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Growth Hormone Action: growth hormone receptor, growth and metabolic effects

10.4008/jcrpe.v1i1.22

  • Ömer Tarım

J Clin Res Pediatr Endocrinol 2009;1(1):0-0

Growth hormone (GH) therapy has been very successful in patients with GH deficiency in promoting short and long term growth. GH is being used not only in GH deficiency but also in several non GH deficient conditions. The structure, function, and physiology of GH are still being investigated with respect to its growth promoting and also metabolic effects. The aim of this review is to give a brief summary of the history, structure, secretion and control of GH and its effects on growth and metabolism.

Keywords: Growth hormone, growth hormone receptor, growth hormone effects

HISTORY

Dr. Harvey Cushing, in 1912, proposed that acromegaly and gigantism were results of hyperpituitarism.(1) Nine years later, rats treated with bovine pituitary extracts were observed to grow faster.(2) In 1930, growth retardation caused by hypophysectomy in rats was reported to be treated by administration of bovine anterior pituitary extracts.(3) In 1945 growth hormone (GH) was isolated and in 1949 a standard bioassay called ‘tibia test’ was developed for measurement of GH effect in hypophysectomized rats by observation of dose dependent widening of the epiphysis of the proximal tibia.(4, 5)

GH replacement therapy was started about forty years ago with pituitary extracts derived from cadavers. However, this practice was abandoned after its association with Creutzfeldt-Jacob slow virus disease.(6) GH produced by recombinan DNA technology has been used since 1985.(7)


STRUCTURE OF GH

Two genes occupying a 48-kb region on the 17th chromosome designated as hGH-N (or GH-1) and hGH-V (or GH-2) are responsible for coding the GH. Within the same domain, three other genes encode chorionic somatomammotropin (placental lactogen). These genes and prolactin gene on the 6th chromosome are homologous and they consist of five exons and four introns. The homologous genes, also called ‘hGH subfamily’ probably originate from the same ancestral gene. HGHN is expressed in the pituitary somatotrope cells for the synthesis of GH in the circulation. On the other hand, hGH-V is expressed only in the placenta to encode a 22-kd GH variant (GH-V) which differs from GH-N by 13 aminoacids. The role of GH-V in the physiology of the placenta and the fetus is not well known.(8, 9)

The main product of hGH-N is 22-kd GH which consists of 191 aminoacids and constitutes 75% of the GH in the circulation. Alternative splicing from the same gene gives rise to the 20-kd GH which is 14 aminoacids shorter than the 22-kd variant constituting 5-10% of the GH in the circulation. The remaining 15-20% of the GH in the circulation consist of various GH molecules which is responsible for the discrepancybetween different methods of GH measurement which are sensitive to diffrerent epitopes of the GH such as 20 kd vs 22 kd.(10)

The tertiary structure of the GH is known to involve four long alpha chains connected with each other and two receptor-binding sites (sites 1 and 2).(11)


GH SECRETION

GH starts to be synthesized in the fetal pituitary at the 12th week of gestation and GH mRNA increases by 15-fold between the 16th and 27th weeks. Consequently, GH concentration rises from 50 ng/ml at the 12th week to 150 ng/ml around midpregnancy. GH concentration decreases during the third trimester approaching 20 ng/ml at birth. Therefore, GH concentration of a fullterm is lower than that of a premature baby. This decline may be due to the maturation of the negative feedback of insulin-like growth factors (IGF) suppressing GH secretion as the fetus approaches maturity.

GH concentration in serum differs by 300% throughout the different stages of life. It drops immediately after birth and remains stable until puberty. Its peak frequency and amplitude increases during puberty leading to elevation of the serum GH concentration. During this period, GH concentration increases 2.5 fold in males, and 2.3 fold in females. GH response to the stimulation tests is also increased during puberty. GH starts to decrease after the third or the fourth decade of life and reaches its nadir later in life, a period called ‘somatopause’. While GH level at 40 years of age is similar to prepubertal levels, it is only 68% of the prepubertal and 27% of the pubertal levels at 60 years. Somatopause is due to the decrease in androgen/estrogen levels as well as the drop in GH-releasing hormone (GHRH) secretion and increase in fat mass.(12, 13, 14, 15)

