Remarkable research over the past 4 decades has advanced our knowledge of the physiology of the growth hormone (GH) axis.
Human pituitary-derived growth hormone
More than 40 years have elapsed since human pituitary-derived growth hormone (pit-hGH) was purified and the first patient, a 17-year-old male adolescent with growth hormone deficiency (GHD), was treated successfully with pit-hGH. For many years, pituitary glands harvested from human cadavers provided the only practical source of GH with which to treat GHD. Worldwide, more than 27,000 children with GHD received pit-hGH from the 1950s to the mid 1980s.
Pit-hGH was a suboptimal therapy for 3 reasons.
The shortage of pit-hGH limited its use and the dosages administered.
The biopotency of preparations varied. Strict diagnostic criteria for GHD were used to address these problems (eg, peak plasma immunoreactive GH levels of more than 3.5-5 ng/mL after provocative stimuli).
Treatment was often interrupted. The mean age for starting treatment with pit-hGH was often 12-13 years (late in childhood), and severe growth failure (height Z score -4 to -6) was required. As a result, pit-hGH therapy was often discontinued when girls attained a height of 60 inches and when boys attained a height of 65 inches.
Nonetheless, pit-hGH had dramatic effects. Among patients with isolated GHD, final height standard deviation scores increased to approximately -2 in boys and -2.5 to -3 in girls. For children with multiple pituitary-hormone deficiencies, height standard deviation scores increased to between -1 and -2.
The number of patients with GHD who were treated with pit-hGH increased from approximately 150 to more than 3000 by 1985. However, in 1985, studies indicated that pit-hGH was the likely source of contaminated material (prions) responsible for Creutzfeldt-Jakob disease (a slowly developing, progressive, fatal neurologic disorder) in 3 young men. As a consequence, production and distribution of pit-hGH for therapy was discontinued.
Recombinant human growth hormone
The commercial introduction of recombinant human growth hormone (rhGH) in 1985 dramatically changed the field of therapy for GH. Since then, rhGH has been administered to more than 50,000 children worldwide, making it one of the most extensively studied therapies in the pediatric pharmacopoeia.
US Food and Drug Administration (FDA)–approved indications for the administration of rhGH in children include treatment of the following conditions:
Growth failure associated with GHD (approved in 1985)
Chronic renal failure (approved in 1993)
Turner syndrome (approved in 1996-1997)
Prader-Willi syndrome (approved in 2000)
Small size for gestational age, with failure to catch up (approved in 2001)
Idiopathic short stature (approved in 2003)
SHOX gene deficiency (approved in 2006)
Noonan syndrome (approved in 2007)
Achievement of final adult height consistent with a child's genetic potential remains the primary therapeutic endpoint for rhGH therapy in the pediatric population. In addition to its effects on bone mass, GH regulates muscle mass, muscular strength, body composition, lipid and carbohydrate metabolism, and cardiac function. Patients with GHD typically have hyperlipidemia, increased body fat, premature atherosclerotic plaques, delayed bone maturation, and impaired cardiac function.
At present, GHD in adults is recognized as a distinct clinical syndrome that encompasses reduced psychological well-being and specific metabolic abnormalities. Such abnormalities, including hypertension, central obesity, insulin resistance, dyslipidemia, and coagulopathy, closely resemble those of metabolic insulin resistance syndrome.  The increased rates of cardiovascular morbidity and mortality reinforce the close association between the syndromes.
Replacement of GH in adults with GHD markedly reduces central obesity and substantially reduced total cholesterol levels but has produced little change in other risk factors, particularly, insulin resistance and dyslipidemia.  For these patients, concerns are the persistent insulin resistance and dyslipidemia, together with the elevated plasma insulin and lipoprotein(a) levels observed with GH replacement. Long-term follow-up data are required to assess the effect of GH replacement on cardiovascular morbidity and mortality in adults with GHD.
The large commercial supply of rhGH fuels research and debate over the proper indications for this potent and expensive therapy. Few disagree that many patients with childhood-onset GHD require continuous GH replacement therapy into adulthood. However, the diagnostic criteria for GHD in patients of any age remain controversial. This ambiguity stems from the wide variability in current tools used to diagnose GHD, as discussed below (see Workup).
Clinicians and researchers alike will continue to grapple with these dilemmas in the foreseeable future. However, commercial interests and patient advocates continue to pressure the medical community to expand the accepted indications for rhGH. Therefore, the clinician and the clinical researcher must examine published data critically and must educate individual patients and their families about the risk-benefit ratio of rhGH therapy for them.
Most of the pituitary gland is dedicated to synthesizing and secreting GH from somatotrophs of the adenohypophysis (anterior pituitary). See the image below.
The adenohypophysis derives from the Rathke pouch, a diverticulum of the primitive oral cavity. The adenohypophysis consists of 3 lobes, namely, the pars distalis, the pars intermedia (which is vestigial in humans), and the pars tuberalis. The pars distalis is the largest lobe and contains most of the somatotrophs. The pituitary gland lies within the sella turcica, covered superiorly by the diaphragma sellae and the optic chiasm.
The hypothalamus communicates with the anterior pituitary gland by releasing of hypothalamic peptides, which are subsequently transported in the hypophyseal portal circulation (ie, the blood supply and communication between the hypothalamus and the adenohypophysis). GH is secreted in a pulsatile pattern as a single-chain, 191-amino acid, 22-kDa protein.
