INTRODUCTION — Growth hormone (GH) is produced by the pituitary somatotroph cells. GH production begins early in fetal life and continues throughout life, although at a progressively lower rate.
The basic aspects of GH physiology will be reviewed here. This discussion will include the GH gene, the mechanisms and regulators of GH secretion, and a summary of the actions of GH. The physiology of insulin-like growth factor 1 (IGF-1), which mediates most peripheral actions of GH, is discussed separately. (See "Physiology of insulin-like growth factor 1".)
Clinical issues related to GH excess (acromegaly) or GH deficiency in children and adults are also presented separately. (See "Treatment of growth hormone deficiency in children" and "Pituitary gigantism" and "Growth hormone deficiency in adults" and "Causes and clinical manifestations of acromegaly".)
GH GENE
●GH gene family – The human growth hormone (GH) gene family comprises five distinct genes, all located on chromosome 17q22 [1]. The pituitary GH gene (GH1) encodes two alternatively spliced mRNA products, which give rise to the abundant circulating 22 kDa GH molecule and a less abundant (10 percent of circulating GH) 20 kDa GH lacking amino acids 32 to 46. Placental syncytiotrophoblast cells express a GH variant (hGH-V), as well as three other genes for human chorionic somatotropin (hCS). During pregnancy, maternal GH secretion declines and is replaced by rising placental-derived GH.
●Regulation of pituitary GH1 gene – Regulation of the pituitary GH1 gene appears to be under complex hormonal, developmental, and tissue-specific control mediated by regulatory elements of the gene [2]. The tissue-specific development of somatotrophs and expression of GH appear to be largely determined by the POU1F1 (Pit-1) transcription factor [3]. (See "Basic genetics concepts: DNA regulation and gene expression".)
Rarely, dominant-negative mutations in the GH gene are associated with inherited isolated GH deficiency syndromes [4]. Mutations in the Prop-1 gene (which is necessary for the differentiation of a cell type that is a precursor to somatotroph, lactotroph, thyrotroph, and gonadotroph cells) and in the POU1F1 (Pit-1) gene (which acts temporally just after Prop-1 and is necessary for the differentiation of a cell type that is a precursor of somatotroph, lactotroph, and, to a lesser degree, thyrotroph cells) also account for rare cases of GH deficiency that are usually accompanied by other pituitary hormone deficiencies [4-8]. (See "Diagnosis of growth hormone deficiency in children", section on 'Molecular genetics of growth hormone deficiency' and "Causes of hypopituitarism".)
GH SECRETION
●Regulators – Growth hormone (GH) secretion is directly controlled by hypothalamic and peripheral factors acting on the somatotrophs [9-12]. Hypothalamic growth hormone-releasing hormone (GHRH) and somatostatin (SRIH) stimulate and inhibit GH secretion, respectively [2,13]. These hormones act by binding to specific cell-surface receptors on the somatotroph cells (figure 1).
●Daily secretory rates – Daily GH secretory rates decline from a peak of approximately 150 mcg/kg during puberty to approximately 25 mcg/kg by age 55 years; this decline parallels the age-related decline in body mass index [14]. Thus, GH production falls by approximately 50 percent every seven years [14]. The serum half-life of GH is approximately 14 minutes.
●Other nonpituitary tissues – GH is also produced in nonpituitary tissues, including colon and breast, and appears to regulate local cell proliferation [15].
Growth hormone-releasing hormone — GHRH stimulates GH transcription and secretion and also somatotroph proliferation [16]. The GHRH receptor is a cell surface-associated, seven membrane-spanning domain protein linked to a G protein (Gs) that, after ligand-induced activation, stimulates intracellular cyclic adenosine monophosphate (cAMP) production [17]. (See "Peptide hormone signal transduction and regulation".).
The gastrointestinal peptide, ghrelin, specifically induces GH secretion [18], and the ghrelin receptor is expressed on the anterior pituitary [19]. Ghrelin is synthesized in the stomach and is an important nutritional regulator of GH secretion. Mediated by GH, ghrelin acts to maintain blood sugar levels during starvation [20]. (See "Ghrelin".)
Hypothalamic somatostatin — Somatostatin binds to five distinct receptor subtypes (SST1-SST5) [21]. Although somatotrophs express four of these subtypes (to the exclusion of SST-4), SST2 and SST5 preferentially signal to suppress the secretion in the pituitary of GH (and thyrotropin [TSH]) [22]. The role of pituitary SST1 and SST3 receptors is not known. (See "Physiology of somatostatin and its analogues", section on 'Receptors'.)
Other regulators — Insulin-like growth factor 1 (IGF-1), which mediates most of the peripheral actions of GH, inhibits GH secretion (figure 1). (See "Physiology of insulin-like growth factor 1".)
