Disorders of the pituitary-somatotroph axis
The pituitary gland is a complex organ secreting six hormones from five different cell types. A complex cascade of transcription factors is mandatory for normal development of the pituitary gland. The lack of one or more mechanisms during different phases may lead to various degrees of pituitary dysmorphogenesis and/or function impairment. Some transcription factors directing embryologic development of the anterior pituitary have mutations that result in congenital defects affecting the synthesis of growth hormone (GH) and additional pituitary hormones. Mutations in a number of genes encoding transcription factors (e.g., HESX1, SOX2, SOX3, LHX3, LHX4, PROP1, POU1F1, PITX, GLI3, GLI2, OTX2, ARNT2, IGDF1, FGF, FGFR1, PROKR2, PROK2, CHD7, WDR11, NFKB2, PAX6, TCF7L1, ITF72, GPR161 and CDON) have been associated with pituitary dysfunction and abnormal pituitary gland development . Mutations of transcription factors are involved in the etiology of isolated GH deficiency or in combination with other pituitary hormone deficiencies.
Somatotrophs are the most abundant cell type in the pituitary. They are highly metabolically active cells therefore diseases that involve the hypothalamus or pituitary often results in attenuation of GH secretion. The GH secretion is controlled by hypothalamic as well as intrapituitary and peripheral signals, all of which converge upon the somatotroph, resulting in integrated GH synthesis and secretion. The somatotroph cells receive the positive signal to produce GH that is mediated by the growth hormone-releasing hormone (GHRH). GH secretion is suppressed by somatostatin produced by the hypothalamus. Refer to .
The development and proliferation of somatotroph cells are determined by a gene called PROP1 (Prophet of Pit-1), which controls the embryonic development of cells of the Pit-1 transcription factor lineage as well as the cells of the gonadotropic hormones. Pit-1 binds to the GH promoter within the cell nucleus, a step that leads to the proliferation of the somatotrophs and GH transcription. Once translated, the GH produced is secreted into the circulation by the anterior pituitary gland in a pulsatile fashion. Besides the dual control of GH release by GHRH and somatostatin, GH is also regulated by ghrelin, which is synthesized in the gastrointestinal tract in response to the availability of nutrients .
The action of GH is mediated by the GH receptor (GHR) which is located mainly in the liver and the cartilage of the epiphyseal growth plate of the bone. GHR is also expressed in adipose tissue, in the heart, kidney, intestine, lung, and skeletal muscle. The GHR is a dimer which, after binding GH, undergoes conformational change and performs signaling to the cell nucleus via the Janus kinase 2 proteins and signal transducers and activators of transcription (STAT) proteins (). The extracellular domain of the GHR is shed from the cell membrane and then circulates as GH binding protein (GHBP). It mediates the transport of GH and prolongs its half life . The receptors for GH and IGF-1 are expressed in the vascular endothelium and myocardium and it is postulated that short-term GH administration could be useful treat cardiovascular diseases .
When GH deficiency is suspected, GH stimulation tests are usually essential to confirm the deficiency as compared to single measurements. However, biochemical testing may not be required in patients with clear-cut features of GH deficiency and three other documented pituitary hormone deficiencies. In patients with clear pituitary lesion and markedly subnormal insulin-like growth factor 1, a stimulation test may also not be absolutely necessary .
Insulin-like growth factor I (IGF-I)
In the liver, GH induces the synthesis of IGF-I and of IGF-3 binding protein (IGFBP-3) and its acid labile subunit (ALS). Both, circulating (endocrine) and local (autocrine and paracrine) IGF-I induce cell proliferation and inhibit apoptosis. IGFBPs prevent the breakdown of IGF-1, prolong its half life from a few minutes to hours and regulate the access to the IGF-I receptor, either enhancing or attenuating the action of IGF-1 . Less than 1% of IGF-I circulates as free molecule. IGF-I serum levels reflect the integrated secretory activity of GH on the metabolism of the body. When IGF-I is produced by peripheral tissues, it is under the control of various hormones and growth factors. In the chondrocytes it is controlled by GH and in the osteoblasts by parathyroid hormone.
IGF binding proteins (IGFBPs)
IGFBPs are a family of evolutionary conserved proteins, which bind IGF-I and IGF-II. These binding proteins have differential affinity to IGF-I and IGF-II and modulate their cellular effects. By binding IGFs, IGFBPs sequester the growth factor and preclude its interactions with cell surface receptors. IGFBP-3 is a major component of the circulating IGF-IGFBP complex, and its concentration is GH dependent .
1. Di Iorgi N, Morana G, Allegri ELM, Napoli F, Gastaldi R, Calcagano A, et al. Classical and non-clasical causes of GH deficiency in the paediatric age. Best Practice & Research Clinical Endocrinology & Metabolism 2016; 30: 705–36.
- From hypothalamic GHRH production or release
- From genetic or congenital disorders of pituitary development affecting either the somatotrophs or other pituitary specialized cells
- Secondary to central nervous system (CNS) insults including tumors, surgery, trauma, radiation or infiltration from inflammatory diseases.
GH deficiency can present at any time of life from neonatal period to adulthood. GH deficiency can be an isolated problem (IGHD) or in combination with other pituitary hormone deficiencies and is often referred to as combined pituitary hormone deficiency (CPHD) or panhypopituitarism. Children without any identifiable cause of GHD are commonly placed as having idiopathic hypopituitarism . Although the majority of patients with GH deficiency are idiopathic in origin, familial inheritance accounts for 5–30% of all cases .
Congenital GHD can be found in association with brain and midline facial abnormalities in hypothalamo-pituitary development or can be due to mutations in genes involved in the GHRH-GH pathway.
GH deficiency is a rare disorder, with estimated prevalence being approximately 1 in 4.000. It is important to rule out other causes of short stature on initial assessment such as familial short stature, constitutional delay in growth and puberty, hypothyroidism, chronic renal disease, Turner’s syndrome and skeletal dysplasia.