Two specific hypothalamic peptides play major regulatory roles in GH secretion: growth hormone-releasing hormone (GHRH) and somatotropin-releasing factor. Amplitudes and frequencies for release of GHRH and somatotropin-releasing factor, as well as GH, differ between boys and girls and may partially account for differences in the phenotypes between the sexes.
Several neurotransmitters and neuropeptides also control GH secretion by directly acting on somatotrophs or by indirectly acting by means of hypothalamic pathways. These neurotransmitters include pituitary adenylate cyclase activating polypeptide (PACAP), galanin, pituitary-specific transcription factor-1 (Pit-1), prophet of Pit-1 (PROP1), HESX1, serotonin, histamine, norepinephrine, dopamine, acetylcholine, gamma-aminobutyric acid, thyrotropin-releasing hormone, vasoactive intestinal peptide, gastrin, neurotensin, substance P, calcitonin, neuropeptide Y, vasopressin, and corticotropin-releasing hormone.
Insulinlike growth factors
Insulinlike growth factors (IGFs) are a family of peptides that partially depend on GH and that mediate many of its anabolic and mitogenic actions.
Two theories have been proposed regarding the relationship between GH and IGFs: the somatomedin hypothesis and the dual-effector hypothesis. According to the somatomedin hypothesis, IGF mediates all of the anabolic actions of GH. Although this theory is partially correct, GH also has various other independent metabolic actions, such as enhancement of lipolysis, stimulation of amino acid transport in the diaphragm and the heart, and enhancement of hepatic protein synthesis. The attempt to resolve this discrepancy lies in the dual-effector model. According to this theory, GH stimulates precursor cells to differentiate and secrete IGF, which, in turn, exerts mitogenic and stimulatory effects.
Insulinlike growth factor binding proteins
Six high-affinity insulinlike growth factor binding proteins (IGFBPs) bind IGFs in the circulation and tissues, regulating IGF bioavailability to the IGF receptors. Under most conditions, IGFBPs appear to inhibit the action of IGFs by competing with IGF receptors for IGF peptides. However, under specific conditions, several IGFBPs can enhance IGF actions or exert IGF-independent actions.
Relative concentrations of the IGFBPs vary among biologic fluids. IGFBP-3 is the most abundant IGFBP species in human serum and circulates as part of a ternary complex consisting of IGFBP-3, an IGF molecule, and a glycoprotein called the acid-labile subunit. IGFBP-3 is the only IGFBP that clearly demonstrates GH dependence. Therefore, IGFBP-3 is a clinically useful tool for the diagnosis of GHD and the follow-up care of patients.
Androgens and estrogens substantially contribute to growth during the adolescent growth spurt. Children with GHD lack the normal growth spurt despite adequate amounts of exogenous or endogenous gonadal steroids. The relationship among the sex steroids, GH, and skeletal maturation is not clearly understood. However, GH secretion is lower in frequency and higher in amplitude among males than in among females.
Androgen and estrogen receptors have been identified in the hypothalamus and are suspected to play an important regulatory role in the release of somatostatin, the hypothalamic hormone that inhibits GH secretion. Somatostatin regulation is believed to direct the frequency and amplitude of GH secretion. Therefore, it may be one of the sources of the differences between male and female individuals.
Thyroid hormone is essential for postnatal growth. Growth failure, which may be profound, is the most common and prominent manifestation of hypothyroidism. The interrelationships between the thyroid and the pituitary-GH-IGF axis are complex and not yet fully defined. Hypotheses include a direct effect of thyroid hormone on the growth of epiphyseal cartilage and a permissive effect on GH secretion. Proof of the permissive effect on GH secretion derives from studies revealing that spontaneous GH secretion is decreased and that the response to provocative GH testing is blunted in patients with hypothyroidism (see Workup).
In addition, growth velocity is markedly decreased among rhGH-treated patients with GHD and hypothyroidism until thyroid hormone replacement is begun. Downregulation of GH receptors and decreased production of IGF-1 and IGFBP-3 have been reported in the hypothyroid state. An unexplained relationship exists between the treatment of patients with GHD by using rhGH and the development and unmasking of hypothyroidism.
The prevalence is 1 case per 3480 children or adolescents aged 4-15 years.
No strong data about the international prevalence of hyposomatotropism are available.
Sequelae of hyposomatotropism include the following:
Behavioral and educational difficulties
Peripheral vascular disease and reduced myocardial function
Lean body mass, reduced muscular strength, and reduced exercise capacity
Abnormal metabolism of thyroid hormone
Impaired psychosocial well-being
Decreased bone mineral content
The overall crude mortality rate for patients with tumor-related, trauma-related, or iatrogenic GHD is 2.7%.
Clinicians must be cognizant of the increased incidence of mortality among patients with multiple pituitary hormone insufficiency secondary to adrenal crisis.
A racial ascertainment bias may be noted. Demographic and diagnostic features of GHD in children in the United States reveal that black children with idiopathic GHD are shorter than white children are at the time of diagnosis. The low overall representation of black children in the population with GHD (6%) compared with their representation in the at-risk population (12.9%) also suggests an ascertainment bias between the races.
A male ascertainment bias may be observed. The predominance of GHD diagnosed in boys in the United States and the observation that girls with idiopathic GHD are comparatively shorter than boys at the time of diagnosis suggest a sex-based ascertainment bias.
The age of patients with GHD is depends on the etiology of the disease (see Causes). 
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