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Growth Hormone

1. ÇÕ¼º

GH-secreting somatotrope cellÀº ant. pituitary cellÀÇ 50%¸¦ Â÷ÁöÇÑ´Ù.

mammosomatotrope cellÀº PRL & GHÀ» ÇÔ²² »ý¼ºÇÑ´Ù.

2. ºÐºñ

GHRH -> GH synthesis & release ÀÚ±Ø(GH spike)

somatostatin(SRIF) -> hypothalamusÀÇ medial preoptic area¿¡¼­ ÇÕ¼ºµÇ¾î GH

secretionÀ» ¾ïÁ¦, basal GH toneÀ¯Áö

cf. SRIF´Â ¸¹Àº extrahypothalamic tissue¿¡¼­ ¹ßÇö: CNS, GI system, pancreas

-> hormone secretion¾ïÁ¦

IGF-I : GHÀÇ peripheral target hormoneÀ¸·Î GH feedback inhibition

estrogenÀº GH À¯µµ

glucocorticoid GH¾ïÁ¦

¨ç GHRHÀÇ 2 distinct surface receptors

i) GPCR : cAMP pathwayÀ» ÅëÇÏ¿© ½ÅÈ£Àü´Þ -> somatotrope cell proliferationÀÚ±Ø

GHRH receptor mutationÀº dwarfismÀ» ÀÏÀ¸Å´

ii) GHRP(GH-releasing peptide) receptor

: hypothalamus & pituitary¿¡¼­ ¹ßÇö

ghrelinÀ̶õ natural ligand(stomach¿¡ dzºÎ)°¡ °áÇÕÇϴµ¥ physiologic roleÀº

¾Ë·ÁÁ® ÀÖÁö ¾Ê´Ù.

¨è somatostatinÀÇ 5 distinct receptor subtypes

SSTR1 - SSTR5

SSTR2 & SSTR5°¡ GH & TSH secretionÀ» ÁÖ·Î ¾ïÁ¦

GH´Â ¹Úµ¿¼ºÀ¸·Î ºÐºñµÇ´Âµ¥ ÁÖ·Î ¹ã¿¡, ¼ö¸éÁß¿¡ ÀϾ´Ù.

³ªÀ̰¡ µé¸é¼­ ºÐºñ°¡ °¨¼ÒÇϸç Á߳⿡ GH »ý¼ºÀº »çÃá±â¶§ÀÇ 15%¿¡ ºÒ°úÇÏ´Ù.

ºñ¸¸È¯ÀÚ¿¡¼­µµ ºÐºñ°¡ °¨¼ÒÇϴµ¥ feedback controlÀÇ setpoint°¡ º¯È­µÈ ¶§¹®À¸·Î

»ý°¢µÈ´Ù.

* GH levelÀÌ Áõ°¡ÇÏ´Â °æ¿ì

: deep sleep, exercise, physical stress, trauma, sepsis, ¿©¼º(ƯÈ÷, estrogen

replacement¸¦ ¹Þ°í ÀÖÀ» ¶§), natural factor

natural factor i) high-protein meal(L-arginine)

ii) dopamine & apomorphine(dopamine-receptor agonist)

iii) ¥á-adrenergic pathway

iv) ¥â-blocker : basal GH¡è

GHRH- & insulin-evoked GH release¡è

3. ÀÛ¿ë

GH secretion male = pulsatile, female = continuous secretion

-> linear growth & liver enzyme inductionÀÇ Áß¿äÇÑ »ý¹°ÇÐÀû °áÁ¤ÀÎÀÚ

GH -> GH receptor(cytokine receptor)¿¡ °áÇÕ

-> JAK/STAT family¿Í »óÈ£ÀÛ¿ë

-> ÇÙÀ¸·Î À̵¿ÇÏ¿© GH-regulated target gene expression

GH potent antagonist°¡ acromegaly & diabetic microangiopathyÄ¡·á¿¡ »ç¿ëÇÒ¼ö ÀÖ´ÂÁö

¿¬±¸ÁßÀÌ´Ù.

±âŸ GHÀÛ¿ë : protein synthesis, nitrogen retention, glucose intolerance,

lipolysis(circulating fatty acid¡è, ometal fat mass¡é, lean body mass¡è)

sodium, potassium, water retention, inorganic phosphate¡è

epiphyseal prechondrocyte differentiation¡è

4. Insulin-like growth factors

GHÀÌ target tissue¿¡ direct effect¸¦ ³ªÅ¸³»±âµµ ÇÏÁö¸¸ ¸¹Àº physiologic effect´Â IGF-IÀ»

ÅëÇÏ¿© °£Á¢ÀûÀ¸·Î ÀÌ·ç¾îÁø´Ù.

