Growth hormone therapy explained

Growth hormone therapy
Specialty:endocrinologist

Growth hormone therapy refers to the use of growth hormone (GH) as a prescription medication—it is one form of hormone therapy. Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. In the past, growth hormone was extracted from human pituitary glands. Growth hormone is now produced by recombinant DNA technology and is prescribed for a variety of reasons. GH therapy has been a focus of social and ethical controversies for 50 years.

This article describes the history of GH treatment and the current uses and risks arising from GH use. Other articles describe GH physiology, diseases of GH excess (acromegaly and pituitary gigantism), deficiency, the recent phenomenon of HGH controversies, growth hormone in sports, and growth hormone for cows.

Medical uses

HGH deficiency in children

Growth hormone deficiency is treated by replacing growth hormone.[1] [2] [3]

Lonapegsomatropin was approved for medical use in the United States in August 2021.[4] [5]

HGH deficiency in adults

The Endocrine Society has recommended that adult patients diagnosed with growth hormone deficiency (GHd) be administered an individualized GH treatment regimen.[6] With respect to diagnosis, their guidelines state that "adults patients with structural hypothalamic/pituitary disease, surgery or irradiation in these areas, head trauma, or evidence of other pituitary hormone deficiencies be considered for evaluation for acquired GHd" and that "idiopathic GHd in adults is very rare, and stringent criteria are necessary to make this diagnosis. Because in the absence of suggestive clinical circumstances there is a significant false-positive error rate in the response to a single GH stimulation test, we suggest the use of two tests before making this diagnosis."[6]

GH replacement therapy can provide a number of measurable benefits to GH-deficient adults.[6] These include improved bone density,[7] increased muscle mass, decrease of adipose tissue, faster hair and nail growth, strengthened immune system, increased circulatory system, and improved blood lipid levels, but long term mortality benefit has not yet been demonstrated.[8] [9] [10] [11]

A peer-reviewed article published in 2010 indicates that "Growth hormone (GH) replacement unequivocally benefits growth, body composition, cardiovascular risk factors and quality of life. Less is known about the effects of GH on learning and memory."[12]

Other

As of 2004, GH has been approved by the U.S. Food and Drug Administration for treatment of other conditions such as:

Adverse effects

The New England Journal of Medicine published two editorials in 2003 expressing concern about off-label uses of HGH and the proliferation of advertisements for "HGH-Releasing" dietary supplements, and emphasized that there is no evidence that use of HGH in healthy adults or in geriatric patients is safe and effective – and especially emphasized that risks of long-term HGH treatment are unknown. One editorial was by Jeffrey M. Drazen, M.D., the editor-in-chief of the journal;[21] the other one[22] was by Mary Lee Vance, who provided the NEJM's editorial original, cautious comment on a much cited 1990 study on the use of HGH in geriatric patients with low growth hormone levels.

A small but controlled study of GH given to severely ill adults in an intensive care unit setting for the purpose of increasing strength and reducing the muscle wasting of critical illness showed a higher mortality rate for the patients having received GH.[23] The reason is unknown, but GH is now rarely used in ICU patients unless they have severe growth hormone deficiency.

GH treatment usually decreases insulin sensitivity,[24] but some studies showed no evidence for increased diabetes incidence in GH-treated adult hypopituitary patients.[25]

In past it was believed that GH treatment could increase the cancer risk; a large study recently concluded that "With relatively short follow-up, the overall primary cancer risk in 6840 patients receiving GH as adults was not increased. Elevated SIRs (which is risk of getting cancer) were found for subgroups in the USA cohort defined by age <35 years or childhood onset GH deficiency."[26]

The FDA issued a Safety Communication in August 2011, stating that the evidence regarding recombinant human growth hormone and increased risk of death is inconclusive after reviewing sources including a French study which compared persons with certain kinds of short stature (idiopathic growth hormone deficiency and idiopathic or gestational short stature) treated with recombinant human growth hormone during childhood and who were followed over a long period of time, with individuals in the general population of France.[27]

History

Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838–1883), who was exhibited by P. T. Barnum as General Tom Thumb, and married Lavinia Warren. Pictures of the couple show the typical adult features of untreated severe growth hormone deficiency. Despite the severe shortness, limbs and trunks are proportional.