Types of inhereted isolated GH deficiency have GHRH or GHRH receptor mutations, often deficiency of GH, prolactin, and TSH, or global deletion of GH receptors. Types of inhereted isolated GHD (IGHD) are:
- Type 1 A: inhertance autosomal recessive, serum GH absent, development of GH antibodies frequent, genes involved GH1 (large deletions)
- Type 1 B: inhertance autosomal recessive, serum GH low, no development of GH antibodies, genes involved GH1 (rare), GHRH receptor
- Type II: inhertance autosomal dominant, serum GH low, no development of GH antibodies, genes involved GH1 (exon 3 deletions), GHRH signal peptide mutation
- Type III: inhertance X-linked, serum GH low, no development of GH antibodies, genes involved unknown.
- Short stature with a poor growth velocity. About 2.3% of the population will have short stature defines as a height below –2 SD score. Once commoner causes of short stature are ruled out or if a short stature is severe, GH deficiency needs to be considered
- In the history and physical examination: neonatal hypoglycemia, prolonged jaundice, traumatic delivery, microcephalus with undescended testes, history of cranial irradiation, head trauma or CNS infection, consanguinity, craniofacial midline abnormalities
Risk progression from isolated GH deficiency (IGHD) to combination with other pituitary hormone deficiencies (CPHD) in children varies depending on the etiology (5.5% idiopathic versus 20.7% organic) . The highest risk is observed in children with abnormalities in the hypothalamic pituitary region. Most cases have pituitary stalk dysgenesis. Besides GH, TSH deficiency is the most frequent and earliest additional deficit and LH/FSH the latest. Children who developed CPHD had more frequently a diagnosis of intracranial tumor or mutations in genes controlling the hypothalamic pituitary development and/or function as compared to those with idiopathic GHD .
Recombinant human GH therapy is used in cases
- That lack proven GH deficiency such as Turner’s syndrome, Prader-Willi syndrome, Noonan syndrome, idiopathic short stature and chronic renal failure
- In conditions for which there is a short stature hometex (Shox) gene deficiency
- In children born small for gestational age without catching-up growth.
Recombinant human GH therapy before start of puberty is very important, because prepubertal height gain is highly correlated with total height gain. The mean adult height standard deviation score of patients with GHD was reported to be approximately –1.0 according to the GH treatment Guideline from the Endocrine Society , whereas the mean adult height deviation score of untreated patients with idiopathic GHD was reported to be –4.7 ranging from –3.9 to –6.
GH deficiency (GHD) in adulthood is characterized by alterations in body composition, decreased capacity for exercise and quality of life, as well as a series of unfavorable changes in cardiovascular function, and lipid and carbohydrate metabolism . Its diagnosis is based on the combination of pituitary disease, hypopituitarism and a reduction in the level of insulin-like growth factor (IGF-I) or in diminished GH responses to different stimuli. A concentration of IGF-I below normal for age and sex in a patient with involvement of three or more pituitary axes is diagnostic of GH deficiency. Severe GH deficiency is defined as a GH response peak after insulin hypoglykemia below 3 μg/L.
- With signs and symptoms of hypothalamo-pituitary disease
- Who have received prior head/neck irradiation
- Who have an expanding pituitary mass causing functional somatotroph compression
- With traumatic brain injury or subarachnoid hemorrhage
- With clinical features of Langerhans cell histiocytosis and sarcoidosis
Pituitary adenomas and parasellular masses and their attendant therapies, including surgery and radiation, account for approximately 80% of documented acquired GHD causes. About 15% of patients with adult GH deficiency and receiving GH replacement in open-label surveillance studies are reported as being due to an idioapathic cause. Somatotroph impingement, compression, inflammation or vascular insult leads to attenuated GH synthesis and secretion, with the resultant clinical sequelae of adult hyposomatotrophism.
Because the somatotroph cells are most sensitive to early pituitary insults adult GH deficiency usually precedes development of multiple hormone deficits, including more readily recognizable gonadal, thyroid, or adrenal failure /, /.
Based on data from the register of GH replacement therapy , 38.6% of cases of adult GH deficiency are due to a pituitary adenoma, 8.4% due to a craniopharyngioma, 2.8% due to intracranial hemorrhage, 19.3% due to idiopathic GH deficiency, 7.4–15.8% due to less common diagnoses, and 1.3–8.6% due to unknown diagnoses.
GH deficiency is associated with changes in body composition (visceral obesity), bone mineral density and lipid profile as well as reduced exercise capacity and cardiac function. Cardiac mortality is said to be increased by a factor of two. Adult GH deficiency causes low bone turnover osteoporosis with a high risk of vertebral and non vertebral fractures .
Adults with GH deficiency experience symptoms similar to those seen in insulin resistance, with multiple metabolic abnormalities, such as elevated blood pressure, abdominal obesity, dyslipidemia, and increased thrombotic risk. They may also develop true insulin resistance.
A state of partial GH deficiency has been described. The phenotype of this group includes excess abdominal fat mass, reduced lean body mass, altered cardiac function and insulin resistance, all features indistinguishable, except for the degree of severity, from those of adult GH deficiency /, /.
The prevalence of progression from IGHD to CPHD in adult-onset organic severe GH deficiency, has been reported as 35%.
The management of GH treated children in the transition from late puberty to adulthood is regulated by the Guidelines of the European Society for Paediatric Endocrinology . GH and IGF-I levels usually peak in late puberty and gradually decline thereafter. While in childhood all degrees of GH deficiency are considered for GH therapy, in adult life only patients with severe GH deficiency are treated with recombinant human GH. Therefore, GH therapy should be stopped and the GH status re-evaluated during transition. GH reserves should be assessed by measurement of IGF-1 or provocative testing. The extent of re-evaluation depends on the a priori likelihood of GH deficiency.