GH is secreted in a pulsatile manner and makes 12 peaks in 24 hours in a young male. It is secreted mostly during the night and at the beginning of the slow-wave sleep (stage III and IV). This period usually occurs within 120 minutes after falling asleep. On the other hand, GH secretion decreases during REM (rapid eye movement) sleep. Due to the variability of GH levels during the day, a random GH measurement is not sufficient to diagnose GH deficiency. Therefore, stimulation tests and/or 24 hour monitoring of GH levels with frequent sampling are necessary.( 16) Although GH monitoring is costly and not practical, this method provides important information about the physiology of GH secretion which is controlled by GHRH, somatostatin, ghrelin, and leptin. The amplitude of GH secretion is probably controlled by GHRH and its frequency of secretion is controlled by somatostatin. This suggestion is supported by the observation of intact pulsatile GH secretion despite an inactivating mutation of the GHRH receptor.(17) It has been reported that GH secretion makes 4.5 peaks during the night and mean serum concentration is 2.7 ng/ml. These norms were accepted by the National Cooperative Growth Study in 1996. It was later reported that 24-hour pattern of GH secretion varies with the stage of puberty and its mean serum concentration ranges between 4.4-5.8 ng/ml.(18, 19)

The frequency and amplitude of GH peaks are higher in tall and rapidly growing children compared to shorter children with slower growth velocity. However, higher GH concentration does not guarantee a higher GH bioactivity. Abnormal GH secretory pattern may cause GH unresponsiveness. The pulsatile release constitutes 97% of the total GH release. Therefore, the pulsatile peaks above baseline seem to be more informative than the ‘area under the curve’. The rhythmicity of the pulsatile character may also be important.(20)

Many physiologic and hormonal factors affect GH secretion. Sex hormones increase GH secretion during puberty. GH concentration is higher in women during adult life suggesting a predominant role of estradiol compared to testosterone. The difference between genders is in the amplitude and duration of the peaks rather than the frequency. GH level in prepubertal girls is 30% higher than in boys and this difference may increase even more with puberty. Estrogen affects both GHRH and somatostatin to cause this difference. In contrast, testosterone through its effect on GHRH, decreases GH synthesis and frequency of the peaks, but increases the amplitude and duration of the peaks. Testosterone probably causes these changes through aromatization to estradiol, because unaromatizable androgens do not increase GH as much as testosterone. Spontaneous and stimulated GH secretion is blunted in hypothyroidism and hypercortisolism. Obesity is associated with a decreased number of GH pulses. Body mass index and GH concentration are inversely correlated both in children and in adults. The number and amplitude of GH peaks are increased during fasting.(21, 22)


CONTROL OF GH SECRETION

GH secretion is under the control of GHRH which is synthesized in the arcuate nucleus of the hypothalamus and somatostatin synthesized in the periventricular nucleus. The gene that encodes GHRH is located on the 20th chromosome and consists of 5 exons responsible for the synthesis of GHRH which is made of 44 aminoacids. There are also functional 40 and 37 aminoacid GHRH molecules which are probably formed by proteolysis of the 44 aminoacid molecule. The amino terminal of GHRH molecule is needed for the stimulation of GH secretion.(23)

GHRH receptor is expressed on the pituitary somatotrope cells and belongs to the secretin family of the G protein associated seven membrane domain receptor family. The structure of the GHRH receptor shows partial homology with the receptors of vasoactive intestinal peptide, secretin, calcitonin, and parathyroid hormone. After binding of GHRH to its receptor, adenylate cyclase is stimulated and intracellular adenosine monophosphate is increased leading to a rise in intracellular calcium concentration. This in turn increases the transcription of GH.(24)

Somatostatin is a protein that includes 14 aminoacids which is encoded on the 3rd chromosome. It exerts its suppressive effect on the pituitary somototropes by two G protein inhibitory receptors: receptors 2 and 5. The binding of somatostatin to these receptors causes a decrease in intracellular calcium concenration and GH synthesis.(25)

In addition, a complicated neurotransmitter and neuropeptide system regulates GH secretion in response to physiologic stimuli. The molecules in this system include serotonin, histamine, norepinephrine, dopamine, acetylcholine, gamma-aminobutyric acid, thyrotropin releasing hormone (TRH), vasoactive intestinal peptide, gastrin, neurotensin, substance P, calcitonin, neuropeptide Y, vasopressin, and corticotropin-releasing hormone. In general, these peptides regulate GH through GHRH and somatostatin secretion, but they also have some direct effects.(26)

The discovery of ghrelin provided important information for understanding GH physiology. Most abundant in the stomach, this 28 aminoacid peptide needs acetylation to gain function and plays an important role in appetite and energy intake. Ghrelin is increased during fasting and administration of ghrelin increases food intake leading to obesity. In addition, ghrelin increases GH production and to a lesser extent the synthesis of prolactin, adrenocorticotrop hormone (ACTH) and cortisol. Therefore, increased GH synthesis during fasting may be due to the rise in ghrelin. The increased concentration of ghrelin in Prader-Willi syndrome suggests that it may be responsible for hyperphagia.( 27)