By the middle of the twentieth century, endocrinologists understood the clinical features of growth hormone deficiency. GH is a protein hormone, like insulin, which had been purified from pig and cow pancreases for treatment of type 1 diabetes since the 1920s. However, pig and cow GH did not work at all in humans, due to greater species-to-species variation of molecular structure (i.e., insulin is considered more "evolutionarily conserved" than GH).

Extraction for treatment

Extracted growth hormone was used since the late 1950s until the late 1980s when its use was replaced by recombinant GH.

In the late 1950s, Maurice Raben purified enough GH from human pituitary glands to successfully treat a GH-deficient boy. A few endocrinologists began to help parents of severely GH-deficient children to make arrangements with local pathologists to collect human pituitary glands after removal at autopsy. Parents would then contract with a biochemist to purify enough growth hormone to treat their child. Few families could manage such a complicated undertaking.

In 1960, the National Pituitary Agency was formed as a branch of the U.S. National Institutes of Health. The purpose of this agency was to supervise the collection of human pituitary glands when autopsies were performed, arrange for large-scale extraction and purification of GH, and distribute it to a limited number of pediatric endocrinologists for treating GH-deficient children under research protocols. Canada, UK, Australia, New Zealand, France, Israel, and other countries establish similar government-sponsored agencies to collect pituitaries, purify GH, and distribute it for treatment of severely GH-deficient children.

Supplies of this "cadaver growth hormone" were limited, and only the most severely deficient children were treated. From 1963 to 1985 about 7700 children in the U.S. and 27,000 children worldwide were given GH extracted from human pituitary glands to treat severe GH deficiency. Physicians trained in the relatively new specialty of pediatric endocrinology provided most of this care, but in the late 1960s there were only a hundred of these physicians in a few dozen of the largest university medical centers around the world.

In 1977, the NPA GH extraction and purification procedure was refined and improved.

A shortage of available cadaver GH worsened in the late 1970s as the autopsy rate in the U.S. declined, while the number of pediatric endocrinologists able to diagnose and treat GH deficiency increased. GH was "rationed." Often, treatment would be stopped when a child reached an arbitrary minimal height, such as . Children who were short for reasons other than severe GH deficiency were lied to and told that they would not benefit from treatment. Only those pediatric endocrinologists that remained at university medical centers with departments able to support a research program had access to NPA growth hormone.

In the late 1970s, a Swedish pharmaceutical company, Kabi, contracted with a number of hospitals in Europe to buy pituitary glands for the first commercial GH product, Crescormon. Although an additional source of GH was welcomed, Crescormon was greeted with ambivalence by pediatric endocrinologists in the United States. The first concern was that Kabi would begin to purchase pituitaries in the U.S., which would quickly undermine the NPA, which relied on a donation system like blood transfusion. As the number of autopsies continued to shrink, would pathologists sell pituitaries to a higher bidder? The second offense was Kabi-Pharmacia's marketing campaign, which was directed at primary care physicians under the slogan, "Now, you determine the need," implying that the services of a specialist were not needed for growth hormone treatment anymore and that any short child might be a candidate for treatment. Although the Crescormon controversy in the U.S. is long forgotten, Kabi's pituitary purchase program continued to generate scandal in Europe as recently as 2000.

Recombinant human growth hormone (rHGH)

In 1981, the new American corporation Genentech, after collaboration with Kabi, developed and started trials of recombinant human growth hormone (rHGH) made by a new technology (recombinant DNA) in which human genes were inserted into bacteria so that they could produce unlimited amounts of the protein. Because this was new technology, approval was deferred as lengthy safety trials continued over the next four years.[28]

In 1985, four young adults in the U.S. having received NPA growth hormone in the 1960s developed CJD (Creutzfeldt–Jakob disease). The connection was recognized within a few months, and use of human pituitary GH rapidly ceased. Between 1985 and 2003, a total of 26 cases of CJD occurred in adults having received NPA GH before 1977 (out of 7700), comparable numbers of cases occurred around the world. By 2003 there had been no cases in people who received only GH purified by the improved 1977 methods.