Two patient groups are defined:
- High likelihood of GH deficiency. Patients with severe deficiency in childhood (two or three additional hormone deficiencies, genetic cause, structural abnormality of the growth hormone-IGF-I axis, central nervous system tumors, high dose cranial irradiation).
- Low likelihood of GH deficiency (childhood isolated GH deficiency, idiopathic GH deficiency or one additional hormone deficiency).
The following tests are recommended:
- In patients with a high likelihood of persistent GH deficiency, an IGF-I concentration below –2 SD deviations of the mean for age and sex should be considered sufficient evidence of profound GH deficiency. The measurement should be performed several times within 4 weeks. If the IGF-I concentration is within the mean value –2 SD, a provocative test should be performed.
- Patients with a lower likelihood of retesting GH deficient should have an IGF-I measurement and one provocative test.
The provocative tests currently recommended are the insulin hypoglycemia test and the GHRH-arginine test, the latter being preferred due to its better reproducibility. For the insulin hypoglycemia test, a peak GH cutoff of ≤ 6,1 μg/L for the diagnosis of GH deficiency has a diagnostic sensitivity of 96% and a specificity of 100% . For the GHRH-arginine test, a peak GH cutoff of ≤ 19 μg/L for the diagnosis of GH deficiency results in a diagnostic sensitivity of 100% and a specificity of 97% .
1. Di Iorgi N, Morana G, Allegri ELM, Napoli F, Gastaldi R, Calcagano A, et al. Classical and non-clasical causes of GH deficiency in the paediatric age. Best Practice & Research Clinical Endocrinology & Metabolism 2016; 30: 705–36.
6. Blum WF, Deal C, Zimmermann AG, Shavrikova WP, Child CJ, Quingley CA, et al. Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic GH deficiency. Eur J Endocrinol 2014; 170: 13–21.
8. Grimberg A, Divall SA, Polychronakos C, Allen DB, Cohen LE, et al. Guidelines from growth hormone and insulin-like growth factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature, and primary insulin-like growth factor-I deficiency. Horm Res Paediatr 2016; 86: 361–7.
13. Webb SM, Strasburger CJ, Mo D, Hartman ML, Melmed S, Jung H, et al. Changing patterns of adult growth hormone deficiency diagnosis documented in a decade-long global surveillance database. J Clin Endocrinol Metab 2009; 94: 392–9.
15. Murray RD, Bidlingmaier M, Strasburger CJ, Shalet SM. The diagnosis of partial growth hormone deficiency in adults with a putative insult to the hypothalamo-pituitary axis. J Clin Endocrinol Metab 2007; 92: 1705–9.
16. Clayton PE, Cuneo RC, Juul A, Monson JP, Shalet SM, Tauber M & European Society of Paedriatric Endocrinology. Consensus statement on the management of the GH treated adolescent in the transition to adult care. Eur J Endocrinol 2005; 152: 165–70.
GH excess is essentially due to anterior pituitary adenomas. Clinical relevant pituitary adenomas are relatively common, present in 0.1% of the general population. They are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior pituitary gland, and cause disease due to hormonal alterations and local space occupying effects . Approximately 20% of endocrine active pituitary adenomas produce GH.
Prolonged over secretion of GH is associated with elevated GH as well as somatomedin levels C levels and the clinical signs and symptoms of acromegaly and gigantism. Acromegaly is the consequence of excess GH secretion after epiphyseal fusion. GH hypersecretion before cessation of linear growth results in gigantism, with epiphyseal fusion being delayed due to gonadotropin and sex steroid deficiency as a mass effect of the pituitary adenoma . Magnetic resonance imaging of the pituitary in acromegaly or gigantism reveals the presence of an adenoma, approximately 70% of which are greater than 1 cm in diameter, in 99% of patients.
Hypothalamic and paracrine GHRH and somatostatin C as well as growth factors promote the expansion of tumor cells in adenomas. Paracrine production of GHRH may occur in foregut carcinoid tumor, islet cell tumor, small cell lung cancer, adrenal adenoma, medullary thyroid carcinoma and pheochromocytoma. The increased synthesis of GH may be clinically silent or may manifest as acromegaly .
The gene AIP encodes the 330 amino acid protein aryl hydrocarbon receptor interacting protein (AIP) acting as a tumor suppressor protein which is expressed in somatotroph cells and prolactin secreting cells. AIP mutations predispose individuals to childhood or young adult-onset disease with large, aggressive, poorly responsive mostly GH or prolactin-secreting tumors, leading to giantism in 40% of cases .
GPR101-X-liked acrogigantism (XLAG) is a genetic cause of GH excess that usually presents at a very early age as a sporadic disease due to a de novo micro duplication on the X chromosome involving GPR101 gene in patients with gigantism. The majority of cases are females with germ line micro duplication .
GH excess has been reported in:
5. Josefson J, Listernick R, Fangusaro JR, Charrow J, Habiby R. Growth hormone excess in children with neurofibromatosis type 1-associated and sporadic optic pathway tumors. J Pediatr 2011; 158: 433–6.
Growth hormone (GH) is produced by the anterior pituitary and the placenta. The physiological role of GH includes control of postnatal longitudinal growth, regulation of carbohydrate and lipid metabolism, stimulation of differentiation and potentially mitogenic changes in various cell types, development and maintenance of the immune system, and effects on cardiac and brain tissue .
- Severe short stature, defined as a height more the 3 standard deviations (SD) score below the mean
- Height more than 1.5 SD score below the mid-parental height
- Height more than 2 SD score below the mean, and height velocity over 1 year more than 1 SD score below the mean for chronological age, or a decrease in height SD of more than 0.5 over 1 year in children over 2 years of age
- In the absence of short stature, a height velocity more than 2 SD score below the mean over 1 year or more than 1.5 SD score sustained over 2 years
- Signs indicative of an intracranial lesion
- Signs of multiple pituitary hormone deficiency
- Neonatal symptoms and signs of GH deficiency.