Ghrelin exerts its effects through GH secretagouge receptor (GHS-R) which is a G protein-coupled receptor. This receptor has two subtypes namely GHS-R type 1a which is functional and type 1b which is nonfunctional. GHS-R type 1a is mainly expressed on the pituitary somatotropes suggesting that ghrelin directly stimulates GH secretion. GHS-R had been identified before the discovery of ghrelin as a receptor that was stimulated by certain GH secretagouges. Among these GH analogs, heptapeptides (GHRP-1) and hexapeptides (GHRP-2, GHRP-6, hexarelin) were shown to increase GH secretion in animals and humans. Additionally, penta-, tetra-, and pseudo-tripeptides have also been developed as synthetic secretagouges of GH release.(28)

Leptin is a cytokine-like hormone produced in fat cells and increases both spontaneous GH secretion and the response to GHRH stimulation. The leptin receptor OBR type 1 belongs to the cytokine receptor super family. Although it is abundant in the hypothalamus, it is not expressed in the pituitary gland. Therefore, it is suggested that the effect of leptin on GH secretion is through GHRH and somatostatin modulation.(29)

Galanin and pituitary adenylate cyclaseactivating peptide are two peptides that are produced in the hypothalamus and play a role in the control of GH physiology. Galanin consists of 29 aminoacids and increases the response to GHRH stimulation through its own receptor. The pituitary adenylate cyclase-activating peptide belongs to the secretin-glucagon-vasoactive intestinal peptide family, and after binding to its own receptor, it increases the intracellular cyclic adenosine monophospate and calcium leading to increase in GH.(30)

IGF-I and IGF-II inhibit GH secretion at the pituitary level.(31)


GH RECEPTOR

The effects of GH are mediated by its transmembrane protein receptor which consists of 620 aminoacids. GH receptor (GHR) gene is located at 5p13.1-p12 region and occupies 87 kb with 9 exons (exon 2-10). Exon 2 encodes secretion signal peptide, exons 3-7 encode the extracellular domain, exon 8 encodes the transmembrane domain, and exons 9 and 10 encode the intracellular (cytoplasmic) domain. Exon 10 is larger than the others and encodes most of the intracellular domain.(32)

After the cleavage of the signal peptide, the mature GHR contains 620 aminoacids and has a weight of 65 kd. The extracellular hormone-binding domains consists of 246aminoacids. The next 350 aminoacids cover the cell membrane and include the intracellular domain as well. GHR is homologous with the prolactin receptor and share common sequences with 25 other hormones including leptin, erythropoietin, multiple interleukins, granulocyte-macrophage colonystimulating hormone, and interferon which are collectively defined as the cytokine/ hematopoietin (or class 1 cytokine) receptor superfamily. One GH molecule binds to two GHRs. The extracellular domain of the GHR is separated to two sandwich subdomains (subdomain 1 and 2) and bound by four residual hinge regions. Initially, one GH molecule is bound to one GHR at its 1st region. Subsequently, the second face of the GH (2nd region) is bound to another GHR and stabilizes the GHR dimer.(33)

After the binding of GH and activation of the GHR, ‘Janus-associated’ kinase 2 (JAK 2) bind with GHR. This is a 120 kd tyrosine kinase which belongs to the Janus kinase family. The region called ‘box 1’ is probably the binding site of JAK 2; because mutation or deletion of this region abolishes GHR-JAK 2 activation. The configurational change of the receptor after GH binding increases the affinity of the GHR to JAK 2. Subsequently, the two JAK 2 molecules bound to GHRH mutually phosphorylate each other’s tyrosine locking the JAK 2 in an active form. The activated JAK 2 phosphorylates itself again and other intracellular sites creating high affinity binding regions for a number of signal proteins. Considering the many metabolic effects of GH, the stimulatory effect of GH-GHR-JAK 2 complex on various pathways is not surprising.(34)

The STAT (signal transducers and activators of transcription) molecules have a key role on the GH signaling system. These molecules are particularly important in gene transcription. GH has been reported to phosphorylate STAT 5a, STAT 5b, STAT 3, and STAT 1. STATs after phosphorylation, dimerize and pass to the nucleus to bind to specific DNA regions and start transcription. STAT 5b in the liver in rats is shown to be activated by only pulsatile GH stimulation and not by continuous stimulation. GH secretion in rats is pulsatile only in males and STAT 5b knockout studies have led to growth retardation and obesity with GH resistance associated with high GH and low IGF-I concentration. A similar mutation reported in humans suggests a vital role for STAT 5b on human GHR signal transduction.(35)

