GHRH (Somatorelin)

Growth hormone–releasing hormone (GHRH)

Growth-hormone-releasing hormone (GHRH; Somatocrinin, Somatorelin) is endogenous peptide hormone consisting from 44-amino acids that is produced in the arcuate nucleus of the hypothalamus. Once Growth-hormone-releasing hormone is released from neurosecretory nerve terminals of arcuate neurons, is carried by the hypothalamo-hypophyseal portal system to the anterior pituitary gland, where it stimulates growth hormone (GH) production by binding to the growth hormone-releasing hormone receptor (GHRHR). 

The GHRHR is a member of the secretin family of G protein-coupled receptors, and is located on chromosome 7. This protein is transmembranous with seven folds, and its molecular weight is approximately 44 kD. Growth-hormone-releasing hormone is released in a pulsatile manner, stimulating similar pulsatile release of GH, and also promotes slow-wave sleep directly. During pregnancy, GHRH first appears in the hypothalamus of human fetuses between the 18th and 29th week, which corresponds to the start of production of growth hormone and other somatotropes in human fetuses. Expression of Growth-hormone-releasing hormone has been demonstrated in peripheral cells and tissues outside its major site in the hypothalamus, for example, in the pancreas, epithelial mucosa of the gastrointestinal tract, and pathologically also in tumor cells.

GHRH Mechanism of action and Signal transduction

GHRH binding to GHRHR results in increased GH production mainly by the cAMP-dependent pathway, but also by the phospholipase C pathway (IP₃/DAG pathway), and other minor pathways.

The cAMP-dependent pathway is initiated by the binding of GHRH to its receptor, causing receptor conformation that activates  G_s alpha subunit of the closely associated G-Protein complex on the intracellular side. This results in stimulation of membrane-bound adenylyl cyclase and increased intracellular cyclic adenosine monophosphate (cAMP). cAMP binds to and activates the regulatory subunits of protein kinase A (PKA), allowing the free catalytic subunits to translocate to the nucleus and phosphorylate the transcription factor cAMP response element-binding protein (CREB). Phosphorylated CREB, together with its coactivators, p300 and CREB-binding protein (CBP) enhances the transcription of GH by binding to CREs cAMP-response elements in the promoter region of the GH gene. It also increases transcription of the GHRHR gene, providing positive feedback.

In the phospholipase C pathway, GHRH stimulates phospholipase C (PLC) through the βγ-complex of heterotrimeric G-proteins. PLC activation produces both diacylglycerol (DAG) and inositol triphosphate (IP₃), the latter leading to release of intracellular Ca²⁺ from the endoplasmic reticulum, increasing cytosolic Ca²⁺ concentration, resulting in vesicle fusion and release of secretory vesicles containing premade growth hormone.

Some Ca²⁺ influx is also a direct action of cAMP, which is distinct from the usual cAMP-dependent pathway of activating protein kinase A. Activation of GHRHRs by GHRH also conveys opening of Na+ channels by phosphatidylinositol 4,5-bisphosphate, causing cell depolarization. The resultant change in the intracellular voltage opens a voltage-dependent calcium channel, resulting in vesicle fusion and release of GH.

Somatostatin (growth-hormone-inhibiting hormone)

Somatostatin (growth hormone inhibiting hormone) is an opposing hormone that acts against the effects of GHRH. Somatostatin is released from the neurosecretory nerve terminals of periventricular somatostatin neurons and is transmitted by the hypothalamic-pituitary portal circulation to the anterior pituitary where it inhibits Growth hormone secretion. Both hormones, Somatostatin and GHRH, are secreted alternately, resulting in markedly pulsatile GH secretion.

Regulation of GHRH and balanced hormone production

In order to maintain a normal balanced hormone production, GHRH, somatostatin, GH and IGF-1 levels are regulated by each other. The consequence of GHRH action is an increase in the circulating levels of GH and IGF-1 which, in turn, act back on the hypothalamus to prevent GHRH production and to stimulate somatostatin secretion. Somatostatin then prevents the release of GH from the pituitary gland and GHRH production by the hypothalamus, acts as a powerful suppressor of GH secretion. Many other factors and physiological conditions such as sleep, stress, exercise and food intake also affect the hypothalamic release of GHRH and somatostatin.

GHRH results of action, benefits, side effects

The main function of GHRH is stimulation of Growth hormone secretion by the pituitary gland. It is also believed that GHRH has the ability to stimulate somatotroph proliferation. The end results of GHRH activity are the final results mediated by Growth hormone activity; as well as possibly undesirable effects. Growth hormone (GH) is an key protein hormone in the body involved in many important biological processes and functions (stimulates the production of IGF-1, growth / cell proliferation & differentiation, protein, lipid and carbohydrate metabolism etc). 