- Young adult patients, having received prior GH therapy for childhood GH deficiency to maximize linear growth, now requiring retesting as adults to confirm the GH deficiency diagnosis
- Those patients who have undergone surgery or radiation therapy for pituitary or brain lesion. GH secretion is impaired in approximately 50% of brain tumor patients, likely as a consequence of surgery and radiation
- Patients harboring a known hypothalamic-pituitary lesion, including pituitary adenoma, craniopharyngioma, cyst, hypothalamic tumor, or rare mass due to secondary tumor metastasis
- Those patients who may have experienced compromised functional pituitary integrity due to prior motor vehicle accident, with head trauma, contact sports injury, treatment of brain lesion or cerebrovascular accident
- Those patients with systemic illness known to also impact the hypothalamic-pituitary axis including a granulomatous disorder, viral, bacterial, or fungal infections, or malignancy.
GH determination in suspected GH excess:
- Acromegalic features
- X-linked acrogigantism
- Detection of GH abuse e.g., in athletes.
In most cases, immunometric assays are employed. Some assays measure only 22-kDa GH, the most common isoform of GH, but most also measure the 20-kDa isoform. The detection limit as stated by the manufacturers is between 0.0016 and 0.05 μg/L .
Calibration: Second International Standard for Somatotropin [a recombinant DNA-derived human GH international standard (IS) 98/574]. IS 98/574 has an assigned quantity of 1.95 mg per ampoule. By definition, 1 mg equals 3 IU. It is recommended that the GH result be reported in mass units (μg/L or ng/mL) .
Isotope dilution mass spectrometry
Because of the pulsatile nature of GH secretion, diagnosis should rely on provocative tests rather than reference intervals of basal GH levels.
A single serum GH measurement does not accurately reflect the appropriate somatotrophic function because
- GH secretion is pulsatile and the measured level is integrated over seconds, minutes and hours
- Different forms of GH are secreted from the anterior pituitary
- GH immunoassays are not harmonized and accurately measuring serum GH is only possible using LC-MS/MS methods
- Measurement of serum IGF-1 as a surrogate marker of integrated GH secretion does not consistently reflect attenuated GH secretion because normal IGF-1 levels may also be encountered in adult patients with validated GH deficiency .
Beyond the neonatal period, determination of random GH is not useful and diagnosis of GH deficiency requires provocation tests.
- Insulin induced hypoglycemia (insulin tolerance test). The insulin tolerance test is the reference standard for the diagnosis of adult GH deficiency.
- GHRH plus arginine (suppression of somatostatin, arginine enhances GH secretion by GHRH). Diagnostic sensitivity 79%, specificity 95%.
- Ghrelin binds the GH secretagogue receptor of the somatotroph cell and stimulates growth hormone secretion. Macimorelin, an oral active ghrelin mimetic is used in several countries. Diagnostic sensitivity 92%, specificity 96%.
Because of the limited reproducibility of provocation tests the cut-off peak GH concentration of these tests to diagnose patients with GH deficiency has a limited evidence and the diagnosis of an appropriately blunted GH response requires the result of at least a second provocation test. According to the Endocrine Society Clinical Practice Guidelinethe insuline tolerance test and the GHRH-arginine test have sufficient sensitivity and specificity to establish the diagnosis of GH deficiency.
According to the Consensus Statement on the Diagnosis and Treatment of Children with Idiopathic Short Stature (ISS) , the ISS is defined as a condition in which the height of an individual is more than –2 SD score below the corresponding mean height for a given age, sex, and population group without evidence of systemic, endocrine, nutritional, or chromosomal abnormalities (evaluated by a pediatric endocrinologist).
Specifically children with ISS have normal birth weight and are GH sufficient. ISS describes a heterogenous group of children consisting of many unidentified causes of short stature. It is estimated that approximately 60–80% of all short children at or below –2 SD score fit the definition of ISS. This definition of ISS includes short children labeled with constitutional delay of growth and puberty and familial short stature .
- A skeletal survey to diagnose if short stature is proportionate and of prenatal origin. Chromopathy and syndromes should be analyzed.
- If short stature is proportionate, of postnatal origin and not severe in most cases the diagnosis will be a normal variant of short stature or of ISS. If short stature is more severe (over -3 SD score) the diagnosis must be explored (e.g., celiac disease, Crohn’s disease, renal failure, renal tubular disorders, hypothyroidism)
- Screening laboratory tests are indicated. These include a complete blood count, erythrocyte sedimentation rate, creatinine, electrolytes, calcium, phosphate, alkaline phosphatase, albumin, TSH, FT4, blood gas analysis and the concentration of IGF-I .
In a child with clinical criteria of short stature a peak cut-off value for GH concentration (using arginine and either glucagon or insulin provocation testing) below 7.09 ug/L was concluded . It is strongly recommended that IGF-1 levels be obtained as part of the evaluation. One positive provocation test is sufficient in children with evidence of cranial pathology, irradiation, combined pituitary hormone deficiency or genetic mutation associated with GH deficiency .
About 30% of children aged 2–15 years are classed as overweight or obese. Spontaneous release of GH is known to inversely correlated to body mass index (BMI). The prevalence of GH deficiency rises with increasing BMI. Using a cutoff of 3 ug/L in provocation testing (glucagon stimulation test) in adults 45% of the control persons are incorrectly classified as GH deficiency whilst 95% of patients with hypopituitarism are correctly identified as GH deficient. By reducing the cutoff to 1 ug/L for this obese cohort the rate of false positives was reduced to 6% whilst 90% of the patients with hypopituitarism were correctly classified as GH deficient /, /. The American Association of Clinical Endocrinologists recommended the cutoff of 1 ug/L in overweight/obese adult patients. However, BMI specific data are not available within the pediatric population.