1) IGF-I : a potent growth & differentiation factor

circulating IGF-IÀÇ major source = liver

peripheral tissue IGF-IÀº GH¿¡ ÀÇÁ¸ ¹× ºñÀÇÁ¸ÀûÀ¸·Î local paracrine actionÀ» º¸ÀδÙ.

µû¶ó¼­ GH¸¦ Åõ¿©ÇÏ¸é ¸¹Àº Á¶Á÷¿¡¼­ IGF-I expressionÀ» ÀÚ±ØÇÒ »Ó¸¸ ¾Æ´Ï¶ó circulating

IGF-I levelÀÌ Áõ°¡ÇÑ´Ù.

IGF-I & II µÑ´Ù IGF bioactivity¸¦ Á¶ÀýÇÏ´Â ¿©¼¸ °³ÀÇ high-affinity circulating IGF-binding

proteins(IGFBPs)Áß Çϳª¿¡ °áÇÕÇÑ´Ù. IGFBPsÁß¿¡¼­ IGFBP3´Â GHÀÇÁ¸ÀûÀ̸ç circulating

IGF-I¿¡ ´ëÇÑ major carrier proteinÀ¸·Î ÀÛ¿ëÇÑ´Ù. GH deficiency & malnutrition¶§´Â

IGFBP3 levelÀÌ ³·´Ù. IGFBP1 & 2´Â local tissue IGF actionÀ» Á¶ÀýÇÏÁö ¾Ê°í ´«¿¡ ¶é Á¤µµ

ÀÇ circulating IGF-IÀÌ °áÇÕÇÏÁö´Â ¾Ê´Â´Ù.

serum IGF-I ³óµµ´Â ¿©·¯ °¡Áö »ý¸®ÇÐÀû ÀÎÀÚ¿¡ ÀÇÇØ Å©°Ô ¿µÇâÀ» ¹Þ´Â´Ù. »çÃá±â¶§ Áõ°¡

ÇÏ¿© 16¼¼¶§ peak¸¦ ÀÌ·ç¾ú´Ù°¡ ±×Èķδ Á¡Â÷ °¨¼ÒÇÏ¿© ³ªÀ̰¡ µé¸é¼­ 80%ÀÌ»ó °¨¼Ò

ÇÑ´Ù. ³²ÀÚº¸´Ù´Â ¿©ÀÚ¿¡¼­ ´õ ³ô´Ù. GHÀÌ hepatic IGF-I synthesisÀÇ major determinant

À̹ǷΠGHÇÕ¼º°ú ÀÛ¿ë¿¡ ÀÌ»ó(¿¹, pituitary failure, GHRH receptor defect, or GH receptor

defect)ÀÌ »ý±â¸é GF-I levelÀÌ °¨¼ÒÇÑ´Ù. hypocaloric state´Â GH resistance¿Í °ü·ÃÀÖ´Ù.

±×·¯¹Ç·Î cachexia, malnutrition, and sepsis¶§´Â IGF-I levelÀÌ ³·´Ù.

2) IGF-I physiology

high doses of injected IGF-I(100 ug/kg)ÇßÀ» ¶§ ÀÏÂ÷ÀûÀ¸·Î´Â insulin receptor¸¦ ÅëÇØ

ÀÛ¿ëÇϹǷΠhypoglycemia¸¦ À¯¹ßÇÑ´Ù. low IGF-I dose´Â severe insulin resistance &

diabetes¸¦ °¡Áø ȯÀÚ¿¡¼­ insulin sensitivity¸¦ È£Àü½ÃŲ´Ù.

cachexicÇÑ È¯ÀÚ¿¡¼­ insulin infusion(12 ug/kg/hr)ÇÏ¿´À» ¶§ nitrogen retentionÀ» Áõ°¡

½Ã۰í cholesterol levelÀ» ³·Ãá´Ù. long-term subcutaneous IGF-I injection½Ã marked

anabolic effect¸¦ ³ªÅ¸³»¾î protein synthesis¸¦ Áõ°¡½ÃŲ´Ù. bone mineral content¿¡ ³¢Ä¡

´Â IGF-I Àå±âÅõ¿©ÀÇ ¿µÇâÀº ºÐ¸íÇÏÁö ¾Ê´Ù. ºñ·Ï bone formation marker°¡ À¯µµµÇÁö¸¸

IGF-I¿¡ ÀÇÇÑ bone turnover ¶ÇÇÑ ÀڱصȴÙ. IGF-IÀÇ ºÎÀÛ¿ëÀº dose-dependentÇѵ¥ acute

overdose´Â hypoglycemia & hypotensionÀ» ÀÏÀ¸Å²´Ù. fluid retention, temporomandiular

jaw pain, and IICP´Â °¡¿ªÀûÀÌ´Ù.

femoral headÀÇ avascular necrosis°¡ º¸°íµÈ ¹Ù ÀÖ´Ù. chronic excess IGF-IÀº

acromegaly¸¦ ÃÊ·¡ÇÑ´Ù.

