Research suggests benefits from using growth hormone in cases of encephalopathy, epilepsy, and regression.

Growth hormone (GH) is much more than a regulator of physical development. Recent studies reveal its direct impact on the central nervous system, neurogenesis, and its therapeutic potential for brain injuries and neurodevelopmental disorders such as autism.

A hormone present beyond growth

Growth hormone (GH) is a pleiotropic peptide hormone produced by the anterior pituitary gland and secreted under the control of the hypothalamus. It plays a vital role in child growth, differentiation, function, and development. It is also expressed on all tissue surfaces in our bodies. Therefore, it plays a crucial role in regulating the proliferation and survival of many tissues, including the central nervous system. In addition to numerous developmental effects, there are behavioral and psychological effects related to brain neurotransmitters and how they can be modulated in conjunction with growth hormone.

The role of growth hormone in neurogenesis

Studies on growth hormone treatment on adult neurogenesis have been demonstrated in laboratory animals, given that it generates neurogenesis that may also depend on the local production of the hormone in neuronal stem cells, which is activated under physiological conditions but also in pathological conditions such as encephalopathies.

When brain damage occurs, a cellular repair process must be initiated, and stem cells have the capacity to self-regenerate or differentiate, so it is important to understand how neurogenesis occurs. It occurs in two key areas of the CNS: the subventricular zone, which runs along the walls of the anterior lateral ventricles, and the subgranular zone in the dentate gyrus of the hippocampus. Therefore, alterations in these areas can lead to problems with the self-renewal of neuronal lineages, and therefore an imbalance between cell death and regeneration or cell renewal.

Factors that modulate brain regeneration

The factors that modulate signaling for the acquisition of new neural lineages are mediated both intrinsically and extrinsically. For example, environments with poor diets and low levels of physical exercise can diminish these signals of cellular regeneration. Furthermore, trauma, injury, and cellular stress mediate the regeneration of affected areas and thus repair tissue wounds.

Some of the functions of growth hormone that have been demonstrated include stimulating the genesis of neurons, astrocytes, endothelial cells, and oligodendrocytes, and promoting myelination and neuronal arborization. In some animal models of growth hormone deficiency, reduced neurogenesis, hypomyelination, and deficient synaptogenesis have been observed.

Studies have shown that growth hormone also plays an important role in differentiation in the CNS. This effect is particularly observed at high concentrations, and it has been reported that growth hormone concentrations that promote the differentiation of neuronal precursors reduce neuronal proliferation.

Therefore, there is a possibility that low concentrations of growth hormone may promote proliferation of progenitor cells at the expense of their differentiation; whereas with higher concentrations of growth hormone, proliferation is suppressed by differentiation. Other effects studied include its action on the migration and survival of neuronal cells, preventing CNS cell apoptosis.

Growth hormone generally uses multiple receptors, but in addition to its own, it can use prolactin receptors to mediate neuronal cell migration. Prolactin receptors mediate not only migration and development but also the immune system. The use of these receptors can have paracrine and autocrine effects and has been linked to some autoimmune processes.

GH and IGF-1: a key combination for brain repair

As in other areas, some of the actions of growth hormone on the CNS are mediated by increased expression of insulin-like growth factor-1 (IGF-1), the scope of these actions reaching the point of influencing certain neuronal cells such as glial cells, lining cells, endothelial cells and microglia.

Another factor as a treatment is that growth hormone can cross the blood-brain barrier, so systemic growth hormone induction plus the use of IGF-1, among other neurotrophic factors, can promote neuronal protection and repair. As a treatment, it confers neuroprotection and accelerates the recovery of many neuronal functions. Its production is particularly observed to increase in the face of damaging events, as seen in trauma, encephalopathy, and oxidative stress.

Encephalopathies, autism and developmental regression

Encephalopathies are a group of disorders that affect brain function and can have a variety of causes, including infections, toxicity, metabolic problems, and others. Some encephalopathies can cause long-term brain damage and affect cognitive and physical development, especially in children.

In brain injuries caused by hypoxic-ischemic encephalopathies due to decreased oxygen or blood supply in the fetal or postnatal stage, both cell necrosis and apoptosis will occur. Symptoms in the newborn include seizures, sensory and/or motor disturbances, and cognitive, emotional, and behavioral disorders. The severe brain damage that encephalopathy can cause during the perinatal period can also lead to learning disabilities, epilepsy, cerebral palsy, and mental retardation.

In brain injuries of any etiology, growth hormone activates protective genes that recognize hypoxia or damage. This is how it activates IGF-1, erythropoietin, dermal growth factor, and vascular endothelial growth factor. All of these factors will be upregulated after the use of growth hormone as a treatment.

After or during an encephalopathy, symptoms may occur that suggest or suggest a diagnosis of Autism Spectrum Disorders (ASD), which is a neurodevelopmental disorder characterized by impaired social integration and communication associated with restricted interests and stereotyped behaviors.

A high percentage of cases also present with language impairment, sensory dysfunction, attention deficit disorder, bipolar disorder, intellectual disability, and epilepsy, among other comorbidities.

Due to the so-called instability of symptoms, the definitive diagnosis is made at 36 months, although at 12 months, when a child does not point to what he wants, does not look at what is pointed to him, does not respond to his name and/or does not have shared attention, a possible diagnosis should be suspected and action taken accordingly, trying to identify an associated medical entity and begin an appropriate therapeutic intervention with guidance from the family.