- Pituitary related GH deficiency (classic GH deficiency) has a prevalence of 1 per 6,000 children
- Polymorphisms in GH and IGF-I genes
- Deficiency in IGF-I; if IGF-I synthesis is reduced in the presence of normal anterior pituitary function, then growth is also reduced, but GH secretion is normal or even elevated
- Mutations in the gene of the GH receptor (GHR) cause GH insensitivity (GHI), also known as Laron syndrome or GHI syndrome (GHIS). Over 60 different GHR molecular defects have been identified. In classic GHIS, the concentration of GH is high while IGF-I and IGFBP-3 levels are low. Besides the classic GHIS there are milder forms that are different from the Laron type and may be classified as idiopathic short stature .
- Defects in the intracellular JAK-STAT signal transduction cascade.
Severe IGF-I deficiency, mutations in the GHR gene, mutations in the JAK-STAT signal transduction cascade, and a defect in the IGF-I gene are rare (prevalence below 1 : 10,000).
Because the somatotroph axis is attenuated with age the use of random GH determination may lead to an in adverted diagnosis of GH deficiency. Spontaneous GH secretion becomes less pulsatile in persons more than 50 years old and GH responses to provocation are also blunted . The comparative validation of the GHRH-arginine test for the diagnosis of adult GH deficiency was compared with the insulin tolerance test (ITT) considered the gold standard. Peak GH responses in the two tests were strongly correlated . A cutoff value of 8 ug/L for GHRH-arginine corresponding to 5 ug/L for the ITT was calculated. Refer to .
Unless one of the conditions shown under the topic indication (refer to ) is met, provocative GH testing should be avoided in adult patients presenting with generalized complaints of weakness, frailty, lethargy, or abdominal obesity .
GH excess is rare and phenotypically resembles the opposite of the GH deficiency.
The most severe form of GHI is known as GHI syndrome (GHIS) or Laron syndrome . Untreated children have severe growth impairment in childhood which results in short stature in adulthood. Intrauterine growth is not affected, although the birth size and weight of these children may be borderline. However, postnatally, the growth rate declines rapidly. Untreated, the height of the adult GHIS patient is 4–10 SD score below the median for age and sex; the musculoskeletal system is underdeveloped.
Patients with classic GHIS have mid facial hypoplasia and the sphenoid bone and mandible are underdeveloped.
GHI can be primary or secondary. Primary GHI is a genetic disorder caused by more than 60 mutations or deletions of the GH receptor gene. Secondary GHI can have many causes, such as malnutrition, liver disease, poorly controlled diabetes mellitus, or antibodies to the GH receptor ().
Acquired GH resistance (GH insensitivity) is characterized by elevated GH levels in combination with a low IGF-I concentration and a low anabolic effect of therapy using recombinant human GH. Elevated GH levels in the presence of a catabolic state have been described in the critically ill, fasting states, and in patients with end-stage kidney disease, trauma or AIDS . The elevated GH level can result from increased secretion of GH, an extended half life of GH, or an elevated concentration of GH binding protein.
Most patients with classic GHI have an elevated level of GH and reduced concentrations of GHBP, IGF-I and IGFBP-3. Some children have partial GHI, less deviating laboratory test results and normal facial appearance. Provocative tests, which often elicit a subnormal response, do not always allow clear differentiation between GHI and idiopathic short stature .
More than 90% of patients with acromegaly have a benign GH secreting adenoma. Approximately 25% of these adenomas additionally secrete prolactin. More than 70% of GH secreting adenomas are macro adenomas. The adenomas grow slowly and patients are usually over 50 years of age and have elevated GH and IGF-I levels since 10 to 20 years. Acromegaly has a prevalence of 40–70 cases per million and an annual incidence of 3–4 cases per million. Acromegalic patients have markedly increased morbidity and mortality.
Acromegaly is associated with the following clinical symptoms:
- Central symptoms such as headache and impaired vision, especially in macro adenomas
- Excessive skeletal growth due to increased IGF-I-stimulated periosteal bone growth
- Arthropathy due to irregular cartilage growth in the joints
- Cutaneous changes in the form of oily skin and hyperhidrosis
- Cardiovascular disease, which accounts for approximately 60% of deaths in acromegaly
- Respiratory dysfunction due to thickening of the tissue in the upper respiratory tract
- Neuromuscular disorders with myalgia, peripheral neuropathy and carpal tunnel syndrome
- Endocrine disorders; approximately 30% of the patients have hyperprolactinemia of greater than 100 μg/L
- Benign colon polyps, which are detected in 45% of the patients
- Metabolic disorders with carbohydrate intolerance or insulin dependent diabetes mellitus, which is due to the direct anti-insulin effect of GH. In addition, GH stimulates renal 25-OHD-1α-hydroxylase, resulting in an elevated serum concentration of 1,25(OH)2D3 and increased enteral calcium absorption and hypercalcuria.
Autonomous GH secretion and its peripheral biological effects are mediated by elevated IGF-I levels. The following decision oriented tests are recommended:
- Primarily measurement of IGF-I. If the result is within the age- and sex-specific reference range, active acromegaly can be excluded; if IGF-I is elevated, active acromegaly may be present
- Secondarily the oral glucose tolerance test (oGTT) with measurement of GH (). The GH nadir is evaluated. A GH nadir below 1 μg/L excludes acromegaly. However, if an ultra sensitive GH test with a detection limit of 0.05 μg/L is used, 25% of acromegaly patients are not detected with a cutoff of 1 μg/L. Many of these patients additionally have elevated IGF-I levels. A GH cutoff below 0.3 μg/L excludes all patients with active acromegaly.
- In some patients, GH is insufficiently suppressed in the oGTT. This may be due to liver disease, renal failure, diabetes mellitus, malnutrition, anorexia, pregnancy, or estrogen therapy. In addition to GH, it is recommended to measure IGF-I in the oGTT.