5. Growth & developmental disorders

1) skeletal maturation & somatic growth

linear bone growth´Â epiphyseal & diaphyseal boneÀÌ ossify & fusionµÉ ¶§ ÁߴܵȴÙ.

growth plate´Â ¿©·¯ °¡Áö È£¸£¸óÀÇ ÀÚ±ØÀ» ¹Þ´Â´Ù.

: GH, IGF-I, sex steroids, thyroid hormones, paracrine growth factors & cytokines

GH´Â prechondrocyte differentiation & clonal expansionÀ» Á÷Á¢ ÀÚ±ØÇÏ¿© IGF-I receptor

& IGF-I proteinÀ» ¹ßÇöÇÏ´Â chondrocyte°¡ µÇ°Ô ÇÑ´Ù.

growth-promoting process¿¡´Â caloric energy, amino acids, vit, trace minerals µîÀÌ ÇÊ¿ä

Çϸç normal energy productionÀÇ 10%¸¦ ¼ÒºñÇÑ´Ù.

malnutritionÀº chondrocyte activity¸¦ ¹æÇØÇÏ¿© circulating IGF-I & IGFBP3 levelÀ» °¨¼Ò

½ÃŲ´Ù.

¨ç bone age

i) true GH deficiency or GH receptor defect½Ã delayµÈ´Ù.

ii) thyroid hormoneµµ normal circulating IGF-I & binding protein levelsÀ» À¯ÁöÇϰí, GH

ÇÕ¼º ¹× ºÐºñ¿¡ ÀÖ¾î permissive.

thyroid hormone °áÇ̽ÿ£ bone age delay

iii) pubertal sex steroid(ƯÈ÷ estrogen)

-> GHRH-GH-IGF-I axis ÀÚ±Ø & epiphyseal growth¸¦ Á÷Á¢ ÀÚ±Ø

°í¿ë·®ÀÇ estrogen => epiphyseal closure¸¦ ÀÏÀ¸Å´

estrogen receptor ¥á mutation => epiphyseal closure ¹æÁö

ÀÌ´Â estrogenÀÌ bone maturation pathway¿¡¼­ Áß¿äÇÑ ¿ªÇÒÀ» ÇÔÀ» ÀǹÌ

sex steroid levelÀÇ Áõ°¡(precocious puberty), androgen exposure(exogenous or

endogenous), congenital adrenal hyperplasia & obesity => bone maturationÃËÁø

iv) glucocorticoid

sex steroid¿Í´Â ¹Ý´ë·Î glucocorticoid´Â linear growth ¾ïÁ¦.

¶ÇÇÑ SRIF ÀÚ±Ø & peripheral GH & IGF-I receptor signaling¾ïÁ¦

¨è short stature Tab 328-9 ¿øÀÎ ¹× Áø´Ü

i) intrauterine growth retardation

¿øÀÎ: specific congenital anomaly(¿¹, IGF-I deficiency)

Russel-Silver syndrome, chromosomal disomy or maternal factor(DM, infections,

hypoxia, drug addiction, or placental dysfunction)

ii) Turner syndrome : short stature, gonadal dysgenesis

GH & anabolic steroid(oxandrolone)·Î short stature´Â ÁÁ¾ÆÁú¼ö ÀÖ´Ù.

sexual development¸¦ À§Çؼ­´Â estrogenÀÌ ÇÊ¿äÇÏ´Ù.

iii) Noonan syndrome: ¸ð¾çÀº Turner syndrome°ú À¯»çÇϳª sex chromosomeÀº Á¤»ó

ÀÌ´Ù.

delayed pubertal development´Â ÀÖÁö¸¸ primary gonadal failure´Â ¾ø´Ù.

2) GH deficiency in children

¨ç GH deficiency

short stature, micropenis, fat¡è, high-pitched voice, hypoglycemia

1/3¿¡¼­ familial inheritance(AD, AR, X-linked)

= multiple genetic abnormality

idiopathic GH deficiency(IGHD)·Î Áø´ÜÇϱâ À§Çؼ­´Â ¾Ë·ÁÁø molecular defect¹èÁ¦Çؾß

ÇÑ´Ù.

