects the hippocampus and amygdala functional networks. Therefore, depending on the neuronal populations that receive the GnRH information, the action of generation would be different, but as a whole, it could improve the ability of the person to perform cognitive tasks.
You mentioned the treatment is well tolerated - are there any notable side effects?
Regarding side effects, because we’re using a natural molecule and mimicking the natural rhythm, there are no notable side effects, except perhaps some irritation at the injection site. However, other therapies, such as those given to suppress puberty in children with precocious puberty or transgender children, may involve different approaches — and these may be either agonists or antagonists.
Are there sex differences in treatment effects for DS?
This is indeed a great question. Initially, our intention was not to focus solely on men. However, for women, the inclusion criteria are more stringent and challenging. They must avoid contraceptive pills to prevent interference with the treatment. Additionally, they need to undergo testing during specific phases of the menstrual cycle to avoid hormonal interference with functional MRI assessments.
We are also currently developing a new study. It will be double-blind, including a placebo arm, with 30 men and 30 women. So, moving forward, we’ll have a balanced representation.
How do you implant the pumps? Do you have to reimplant during the study or are they pre-loaded with the correct amount of treatment?
We began using these pumps soon after they became available on the market. We’ve utilized both the first and second generations. The exciting part is that you can refill the pump.
The same applies to patients. They need to change the pump every three days. Fortunately, in mice, the pumps last a bit longer. Regarding the reservoir, we typically need to refill it every 15 days, approximately 2 or 3 times. However, the limitation lies in the power—the battery—especially with the first-generation pumps.
Additionally, the energy demand varies based on the modifications we make to the pump. Initially, we could conduct experiments for about two weeks using the first pumps. But with the new generation, we can extend it to 50 days. Of course, you still need to refill through the skin, but overall, it’s a significant improvement.
In the GnRH neuron projection studies, can iDISCO data indicate the presence of GnRH neurons between the hypothalamus and hippocampus?
Indeed, we conducted a fascinating experiment. We injected a retrograde virus into the median eminence — the projection site of GnRH neurons that communicate with the pituitary. The retrograde tracing revealed that most of the fibers reaching the hippocampus and cortex in mice originate from the same neurons that regulate reproduction.
Along the way, you may encounter some cell bodies of GnRH neurons outside the hypothalamus. This becomes even more significant in humans. While mice have around 800 neurons in the basal hypothalamus and the median eminence, humans have approximately 2,000. Moreover, during fetal development, up to 10,000 neurons migrate from the nose to the hypothalamus, cortex, and hippocampus.
Do you think GnRH pulse injection would be as effective in menopause or ovariectomized mice as in minipuberty?
Indeed, this is a fantastic question. Unfortunately, women transitioning into menopause often experience cognitive decline. However, fortunately, they tend to recover from this cognitive loss over time.
There was an American study conducted on 2,000 women, which demonstrated cognitive recovery after the transition into menopause. However, unfortunately, when analyzing the same women four years later, they observed that cognitive performance had worsened compared to the period before menopause. This suggests that menopause itself could induce cognitive alterations due to an exacerbated pattern.
Considering this, perhaps the pump could also be useful for women during menopause. Moreover, it might even be safer than administering a combination of steroids or other treatments. The pump specifically targets a single receptor in neurons.
Is giving more GnRH (with pulse injection) helpful though GnRH level will already be saturated (overexpressed) in menopause? Can too much GnRH act as an antagonist and down-regulate the GnRH receptor?
It’s a peculiar system because both agonists and antagonists play a role. Agonists act longer on the receptor, while antagonists inhibit it. Both types internalize the receptor and have an inhibitory effect. For instance, consider men with prostate cancer. They are often treated with gonadotropin agonists to suppress testosterone and regulate the axis. However, it’s well-documented that these patients experience cognitive decline and even face a higher risk of developing Alzheimer’s disease.
Additional references:
Prévot, Vincent, Manuel Tena-Sempere, and Nelly Pitteloud. “New horizons: gonadotropin-releasing hormone and cognition.” The Journal of Clinical Endocrinology & Metabolism 108.11 (2023): 2747-2758. https://academic.oup.com/jcem/article-abstract/108/11/2747/7187944
Manfredi-Lozano, Maria, et al. “GnRH replacement rescues cognition in Down syndrome.” Science 377.6610 (2022): eabq4515. https://www.science.org/doi/full/10.1126/science.abq4515
Chachlaki, Konstantina, et al. “NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice.” Science translational medicine 14.665 (2022): eabh2369. https://www.science.org/doi/full/10.1126/scitranslmed.abh2369
Sauve, Florent, et al. “Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death.” EBioMedicine 96 (2023). https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00350-X/fulltext
Sauvé, Florent, Loïc Kacimi, and Vincent Prévot. “The hypothalamic–pituitary–gonadal axis and the enigma of Alzheimer disease sex differences.” Nature Reviews Endocrinology (2024):1-2. https://www.nature.com/articles/s41574-024-00981-1
Clinical Trial mentioned in webinar:
GnRH Therapy on Cognition in Down Syndrome
ClinicalTrials.gov ID NCT04390646 : https://clinicaltrials.gov/study/NCT04390646
Sponsor Nelly Pitteloud
Information provided by Nelly Pitteloud, Centre Hospitalier Universitaire Vaudois (Responsible Party)
Alternative: CTV https://ctv.veeva.com/
GnRH Therapy on Cognition in Down Syndrome https://ctv.veeva.com/study/gnrh-therapy-on-cognition-in-down-syndrome