REVIEW ARTICLE

Regulation of HumanGrowth HormoneSecretion andIts Disorders

Yuzuru Kato, Yoshio Murakami, Motoi Sohmiya and Masateru Nishiki

Abstract

Growth hormone (GH) secretion from anterior pituitaryis regulated by the hypothalamus and the mediators of GHactions. Major regulatory factors include GHreleasinghormone (GHRH), somatostatin (SRIF), GH releasing pep-tide (ghrerin) and insulin-like growth factor (IGF-I). Theprincipal physiological regulation mechanisms of GHse-cretion are neural endogenousrhythm, sleep, stress, exer-cise, and nutritional and metabolic signals. GHdeficiencyresults from various hereditary or acquired causes, whichmay be isolated or combined with other pituitary hormonedeficiencies. GHdeficiency can be treated with recombinanthumanGH, which results in accelerating growth in chil-dren and normalization of intermediary metabolism inadults. GHhypersecretion mostly results from a pituitarytumor and causes acromegaly or gigantism. Hypersecre-tion of GHcan be treated by transshenoidal surgery. Medi-cal treatment with octreotide and analogs is also effectiveto reduce GHsecretion in combination with or without thesurgery.(Internal Medicine 41: 7-13, 2002)

Key words: GH, GHRH, SRIF, ghrelin, IGF-I, GH deficiency,acromeg aly

Introduction

Growth hormone (GH) plays the central role in the modula-tion of growth from birth until the completion of puberty. GHalso plays a role in the control of body composition, somaticgrowth and intermediary metabolism in the body throughoutlife. GHis a memberof a family of normones that includespituitary prolactin (PRL) and human placental lactogen (hPL).GHis secreted from the anterior pituitary under both positiveand negative control of the hypothalamus as well as short andlong feedback control of the mediators of GHactions (Fig. 1).GHis species specific in structure and functions, and GHregu-lation also differs from other species. In this review article, we

focus on the regulation of humanGHsecretion and its disor-ders, although there have been a number of basically relatedreports in more detail (1).

GHSecretion in Normal SubjectsGrowth hormonePituitary GHis a polypeptide produced by the somatotropecells in the pituitary. In humans, pituitary GH is encoded byGH-1gene on the long arm of chromosome17, which is com-posed of two exons and four introns (2). HumanGHis hetero-geneous, consisting of several molecular variants including 22K and 20 K forms (3). The main form is a 191 amino acid,single chain protein with a molecular weight of 22, 000, whichis most abundantly in pituitary GHand is referred to as 22 KGH. The second most abundant GHwith a molecular weightof20, 000 is known as 20 K GH, a mRNAsplice variant whichlacks an internal sequence of 15 amino acids, and accounts for5-7% of pituitary GH. GHhas a three-dimensional structurewith a twist bundle of four oc-helixes (4) and two independentreceptor binding sites are located on opposite surfaces of GH.

Developmentof somatotropeSeveral pituitary transcription factors are involved in pitu-itary somatotrope development. They include Prop- 1 , Pit- 1 andGH-releasing hormone receptor (GHRH-R)genes. These genesare expressed sequentially during anterior pituitary develop-ment (5). Prop- 1 and Pit-1 are POU-homeodomaintranscrip-tion factors and are critical for tissue differentiation during pi-tuitary ontogeny. Prop-1 is important for development of thegonadotrope, somatotrope, lactotrope and thyrotrope lineages.Pit- 1 is involved in the differentiation of somatotropes, lactotropesand thyrotropes under the direction of Prop-1. GH-releasinghormone (GHRH)is markedly expressed in somatotropes un-der the direction of Pit-1, and it is critical for the normal ex-pansion of the somatotrope population. The GHRH-receptor(GHRH-R)is also required for GHsynthesis and secretion.

