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Group v - Physiology of Growth Hormone Secretion

Group v - Physiology of Growth Hormone Secretion

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Published by iqbal tambunan
Dari Prof. Dr. Herbert SIpahutar M.Sc.,M.Si
sebagai tugas fisiologi hewan.
Dari Prof. Dr. Herbert SIpahutar M.Sc.,M.Si
sebagai tugas fisiologi hewan.

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Categories:Types, Research, Science
Published by: iqbal tambunan on Apr 04, 2012
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 JClin Res Ped Endo
2009;(Suppl1):1–7DOI: 10.4008/jcrpe.v1i1.29©2009Journal of Turkish Pediatric Endocrinology and Diabetes SocietyPubbiz/Probiz Ltd. fiti.
Physiology of Growth Hormone Secretion
 Aysun Bideci, Orhun Çamurdan
Gazi University Medical School, Pediatric Endocrinology Unit, Ankara, Turkey
growth hormone,physiology, secretion
13October, 2008
22October, 2008
Corresponding Author:
Aysun Bideci 
Gazi University MedicalSchool, PediatricEndocrinology Unit, Ankara,Turkey E-mail:bideci@gazi.edu.tr
Growth hormone (GH) is secreted in a pulsatile fashion from the anterior pituitary gland. Thesynthesis and the secretion of GH are regulated mainly by two hypothalamic neuropeptides, thegrowth hormone-releasing hormone (GHRH) and somatostatin. A wide variety of physiologicand hormonal factors exert an effect on GH secretion.This paper will review physiology of GH secretion and the factors that regulate it.
Conflict of interest:
None declared
Growth hormone (GH) is secreted in apulsatile fashion from the anterior pitu-itary gland. GH has a 191-aminoacid pep-tide structure containing two disulphidebonds. It is found in the circulation in dif-ferent isoforms of which the 20 and therelatively more active 22 kdisoforms arebiologically more important. There are 5known genes related to the GH moleculeof which the GH-N, the main gene, hasthe locus on 17q22-24. The others are theGH-2 (GH-V) coding for placental GH, theCS1 and CS2 coding for the human chori-onic somatomammotropin, and thepseudogene CSP.(1,2,3,4) GH exists in two forms in the circula-tion, in the free, active form and thebound from which is bound to the growthhormone binding protein (GHBP),(1) without loss of immunoreactivity so thatthe measured GH levels reflect the levelsof both forms.(5) The synthesis and the secretion of GHare regulated by two hypothalamic neu-ropeptides;the growth hormone-releas-ing hormone (GHRH) and somatostatin orthe somatotropin release inhibiting factor.GHRH stimulates both the synthesis andthe release of GH. It is the amplitude andnot the frequency of the pulsatile releasethat is changed. Somatostatin has noeffect on the synthesis but inhibits therelease of GH.(1,2,3,4)In the rat, administration of somatostatin antibody resulted in an increase of the GH levelsbetween the pulses without an effect onthe freqency of the pulses. In humans, inboth male and female, endogenoussomatostatin suppresses the GH levelsbetween the pulses and the amplitude of the pulses but, again, without a change inthe frequency of the pulses. These obser- vations have led to the conclusion that inthe human the biological role of somato-statin is limited to the adjustment of thequantity of the basal and the pulsatilesecretion of GH without alteration of thepulse rate.(2)
ISSN: 1308-5727Online ISSN: 1308-5735
Those agents which influence the secre-tion of GH act through their effects on therelease of GHRH and somatostatin. The
-adrenergic agonists, dopaminergic agonists,clonidine and levodopa increase the releaseof GHRH, while pyridostigmine and cholin-ergic agents achieve augmentation of GHlevels through the inhibition of somatostatinrelease.(6, 7)Insulin induced hypoglycaemia and arginine infusion result in an increasedGH release through both of these mecha-nisms. The latest studies have shown, how-ever, that GHRH receptor agonists signifi-cantly inhibit the acute GH response to thestimulatory effects of pyridostigmine, cloni-dine, levodopa, arginine, insulin inducedhypoglycaemia and the synthetic ghrelinagonist growth hormone releasing peptide(GHRP-6).(1,5) Insulin-like growth factor (IGF)-I, theendproduct of GH bioeffect, has a negativefeedback effect on GH secretion. IGF-I stim-ulates the hypothalamic release of somato-statin and has been observed in hypophy-seal cultures to inhibit the GHRH-dependentGH release by direct action.(4)In addition to the influence of IGF-I, the quantity and thepattern of release of GH are also dependenton the nutritional state, type of foods ingest-ed and the gonadal steroid environment.The role of ghrelin is also under considera-tion. Thyroid hormones are known to influ-ence GH levels and they act via the recep-tors on the cell nuclei by stimulating thetranscription of GH.(1,2,4)  Although GH exerts its biological func-tion through the IGF system, both GH andIGF-I have been shown to have specificeffects. Accordingly, GH and IGF-I influencegrowth at different stages of cell matura-tion.(1,4)GH is effective on the growth plate and the osteoblasts both directly andindirectly, through the IGF system.The indirect effects of GH are exertedprimarily through IGF-I. In the liver andother tissues(e.g., the epiphyses and themuscle), GH increases the synthesis of IGF-I, IGF bindig protein (IGFBP)-3 and the acidlabile subunit (ALS). The direct effect of GHis mostly on the adipose tissue.(8) The specific receptor of GH (GHR) is a638-aminoacid protein, a receptor of theextrinsic tyrosine kinase group encoded onchromosome 5. It consists of an extracellularpart to bind GH, a transmembranal sequenceand a cytoplasmic part. The GHBP is theproteolytic part of the extracellular sequenceof GHR and it probably releasedto the cir-culation by the action of a tumour necrosisfactor (TNF-