Discontinuation of human cadaver growth hormone led to rapid Food and Drug Administration approval of Genentech's recombinant human growth hormone, which was introduced in 1985 as Protropin in the United States. Although this previously scarce commodity was suddenly available in "bucketfuls", the price of treatment (US$10,000–30,000 per year) was the highest at the time. Genentech justified it by the prolonged research and development investment, orphan drug status, and a pioneering post-marketing surveillance registry for tracking safety and effectiveness (National Cooperative Growth Study).

Within a few years, GH treatment had become more common and competitors entered the market. Eli Lilly launched a competing natural sequence growth hormone (Humatrope). Pharmacia (formerly Kabi, now Pfizer) introduced Genotropin. Novo Nordisk introduced Norditropin. Serono (now EMD Serono) introduced Saizen and Serostim. Ferring has introduced Zomacton. Genentech eventually introduced another HGH product, Nutropin, and stopped making Protropin in 2004. Price competition had begun. Teva, which is primarily a generics company, has introduced Tev-tropin. Chinese companies have entered the market as well and have introduced more pricing competition: NeoGenica BioScience Ltd. introduced Hypertropin, GeneScience introduced Jintropin, Anhui Anke Biotechnology introduced Ansomone, Shanghai United Kefei Biotechnology introduced Kefei HGH,[29] and Hygene BioPharm introduced Hygetropin. These are all recombinant human growth hormone products and they have competed with various marketing strategies. Most children with severe deficiency in the developed world are now likely to have access to a pediatric endocrinologist and be diagnosed and offered treatment.

Pediatric endocrinology became a recognizable specialty in the 1950s, but did not reach board status in the U.S. until the late 1970s. Even 10 years later, as a cognitive, procedureless specialty dealing with mostly rare diseases, it was one of the smallest, lowest-paid, and more obscure of the medical specialities. Pediatric endocrinologists were the only physicians interested in the arcana of GH metabolism and children's growth, but their previously academic arguments took on new practical significance with major financial implications.

The major scientific arguments dated back to the days of GH scarcity:

It was the ethical questions that were new. Is GH not a wise use of finite healthcare resources, or is the physician's primary responsibility to the patient? If GH is given to most extremely short children to make them taller, will the definition of "extremely short" simply rise, negating the expected social benefit? If GH is given to short children whose parents can afford it, will shortness become a permanent mark of lower social origins? More of these issues are outlined in the ethics section. Whole meetings were devoted to these questions; pediatric endocrinology had become a specialty with its own bioethics issues.

Despite the price, the 1990s became an era of experimentation to see what else growth hormone could help. The medical literature of the decade contains hundreds of reports of small trials of GH use in nearly every type of growth failure and shortness imaginable. In most cases, the growth responses were modest. For conditions with a large enough potential market, more rigorous trials were sponsored by pharmaceutical companies that were making growth hormone to achieve approval to market for those specific indications. Turner syndrome and chronic kidney failure were the first of these "nonGH-deficient causes of shortness" to receive FDA approval for GH treatment, and Prader–Willi syndrome and intrauterine growth retardation followed. Similar expansion of use occurred in Europe.

One obvious potential market was adult GH deficiency. By the mid-1990s, several GH companies had sponsored or publicized research into the quality of life of adults with severe GH deficiency. Most were people having been treated with GH in childhood for severe deficiency. Although the injections are painless, many of them had been happy to leave injections behind as they reached final heights in the low-normal range. However, as adults in their 30s and 40s, these people, who had been children with growth hormone deficiency, were now adults with growth hormone deficiency and had more than their share of common adult problems: reduced physical, mental, and social energy, excess adipose and diminished muscle, diminished libido, poor bone density, higher cholesterol levels, and higher rates of cardiovascular disease. Research trials soon confirmed that a few months of GH could improve nearly all of these parameters. However, despite marketing efforts, most GH-deficient adults remain untreated.

