Growth hormone therapy refers to the use of
growth hormone
Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...
(GH) as a
prescription medication
A prescription drug (also prescription medication or prescription medicine) is a pharmaceutical drug that legally requires a medical prescription to be dispensed. In contrast, over-the-counter drugs can be obtained without a prescription. The rea ...
—it is one form of
hormone therapy
Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are oncologic horm ...
. Growth hormone is a
peptide hormone
Peptide hormones or protein hormones are hormones whose molecules are peptide, or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocrine system of animals, including h ...
secreted by the
pituitary
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypop ...
gland that stimulates
growth
Growth may refer to:
Biology
* Auxology, the study of all aspects of human physical growth
* Bacterial growth
* Cell growth
* Growth hormone, a peptide hormone that stimulates growth
* Human development (biology)
* Plant growth
* Secondary growth ...
and
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
reproduction. In the past, growth hormone was extracted from human pituitary glands. Growth hormone is now produced by
recombinant DNA
Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be foun ...
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
Acromegaly is a disorder that results from excess growth hormone (GH) after the growth plates have closed. The initial symptom is typically enlargement of the hands and feet. There may also be an enlargement of the forehead, jaw, and nose. Other ...
and
pituitary gigantism),
deficiency
A deficiency is generally a lack of something. It may also refer to:
*A deficient number, in mathematics, a number ''n'' for which ''σ''(''n'') < 2''n''
* , the recent phenomenon of
HGH controversies Controversies regarding the use of human growth hormone (HGH) as treatment method have centered on the claims, products, and businesses related to the use of growth hormone as an anti-aging therapy. Most of these controversies fall into two categor ...
,
growth hormone in sports
Growth hormones in sports refers to the use of growth hormones (GH or HGH) for athletic enhancement, as opposed to growth hormone treatment for medical therapy. Human Growth Hormone is a prescription medication in the US, meaning that its distribu ...
, and
growth hormone for cows.
Medical uses
HGH deficiency in children
Growth hormone deficiency
Growth hormone deficiency (GHD), or human growth hormone deficiency, is a medical condition resulting from not enough growth hormone (GH). Generally the most noticeable symptom is that an individual attains a short height. Newborns may also presen ...
is treated by replacing growth hormone.
Lonapegsomatropin was approved for medical use in the United States in August 2021.
HGH deficiency in adults
The Endocrine Society
The Endocrine Society is a professional, international medical organization in the field of endocrinology and metabolism, founded in 1916 as The Association for the Study of Internal Secretions. The official name of the organization was changed ...
has recommended that adult patients diagnosed with growth hormone deficiency (GHd) be administered an individualized GH treatment regimen.
[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. 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."
[
GH replacement therapy can provide a number of measurable benefits to GH-deficient adults.][ These include improved ]bone density
Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optica ...
, increased muscle mass, decrease of adipose tissue
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
, faster hair and nail growth, strengthened immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
, increased circulatory system
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
, and improved blood lipid
Blood lipids (or blood fats) are lipids in the blood, either free or bound to other molecules. They are mostly transported in a protein capsule, and the density of the lipids and type of protein determines the fate of the particle and its influence ...
levels, but long term mortality benefit has not yet been demonstrated.
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."
Other
As of 2004, GH has been approved by the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
for treatment of other conditions such as:
* In adults, wasting (or cachexia
Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart f ...
) caused by AIDS.
* Turner syndrome
Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hair ...
epitomizes the response of non-deficient shortness. At doses 20% higher than those used in GH deficiency, growth accelerates. With several years of treatment the median gain in adult height is about on this dose. The gains appear to be dose-dependent. It has been used successfully in toddlers with Turner syndrome, as well as in older girls.
* Short-stature homeobox gene
The short-stature homeobox gene (SHOX), also known as short-stature-homeobox-containing gene, is a gene located on both the X and Y chromosomes, which is associated with short stature in humans if mutated or present in only one copy (haploinsuffi ...
deficiency
* Chronic kidney failure
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vom ...
results in many problems, including growth failure. GH treatment for several years both before and after transplantation may prevent further deceleration of growth and may narrow the height deficit, though even with treatment net adult height loss may be about
* Prader–Willi syndrome
Prader–Willi syndrome (PWS) is a genetic disorder caused by a loss of function of specific genes on chromosome 15. In newborns, symptoms include weak muscles, poor feeding, and slow development. Beginning in childhood, those affected become c ...