GH secretion is also affected by nutritional factors. GH secretion is increased in subjects who are malnourished or fasting [14], and it is stimulated by high protein meals and intravenously administered amino acids [23]. In contrast, hyperglycemia and leptin inhibit GH secretion [24].
Thus, there appears to be a complex interaction of nutritional factors and hypothalamic appetite-regulating peptides in mediating GH secretion. Insulin-induced hypoglycemia is a powerful stimulus to GH release that may be used as a provocative test for the diagnosis of impaired GH reserve. (See "Diagnostic testing for hypopituitarism", section on 'Growth hormone'.)
A number of other factors influence GH secretion; these effects on GH secretion include:
●Stimulation by estrogen and inhibition by glucocorticoid excess [25].
●Stimulation by dopamine, apomorphine (a dopamine-receptor agonist), alpha-adrenergic agonists, and beta-adrenergic antagonists. In addition to increasing basal GH secretion, beta-adrenergic antagonists augment the responses to GHRH and insulin-induced hypoglycemia.
Pulsatile secretion — GH secretion is pulsatile; between pulses, serum GH concentration may be undetectable unless an ultrasensitive assay is employed. It is thought that the pulsatile bursts of GH release are mediated by reduction in tonic inhibition by somatostatin, perhaps in association with bursts of GHRH [13,25].
24-hour sampling — Twenty-minute GH sampling for 24 hours allows accurate assessment of mean serum GH concentrations. Mean (±SE) nighttime serum GH concentrations are 1.0±0.2 ng/mL and mean daytime concentrations are 0.6±0.1 ng/mL in normal adults. Using ultrasensitive GH assays, normal GH concentrations may even be lower. Peak serum GH concentrations are 4.3±0.7 ng/mL at night and 2.7±0.5 ng/mL during the day [26]. GH secretion is lower in older and obese subjects and is higher during puberty and when corrected for body surface area in neonates [27,28].
Peak GH secretory activity occurs within an hour after the onset of deep sleep. Exercise, physical activity, trauma, and sepsis are associated with increased GH secretion. With exercise, as an example, serum GH concentrations may increase to 20 to 30 ng/mL [29]. Integrated 24-hour GH secretion is higher in women than in men and increases in postmenopausal women during estrogen replacement [30].
The development of ultrasensitive GH assays has facilitated detailed studies of GH secretory dynamics. Studies in which serum GH was measured using an ultrasensitive, chemiluminescence-based assay with a sensitivity of 0.002 ng/mL have revealed the following results:
●There are approximately 10 pulses of GH secretion per day, lasting approximately 90 minutes and separated by approximately 128 minutes [26]. Thus, approximately 50 percent of frequently collected samples collected during the day in normal subjects have undetectable serum GH concentrations, and GH is undetectable in over 95 percent of samples in obese or older subjects [30]. As a result, random measurement of serum GH will likely not distinguish patients with GH deficiency or GH excess from normal subjects [26,31,32]. (See "Diagnostic testing for hypopituitarism", section on 'Growth hormone'.)
●Sex-specific differences in GH pulse amplitude and mass are distinguishable. As an example, glucose loading suppresses serum GH concentrations to <0.7 ng/mL in women and <0.07 ng/mL in men; however, this probably reflects the lower basal concentrations in men rather than a greater suppressive effect of glucose loading [30].
In summary, GH pulsatility and net hormone secretion reflect the tonic interaction of multiple complex inputs but is ultimately determined by the balanced control of GHRH and somatostatin and perhaps ghrelin action. The pattern of GH secretion also impacts upon GH action in that several tissue responses to GH appear to be determined by the secretory patterns of GH rather than the absolute amount of GH that is secreted. The greater GH pulsatility in men, as compared with the relatively continuous GH secretion in women, may be a determinant of linear growth patterns, liver enzyme induction, and GH-signaling molecule (STAT 5b) activity [33,34].
ACTIONS OF GH
Specific effects — Growth hormone (GH) stimulates linear growth in children by acting directly and indirectly (via the synthesis of insulin-like growth factor 1 [IGF-1]) on the epiphyseal plates of long bones. GH also has specific metabolic actions in the adult including [35]:
●Increased lipolysis and lipid oxidation, which leads to mobilization of stored triglyceride
●Stimulation of protein synthesis
●Antagonism of insulin action, which may lead to glucose intolerance, diabetes, and features of the metabolic syndrome when GH is in excess
●Phosphate, water, and sodium retention
These target tissue actions result in maintenance of adult cardiac function, glucose homeostasis, maintenance of bone mineralization, appropriate balance of adipose lipogenesis and lipolysis, and skeletal muscle anabolism. All these functions are attenuated in patients with GH deficiency, and replacement of GH reverses the abnormalities (figure 2).