Though GH use was slow to be accepted among adults with GH deficiency, similar research to see if GH treatment could slow or reverse some of the similar effects of aging attracted much public interest. The most publicized trial was reported by Daniel Rudman in 1990.[30] As with other types of hormone supplementation for aging (testosterone, estrogen, DHEA), confirmation of benefit and accurate understanding of risks has been only slowly evolving.

In 1997, Ronald Klatz of the American Academy of Anti-Aging Medicine published Grow Young With HGH: The Amazing Medically Proven Plan To Reverse the Effects Of Aging,[31] an uncritical touting of GH as the answer to aging.[32] [33] This time, the internet amplified the proposition and spawned a hundred frauds and scams. However, their adoption of the "HGH" term has provided an easy way to distinguish the hype from the evidence. In 2003, growth hormone hit the news again, when the US FDA granted Eli Lilly approval to market Humatrope for the treatment of idiopathic short stature. The indication was controversial for several reasons, the primary one being the difficulty in defining extreme shortness with normal test results as a disease rather than the extreme end of the normal height range[34]

Recombinant growth hormone available in the U.S. (and their manufacturers) include Nutropin (Genentech), Humatrope (Eli Lilly and Company), Genotropin (Pfizer), Norditropin (Novo Nordisk), Tev-Tropin (Teva) and Saizen (Merck Serono). The products are nearly identical in composition, efficacy, and cost, varying primarily in the formulations and delivery devices.

Somapacitan-beco (Sogroya) is first once-per week subcutaneous human growth hormone (hGH) therapy that was approved in the United States.[35] It was approved for medical use in the United States in August 2020.[36]

Terminology

Growth hormone (GH l) is also called somatotropin (British: somatotrophin). The human form of growth hormone is known as human growth hormone, or hGH (ovine growth hormone, or sheep growth hormone, is abbreviated oGH). GH can refer either to the natural hormone produced by the pituitary (somatotropin), or biosynthetic GH for therapy.

Cadaver growth hormone is the term for GH extracted from the pituitary glands of human cadavers between 1960 and 1985 for therapy of deficient children. In the U.S., cadaver GH, also referred to as NPA growth hormone, was provided by the National Pituitary Agency, and by other national programs and commercial firms as well. In 1985 it was associated with the development of Creutzfeldt–Jakob disease, and was withdrawn from use.

RHGH (rHGH, rhGH) refers to recombinant human growth hormone, that is, somatropin (INN). Its amino acid sequence is identical with that of endogenous human GH.

It is coincidental that RHGH also refers to rhesus monkey GH (RhGH), using the accepted naming convention of Rh for rhesus. Rhesus growth hormone was never used by physicians to treat human patients, but rhesus GH was part of the lore of the underground anabolic steroid community in those years, and fraudulent versions may have been bought and sold in gyms.

met-GH refers to methionyl–growth hormone, that is, somatrem (INN). This was the first recombinant GH product marketed (trade name Protropin by Genentech). It had the same amino acid sequence as human GH with an extra methionine at the end of the chain to facilitate the manufacturing process. It was discontinued in 2004.[37]

rBST refers to recombinant bovine somatotropin (cow growth hormone), or recombinant bovine GH (rbGH, RBGH).