, a generally non-hereditary genetic condition, is a case where GH is prescribed for benefits in addition to height. GH is one of the treatment options an experienced endocrinologist may use when treating a child with PWS. GH can help children with PWS in height, weight, body mass, strength, and agility. . Reports have indicated increase of growth rate (especially in the first year of treatment) and a variety of other positive effects, including improved body composition (higher muscle mass, lower fat mass); improved weight management; increased energy and physical activity; improved strength, agility, and endurance; and improved respiratory function. The Prader-Willi Syndrome Association (USA) recommends that a sleep study be conducted before initiating GH treatment in a child with PWS. At this time there is no direct evidence of a causative link between growth hormone and the respiratory problems seen in PWS (among both those receiving and those not receiving GH treatment), including sudden death. A follow-up sleep study after one year of GH treatment may also be indicated. GH (specifically Pfizer's version, Genotropin) is the only treatment that has received an FDA indication for children with PWS. The FDA indication only applies to children.
* Children short because of intrauterine growth retardation
Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...
are small for gestational age at birth for a variety of reasons. If early catch-up growth
Compensatory growth, known as catch-up growth and compensatory gain, is an accelerated growth of an organism following a period of slowed development, particularly as a result of nutrient deprivation. The growth may be with respect to weight or ...
does not occur and their heights remain below the third percentile by 2 or 3 years of age, adult height is likely to be similarly low. High-dose GH treatment has been shown to accelerate growth, but data on long term benefits and risks are limited.
* Idiopathic short stature
Idiopathic short stature (ISS) refers to extreme short stature that does not have a medical diagnosis, diagnostic explanation (''idiopathic'' designates a condition that is unexplained or not understood) after an ordinary growth evaluation. The te ...
(ISS) is one of the most controversial indications for GH as pediatric endocrinologists do not agree on its definition, diagnostic criteria
Medical diagnosis (abbreviated Dx, Dx, or Ds) is the process of determining which disease or condition explains a person's symptoms and signs. It is most often referred to as diagnosis with the medical context being implicit. The information req ...
, or limits. The term has been applied to children with severe unexplained shortness that will result in an adult height below the 3rd percentile. In the late 1990s, the pharmaceutical manufacturer Eli Lilly and Company
Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...
sponsored trials of their brand of rHGH
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 Cell growth, growth and cell (b ...
(Humatrope) in children with extreme ISS, those at least 2.25 standard deviations below mean (in the lowest 1.2 percent of the population). These boys and girls appeared to be headed toward heights of less than 63" (160 cm) and 59" (150 cm) respectively. They were treated for about 4 years and gained in adult height. Controversy has arisen as to whether all of these children were truly "short normal" children, since the average IGF1
Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults.
IGF-1 is a protein that in humans is ...
was low. Approval of HGH for the treatment of this extreme degree of shortness led to an increase in the number of parents seeking its use to make otherwise normal children a little taller.
Adverse effects
''The New England Journal of Medicine'' published two editorials in 2003 expressing concern about off-label use
Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ...
s 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; the other one was by Dr. 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
Intensive care medicine, also called critical care medicine, is a medical specialty that deals with seriously or critically ill patients who have, are at risk of, or are recovering from conditions that may be life-threatening. It includes pro ...
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. 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
Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood sugar) ...
, but some studies showed no evidence for increased diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
incidence in GH-treated adult hypopituitary patients.
In past it was believed that GH treatment could increase the cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
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."
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
Growth hormone deficiency (GHD), or human growth hormone deficiency, is a medical condition resulting from not enough growth hormone (GH). Generally the most noticeable symptom is that an individual attains a short height. Newborns may also presen ...
and idiopathic or gestational short stature
Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called '' ...
) 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.
History
Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency
Growth hormone deficiency (GHD), or human growth hormone deficiency, is a medical condition resulting from not enough growth hormone (GH). Generally the most noticeable symptom is that an individual attains a short height. Newborns may also presen ...
was Charles Sherwood Stratton
Charles Sherwood Stratton (January 4, 1838 – July 15, 1883), better known by his stage name "General Tom Thumb", was an American dwarf who achieved great fame as a performer under circus pioneer P. T. Barnum.
Childhood and early life
B ...
