DO Division of Pediatric Endocrinology, Nemours/Alfred I. Dupont Hospital for Children, Wilmington, DE, United States.
Baystate Children's Hospital, UMassMedical School-Baystate, Springfield, MA, United States.
Front Endocrinol (Lausanne). 2021 Jul 5;12:709936. doi: 10.3389/fendo.2021.709936. eCollection 2021.
Since antiquity Man has been fascinated by the variations in human (and animal) growth. Stories and art abound about giants and little people. Modern genetics have solved some of etiologies at both extremes of growth. Serious study began with the pathophysiology of acromegaly followed by early attempts at treatment culminating in modern endoscopic surgery and multiple pharmacologic agents. Virtually at the same time experiments with the removal of the pituitary from laboratory animals noted the slowing or stopping of linear growth and then over a few decades the extraction and purification of a protein within the anterior pituitary that restored, partially or in full, the animal's growth. Human growth hormone was purified decades after those from large animals and it was noted that it was species specific, that is, only primate growth hormone was metabolically active in primates. That was quite unlike the beef and pork insulins which revolutionized the care of children with diabetes mellitus. A number of studies included mild enzymatic digestion of beef growth hormone to determine if those "cores" had biologic activity in primates and man. Tantalizing data showed minimal but variable metabolic efficacy leading to the "active core" hypothesis, for these smaller peptides would be amenable to peptide synthesis in the time before recombinant DNA. Recombinant DNA changed the landscape remarkably promising nearly unlimited quantities of metabolically active hormone. Eight indications for therapeutic use have been approved by the Food and Drug Administration and a large number of clinical trials have been undertaken in multiple other conditions for which short stature in childhood is a sign. The future predicts other clinical indications for growth hormone therapy (and perhaps other components of the GH?IGF-1 axis), longer-acting analogues and perhaps a more physiologic method of administration as virtually all methods at present are far from physiologic.
自古以来，人类（和动物）的生长变化一直令人类着迷。关于巨人和小矮人的故事和艺术作品层出不穷。现代遗传学已经解决了生长极端的一些病因。对肢端肥大症的病理生理学的认真研究始于此，随后是早期的治疗尝试，最终发展为现代内窥镜手术和多种药物治疗。几乎与此同时，实验室动物的垂体切除术实验注意到线性生长的减缓或停止，然后在几十年内，从前垂体中提取和纯化一种蛋白质，部分或完全恢复了动物的生长。人类生长激素在大型动物生长激素几十年后被纯化，人们注意到它具有种属特异性，也就是说，只有灵长类动物的生长激素在灵长类动物中具有代谢活性。这与牛胰岛素和猪胰岛素完全不同，它们彻底改变了糖尿病儿童的护理。许多研究包括对牛生长激素进行轻度酶消化，以确定这些“核心”在灵长类动物和人类中是否具有生物活性。诱人的数据显示出最小但可变的代谢功效，导致“活性核心”假说，因为这些较小的肽在重组 DNA 之前更容易进行肽合成。重组 DNA 彻底改变了前景，有望提供几乎无限数量的具有代谢活性的激素。美国食品和药物管理局已经批准了 8 种治疗用途的适应症，并且已经在多种其他情况下进行了大量的临床试验，这些情况下儿童身材矮小是一个迹象。未来预测了生长激素治疗的其他临床适应症（也许还有 GH？IGF-1 轴的其他成分），作用时间更长的类似物，也许还有更生理的给药方法，因为目前几乎所有的方法都远非生理。