Further reading

Notes and References

  1. Web site: Humatrope- somatropin kit . DailyMed . 26 August 2021.
  2. Web site: Nutropin AQ NuSpin 5- somatropin injection, solution Nutropin AQ NuSpin 10- somatropin injection, solution Nutropin AQ NuSpin 20- somatropin injection, solution . DailyMed . 26 August 2021.
  3. Web site: Genotropin- somatropin kit . DailyMed . 26 August 2021.
  4. Web site: Skytrofa: FDA-Approved Drugs . U.S. Food and Drug Administration (FDA) . 25 August 2021.
  5. Ascendis Pharma A/S Announces U.S. Food and Drug Administration Approval of Skytrofa (lonapegsomatropin-tcgd), the First Once-weekly Treatment for Pediatric Growth Hormone Deficiency . Ascendis Pharma . 25 August 2021 . 25 August 2021.
  6. Molitch ME et al. (2011) Evaluation and Treatment of Adult Growth Hormone Deficiency:An Endocrine Society Clinical Practice Guideline The Endocrine Society, 2011. First published in Journal of Clinical Endocrinology & Metabolism, 96(6):1587–1609.
  7. Götherström G, Bengtsson BA, Bosaeus I, Johannsson G, Svensson J . Ten-year GH replacement increases bone mineral density in hypopituitary patients with adult onset GH deficiency . Eur. J. Endocrinol. . 156 . 1 . 55–64 . January 2007 . 17218726 . 10.1530/eje.1.02317 . free .
  8. Alexopoulou O, Abs R, Maiter D . 24874132 . Treatment of adult growth hormone deficiency: who, why and how? A review . Acta Clin Belg . 65 . 1 . 13–22 . 2010 . 20373593 . 10.1179/acb.2010.002.
  9. Ahmad AM, Hopkins MT, Thomas J, Ibrahim H, Fraser WD, Vora JP . Body composition and quality of life in adults with growth hormone deficiency; effects of low-dose growth hormone replacement . Clin. Endocrinol. . 54 . 6 . 709–17 . June 2001 . 11422104 . 10.1046/j.1365-2265.2001.01275.x . 12681649 . free .
  10. Savine R, Sönksen P . 30263334 . Growth hormone - hormone replacement for the somatopause? . Horm. Res. . 53 Suppl 3 . 3. 37–41 . 2000 . 10971102 . 10.1159/000023531 .
  11. Götherström G, Bengtsson BA, Bosaeus I, Johannsson G, Svensson J . A 10-year, prospective study of the metabolic effects of growth hormone replacement in adults . J. Clin. Endocrinol. Metab. . 92 . 4 . 1442–5 . April 2007 . 17284638 . 10.1210/jc.2006-1487 . 20662903 .
  12. Wass JA, Reddy R . Growth hormone and memory . J. Endocrinol. . 207 . 2 . 125–6 . November 2010 . 20696696 . 10.1677/JOE-10-0126 . free .
  13. Web site: Archived copy . 2011-12-31 . https://web.archive.org/web/20111110015930/http://www.serostim.com/Files/PDFs/Full_Prescribing_Information.pdf . 2011-11-10 . dead .
  14. Bolar K, Hoffman AR, Maneatis T, Lippe B . Long-term safety of recombinant human growth hormone in turner syndrome . J. Clin. Endocrinol. Metab. . 93 . 2 . 344–51 . February 2008 . 18000090 . 10.1210/jc.2007-1723 . free .
  15. Davenport ML, Crowe BJ, Travers SH, Rubin K, Ross JL, Fechner PY, Gunther DF, Liu C, Geffner ME, Thrailkill K, Huseman C, Zagar AJ, Quigley CA . Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial . J. Clin. Endocrinol. Metab. . 92 . 9 . 3406–16 . September 2007 . 17595258 . 10.1210/jc.2006-2874 . free .
  16. Backeljauw P . 21398653 . Does growth hormone therapy before 4 years of age enhance the linear growth of girls with Turner's syndrome? . Nat Clin Pract Endocrinol Metab . 4 . 2 . 78–9 . February 2008 . 17971794 . 10.1038/ncpendmet0678 .
  17. Web site: Prader-Willi syndrome – Symptoms and causes. mayoclinic.com. 14 April 2018.
  18. Chatelain P, Carrascosa A, Bona G, Ferrandez-Longas A, Sippell W . Growth hormone therapy for short children born small for gestational age . Horm. Res. . 68 . 6 . 300–9 . 2007 . 17823537 . 10.1159/000107935 . free .
  19. Czernichow P . 33810401 . Which children with idiopathic short stature should receive growth hormone therapy? . Nat Clin Pract Endocrinol Metab . 4 . 3 . 118–9 . March 2008 . 18040291 . 10.1038/ncpendmet0700 .