(1838–1883), who was exhibited by P. T. Barnum
Phineas Taylor Barnum (; July 5, 1810 – April 7, 1891) was an American showman, businessman, and politician, remembered for promoting celebrated hoaxes and founding the Barnum & Bailey Circus (1871–2017) with James Anthony Bailey. He was ...
as General Tom Thumb
Charles Sherwood Stratton (January 4, 1838 – July 15, 1883), better known by his stage name "General Tom Thumb", was an American dwarf who achieved great fame as a performer under circus pioneer P. T. Barnum.
Childhood and early life
Bo ...
, 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
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
, which had been purified from pig and cow pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...
es 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 gland
In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...
s to successfully treat a GH-deficient boy. A few endocrinologists began to help parents of severely GH-deficient children to make arrangements with local pathologist
Pathology is the study of the causal, causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when us ...
s to collect human pituitary glands after removal at autopsy
An autopsy (post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of death or to evaluate any di ...
. Parents would then contract with a biochemist
Biochemists are scientists who are trained in biochemistry. They study chemical processes and chemical transformations in living organisms. Biochemists study DNA, proteins and Cell (biology), cell parts. The word "biochemist" is a portmanteau of ...
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 National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
. 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 Pediatric endocrinology (British: Paediatric) is a medical subspecialty dealing with disorders of the endocrine glands, such as variations of physical growth and sexual development in childhood, diabetes and many more.
By age, pediatric endocrin ...
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 physician
A primary care physician (PCP) is a physician who provides both the first contact for a person with an undiagnosed health concern as well as continuing care of varied medical conditions, not limited by cause, organ system, or diagnosis. The term ...
s 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
Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be foun ...
) in which human gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s 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.
In 1985, four young adults in the U.S. having received NPA growth hormone in the 1960s developed CJD (Creutzfeldt–Jakob disease
Creutzfeldt–Jakob disease (CJD), also known as subacute spongiform encephalopathy or neurocognitive disorder due to prion disease, is an invariably fatal degenerative brain disorder. Early symptoms include memory problems, behavioral changes, ...
). 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
An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases.
The assignment of ...
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
Eli Lilly (July 8, 1838 – June 6, 1898) was an American soldier, pharmacist, chemist, and businessman who founded the Eli Lilly and Company pharmaceutical corporation. Lilly enlisted in the Union Army during the American Civil War and r ...
launched a competing natural sequence growth hormone (Humatrope). Pharmacia (formerly Kabi, now Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
) introduced Genotropin. Novo Nordisk
Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, Denmark, with production facilities in nine countries, and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder ...
introduced Norditropin. Serono
Serono was a biotechnology company headquartered in Geneva, Switzerland. It was acquired by the German pharmaceutical company Merck in 2006. The company was founded as the Serono Pharmacological Institute by Cesare Serono in 1906 in Rome, Italy ...
(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, 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 Pediatric endocrinology (British: Paediatric) is a medical subspecialty dealing with disorders of the endocrine glands, such as variations of physical growth and sexual development in childhood, diabetes and many more.
By age, pediatric endocrin ...
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:
* Everyone agrees on the nature and diagnosis of severe GH deficiency, but what are the edges and variations?
* How should marked constitutional delay
Constitutional delay of growth and puberty (CDGP) is a term describing a temporary delay in the skeletal growth and thus height of a child with no physical abnormalities causing the delay. Short stature may be the result of a growth pattern inher ...
be distinguished from partial GH deficiency?
* To what extent is "normal shortness" a matter of short children naturally making less growth hormone?
* Can a child make GH in response to a stimulation test but fail to make enough in "daily life" to grow normally?
* If a stimulation test is used to define deficiency, what GH cutoff should be used to define normal?
It was the ethical
Ethics or moral philosophy is a branch of philosophy that "involves systematizing, defending, and recommending concepts of right and wrong behavior".''Internet Encyclopedia of Philosophy'' The field of ethics, along with aesthetics, concerns ma ...
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
Bioethics is both a field of study and professional practice, interested in ethical issues related to health (primarily focused on the human, but also increasingly includes animal ethics), including those emerging from advances in biology, med ...
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
Turner syndrome (TS), also known as 45,X, or 45,X0, is a genetic condition in which a female is partially or completely missing an X chromosome. Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hair ...
and chronic kidney failure
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vom ...
were the first of these “nonGH-deficient causes of shortness” to receive FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
approval for GH treatment, and Prader-Willi syndrome and intrauterine growth retardation
Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...