Hypophysio tropic hormonesGHsecretion from the pituitary is under neural control fromthe hypothalamus through at least three hypophysiotropic fac-

From the First Division, Department of Medicine, Shimane Medical University, IzumoReprint requests should be addressed to Dr. Yuzuru Kato, the First Division, Department of Medicine^Shimane Medical University, Izumo 693-8501

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Kato et al

N ED A5-H TO pioids

'S

/^ *

G H

G H R

i

IG F -I

StressH ypoglycem iaE xerciseS leep

e

G H R H

G hrelin

rr%d

d

ｩ

SR IF

C+)

G H B P

H ypothalam us

P ituitary

r N utrition

F FA

Body FatM uscleB one

K idneys

Steroids

Blood cells

G ut

r L iver

P rotease

des(l-3)IGF-I 1 IGFBPs l 'e

Figure 1. Schematicregulation of pituitary GHsecretion by hypothalamicneuronal factors and feedback mecha-nisms in humans.

tors: GHRH,somatostatin (SRIF) and ghrelin. The GHRHneu-rons are located in the arcuate and ventromedialnuclei, andSRIFneuronsare located in the anterior periventricular area.GHRHand SRIFrelease are controlled by a complexneuronalnetwork, in which oc-adrenergic, dopaminergic and serotoni-nergic signals stimulate GHsecretion.GHRHis a 40- to 44-amino acid peptide, of which the geneis located on chromosome20 q and encodes a 108 amino acidprecursor. GHRHis released from the medianeminenceintothe pituitary portal system, reaching the somatotropes. GHRH

interacts with the GHRH-R,whichis a seven transmembrane,Gsoc-coupledreceptor that signals the CAMPand Ca2+-channelpathways, and stimulates GHrelease from secretary granulesas well as GHtranscription (6).SRIF is a cyclical peptide that exists in two forms: SRIF-14and SRIF-28. Both SRIFare encodedby a single gene on thelong arm of chromosome3, and a 92-aminoacid precursor ispredominantly processed to SRIF- 14 in the hypothalamus. FiveSRIFreceptor subtypes are known,of which subtypes 1 , 2 and5 are expressed in normalhumanpituitary (7). These receptors

8

Internal Medicine Vol. 41, No. 1 (January 2002)

Regulation of GHSecretion in Man

N H 2 G s S I F L S X P E H Q R

蝣 I I I 蝣 蝣 V I I0Ic = oI

sK

E K R QQ

H C HI

H C H

Kp p A K L Q p R C O O H

I I 蝣 蝣 m 蝣H G H 蝣 蝣 蝣 蝣

I I I 蝣 蝣 蝣H C H 蝣 蝣 蝣

蝣 I I I 蝣 蝣 蝣 蝣 蝣 蝣H C H 蝣 蝣 蝣 蝣

I I 蝣 蝣 蝣H C H 蝣 蝣 蝣 蝣

I I 蝣 蝣 蝣 蝣蝣 H C H 蝣 蝣 蝣 蝣 蝣 蝣

I I I 蝣 蝣蝣 H 蝣 蝣 蝣 蝣

Figure 2. Schematicstructure and aminoacid sequenceof humanghrelin.

Table 1. Effects of TRHon the Secretion of Pituitary Hor-monesin Humans

1) Stimulation 2) InhibitionTSH GH in normalProl actin basalGH in pathological states sleep-induced

acromag aly arginine-induced

anorexia nervosa L-dopa-induced

depres sionliver dysfunctionrenal dysfunction

ACTH in pathologic statesCushing's disease

are membersof the seven transmembranedomain,G protein-coupled class. Interaction of SRIF with its receptors inducescoupling in Gj and Goproteins, which in turn inhibits CAMPproduction and Ca2+-channel fluxes, thereby blocking GHre-lease .

GHreleasing peptides (GHRP)are a class of short peptidesthat are extremely potent as pharmacologicalGHsecretagogues(GHS) (8). The cloning of a specific GHRPreceptor (GHRP-R) was followed by recent identification of a natural ligand,ghrelin (9). Ghrelin is a 28-aminoacid peptide with an essen-tial n-octanoyl modification at Ser3 (Fig. 2). The GHRP-Ris aseven transmenbranedomain,G protein-coupledreceptor thatinteracts with Ga. Ghrelin is expressed in the hypothalamusand the pituitary as well as the stomach,and is consideredas apotential physiological regulator of GHsecretion. The actionof ghrelin on GHsecretion is dependent on a functional GHRHsystem, and GHRHand ghrelin have synergic actions in vivo.(10) The principal site of ghrelin action on GHrelease is the

hypothalamus,but a minoreffect is also present at the pitu-itary level.Thyrotropin (TSH) releasing hormone (TRH) plays not onlya stimulating role in TSHand prolactin (PRL), but also an in-hibitory action on GHsecretion inducedby a numberof stimuli(1 1, 12) and during sleep (13) (Table 1). The inhibitory mecha-nismsremainsto be elucidated, but could be explained, at leastpartly, by NOrelease from the pituitary in a paracrine/autocrinefashion (14, 15).