It is a neurodevelopmental disorder of early expression and it is estimated that 30% of children with autism with typical initial development may present regression in the first years of life, with loss of communicative intent, development of stereotyped behaviors and language impairment.

The relationship between epilepsy, encephalopathies, and cognitive and behavioral regression has been observed, where there is evidence that specific cognitive dysfunctions or behavioral disorders may be a direct consequence of epileptic discharges in different brain areas; in some children, few or even no clinical seizures may be seen, or without inconsistent EEG abnormalities.

The combination of cognitive and behavioral symptoms will depend, among other factors, on the cortical area(s) affected by the epileptic process, the age of onset (degree of maturation of the affected area), and its severity. In these cases, we must consider the so-called epileptic encephalopathies, in which cognitive and social impairment is directly related to the epileptic electrical abnormality. As we will see, in some cases, the seizures do not even present guiding epileptic seizures.

When faced with a child showing signs of autistic regression (reduced eye contact, loss of shared attention, decreased interest in the environment, and even stereotyped behavior), it is important to ask about possible "spasm-like" seizures, which can be misinterpreted as "abdominal cramps" that occur in bursts and occur several times a day. These seizures can be flexion, extension, or a combination of these, or in some cases, they can be unilateral, asymmetric, or other.

Given this condition, we may be considering West Syndrome or Infantile Spasms with Hypsarrhythmia (WS), and an electroencephalogram (EEG) is essential to confirm the diagnosis. WS is an epileptic encephalopathy of the first year of life, with a highest incidence between 4 and 7 months of age. It has a frequency of 1 in 4,000–6,000 live births. It accounts for 3 to 7 cases of epilepsy in the first years of life.

A common feature is the arrest of developmental patterns, and even their loss, coinciding with the onset of epilepsy, although there are cases of autistic regression without detecting the spasms (because they are often subtle at the onset). In the presence of this type of regression and suspected spasms, it is essential to perform a sleep EEG, which will allow us to confirm the diagnosis.

However, this is not the end of the story, as it is time to consider the etiology, and in some cases, identifying it allows for the child's recovery with neurological recovery. Etiologies can be prenatal, perinatal, or postnatal, with the causes defined by the type of disease: structural/malformative or genetic/metabolic.

Other associated causes may include brain malformations, which are the most commonly identified cause of infantile spasms. They may result from disorders in neurogenesis, anterior cleavage, neuronal migration, and/or organization. These include holoprosencephaly, agenesis of the corpus callosum, cortical dysplasias, microcephaly, agyria/pachygyria complex, schizencephaly, and gray matter heterotopias.

An interesting syndrome is Aicardi syndrome, which occurs in girls, with agenesis of the corpus callosum, alternating hypsarrhythmia, asymmetric spasms, ocular disorders, hemivertebrae, chorioretinal lesions, among other clinical characteristics, with severe psychomotor impairment and poor outcome.

Other etiologies to take into account are cytomegalovirus encephalitis, toxoplasmosis, rubella, vascular etiologies: intrauterine, stroke, destructive phenomenon such as hydranencephaly, and perinatal and postnatal etiologies, such as hypoxic-ischemic encephalopathy, infections (meningitis, bacterial encephalitis and brain abscesses) and even rare cases of benign or malignant brain neoplasms.

In all of these, neuronal tissue damage is present, so the specific conditions of certain encephalopathies must be studied to weigh the benefits of treatment that includes growth hormone and thus be able to manage the underlying conditions.

Growth hormone immunoreactivity has also been detected in several brain areas including germinal regions of the embryonic brain as well as brain regions involved in postnatal neurogenesis, and has also been detected in injured neurons, myelinated axons, and glial cells within and around infarcted areas.

Growth hormone treatment has achieved new paradigms. In adults, treatment goes beyond just childhood encephalopathies; many of the pathophysiological processes that occur in adulthood are characteristic of non-hemorrhagic forms of stroke.

However, the term "stroke" or cerebral vascular accident (CVA) is generally used to denote an injury resulting from focal or multifocal ischemia (i.e., when the blood supply to one or a few specific areas of the brain is interrupted), in contrast to the global exposure of the brain to hypoxia and/or hypoxia-ischemia that can be seen in infancy due to typical hypoxic-ischemic encephalopathies in neonates.

In any case, rather than a singularly defined disease, stroke is a syndrome with heterogeneous mechanisms and multiple etiologies, including a small number of hemorrhagic strokes. Growth hormone treatment can provide benefits in both cognitive and motor recovery.

GH as a therapeutic support strategy for brain damage

Studies in experimental animals suggest that growth hormone treatment increases the number of proliferating neural precursor cells and postmitotic migratory neuroblasts after focal ischemia, suggesting that, in addition to its role in neuroprotection, growth hormone may enhance endogenous neurorestorative processes that occur after brain injury.

Growth hormone treatment in several studies was able to increase the Barthel Index, an indicator of disability and dependency in care. Treatment also showed a reduction in muscle fatigue and fiber loss in patients with complete stroke undergoing active rehabilitation. Changes in functional magnetic resonance imaging were also observed in one of these patients who received growth hormone treatment. 

Advances in the use of growth hormone and IGF-1 treatment are notable and have not only covered injuries caused by encephalopathy but have also opened the door to understanding the process of neurogenesis. Therefore, considering growth hormone treatment for brain injuries may in the future be a more notable line of treatment in care protocols for different encephalopathies.

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Article written by Enevia Health Advisor and Collaborator:

Yohana Cespedes, Chemical Eng.

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