Human growth hormone: Difference between revisions

<StructureSection load='1hgu' size='350' side='right' caption='Human growth hormone (PDB entry [[1hgu]])' scene=''>

Glycosylation helps distinguish between different variants and isoforms as it works as an ID cards for proteins. These carbohydrates are specific to each forms and are recognized by the associated hgH receptors. Though still being a relatively unknown mechanism in hgH, studies have shown that one isoform in particular, a 22kDa variant was identified and discovered due to the specific carbohydrates linked to its polypeptide chain.

==Receptor Binding Site==

The Receptor binds to Residues Phe54 and Glu74 of hGH

It was previously believed that after stimulating HGH secretion, membrane bound secretory vesicles containing the hormone dock at the cell plasma membrane. These vesicles were believed to become completely incorporated into the plasma membrane, and would later be retrieved via endocytosis, thus allowing for passive release of the HGH within the vesicles. However, this mechanism is not supported by experimental evidence, such as the appearance of empty and partially empty vesicles immediately after secretion.  Bhanu Jena’s laboratory has recently elucidated the molecular mechanism of cellular secretion. Their studies suggest that there is actually a new cellular structure called a porosome that is involved with the mechanism. Porosomes are “basket-like” structures residing at the plasma membrane that have a 100-150nm diameter opening to the extracellular environment (Figure 1). Rather than docking directly at the plasma membrane post secretion stimulation, membrane bound secretory vesicles fuse at the base of porosomes, which subsequently expel the vesicular contents (Figure 2). During stimulation, the opening dilates about 20-35% to aid in the expulsion of HGH. The porosome returns to the resting size once the process is complete (Anderson et al., 2004)<ref>PMID:15305891</ref>.

==Mechanism of Action==

The body’s primary mechanism of regulating hGH is to release somatostatin, also known as growth hormone inhibitory hormone (GHIH).  Somatostatin is produced in the hypothalamus and released by the anterior pituitary gland, pancreas, and GI tract (Somatostatin, 2011).  This hormone works together with growth hormone releasing hormone (GHRH) to properly regulate the secretion of hGH from the pituitary gland.  Somatostatin levels are directly affected by levels of circulating hGH.  Specifically, levels of somatostatin are high when hGH concentrations are high, and low when hGH is low.

There are two forms of somatostatin found in the body.  One form, known as SS-14, is 14 amino acids long and found primarily in the nervous system and pancreas.  The other has an amino acid chain length of 28 and is called SS-28.  This form is found predominantly in the GI tract.  SS-28 is a much stronger inhibitor of hGH then SS-14 (Bowen, 2002).  Most of the body’s receptors don’t differentiate between the two forms of somatostatin.  All receptors are G protein-coupled receptors and inhibit adenyl cyclase, which, in turn, affects a number of hormones and second messengers (Bowen, 2002).

Glucocorticoids are a type of steroid hormones that regulate hGH levels two different ways.  Studies have shown that glucocorticoids are able to suppress the release of GHRH as well as reduce GHRH receptor responsiveness (Miller et al., 1997)<ref>PMID:9165036</ref>. Due to the suppression of GHRH, the levels of hGH in the body eventually subside.  There is also data to suggest that glucocorticoids work with somatostatin release in the hypothalamus (Lima et al., 1993)<ref>PMID:8094392</ref>.   

Times of high sugar levels in the body are generally accompanied with higher insulin levels.  In this state, insulin and related hormones like Insulin-like Growth Factor (IGF-1) have been shown to decrease binding affinity between hGH and its receptors (Shaonin et al., 1997). With lower levels of insulin and IGF-1, hGH secretion and levels can quickly and continuously rise.  Although insulin and IGF-1 don't directly act on hGH receptors, they can affect the signaling cascade pathway that hGH uses (Yakar et al., 2004)<ref>PMID:14702113</ref>.  JAK2 is one of the proteins found in this signaling pathway and has been known to be affected during hGH/insulin feedback and regulation loops (Shaonin et al., 1997).

Deficiency in somatostatin can occur in childhood or adulthood. Congenital deficiency is typically associated with an abnormal pituitary gland but can also be part of a larger syndrome or condition1. Acquired deficiency can develop from multiple sources including infection, brain tumors, injury, brain surgery or radiation to the head1. There are cases in which no direct cause can be identified. Pituitary tumors which have been treated with surgery or radiation are the typically cause of GH deficiency in adults.

 

Symptoms of deficiency in children include short stature, slow growth, late onset of puberty, increased fat around the waist, and delayed tooth development1. Pituitary dwarfism can result from untreated deficiency in children. In adults the symptoms include low energy, decreased strength and muscle mass, low stamina, weight gain (especially around the waist), anxiety, depression and thin, dry skin1.

Deficiency can also cause increased total cholesterol, LDL (low density lipoprotein), apolipoprotein B, and triglyceride levels and can reduce bone density.

The general treatment for dwarfism is HgH injections. The sooner this treatment is started, the more effective it will be in overcoming the deleterious effects of deficient HgH. These injections are applied anywhere from several times a week to once a day. Further care for people afflicted with HgH deficient dwarfism involves psychological therapy to help deal with the social ramifications of such a short stature (A.D.A.M. Growth hormone).  

 

Diseases can also result from levels of GH being too high. The effects of excess GH vary based on age. Gigantism is excess of GH during childhood and Acromegaly is excess of GH during adulthood (after bone growth has stopped). Symptoms of gigantism include delayed puberty, double vision, headache, increased sweating, large hands and feet, and weakness3. Symptoms of acromegaly vary slightly and include body odor, carpal tunnel syndrome, fatigue, weakness, increased sweating, joint pain, large hands and feet, sleep apnea, thickening of skin, widely spaced teeth, and unintentional weight loss4.  

Acromegaly, or gigantism, is most commonly treated with surgery. Removing the tumor in the pituitary gland can stop the excess release of growth hormone. This is completely successful in approximately 60 percent of cases. Incomplete success is often attributed to the size of the tumor; large tumors cannot always be completely removed, resulting in continued high levels of hormone release (Freda, 2002)<ref>PMID:9814451</ref>.  

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