GrowthhormonereceptorThe GHreceptor (GHR)is a 620-amino-acid, single chainglycoproteinwith a single transmembranedomainand an ex-tracellular domain involved in GHsignalling (16). The extra-cellular domainalso occurs separately as a soluble GHbind-ing protein (GHBP).The GHRis encodedby a single gene located on the shortarm of chromosome5. The gene includes 10 exons and 9 in-trons (17), of which exons 2-7 encode the extracellular do-main, exon 8 the transmembranedomain, and exons 9 and 10the intracellular domain. The GHRis expressed ubiquitouslyand mostenriched in the liver.GHinitiates its action by binding to site 1 of the GHRonone of its surfaces, then followed by binding to site 2 on theother surface of GH(1 8). This results in a complexcontainingtwo GHRsin association with GH.This GH-induceddimer-ization of the GHRis critical for GHRsignaling and GHac-tion. Intracellular signaling is initiated by binding of Janus ki-nase 2 (JAK2) to a proline-rich region (Box 1) in the proximalintracellular part of the GHR,followed by a JAK2-mediatedtyrosine phosphorylation cascade involving JAK2itself, theGHR,signal transducers and activators of transcription (Stats) 1 ,3 and 5, insulin-receptor substances (IRS) 1 and 2, compo-

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Kato et al

nents of the mitogen-activated protein kinase (MAPK),the pro-tein kinase C, and phosphatidyl inositol-3 kinase pathways,and several other intracellular signaling and adaptor proteins

(19).

GHBP

The GHBPis the soluble, extracellular domain of the GHR,and is generated from the GHRby proteolysis (20). The GHBPcirculates in plasma in nanomolar concentrations, sufficientenough to complex a substantial part of plasma GH. PlasmaGHBPlevels reflect the GHRabundance in the liver. The GHBPmodulates GHaction through a variety of mechanisms. It in-hibits GHaction by competing with the GHRfor ligand andby generating unproductive heterodimers with the GHRat thecell surface. The GHBPprolongs the half-life of GHin thecirculation by complexing GH, and by delaying its elimina-

tion. After secretion, GHbinds to GHBPin the circulation,depending on the GHBPlevel and the GHconcentration, andan average of 40-50% of plasma GH is bound to the GHBP.

Insulin-like growth factorThe action of GHis mediated by GH-dependent factors.Amongthem, insulin-like growth factor I (IGF-I) is producedin manytissues in response to GHand other regulators. IGF-Iacts locally as in a paracrine/autocrine fashion and distantly ina hormone-like mode. IGF-I has mitogenic and metabolic ac-tivities. Six binding proteins for IGF (IGFBP) and three IGFBP-related proteins are present in serum and interstitial fluid (21).IGFBP-3 is the major IGFBP in serum and is highly GH de-pendent, circulating by forming a 150-kDa ternary complexinvolving IGF, IGFBP-3 and another GH-dependent proteincalled acid-labile subunit (ALS). IGF-I is proteolytically con-verted to des (1-3) IGF-I, which has more potent biologicalactivity due to reduced affinity to serum IGFBPs.

Insulin-like growth factor receptorIGF-I binds to the type 1 IGF receptor, which is structurallyhomologousto the insulin receptor and has a tetrametric struc-ture with two extracellular oc-subunits covalently connected totwo (3-subunits through disulfide bonds. The p-subunits haveintrinsic tyrosine kinase activity and signal through a phos-phorylation cascade involving IRS-1 and IRS-2, P113-path-ways. The IGF-I receptor is widely expressed in tissues, withthe exception of liver.

Feedback con trolNegative feedback on GHsecretion is exerted by IGF-I andby GH itself. IGF-I inhibits GH secretion by influencing GHRHand SRIF production in the hypothalamus and by influencingGHRHaction in the pituitary. GHinhibits its own secretion inthe hypothalamus. These feedback effects are superimposedon the neural control.