- A post treatment oGTT GH nadir below 1 μg/L and a normal basal IGF-I level rule out a relapse. Complete normalization of IGF-I is not required for remission.
Human growth hormone is suspected to be widely used in combination with anabolic steroids to enhance the effectiveness of training by increasing muscle mass and promoting more rapid healing although evidence supporting these concepts is lacking . Direct detection of GH remains difficult due to its multiple isoforms. In a study a liquid chromatography-tandem mass spectrometry method to simultaneously quantify the carboxyl-terminal propeptide of type III procollagen (P-III-CP) and type III collagen degradation products in human serum was developed. The concentration of P-III-CP decreased after GH administration and the concentration of split products belonging to the family of P-III-CP and type III collagen increased, which can be used as indirect proof to detect GH administration in athletes.
Method of determination
Commercial assays are calibrated against the IS 98/574 reference preparation. This preparation contains recombinant 22-kDa GH (above 96%). It is recommended to use assays with an imprecision of less than 20% at a limit of detection of 0.005 μg/L. The concentration should be reported in μg/L .
Measured with commercial immunoassays, serum GH shows variations ≤ 20%. The recovery of GH in preparations of IS 98/574 depends on the manufacturer’s reconstitution protocol (> 10-fold differences) and the background matrix . The GH binding protein concentration also has an impact.
In the provocative tests, the ratio of GH 20 kDa to GH 22 kDa does not change, indicating that it is controlled by the pituitary-somatotroph axis. GH does, however, increase significantly in acromegaly and anorexia . One problem with provocative tests are the defined unique cutoffs despite the variation between assays. Using quantile transformation, the inter assay variation of 7 assays was reduced from 24.3% to 11.4% .
If analysis is not performed within 8 h, serum can be stored for 2 days at 2–8 °C. For long term storage, the serum must be frozen. GH is stable in urine for up to 2 days at 20 °C or 4–8 °C. For long term storage, the urine must be frozen .
GH is produced by the anterior pituitary and the placenta. A cluster of 5 genes encoding GH is located on the long arm of chromosome 17 (q22–24). GH produced in the somatotroph cells of the anterior pituitary results from the expression of GH-N (or GH-1) genes, and placental GH is the product of expression of the GH-V (or GH-2) genes.
In plasma, GH is present in genuinely secreted, post translational and oligomeric forms. The dimeric to pentameric forms of 22-kDa GH and 20-kDa GH are present in the form of heterodimers and higher order oligomers . Approximately two thirds are present in a non covalently bound form, one third is bound by disulfide bonds, and 1–2% are present in a covalently bound form. These forms have 10–20% growth promoting activity and 30–120% lactogenic activity, and the immune reactivity in the immunoassays varies from 20% to 100% compared to 22-kDa GH. Oligomers take longer to eliminate from the plasma than monomers. The half life of immunologically measurable GH in plasma is 18 minutes .
Placental GH is similar to 22 kDa GH, but has an N-linked glycosylation site at asparagine 140 and thus is present in the plasma in a glycosylated and non glycosylated form. During the last trimester of pregnancy, all circulating GH is of placental origin. Placental GH has low lactogenic activity.
Approximately 90% of plasma GH exists in a monomeric form and 10% in an oligomeric form . GH mediates its effect in the tissues via the membrane bound GH receptor (GHR). The GHR is a member of the class I cytokine receptor family, which includes more than 30 receptors such as prolactin receptor, erythropoietin receptor, thrombopoietin receptor, interleukin-3 receptor, and interleukin-6 receptor . The GHR is shed continually and circulate in the plasma as growth hormone binding protein (GHBP), a truncated form of the receptor. Under basal conditions, 40–60% of GH is bound to GHBP-1. The second binding protein, GHBP-2, has a lower affinity, but higher binding capacity.
Genes of the Prophet of Pit-1 (PROP1) control the embryonic development and proliferation of somatotrophs. GH enters the circulation in pulsatile fashion under control through hypothalamic releasing and hypothalamic inhibiting hormones. GHRH stimulates the synthesis of GH and somatostatin inhibits the secretion of GH ().
Growth is the developmental and functional process from fertilized egg to adulthood, although growth does not finish here, since many cells continue to proliferate and replace those that die through apoptosis.
- Prenatal growth; by the end of the 40th week of pregnancy, the fertilized egg has undergone 42 cell divisions and then undergoes another 5 divisions during childhood before reaching full adult size. By the end of pregnancy week 10, the fetus has a length of approximately 3 cm, and from week 20 it grows at an average rate of about 2.5 cm/week.
- Growth from birth until puberty; during the first year of life, growth occurs fast, with body weight increasing more than two fold and body length increasing by about 50%, corresponding to a growth rate of 30 cm during the first year of life. The growth rate subsequently declines and, from two years of age, continues to fall, with a nadir occurring just before puberty. While prenatal growth is influenced by maternal factors, postnatal growth is determined by genetic, nutritional and hormonal influences.
- Growth during puberty; this phase is relatively short. It lasts approximately 2 years, with girls entering puberty 2 years earlier than boys. Girls are approximately 10 cm shorter than boys at the beginning of the pubertal growth spurt. In Europe and in the USA, the peak height velocity occurs at 12 years in girls and at 14 years in boys and averages about 10 cm/year for both sexes. During puberty, there is an association between the amount of GH produced and gonadal steroids. In males, for example, the extent of GH release responsible for the linear growth spurt during puberty depends on the androgen stimuli. In girls, estrogens have a similar effect on GH to that of androgens in boys.
The growth process is controlled by hormonal mechanisms. Besides GH and IGF-I, metabolically active hormones such as insulin, thyroid hormones, glucocorticoids, androgens and estrogens are important for growth.
GH and IGF-I are the main determinants of postnatal skeletal and somatic growth. Reduced or increased secretion of these factors or inadequate tissue response to their action are the main causes of growth failure in children and of metabolic disorders in adults.
