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Effects of Growth Hormone on Cognition and Metabolic Activity of the Brain


Both GH and IGF-I play key roles in the development, maturation and function of the brain. In fact, the presence of GHRs in the brain is detected very early during neural development. This means that GH must be present in the brain to interact with its receptor. This cerebral GH may come from the fetal anterior pituitary gland because the presence of this hormone in this gland has been identified towards the 7th week after conception and can be detected in plasma up to 10 weeks of gestation. However, although it is well known that plasma GH can easily reach the central nervous system (CNS), the GH binding sites are located in the choroid plexus, where they can act as carriers for plasma GH.
Thus, a series of data indicates that its GH is also expressed in the CNS, and here its regulation appears to be different from that of pituitary GH, interestingly. IGF-I is also synthesized in the CNS, and its GH-induced expression has been detected in neural stem cells from fetal human forebrain. Both GH and IGF-I play a crucial restorative role after a brain injury, it is a hypothesis and was proposed long ago and later proven by many preclinical and clinical studies regardless of whether experimental animals or human patients have GHD.
With a variety of affections that may arise later in life (increased cardiovascular risk, diabetes mellitus type 2 and kidney disease), these children often show a decrease in intelligence and cognition, especially with reduced short-term memory. Animal studies in which IUGR was induced have shown reduced volume in both the hippocampus and cerebellum, resulting in delayed neuronal migration to the cortex, delayed dendritic and axonal growth. In addition, there is cortical thickness, decreased number of neurons, and clearly reduced myelination. Similar results were found in premature children with IUGR who had a decrease in total brain volume, mainly cerebral cortical gray matter. It was later changed to attention deficit as well as other cerebral defects such as visual affections. Effects of Growth Hormone on Cognition and Metabolic Activity of the Brain
While it is now clear that the GH / IGF-I system plays a key role in the development of the fetal brain, pituitary GH does not have any effect on the longitudinal growth of the fetus. There are no data to suggest that IUGR children suffer from deficient or deficient GH production by neural stem cells during fetal development. How the cerebral production of this hormone is regulated is also unknown, but in any case and based on the data presented, it is reasonable to think that treatment with GH should be done soon in these children with IUGR.
If a short boy is treated with GH to increase height, treatment usually does not begin before the age of 4-5, but by this age the brain is already developed.Similar brain deficiencies, although perhaps more pronounced, occur in untreated GHD children. Attention and perception deficits, insufficient executive functions and poor short-term memory are common cognitive disorders seen in these children who also show behavioral disorders. The same happens in GHD adults, in addition to worsening psychological well-being. These disturbances in cognitive functions, especially sub-normal memory speed, were visualized by functional magnetic resonance imaging. GH replacement therapy leads to significant improvements in quality of life by correcting these deficits in both children and adults.

How Does GH Apply These Important Actions to Cognitive Functions?