Other control mechanismsGHsecretion is stimulated by insulin-induced hypoglyce-mia, arginine infusion, L-dopa administration, and p-adrenegic

blocking agents, whereas oral administration of glucose andincreased serum FFAlevels rather suppress GHsecretion. GHsecretion is also blunted in obesity and by aging (22). Exactroles of GHRH,SRIF and ghrelin in regulating GH secretionin response to these stimuli are not fully elucidated in humans.The principal physiologic short-term regulation mechanismsof GH secretion are 1) neural endogenous rhythm, 2) sleep, 3)stress, 4) exercise and 5) nutritional and metabolic signals. GHsecretion is regulated by the interaction of GHRHand SRIFand is released in 10-20 pulses in each 24-h cycle. Recent obser-vations in humans indicate that the timing of GHpulses is pri-marily supervised by intermittent SRIF withdrawal, and theamplitude of GHpulses is driven by GHRH(23).The highest peaks in plasma GHare found during slow wavesleep, typically one to two hr after falling asleep. GHpulses ofsmaller amplitude occur throughout the day, on average ap-proximately every 2 hours (24). Womenof reproductive agehave higher GHamplitudes as well as higher interpeak plasmaGHlevels. There is no knowndifferential secretion of specificstimulus for any of the GHvariants, indicating that they arecosecreted in response to a variety of physiological and phar-macological stimuli (25). However, they have different plasmahalf lives, and the 20 K variant and oligometric forms havelonger half lives than 22 K GH of 17 minutes (25, 26).

GHsecretion in patientsGHdeficiencyGHdeficiency results from various causes, hereditary oracquired. GHdeficiency may be isolated or combined withother pituitary hormone deficiencies. Congenital GH deficiencypartly occurs on a genetic basis. A numberof genetic causesare known in combined pituitary hormone deficiency. Inacti-vating mutations in the Prop-1 gene results in TSH, LH, FSH,GHand PRL deficiency (27). Mutations in the Pit-1 gene re-sults in patients with GH, PRL and TSHdeficiency (28).Isolated GHdeficiency may be caused by inactivating mu-tations in the GHRH-Rgene and in the GH-1 gene. GHRHisrequired for somatotrope proliferation and for GHsynthesisand secretion. The patients with defective GHRH-Rare mani-fested by pituitary hypoplasia and isolated GH deficiency (29).Inactivating mutations in GH-1 gene directly affect GHpro-duction (30). Typical deletions of 6.7, 7.0 and 7.6 kb of GH-1gene, and other nonsense and frameshift mutations result insevere GH deficiency (type IA). Less disabling mutations ofGH-1 gene cause a milder GHdeficiency (type IB), in whichsome abnormal GH is produced. Biologically inactive GH isproduced in a special case (31). In patients with type IA, sec-ondary resistance to exogenous GHadministration is frequentlyobserved, because serum anti-GH antibodies to the exogenousGHare highly produced, whereas patients with type IB respondwell to exogenous GH.Dominantly inherited GH-1 gene mutations (type II) arecaused by splice-site mutations in one alle that result in skip-ping of exon 3, resulting in producing abnormal GHproteinexerting a dominant negative influence on the normal GHpro-

10 Internal Medicine Vol. 41, No. 1 (January 2002)

Regulation of GHSecretion in Man

Table 2. Serum Anti-human Pituitary Antibodies in 13 Patients with Au-toimmune Lymphocytic Hypophysitis (Modified from 34)

P a tie n ts A g e S e x D u r atio n R e la tio n to G H D A n ti-p itu ita ry

N o . (y r) p re g n a n c y a nt ib od y *

1 4 2 M 3 +

2 3 0 F 7 +

3 5 7 F 2 + 6 8 k D , 4 9 k D

4 2 1 F 1 6 8 k D , 4 3 k D

5 3 5 F 1 9 + +

6 3 8 F 1 + 6 8 k D , 4 9 k D

7 6 9 F 1 + 6 8 k D , 4 9 k D

8 6 7 F 6 +

9 3 1 F 2 + +

1 0 4 2 F 7 + +

l l 6 0 M 3

1 2 2 8 F 5 +

1 3 6 4 M 4 + 6 8 k D , 4 9 k D

*: Serum antibodies to 68, 49, 43 kD human pituitary membrane antigens.

duced by the intact allele. A mutant GHacts as an antagonist atthe level of the GHRin a patient with dwarfism (32). Anothertype of isolated GHdeficiency is inherited in an X-linked man-ner (type III), which is usually associated with hypo- or agam-maglobulinemia.