)converting enzyme.(9)Thus, information can be obtained on GHR by measuring the GHBP level.(5)GHBP plays a regulatory role on the inhibition and activa-tion of the release of the bound GH and itsdistribution to the tissues. GHBP levelsaredecreasedin diabetes mellitus (DM), malnu-trition, hypothyroidism, liver disease and areincreasedin obesity and estradiaol (E
)ther-apy.(2,8)The sequence of events following binding of GH to GHR has been discussed indetail in another paper by Tar›m in thisSupplement.
It was first demonstrated in rats thatsomatic growth was retarded in the absenceof an intact hypothalamus. Subsequently thehypothalamic ventromedial nucleus wasshown to be the site responsible for the reg-ulation of GH release.(2,4, 7)GHRH-medi- ated binding of guanidine triphosphate(GTP) to the
-unit of the G-protein (Gs)activates the Gs, resulting sequentially inincreased cyclic adenosine-mono-phos-phate(cAMP), changes in the intracellularbalance of Na
and Ca
ions and the secre-tion of GH.(10)The neutralisation of GHRH has been shown to have different effects inthe female and the male rat, indicating a dif-ference in the control of GH release in thetwo sexes.(2) While this neutralisation pre-  vented the formation of GH release pulses without a concurrent change in the quantity of the basal GH release between the pulsesin the male, in the female the tonic inter-
Physiology of Growth Hormone Secretion
©2009Journal of Turkish Pediatric Endocrinology and Diabetes Society
pulse GH levels were also lowered. Inhumans there are other gender differences with respect to GH secretion. Although total24 hoursGH releaseis nearly equal in bothsexes; in males most of the GH releaseoccurs in the early hours of the night with ahypopulsatile release during the day hours with low basal levels. In the young female,on the other hand, multiple day time secre-tory episodes occur with high basal levels,but relatively lower nocturnal release.(2,11)  Ahigher GH secretory response to GHRHhas been observed in women.The sensitivity to GHRH antagonists isalso different between the human male andfemale. In the female sensitivity is higherduring the night and the continuity of thebasal secretion is highly dependent onGHRH.(1,12) The decrease in GH secretion with age isdescribed as the somatopause. In the agedindividual, despite the reduction of the GHpulse amplitude, the GH releasing responseto exogenous GHRH is intact, suggestingthat age-related fall in the GH levels is asso-ciated with reduction in the hypothalamicGHRH response.(1,6,13)There are argu- ments, however, that age-related decrease inGH levels is associated with hypersecretionof somatostatin and obesity.(2)
The 14-aminoacid peptide somatostatinis an inhibitory regulator of GH secretionacting as an endocrine, autocrine andparacrine hormone. It is released from bothhypothalamic neurons and the D cells of thepancreatic islets of Langerhans. It has aninhibitory effect on the release of TSH, ACTH, LH, FSH and prolactin as well as alocal inhibition of the gastrointensinal hor-mones, namely, secretin, gastrin and the vasoactive intestinal peptide (VIP). Of thefive types of somatostatin receptors types 2and 5 are the most effective on GH releaseinhibition.(1,2,3)In addition to inhibiting spontaneous GH release, GHRH, hypogly-caemia, arginine and exercise stimulated GHrelease are also inhibited by these receptors.Itshalflife is very short (only 3 minutes). After the termination of somatostatin infu-sion, spontaneous GH immediately peaksup, while the response to GHRH is signifi-cantly augmented indicating that somato-statin has no direct effect on the biosynthe-sis of GH but merely blocks the secretory mechanism resulting in an accumulation of the hormone within the somatotrophic cellsduring the infusion. In the human, therebound in GH release after somatostatindoes not require the presence of GHRH.This finding has led to the postulation thatGHRH and somatostatin are responsible forthe rhythmic release of GH.(1,2,14,15,16)
Ghrelin consists of 28 aminoacids with aserine at the no. 3 position of the primary structure which has to be octanoylated forhormonal action. It is mainly secreted in thestomach, but also secreted in the hypothala-mic arcuate nucleus, the heart, the liver andthe pancreas. Ghrelin has a rate increasingeffect on GH release after entering the gen-
eral circulation via different ways or afterrelease in the central nervous system (CNS)(1),
as shown by the augmentive effect of syn-thetic ghrelin analogues (GHS) alone ortogether with GHRH. It is debated that GHSare functionally somatostatin antagonists andthe GHRH receptors have to be fully func-tionally occupiedfor full effect on the secre-tion of GH. Continuous GHS infusion resultsin homologue desensitization despite elevat-ed GH pulses and augmented response toGHRH which indicates a cross-reactionbetween GHRH and ghrelin. However, arole of endogenous ghrelin on basal GHrelease is doubtful. During fasting, despitethe lack of increase in ghrelin or theoctanoylated ghrelin levels, GH secretion issignificantly increased.(17,18)Furthermore, there is a lack of an increase in GH levels inthe presence of ghrelin releasing tumours in
Bideci A. and Çamurdan O.
 JClin Res Ped Endo

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