Growth and Growth Hormone through the Ages: Art and Science

Abstract

<b><i>Background:</i></b> People have long been fascinated with the size and growth of living things, from the giants of classic mythology and art to the little people who also have appeared in classical art, as well as the courts of European monarchs, and were exploited in “shows.” Serious medical evaluation began in the late 19th century with the description of acromegaly and its association with pituitary tumors. In the early 20th century, multiple investigators attempted to extract a growth-promoting factor from the anterior pituitary and then, over the decades, to purify it and distinguish it from other anterior pituitary hormones. With relatively pure growth hormone (GH), its biological activity in growth promotion and as a metabolic hormone were studied, and species specificity became apparent: primate GH was the only GH active in man. Human GH was prepared from cadaveric pituitaries and distributed by the NIH to treat children with GH deficiency, but there was never enough pituitary hGH for all of the children who required it. When Creutzfeldt-Jakob disease was found in some patients who received pituitary GH, the production and FDA approval of biosynthetic hGH dramatically accelerated. With a large supply, one could treat those who were GH deficient and test its efficacy in other causes of short stature; longer acting versions of hGH have now been developed, tested, and in a few instances received FDA approval. <b><i>Summary:</i></b> It has been a long journey from the description of over- and underproduction of GH in animals to the production and clinical use of the biosynthetic hormones. <b><i>Key Messages:</i></b> The efforts of basic scientists led to the extraction and purification of GH. Clinical scientists have expanded the appropriate use of hGH for short children with conditions in addition to GH deficiency.

The science behind the relations among cancer, height, growth patterns, and growth hormone axis

“…Thus, GH is contraindicated in patients with active malignancies and in particular cases of individuals with cancer predisposition syndromes and proven severe GHD, it must be used with extreme caution (Boguszewski et al 2022). Following these recommendations, cancer surveillance in patients currently or previously treated with GH -including those with pituitary tumor or craniopharyngioma remnants and those with a previous malignancy -does not need to be different than that indicated for the general population (Simon et al 2016, Rogol & Reiter 2022. Amongst GH-deficient childhood cancer survivors, GH replacement does not seem to increase mortality from cancer, while data on GH-deficient adult cancer survivors are scarce and GH replacement therapy should only be considered for adult patients in remission after careful individual risk/benefit judgment (Boguszewski et al 2022).…”

“…In the early years of the twentieth century, experiments with pituitary extracts, hypophysectomy in animals, and the first transsphenoidal surgeries in patients with acromegaly paved the way to associate growth with the anterior pituitary (Lindholm 2006, Ranke & Wit 2018, Rogol & Reiter 2022. In 1921, the American anatomist and embryologist Herbert McLean Evans (1882-1971 and the embryologist Joseph Abraham Long were the first to demonstrate somatic growth in rats that were treated with bovine pituitary extracts, an effect that was later observed also in dogs and other species (Evans & Long 1921).…”

“…Initial experiments after the discovery of somatomedins originated the 'somatomedin hypothesis', which stated that pituitary GH did not act directly on its target tissues to promote growth, but instead by stimulating IGF1 production in the liver, which in turn circulates in an endocrine action model to the cartilage and bones (Le Roith et al 2001). Subsequent evidence, however, has shown that GH directly promotes the differentiation of cartilage cells at the epiphyseal growth plate, while IGF1 is responsible for their clonal expansion (Rogol & Reiter 2022). The degrees of contribution of endocrine IGF1 (produced in the liver) vs that of autocrine/paracrine IGF1 (locally produced in the cartilage) for the promotion of human growth is still a matter of debate (Miller et al 2022).…”

What Factors Spur a Short Individual's Response to Human GH (hGH)?

“…Since the early 20th century, growth of animals, including man, has been inextricably intertwined with an anterior pituitary factor (reviewed in [ 1 ]). In 1944, Li and Evans isolated GH from bovine pituitaries; however, growth was only 1 of many metabolic activities in carbohydrate, lipid, and protein metabolism for the substance named “somatropin,” a factor trophic for the soma or body [ 2 ].…”

“…In the late 1950s, Knobil and colleagues defined species specificity for GH, for only the primate hormone was biologically effective in primates, although primate GH was active in most animals [ 3 ]. This explains why attempts to increase the growth of children with GH deficiency (GHD) using bovine GH or enzyme digests of it were unsuccessful (summarized in [ 1 ]). Until 1985, the small supply of pituitary human GH (hGH) was rate limiting for the treatment of children with GHD.…”