The insulin-like effects of GH are probably mediated by the phosphorylation of insulin receptor substrates (IRS) -1, -2, and -3. In order to accomplish this, phosphatydylinositol 3-kinase is stimulated by JAK 2. IRS molecules are also activated by insulin and type 1 IGF receptors. On the other hand, chronic GH excess leads to both diminished insulin receptors and decreased response of IRS phosphorylation to insulin stimulation. In addition, GH inhibits the expression of glucose transporter-1. These findings explain the long term anti-insulin effects of GH.(34, 36)

Suppressors of cytokine signaling (SOCS) are newly defined gene family that may be activated by cytokines. SOCS-1, -2, and –3 may be stimulated by GH, and reciprocally suppress GH by inhibiting JAK 2 kinase activity. SOCS-2 knockout mice had gigantism while overexpression of CIS [cytokineinducible serc homology 2 (SH2) containing proteins] led to decreased body weight. Certain endotoxins and proinflammatory cytokines such as interleukin-1b and tumor necrosis factor-a cause GH resistance. These molecules also stimulate SOCS proteins. Therefore, SOCS proteins probably provide the link between relative GH resistance and inflammatory states associated with increased cytokine secretion such as septicemia.(37)

GH activation of STAT signaling is probably stopped by dephosphorylation of protein tyrosine phosphatases; but the phosphatases that play role in this mechanism are not known.(38)


GH BINDING PROTEIN

About 50% of the GH in the circulation is bound to its binding protein (GHBP) which is a product of proteolysis of the extracellular domain of GHR. The enzyme that is likely to be responsible for this proteolysis is a metalloprotease called tumor necrosis factor-a converting enzyme (TACE). GHBP is a 55 kd molecule which has high affinity, but limited capacity for GH. Although the specific function of GHBP is not clear, it may serve as a reservoir for GH and increase its half life in the plasma. However, it may also compete with GHR to bind GH. In general, expression of GHBP is parallel to GHR and GHBP concentration is decreased in states of GH resistance such as malnutrition or catabolic diseases. However, there are exceptions to this relationship. For instance, GHBP may be normal or even increased in some cases with genetic GH resistance as observed in Laron syndrome. This finding suggests that the genetic defect involves a step after GHR or some mutations may affect GHR and leave GHBP intact.(39)


EFFECTS OF GH ON GROWTH

The growth promoting effect of GH involves epiphyseal growth, osteoclast differentiation, and increased bone mass through osteoblast activity and endochondral bone formation. In addition, GH increases the number of the cells in the tissues. Salmon and Daughaday, in 1957, showed that incorporation of thymidine and sulfate to the cartilageis increased with rat serum, but this effect was not observed with GH alone. This observation has led to the ‘somatomedin hypothesis’ and the effects of GH over IGFs have been defined. However, this hypothesis was questioned after 1980 when GH addition to the tissues was observed to stimulate IGF-I synthesis by autocrine/paracrine mechanisms. Differentiation of precursor cells was stimulated by GH but not by IGF-I and this observation gave rise to the ‘dual effector’ theory. The initial GH effect which differentiates the precursor cells and enables them to produce IGF-I locally lead to clonal expansion. Therefore, it has been proposed that both GH and IGF-I are necessary for growth.(40)

The synthesis of IGF-I in 1980 increased our understanding of GH physiology. Administration of IGF-I to hypophysectomized rats led to increased body weight, increased epiphyseal width, and longitudinal bone growth as well as trabecular bone formation. Children with GHR deficiency responded to IGF-I therapy; but the response of GH deficient children to GH therapy was better than the response of GHR deficient children to IGF-I therapy. These observations suggested that the direct effect of GH on growth is also important in addition to its growth promoting effect over IGF-I. This view is also supported by the fact that growth retardation is more severe in rats when both IGF-I and GHR are deficient compared to mutations where only one of them is affected. GH/IGF-I signaling system is decisive for both intrauterine and postnatal growth.(41)


THE METABOLIC EFFECTS OF GH

GH deficient children and adults have a decreased lean body mass and bone mineral density and increased fat mass. Some of these effects are mediated by GH while others are regulated by IGF-I. On the other hand, some of the effects of GH and IGF-1 may be opposite. For example, contrary to the diabetogenic effect of GH, IGFs decrease blood glucose. The other positive direct effects of GH involve aminoacid transport, protein synthesis, improved nitrogen balance, lipolysis, and lipid oxidation.(40, 42)

The natural course of aging such as negative nitrogen balance, diminished muscle mass, and osteoporosis mimick GH deficiency. As a matter of fact, GH secretion does decline with aging which suggests that GH may be used as an antiaging therapy especially in GH deficient adults. It has also been proposed for the treatment of intensive care patients who are in a catabolic state.(42, 43)

Corresponding Author: Ömer Tarım, Uludağ University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Bursa, Turkey E-mail:omer@uludag.edu.tr


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