**1. Introduction**

Just one century ago (1921), it was reported that the administration of bovine anterior pituitary gland extracts to rats induced greater growth in these thus treated animals [1]. This fact led to the assumption that a pituitary factor had to be responsible of the longitudinal growth of the organism, something proven some years later when it was shown that human dwarfs could grow when treated with human pituitary extracts. This pioneer treatment was introduced by Dr. Maurice Raben at Tufts New England Medical Center in 1956 [2]. One of the first dwarfs treated in this way, who reached normal height, was in good health 62 years later [3]. However, the discovery of the human growth hormone (GH) took place a year earlier, 1955, by Choh Hao Li, who worked at the University of California, within his studies on the isolation of pituitary hormones. Li himself developed a method for isolating GH from human cadavers and purifying the hormone so that it could be administered to children with GH-deficiency dwarfism. At the program's peak in 1973, 82,500 pituitary glands had been collected for treatment of about 3,000 children. Too many pituitary glands removed from human cadavers for so few GH-deficient children treated, so that the program declined. Furthermore, the extraction techniques could not avoid the fact that some of the pituitaries were contaminated with nerve tissue from the posterior pituitary lobe. This led to the appearance of several cases of iatrogenic Creutzfeldt-Jacob disease in patients who had received pituitary extracts in which pathogenic prions were present in the posterior pituitary lobe, something *a priori* undetectable. In 1962, the Li group made the first approach to the amino acid composition of human pituitary GH [4], a very important finding that allowed him to determine the structure of human GH and synthesize it in small quantities in 1971. This was a very important step forward as it paved the way for the production of the hormone

in genetically engineered bacteria (*Escherichia Coli*), greatly expanding the offer. The product was approved in the United States for sale in October 1985, and a new world began for GH-deficient children, because the advances in the field of genetically engineering permitted to produce practically unlimited quantities of the hormone, pure and safe, by DNA recombinant technology. The hormone was first produced in prokaryotes (*Escherichia Coli*) and later in eukaryotes (*murine fibroblasts*). Apparently, the hormones produced in these different type of cells were the same in terms of their effectiveness in producing further growth in GH-deficient children. However, we suspected that there must be some differences depending on the type of cells used for production of GH. In fact, similar doses expressed in international units (IU), corresponded to different weight of the theoretically identical product. To analyze the reason for these differences, we carried out an electrophoretic study of the different GHs existing on the market, and we saw that the hormone produced in murine fibroblasts contained not only the main GH variant GH 22 kDa but also the minor variant 20 kDa. This is logical, since during the expression of human GH, an alternative splicing occurs in 10% of the primary transcript, giving rise to the 20 kDa GH, but this alternative splicing cannot take place in prokaryotes. Initially, these differences were not considered important in terms of effectiveness at the growth level; and it took many years until a utility or any physiological action could be found for this GH 20 kDa. However, different studies carried out in the last years reveal that this isoform *in vivo* possesses very important properties. For example, it has been seen that GH 20 kDa has several GH-like activities in male high-fat-fed rats, lacking, unlike GH, diabetogenic and lactogenic effects, and failing to increase plasma IGF-I or body length. Instead, treating mice with GH gene deletion (−/−) leads to clear increases in plasma IGF-I, femur length, body length, body weight, and lean body mass and decreased fat mass. These effects are similar to those observed in mice receiving GH treatment. That is, GH 20 kDa can stimulate IGF-I and longitudinal body growth in GH-deficient mice in a similar way to GH 22 kDa, but unlike this main form, the GH isoform promotes growth without inhibiting the actions of insulin and without promoting (*in vitro*) growth of cancers presenting prolactin receptor (PRLR). The authors conclude that this GH isoform may improve current GH therapies especially in patients at risk for metabolic syndrome or PRLR-positive cancers [5]. Another recent study indicates that GH 20 kDa can internalize into the cytoplasm, as GH 22 kDa does, but its functions appear to be different from those exerted by the main form [6]. From these and other studies, it is expected that in the coming years, the possible beneficial effects of GH 20 kDa on the human body will be better known.

From 1985, when treatments with recombinant GH began, the spectrum of therapeutic applications of this hormone, initially restricted to children with proven GH-deficiency, increased significantly, especially in the pediatric population [7]. This is the case in children suffering from idiopathic short stature, or children with growth retardation caused by chronic renal failure, Turner syndrome, *SHOX* gene deficiency, Noonan syndrome, but also in adults with GH deficiency as long as they have any other hormonal pituitary deficiency (with the sole exception of Prolactin), and in patients with acquired immunodeficiency syndrome (AIDSS) wasting [8, 9]. This led to GH being considered a hormone that, in addition to its metabolic properties (hyperglycemic by counteracting the effects of insulin, lipolytic and protein anabolic), was considered as the growth hormone. Consequently, the study of its effects was practically restricted to pediatric doctors, whose main interest in GH was to prescribe it for growth in children with short stature.

*Growth Hormone Gene Family and Its Evolution DOI: http://dx.doi.org/10.5772/intechopen.108412*