GH appears to be a very important regulator of spatial learning and memory linked to the hippocampus. Thus, changes in cholinergic neurons can reverse memory deficits caused by an imbalance in the hippocampal glutamatergic and GABAergic synapses. In addition, GH increases blood flow to the brain and induces the translocation of Glut4 vesicles to the plasma membrane to allow glucose entry into neurons and enhancement of excitatory synaptic transmission through activation of the PI3K / Akt pathways. Although these studies were performed in rats, recent data from an elderly woman was measured by PET scans performed before and 1 month after GH administration. Based on this analysis, it was found that GH supports these effects not only in the hippocampus, but also in practically all cortical areas. These effects of GH on cognition and metabolic activity of the brain are likely to be due to the hormone’s effects on adult neurogenesis, both in physiological conditions and after brain injury.
Besides the direct effects of GH on the brain, it is possible that some of its effects are mediated by the induction of various neurotrophic factors such as IGF-I, brain-derived neurotrophic factor (BDNF), erythropoietin. (EPO), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and some cytokines. As mentioned above, pituitary secretion of GH gradually decreases throughout aging. As a result, human adults suffer from impairments in cognitive functions, particularly short-term memory and quality of life. Therefore, older people suffer from a type of GHD that can be reversed with GH replacement therapy.
There are other pathological conditions in which a non-classical GHD emerges that is susceptible to complete or partial correction with GH administration. This applies, for example, to children with cerebral palsy, traumatic brain injuries, stroke, spinal cord injuries or neurosensory hearing loss on T5-T6, and even injury to the central or peripheral nerves.
Data from the group indicate that 70% of a large number of children with cerebral palsy lack normal GH secretion. It is not known whether this GHD is a result of neonatal injury or a result of high spasticity leading to incomplete production of IGF-I. However, GH administration is very beneficial in these children in any case, and kinesi therapy can also help restore lost brain function. Similar improvements in traumatic brain injuries after stroke were seen after GH administration and rehabilitation in both rats and humans.Effects of Growth Hormone on Cognition and Metabolic Activity of the Brain
In the spinal cord, in injuries on T5-T6, there is a loss of afferent inputs from the spinal cord to the sympathetic ganglionic chain, resulting in a reduced or no supply of catecholamines to the hypothalamus. The result of this condition is an increased hypothalamic somatostatin release and consequently deficient or inadequate GH secretion. These GHD have been reported many years ago in patients with spinal cord injury. However, they were never treated with GH until 2007, when they started treating these patients with hormones and rehabilitation, based on the fact that there were neural stem cells in the spinal cord ependent whose proliferation and differentiation were stimulated by GH. Good or very good results have been achieved in many cases, although the results have still not been published.
For example, a 16-year-old suffered a complete spinal cord injury. Although the patient could only move his arms after 6 years, he could not reach his mouth and had great spasticity. This patient started walking with the help of a walker two years after being treated with rehabilitation and GH, and despite the need for a walker 10 years after discharge from the hospital, he managed to walk 5 km a day alone.
Recently, it has been reported that the administration of GH to such patients is safe and effective. The effects of GH on the spinal cord have been clearly demonstrated in a young child affected by caudal regression syndrome at the L2 level. The treatment was started when the patient was 3 months old, after five years, and although the patient suffered from sacral bone deficiency, he was able to walk with the aid of a cane. And he was able to get up without assistance from the ground, with complete sensitivity in the legs and feet, and had sphincter control. This indicates that although the spine is not growing, new spinal roots are formed that completely disrupt the legs, feet, and sphincters. These effects, the first in the world, can only be attributed to GH.
Neurosensory hearing loss is a very common finding in children with perinatal problems as well as in children with changes in GH secretion or signaling pathways. A child with cerebral palsy was treated with GH and specific auditory stimulation that started at 3.5 months and was completely normal after 14 months. Presumably, hearing loss improved due to the effect of GH on the production of hair cells from stem cells in the cochlear sensory epithelium. These stem cells are found only in very young children and respond to GH proliferation and differentiation. This is the first known case of hearing loss being compensated by the administration of this hormone.
GH is also a promising treatment for central and peripheral nerve injuries. For example, a common finding in children with cerebral palsy is delayed conduction from the retina to the occipital cortex, but this was corrected by GH administration and visual stimulation with a tachystoscope.Effects of Growth Hormone on Cognition and Metabolic Activity of the Brain
In this case, the hormone is likely to increase the number of fibers in the optic nerve and promote their myelination. A similar regeneration was obtained in an untreated GHD patient 15 years after undergoing brain surgery for bulbar astrocytoma, and this is the cause of GHD. Surgery resulted in paralysis of the oropharyngeal structures, vocal cords and lack of primary esophageal peristalsis due to iatrogenic paralysis of the cranial nerve pairs IX, X and XII. Therefore, the patient could not speak and swallow, his tongue was atrophied and his vocal cords were paralyzed. Moreover, there was a need for nighttime volumetric ventilation due to the severity and frequency of sleep apneas, whose mouth was constantly filled with sympathetic high-density mucus saliva.
There was recovery from cranial nerve pair damage 15 years after bulbar surgery. This patient was unable to move his tongue, was atrophic, and had a persistent accumulation of highly concentrated mucus saliva (sympathetic saliva) in the mouth. Four months after treatment with GH (1 mg / day, 5 days / week) and speech therapy increased tongue size and showed significant mobility. Thus, the patient started talking and stopped collecting saliva. After four months, these forward movements clearly improved and the vocal cords began to move normally eight months later, as he was paralyzed at presentation. As a result, the patient practically got rid of his dysfunctions when he was discharged.
Since the patient has undergone extensive oral rehabilitation for almost 15 years, no success has been achieved, it seems clear that GH administration is the factor responsible for the healing of damaged cranial nerves. It also shows that in rats, administration of GH resulted in complete functional recovery of the sciatic nerves after their transections, resulting in the emergence of large numbers of axons and Schwann cells.
In summary, it is clear from these and many other data that GH is a hormone that plays many important roles in the development, functional maintenance of the nervous system, its center and periphery, or repair when an injury occurs. These effects have nothing to do with the longitudinal growth of the organism. However, it does not occur in children or adults with untreated BHH when they really need hormone replacement therapy.

References:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121435/
https://pubmed.ncbi.nlm.nih.gov/30081594/
https://clinicaltrials.gov/ct2/show/NCT01007071

Writer: Ozlem Guvenc Agaoglu


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