Most patients with congenital GHdeficiency are sporadic,and caused by birth trauma and congenital malformations ortumors affecting hypothalamic-pituitary function. MRI mayreveal abnormal scans such as septo-optic dysplasia and pitu-itary stalk transection (33). The incidence of GH deficiency isconsidered to be one per 10, 000 births.Acquired GHdeficiency may be obtained at any time dur-ing the life span by hypothalamic-pituitary lesions, includingsuch tumors as craniophryngioma and non-functioning pitu-itary adenoma. Autoimmunehypophisitis could be involved inadult GHdeficiency in which serum anti-pituitary antbodiesare specifically detectable (34) (Table 2). In patients with pitu-itary lesions, GH, gonadotropin and PRLare lost earlier thanACTH and TSH.In childhood, GHdeficiency is suspected by growth retar-dation, which begins at or shortly after birth. Patients with id-iopathic GHdeficiency have blunted, but not absent, serumGHresponses to secretagogues. In adults, GHdeficiency maynot be recognized or considered clinically important becauseof the lack of subjective manifestations. Adult GHdeficiencycould be suspected by any hypothalamic-pituitary lesion or bythe personal history of childhood GHdeficiency, although abouttwo-thirds of idiopathic GHdeficiency during childhood havenormal GHsecretion as adults (35).GHdeficiency is diagnosed by the demonstration of an un-derlying cause, provocative tests of GHsecretion, and serumIGF-I measurement (36). A normal peak GH level in responseto provocative tests is greater than 7 ng/ml. According to theGrowth Hormone Research Society Consensus Guidelines,adult GHdeficiency is defined by a cut off of 3 ng/ml in re-

Table 3. Effects of GHTreatment for 12 Months on Plasma Levelsof GH, IGF-I and Erythropietin (EPO), Hb, and SerumLevels of LDL Cholesterol (LDL.cho), Triglyceride (TG),Nonesterified Fatty Acids (NEFA), Creatinine (Cr) andUrea Nitrogen (UN) in the Patients with Adult GHD(Modified from 38)

be fo r e tr e at me n t af te r tr ea tm en t p

G H ( n g / m l ) 0 . 2 4+ 0. 09 3 . 3 2 + 0. 5 4 < 0 . 0 5

IG F -I (n g /m l) 7 0 . 1+ 1 3. 8 2 4 6 . 6 + 4 3 . 7 < 0 . 0 5

E P O ( m l U / m l ) 2 5 .9 ｱ 2 . 6 3 7 . 6 ｱ 4. 2 < 0 . 0 5

H b (g / dl ) 1 0 . 3+ 0 .5 10 . 8 + 0. 5 < 0 . 0 5

L D L c h o ( m g / d l ) 1 2 6 . 5 + 9. 2 1 2 4 . 3 +9 . 8 < 0 . 0 5

N E F A ( m g / d l ) 0 . 1 9+0.0 2 0 . 3 1 + 0 . 0 5 < 0 . 0 5

U N ( m g / d l ) 1 9 .0 ｱ 2 .2 16 . 0 + 1. 2 < 0 . 01

C re a tin in e (m g /d l) 1. 1 + 0 .1 8 0.9 6+ 0. 1 < 0 . 0 5

B o dy f a t ( % ) 26 . 4 + 2 . 6 22 . 8 + 3. 1 < 0 . 0 5

*: mean (±SE) values are shown.

sponse to insulin-induced hypoglycemia as severe GH defi-ciency and a gray zone between 3 and 5 ng/ml, using apolyclonal GHassay (37).GHdeficiency can be treated with recombinant human GHgiven sc once daily at bed time. The usual dose of GHis 25-50|Lig/kg/day for children, whereas it is 3-12 |Lig/kg/day for adults.GH therapy is highly effective in children in accelerating growthto obtain normal or even catch-up growth velocity. In adults,the principal effects are normalization of body composition,an increase in lean body mass, body fluid, and bone mineraldensity, and a decrease in serum LDL-cholesterol (Table 3).Improved anemia (38), renal function (39), muscular strength,energy and psychosocial well-being may be obtained. The GHdose is monitored by observation of growth velocity and/orserum IGF-I levels to maintain the age-appropriate normal