GH receptor — Growth hormone (GH) acts by binding to a specific receptor homodimer, located mostly in the liver, and inducing intracellular signaling by a phosphorylation cascade involving the JAK/STAT (signal transducing activators of transcription) pathway. Its predominant action is to stimulate hepatic synthesis and secretion of IGF-1, a potent growth and differentiation factor [1,36].
The GH receptor is a 70 kd protein that is a member of the class of receptors common to the cytokine/hematopoietin superfamily [1]. The receptor consists of an extracellular ligand-binding domain, a single membrane-spanning domain, and a cytoplasmic signaling component. Circulating GH-binding proteins are fragments of the receptor that bind GH [37].
A single GH molecule complexes with two GH receptor molecules, followed by rapid internal rotation, and activation of JAK2 tyrosine kinase, leading to phosphorylation of several cytoplasmic signaling molecules that determine transcription of cell proliferation and differentiated function genes.
The STAT proteins comprise important signaling components for GH action. These cytoplasmic proteins are phosphorylated by JAK2 and directly translocate to the cell nucleus, where they elicit GH-specific target gene effects by binding to nuclear DNA [1]. STAT proteins 1 and 5 may also interact more directly with the GH receptor molecule [38].
As a differentiating and growth factor, IGF-1 is a critical protein induced by GH and is likely responsible for most of the linear growth-promoting activities of GH [39]. Furthermore, IGF-1 also directly inhibits GH secretion [39] and GH receptor function [40] by a negative feedback regulation loop. Other actions of GH include stimulation of c-fos and IRS-1 phosphorylation.
Mutations of the GH receptor are associated with partial or complete GH insensitivity and growth failure (Laron dwarfism) (see "Growth hormone insensitivity syndromes", section on 'Growth hormone receptor mutations (Laron syndrome)'). Laron dwarfism is associated with normal or high serum GH concentrations, low serum GH-binding protein concentrations, and low serum IGF-1 concentrations. Over 30 different homozygous or heterozygous exonic and intronic mutations of the receptor have been described, most of which are found in its extracellular ligand-binding domain. STAT mutations have also reported leading to short stature [1,7,38].
The physiology of IGF-1, which mediates most of the peripheral actions of GH, is discussed separately. (See "Physiology of insulin-like growth factor 1".)
SUMMARY
●Growth hormone production and secretion – Growth hormone (GH), the most abundant anterior pituitary hormone, is produced by the pituitary somatotroph cells. GH production begins early in fetal life and continues throughout childhood and adult life, although at a progressively lower rate in the latter. (See 'Introduction' above.)
●Regulation of the pituitary GH1 gene – Regulation of the pituitary GH1 gene appears to be under complex hormonal, developmental, and tissue-specific control mediated by regulatory elements of the gene. The tissue-specific development of somatotrophs and expression of GH appear to be largely determined by the POU1F1 (Pit-1) transcription factor. Rarely, dominant-negative mutations in the GH gene are associated with inherited isolated GH deficiency syndromes. (See 'GH gene' above.)
●GH secretion – GH secretion is directly controlled by hypothalamic and peripheral factors acting on the somatotrophs. Hypothalamic growth hormone-releasing hormone (GHRH) and somatostatin (SRIH) stimulate and inhibit GH secretion, respectively. These hormones act by binding to specific cell-surface receptors on the somatotroph cells. GHRH stimulates GH transcription and secretion, and also somatotroph proliferation (figure 1). (See 'GH secretion' above.)
Daily GH secretory rates decline from a peak of approximately 150 mcg/kg during puberty to approximately 25 mcg/kg by age 55 years; this decline parallels the age-related decline in muscle mass. (See 'GH secretion' above.)
GH secretion is pulsatile. There are approximately 10 pulses of GH secretion per day, lasting approximately 90 minutes and separated by approximately 128 minutes. Thus, approximately 50 percent of samples collected during the day in normal subjects have undetectable serum GH concentrations. In addition, GH is undetectable in over 95 percent of samples in obese or older subjects. (See 'Pulsatile secretion' above.)
●GH action – The predominant action of GH is to stimulate hepatic synthesis and secretion of insulin-like growth factor 1 (IGF-1), a potent growth and differentiation factor. As a differentiating and growth factor, IGF-1 is a critical protein induced by GH and is likely responsible for most of the growth-promoting activities of GH. (See "Physiology of insulin-like growth factor 1".)
The target tissue actions of GH result in maintenance of adult cardiac function, glucose homeostasis, maintenance of bone mineralization, appropriate balance of adipose lipogenesis and lipolysis, and skeletal muscle anabolism (figure 2).
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