Stimulation and control of growth
Growth is stimulated and controlled by the anabolic and mitogenic activities of GH and IGFs. Like other polypeptide hormones, GH mediates its effect by binding to a high affinity GH receptor (GHR) on the cell membrane. The GHR belongs to the family of prolactin and cytokine receptors. The growth hormone binding protein (GHBP) is the extracellular domain of the GHR and is shed from the cell membrane after proteolytic cleavage .
The growth promoting and mitogenic effect of GH is mediated by IGFs in a paracrine/autocrine and endocrine fashion. IGFs are bound to the IGFBPs in the biological fluids. IGFs are produced by many tissues.
Metabolic effects of GH and IGF-I
GH deficiency is associated with a metabolic profile similar to metabolic syndrome which is characterized by dyslipidemia, insulin resistance, hemostatic alterations, oxidative stress, and chronic inflammation. GH replacement treatment improves these cardiovascular risk factors .
Lipid metabolism metabolic effects of GH and IGF-I
In healthy individuals, morning awakening is associated with small discrete bursts of GH secretion . In terms of lipid metabolism, this results in lipolysis with increased production of free fatty acids, which in turn causes increased lipid oxidation and ketogenesis. Free fatty acid levels reach a peak of about 1 mmol/L after 2–3 hours and can plateau there for up to 8 hours. GH generally leads to lipid deposition in the muscles and liver. It also inhibits the adipose tissue lipoprotein lipase.
Glucose metabolism metabolic effects of GH and IGF-I
GH has an anti-insulin effect. In healthy individuals, GH does not lead to an increase in the blood glucose concentration, even though it stimulates gluconeogenesis.
GH and IGF-I have complex effects on glucose metabolism. Insulin resistance, hyperinsulinemia and increased gluconeogenesis combine to produce a metabolic milieu which leads to the development of diabetes in acromegaly with a prevalence of 12–37% .
Protein metabolism metabolic effects of GH and IGF-I
In healthy individuals, acute increases in GH do not affect protein metabolism. However, under fasting conditions, the protein-conserving effect of GH becomes apparent.
Fasting, exercise and stress
Fasting: during fasting, GH is the only anabolic hormone to increase, whereas IGF-I levels decrease, and levels of catabolic hormones such as glucagon, norepinephrine and cortisol increase. Lack of GH during fasting leads to a rapid breakdown of muscle protein and an increase in urea production.
Exercise: the major metabolic effect of GH during moderate exercise is stimulation of lipolysis, whereas protein and glucose metabolism remain unaffected.
Stress: during acute stress and in the acute phase of critical illness, GH levels are elevated, whereas protracted critical illness suppresses GH release.
Effects of GH and IGF-I on the skeletal system
GH and IGF-I play an important role in postnatal skeletal growth. IGF-I mediates the effects of GH on bone metabolism. It increases bone formation by differentiated regulation of the osteoblast and also controls bone remodeling .
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The liver has important roles related to the function of the GH/IGF-1 axis besides the production and secretion of IGF-1 induced by GH. It also has a role in the production of IGFBP-3 by kupffer cells. IGF-binding proteins (IGFBPs) antagonize the activity of IGFs due to their high affinity to the IGF-1 receptor. Of the six IGFBPs, IGFBP-3 is the major binding protein for IGF-1 that modulates the biological effects. More than 80% of the circulating IGF-1 forms a complex with IGFBP-3 and the acid-labile subunit (ALS) which prolongs the half-life of serum IGF-1 .
Both IGF-1 and IGFBP-3 are reflective of circulating growth hormone (GH). While GH secretion occurs in a pulsatile manner, IGF-1 and IGFBP-3 levels remain stable, vary relatively little throughout the day, are better indicators of GH secretion and can be easily measured as a screening for GH deficiency in children . Approximately 90% of IGF-1 circulates in the plasma as a ternary complex with IGFBP-3.
IGF-1 is the most important peripheral mediator of GH action and is influenced by chronic nutritional status, with lower values in states of poor nutrition. IGFBP-3 may be acutely influenced by meal intake. Age and pubertal-stage specific norms are needed to interpret both IGF-1 and IGFBP-3, and norms for IGF-1 are also gender-specific .
- Screening and monitoring for GH deficiency
- Confirmation of acromegaly and monitoring of treatment efficacy in patients treated with pegvisomant, a GH receptor antagonist.
Determination of IGF-I
IGF-I is bound to IGFBPs. Approximately 90% of IGF-I circulates in the plasma as a ternary complex with IGFBP-3 and the acid-labile subunit (ALS) with a molecular weight of 150 kDa. Smaller proportions are bound to other proteins, and less than 1% of IGF-I circulates in the free form.
- Size exclusion chromatography at acid pH; this method is considered the gold standard
- Dissociation of the ternary complex of IGF-I, IGFBP-3 and ALS by acid and ethanol which, however, cannot be fully achieved
- Addition of IGF-II to the acid ethanol precipitation mixture. Because highly specific antibodies to IGF-I do not cross react with IGF-II, an excess of IGF-II is added during the acid ethanol precipitation step and before IGF-I is measured. The high concentration of IGF-II in this type of assay blocks the IGF-binding sites of the remaining binding proteins, therefore allowing an unbiased measurement of IGF-I .
Determination of IGFBP3
Serum, heparinized and EDTA plasma: 1 mL
Measurement of serum IGF-1 and IGFBP-3 as potential markers of GH activity are comparatively more practical and accessible as GH stimulated values. Hypopituitary patients with low serum IGF-1 concentration have been shown to have high probability of GH deficiency .
Short stature occurs by definition in 2.5% of children and the question of GH deficiency inevitably arises. Non GH deficient conditions such as genetic short stature, constitutional delay of growth and puberty, hypothyroidism, Turner’s syndrome, Noonan syndrome, Prader-Willi syndrome, chronic celiac disease, chronic renal insufficiency are some of the common conditions treated with recombinant human GH.