The benefits of Growth hormone include overall regeneration, cell repair, increased protein synthesis and muscle growth, increased fat utilization by stimulating triglyceride degradation and adipocyte oxidation, increased calcium retention and bone mineralization, can help reduce the risk of cardiovascular diseases, promote health and brain function, etc.

Possible side effects of high levels and excess of Growth hormone include gigantism, acromegaly, swelling of the hands and feet, altered facial features, enlarged organs, high blood pressure and heart disease, joint pain, water retention, low blood sugar, decreased insulin sensitivity and risk of diabetes. However, in most cases, growth hormone overproduction is caused by pituitary tumors that produce growth hormone; only in very rare cases is excess growth hormone caused by overproduction of growth hormone releasing hormone.

Growth hormone deficiency: If the hypothalamus produces too little growth hormone releasing hormone, the production and release of growth hormone from the pituitary is impaired, leading to growth hormone deficiency. Growth hormone deficiency in childhood is associated with growth failure and delayed physical maturity. In adults, the most important consequences of reduced levels of growth hormone are changes in body structure (decreased muscle and bone mass and increased body fat), fatigue and poor quality of life associated with health.

GHRH, research and clinical use

Recombinant version of growth hormone-releasing hormone (GHRH) Somatorelin is a diagnostic agent for determining growth hormone deficiency. GHRH has also been scientifically investigated in many clinical trials studying the treatment of aging, elderly, sleep disorders, hormone deficiency, and mild cognitive impairment.

GHRH FAQ

What triggers GHRH?

Ghrelin and Ghrelin mimetics reduce Somatostatin release from the hypothalamus and trigger / increase release of GHRH from neurosecretory nerve terminals of these arcuate neurons. GHRH is then carried by the hypothalamo-hypophyseal portal system to the anterior pituitary gland, where it stimulates growth hormone (GH) secretion by binding to the growth hormone-releasing hormone receptor.

How is GHRH release controlled?

In order to maintain a normal balanced hormone production, growth hormone-releasing hormone, somatostatin, growth hormone and insulin-like growth factor 1 levels are regulated by each other. But also many other factors and physiological conditions such as sleep, stress, exercise and food intake also affect the hypothalamic release of growth hormone-releasing hormone.

What is the function of GHRH?

The main function of GHRH is stimulation of Growth hormone secretion by the pituitary gland. It is also believed that GHRH has the ability to stimulate somatotroph proliferation.

What stimulates the hypothalamus to release GHRH?

Ghrelin, a 28-amino-acid peptide, is a hypothalamic substance that acts synergistically with GHRH to increase growth hormone secretion. Ghrelin may also stimulate the secretion of GHRH and inhibit the secretion of somatostatin.

Where is GHRH produced?

GHRH is produced in the arcuate nucleus of the hypothalamus. It is released from neurosecretory nerve terminals of these arcuate neurons.

GHRH dosage

In the scientific studies the dosage is often mentioned as 50-150 mcg of GHRH several times (3-5) a day. It is appropriate to distribute them equally over time throughout the day, to mimic the natural, pulsed release of natural GH throughout the day. Administration of GHRH alone may not significantly increase GH levels. Therefore, it is often combined with administration of GHRPs such as Ipamorelim or GHRP-6 etc. to ensure a significant increase in GH levels, and at the same time, their combination works synergistically and increases their effectiveness mutually.

Overview and conclusion

Growth-hormone-releasing hormone (GHRH) is endogenous peptide hormone consisting from 44-amino acids that is produced in the arcuate nucleus of the hypothalamus. It stimulates growth hormone (GH) production by binding to the growth hormone-releasing hormone receptor (GHRHR). The end results of GHRH activity are the final results mediated by Growth hormone activity; as well as possibly undesirable effects. GHRH production is directly stimulated by ghrelin and inhibited by somatostatin.

If the hypothalamus produces an excess of GHRH, this may lead to excessive GH production and then side effects are possible due to high levels and excess of growth hormone. Conversely, if the hypothalamus produces too little GHRH, the production and release of GH from the pituitary is impaired, and there is a lack of growth hormone, which can lead to many serious health problems and diseases. In order to maintain a normal balanced hormone production, GHRH, somatostatin, GH and IGF-1 levels are regulated by each other, and their balance and proper functioning are extremely important for overall health and well-being.