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
Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
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. As with other types of hormone supplementation for aging (testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
, estrogen
Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
, DHEA
Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It functio ...
), 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
The American Academy of Anti-Aging Medicine (A4M) is a United States 501(c)(3) nonprofit organization that promotes the field of anti-aging medicine, and the organization trains and certifies physicians in this specialty. As of 2011, approximate ...
published ''Grow Young With HGH: The Amazing Medically Proven Plan To Reverse the Effects Of Aging'', an uncritical touting of GH as the answer to aging. 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
Eli Lilly (July 8, 1838 – June 6, 1898) was an American soldier, pharmacist, chemist, and businessman who founded the Eli Lilly and Company pharmaceutical corporation. Lilly enlisted in the Union Army during the American Civil War and r ...
approval to market Humatrope for the treatment of idiopathic short stature
Idiopathic short stature (ISS) refers to extreme short stature that does not have a medical diagnosis, diagnostic explanation (''idiopathic'' designates a condition that is unexplained or not understood) after an ordinary growth evaluation. The te ...
. 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
Recombinant growth hormone available in the U.S. (and their manufacturers) include ''Nutropin'' (Genentech
Genentech, Inc., is an American biotechnology corporation headquartered in South San Francisco, California. It became an independent subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within R ...
), ''Humatrope'' (Eli Lilly and Company
Eli Lilly and Company is an American pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 countries. The company was founded in 1876 by, and named after, Colonel ...
), ''Genotropin'' (Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
), ''Norditropin'' (Novo Nordisk
Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, Denmark, with production facilities in nine countries, and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder ...
), ''Tev-Tropin'' ( Teva) and ''Saizen Saizen is a commercial preparation of synthetic somatropin (growth hormone, a.k.a. GH). Manufactured by Merck Serono, Saizen is produced by recombinant DNA technology from a mammalian cell line (mouse C127) that was modified by the addition of the ...
'' (Merck Serono
Merck Serono (EMD Serono in the United States and Canada) is a pharmaceutical company headquartered in Darmstadt, Germany, and a brand and division of Merck focused on biopharmaceuticals.
In September 2006, Merck KGaA announced its intent to pu ...
). 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.[ ] It was approved for medical use in the United States in August 2020.
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 cadaver
A cadaver or corpse is a dead human body that is used by medical students, physicians and other scientists to study anatomy, identify disease sites, determine causes of death, and provide tissue to repair a defect in a living human being. Stud ...
s 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
Creutzfeldt–Jakob disease (CJD), also known as subacute spongiform encephalopathy or neurocognitive disorder due to prion disease, is an invariably fatal degenerative brain disorder. Early symptoms include memory problems, behavioral changes, ...
, and was withdrawn from use.
RHGH (rHGH, rhGH) refers to recombinant human growth hormone, that is, somatropin (INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
). Its amino acid sequence is identical with that of endogenous human GH.
It is coincidental that RHGH also refers to rhesus monkey
The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally b ...
GH (RhGH), using the accepted naming convention of ''Rh'' for ''rhesus''. Rhesus growth hormone
Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...
was never used by physicians to treat human patients, but rhesus GH was part of the lore of the underground anabolic steroid
Anabolic steroids, also known more properly as anabolic–androgenic steroids (AAS), are steroidal androgens that include natural androgens like testosterone (medication), testosterone as well as synthetic androgens that are structurally related ...
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
Somatrem, sold under the brand name Protropin, is an analogue of growth hormone
Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell repro ...
(INN). This was the first recombinant GH product marketed (trade name Protropin by Genentech). It had the same amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
sequence as human GH with an extra methionine
Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
at the end of the chain to facilitate the manufacturing process. It was discontinued in 2004.
rBST refers to recombinant bovine somatotropin
Bovine somatotropin or bovine somatotrophin (abbreviated bST and BST), or bovine growth hormone (BGH), is a peptide hormone produced by cows' pituitary glands.
Like other hormones, it is produced in small quantities and is used in regulating ...
(cow growth hormone), or recombinant bovine GH (rbGH, RBGH).
References
Further reading
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{{DEFAULTSORT:Growth Hormone Treatment
Growth hormones
Pediatrics
Endocrine procedures
Eli Lilly and Company brands
Hoffmann-La Roche brands
Genentech brands