Tools for the diagnosis of GH deficiency include auxology, radiographic assessment of bone age, cranial magnetic resonance imaging (MRI), in certain cases genetic testing, and measurement of IGF-1, IFGBP-3 and provocative GH testing . In general both IGF-I and IGFBP-3 have a good specificity and relatively poor sensitivity for GH deficiency . Although IGF-1, IGFBP-3 are not useful in isolation they can be helpful when combined with GH provocation tests with higher diagnostic sensitivity . Both markers show superior reproducibility in comparison to stimulated GH levels .
The value of serum IGF-1 corrected to a normal level IGFBP-3 is a matter of contention among endocrinologists. Serum IGF-1 levels of less than 2 standard deviations (SD) score below the age matched mean in a well nourished adult with pituitary disease is highly suggestive of GH deficiency .However it is clear that serum IGF-1 and/or IGFBP-3 can be normal with undisputed GH deficiency. Various investigations have reported normal IGF-I concentrations in 37–70% of GH deficient adults .
It is now generally accepted, that, in well nourished patients without liver disease, a low IGF-I in the presence of 3 or more anterior pituitary hormone deficiencies provides very strong evidence of GH deficiency /, /. However, for many patients with suspected GH deficiency, a provocative test of GH reserve is required in addition. It is recommended that adults who appear to have isolated GH deficiency undergo two provocative tests to confirm the diagnosis, particularly if the IGF-1 is not low .
- A normal IGF-I level does not exclude the diagnosis of GH deficiency but makes provocative testing mandatory
- A low IGF-I level, in the absence of catabolic conditions such as poorly controlled diabetes, liver disease, and oral estrogen therapy, is strong evidence for significant GH deficiency and may be useful in identifying patients who may benefit from treatment and therefore require GH stimulation testing
- The presence of deficiencies in three or more pituitary axes strongly suggests the presence of GH deficiency.
In a study the proportion of patients with low GH responses to provocative testing increased with the number of other pituitary hormone deficiencies. The presence of three or more deficits, together with a low serum IGF-I level was a specific predictor as any of the GH provocative tests employed.
For pituitary replete patients who are obese, or those with relative abdominal obesity, GH responses to stimulation testing are usually blunted whereas IGF-I levels are usually normal . Baseline IGF-I is not a useful predictor of GH deficiency in traumatic brain injury. These patients will require provocative tests for evaluation of brain reserve .
Method of determination
Prior to measuring IGF-1, all interfering IGFBPs and ALS must be removed by extraction or acidification to ensure that the antigen-binding sites are free . Commercial assays are calibrated to the IS 02/254 WHO reference preparation , but yield different results. To yield IGF-I determination comparable to the former Nichols assay, for which the most data are available, the results of the assays from two manufacturers can be approximately related to the Nichols values by a linear method transformation .
Insulin-like growth factors (IGFs) are polypeptide chains with five different domains and three intramolecular disulfide bonds. Humans have the isoforms IGF-I and IGF-II.
IGF-I is the most important peripheral mediator of GH action. IGF-I consists of 70 amino acids and has a molecular weight of 7.6 kDa. It circulates bound to binding proteins, in particular IGFBP-3 and its acid labile subunit (ALS). IGF-I has a longer half life in plasma than GH.
Serum IGF-I is an integral marker of GH secretion. While GH secretion occurs in a pulsatile manner, IGF-I and IGFBP-3 levels remain stable throughout the day and are better indicators of GH secretion than the measurement of GH levels.
In biological fluids, IGF-I and IGF-II are bound to IGFBPs, of which the most important one is IGFBP-3, with a molecular weight of 45 kDa. IGFBP-3 circulates as a ternary complex with IGF-I and the acid labile subunit (ALS). The actions of IGF-I on the cell (somatic growth in children and adults, energy homeostasis, and fat distribution in adults) are regulated by IGFBP-3. The structural homology between IGF-I and insulin suggests that IGF-I and IGFBP-3 play a key role in the pathogenesis of glucose homeostasis. The plasma half life of the complex is 15 hours compared to only 10 minutes for free IGF-I.
In contrast to the other IGFBPs, the synthesis of IGFBP-3, like that of IGF-I, depends on the concentration of GH. Since IGFBP-3 levels are less nutritionally dependent than IGF-I levels, IGFBP-3 has proven to be a suitable diagnostic parameter for the initial assessment of GH-related disorders in children .
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For healthy men (n = 35) and women (n = 43). Expressed as medians and ranges for the AutoDelfia-imunoassay* and Immulite 2000-immunoassay**
hGH cutoff (ug/L)
Abbreviations: BMI, Body mass index. Peak serum GH concentrations below 1 ug/L indicate a severe GH deficiency. Some GH response to hypoglycemia can occur despite complete lack of GHRH receptor.
Data expressed in μg/L; values are 2.5th and 97.5th percentiles of the Siemens Immulite 1000 assay
Data expressed in mg/L; values are 2.5th and 97.5th percentiles of the Siemens assay
Figure 35.1-1 Hypothalamic-pituitary-somatotroph axis. Catecholamines activate α-receptors and cause the secretion of growth hormone releasing hormone (GHRH) by the hypothalamus. GHRH activates the eosinophil cells of the anterior pituitary to secrete growth hormone (GH). In the liver, GH, by interaction with its receptor, causes the release of insulin-like growth factor I (IGF-I), which induces cell proliferation and inhibits apoptosis. Somatostatin produced by the hypothalamus inhibits the secretion of GH. Via a feedback mechanism, plasma GH promotes the secretion of somatostatin and inhibits the secretion of GHRH. Neurotransmitters influence the regulatory circuit: α-adrenergic influences such as hypoglycemia and GABA as well as clonidine stimulate GHRH secretion. β-adrenergic neurotransmitters activate the secretion of somatostatin. Dopamine and arginine have an inhibitory effect. Modified from Ref. .