  20. Hannon TS, Danadian K, Suprasongsin C, Arslanian SA . Growth hormone treatment in adolescent males with idiopathic short stature: changes in body composition, protein, fat, and glucose metabolism . J. Clin. Endocrinol. Metab. . 92 . 8 . 3033–9 . August 2007 . 17519313 . 10.1210/jc.2007-0308 .
  21. Drazen JM . Inappropriate advertising of dietary supplements . N. Engl. J. Med. . 348 . 9 . 777–8 . February 2003 . 12606730 . 10.1056/NEJMp030021 . free .
  22. Vance ML . Can growth hormone prevent aging? . N. Engl. J. Med. . 348 . 9 . 779–80 . February 2003 . 12606731 . 10.1056/NEJMp020186 . free .
  23. Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ . Increased mortality associated with growth hormone treatment in critically ill adults . N. Engl. J. Med. . 341 . 11 . 785–92 . September 1999 . 10477776 . 10.1056/NEJM199909093411102 . free .
  24. Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L . Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle . J. Clin. Endocrinol. Metab. . 88 . 4 . 1455–63 . April 2003 . 12679422 . 10.1210/jc.2002-020542 . free .
  25. Attanasio AF, Jung H, Mo D, Chanson P, Bouillon R, Ho KK, Lamberts SW, Clemmons DR . Prevalence and incidence of diabetes mellitus in adult patients on growth hormone replacement for growth hormone deficiency: a surveillance database analysis . J. Clin. Endocrinol. Metab. . 96 . 7 . 2255–61 . July 2011 . 21543424 . 10.1210/jc.2011-0448 . free .
  26. Child CJ, Zimmermann AG, Woodmansee WW, Green DM, Li JJ, Jung H, Erfurth EM, Robison LL . Assessment of primary cancers in GH-treated adult hypopituitary patients: an analysis from the Hypopituitary Control and Complications Study . Eur. J. Endocrinol. . 165 . 2 . 217–23 . August 2011 . 21646285 . 3132593 . 10.1530/EJE-11-0286 .
  27. Web site: FDA Drug Safety Communication: Safety review update of Recombinant Human Growth Hormone (somatropin) and possible increased risk of death . U.S. Food and Drug Administration . Safety Information . August 2011 .
  28. Web site: First Successful Bacterial Production of Human Growth Hormone Announced. Genentech . 18 September 2019.
  29. Web site: HGH – Kefei Biotech HGH Steroids and Peptides. www.kefeibiotech.com. 14 April 2018. https://web.archive.org/web/20180415063324/http://www.kefeibiotech.com/HGH/. 15 April 2018. dead.
  30. Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, Schlenker RA, Cohn L, Rudman IW, Mattson DE . Effects of human growth hormone in men over 60 years old . N. Engl. J. Med. . 323 . 1 . 1–6 . July 1990 . 2355952 . 10.1056/NEJM199007053230101 . free .
  31. Ronald Klatz and Carol Kahn. Grow Young With Hgh: The Amazing Medically Proven Plan to : Lose Fat, Build Muscle, Reverse the Effects of Aging, Strengthen the Immune System, Improve Sexual Performance. Harpercollins; 1st edition (April 1997)
  32. Blackman MR, et al (2002) Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial. JAMA 288(18):2282-92.
  33. Olshansky SJ et al (2002) Position Statement on Human Aging Journal of Gerontology 57A(8):B292–B297
  34. Leona Cuttler (2005) Editorial: Safety and Efficacy of Growth Hormone Treatment for Idiopathic Short Stature. The Journal of Clinical Endocrinology & Metabolism 90(9):5502–5504
  35. FDA approves weekly therapy for adult growth hormone deficiency . U.S. Food and Drug Administration (FDA) . 1 September 2020 . 1 September 2020.
  36. FDA approves once-weekly Sogroya for the treatment of adult growth hormone deficiency . Novo Nordisk . 28 August 2020 . 1 September 2020.
  37. Web site: Genentech: About Us: Nutropin - Historical Sales . 2011-12-31 . https://web.archive.org/web/20120208230323/http://www.gene.com/gene/about/ir/historical/product-sales/nutropin.html . 2012-02-08 . dead .