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Kato et al

Table 4. Potential Clinical Use of GH Administration in Subjectswith Absolute or Relative GH Deficiency (GHD)

I.GHD

1) Child GHDwith short stature2) Adult GHD

II. Short stature without GHD1 ) Renal failure2) Turner syndrome3) Intrauterine growth retardation

III. Catabolic conditions1 ) Malnutrition

2) Sepsis3) Surgery4) Trauma5) Hemodialysis

6)Diets

7) Corticoid treatmentIV. Others

1 ) Motor neuron disease2) Immunedeficiency

3) Osteoporosis4) Anemia

5) Sterility6) CNS dysfunction

7)Aging

range. Furthermore, the potential use of GHin the treatment ofpatients with relative GHdeficiency maybe considered in avariety of clinical situations (Table 4).

GHinsensitivityGH insensitivity clinically resembles GHdeficiency. It maybe congenital or acquired. Genetic GHresistance is well knownas Laron syndrome (40), which is characterized by inactivat-ing mutations in the GHRgene. Most are found in the extra-cellular domain of the GHreceptor, which inactivates the GHbinding site. Other mutations interfere with receptor dimeriza-tion, skipping of exon 8 encoding transmembrane domain, trun-cating the intracellular domain, or interfere with normal recep-tor signaling owing to heterodimer formation between normaland mutant receptor. Although the phenotype is similar to thatof GHdeficiency, serum basal and stimulated GHlevels areelevated and serum IGF-I and IGFBP-3 levels are low, result-ing from a lack of negative feedback by IGF-I and by GH.Acquired GHinsensitivity may be associated with suchmedical conditions as malnutrition, liver cirrhosis, chronic re-nal failure, hypothyroidism and severe illness. They are char-acterized by low serum IGF-I and GHBPin combination withincreased serum GH, resulting from decreased GHRexpres-sion in the liver.

Hypersecretion of GHOverproduction of GH, mostly by a pituitary tumor, causesacromegaly in adults, pituitary gigantism in prepubertal chil-dren, and acrogigantism in puberty. The incidence of acrome-galy is estimated to be one per 20,000 population (41). But the

onset is insidious and not recognized until the striking changesin connectivetissue and appearanceoccur.In acromegaly, GHsecretion remains pulsatile, with in-creased amplitude and failure to completely cease betweenpulses (42). The mixture of GHmolecular variants secreted inacromegaly does not differ from the mixture secreted normally(25, 43). GHlevels are not normally suppressed by glucose to<1 ng/ml. Frequently, patients with acromegaly have a para-doxical GHresponse to TRHor LHRH.Bromocriptine andother dopaminergic agents suppress GHsecretion during thedaytime in most patients with acromegaly (42). Acromegalymay be caused by ectopic hypersecretion of GHRHassociatedwith somatotroph hyperplasia (44). The involvement of ghrelinin the hypersecretion of GHremains to be elucidated althoughghrelin and GHRP-RmRNAare expressed in the somatotrophadenomas (45, 46).

Octreotide, a SRIF agonist, is quite effective for decreasingGHsecretion by sc injection three times a day or by intermit-tent sc infusion with a portable pump (47). Long acting formu-lations (octreotde LAR) or analogs (lanreotide) have been de-veloped and are effective when injected in 20- to 40-mg dosesbiweekly or monthly (48, 49). A GH antagonist at the GHRisalso effective in blocking GHaction in patients with acrome-galy, by the disabling of binding site 2 in the GHmolecule,and by preventing productive GHRdimerization (50), whereascirculating GHlevels are rather increased due to blunted nega-tive feedback by GHand IGF-I.

Acknowledgements:This work was supported in part by grants from theMinistry of Health and Welfare, Japan, Renal Anemia Foundation, Japan, andGrowth Science Foundation, Japan. Weare indebted to Akiko Kawakamiforher secretarial help and Akiko Kanayamafor her technical assistance.

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