¨è GHRH receptor mutation

¨é GH insensitivity

Laron syndrome: partial or complete GH insensitivity + growth failure

GH normal or ¡è

circulating GHBP¡é

IGF-I level¡é

¨ê nutritional short stature

malnutrition, uncontrolled DM, CRF -> proinflammatory cytokineÀÚ±Ø(TNF & ILs)

-> GH-mediated signal transduction block

: GH¡è, IGF-I level¡é

¨ë psychosocial short stature

3) ¹ßÇö ¹× Áø´Ü

3SDÀÌ»ó ÀÛÀ»¶§ evaluation

4) Lab

GH secretionÀº pulsatileÇϹǷΠprovocation test·Î °Ë»çÇØ¾ß ÇÑ´Ù.

random GHÃøÁ¤Àº Á¤»ó°ú true deficiency¸¦ ±¸º°ÇÏÁö ¸øÇÑ´Ù.

provocation testÀü¿¡ adrenal & thyroid hormoneÀ» replacementÇÏ¿©¾ß ÇÑ´Ù.

exercise, insulin-induced hypoglycemia ȤÀº ´Ù¸¥ ¾à¹°·Î½á provocationÇÏ¿© Á¤»ó ¾î¸°ÀÌ

¿¡¼­ GHÀº >7 ug/LÀ¸·Î Áõ°¡µÈ´Ù.

IGF-I levelÀº Áø´Ü¿¡ ¹Î°¨ÇÏÁöµµ, ƯÀÌÀûÀÌÁöµµ ¾ÊÁö¸¸ GH deficiency¸¦ È®ÀÎÇϴµ¥ µµ¿òÀÌ

µÈ´Ù.

5) Ä¡·á

recombinant GH(0.02 - 0.05 mg/kg/d SC)

-> GH-deficient children¿¡¼­ growth velocityȸº¹(¡­10 cm/yr±îÁö)

6. Adult GH deficiency(AGHD)

ÈçÈ÷ hypothalamic or pituitary somatotrope damage°¡ ¿øÀÎ

pituitary hormone deficiencyÀÇ ¼ø¼­

: GH -> FSH/LH -> TSH -> ACTH

1) ¹ßÇö ¹× Áø´Ü Tab 328-10

body composition change : body fat mass¡è, lean body mass¡é

hyperlipidemia, LV dysfunction, hypertension, plasma fibrinogen level¡è

cardiovascular mortality¡è(3¹è)

2) Lab

´ÙÀ½°ú °°Àº predisposing factor°¡ Àִ ȯÀÚ¿¡°Ô¼­ Á¦ÇÑÀûÀ¸·Î test¸¦ ½ÃÇàÇÑ´Ù.

i) pituitary surgery

ii) pituitary or hypothalamic tumor or granuloma

iii) cranial irradiation

iv) radiologic evidence of a pituitary lesion

v) GH replacement tx°¡ ÇÊ¿äÇÑ ¾î¸°ÀÌ

vi) unexplained low age-and sex-matched IGF-I level

* standard provocative test(=insulin-induced hypoglycemia test)¿¡ ´ëÇØ subnormal GH

response(<3 ug/dL)¸¦ º¸ÀÏ ¶§ Áø´ÜÇÑ´Ù.

Á¤»ó: >5 ug/L

pituitary damage, obesity, untreated hypothyroidism, depression or CRF¶§µµ ºñÁ¤»ó

¹ÝÀÀÀ» º¸Àϼö ÀÖ´Ù.

* insulin tolerance test´Â ¾ÈÀüÇÏÁö¸¸ ÁÖÀÇÇØ¼­ ȯÀÚ¸¦ °üÂûÇϸ鼭 °Ë»ç¸¦ ½ÃÇàÇØ¾ß Çϸç

´ÙÀ½ÀÇ °æ¿ì¿¡´Â ±Ý±âÀÌ´Ù.

i) diabestes

ii) ischemic heart disease

iii) cardiovascular disease

iv) epilepsy

v) elderly patient

* alternative stimulating test

L-dopa(500mg PO), IV arginine(30g), GHRH(1ug/kg), GHRP-6(90ug)

3) Ä¡·á Tab 328-8

¨ç ÀÏ´Ü Áø´ÜµÇ¸é GH replacementÇϴµ¥ Ä¡·áÀÇ ±Ý±â´Â ´ÙÀ½°ú °°´Ù.

i) active neoplasm

ii) intracranial hypertension

iii) uncontrolled diabetes & retinopathy

¨è ¿ë·®: 0.15-0.3 mg/d·Î ½ÃÀÛÇØ¼­ Á¶Àý(ÃÖ´ë 1.25 mg/d)

-> IGF-I levelÀ» mid-normal range·Î À¯Áö

¿©¼º¿¡¼± ¿ë·®À» ¿Ã¸®°í, ³ëÀο¡¼­´Â ¿ë·®À» ÁÙÀδÙ.

¨é Ä¡·áÈ¿°ú: body composition change(lean body mass¡è, fat¡é), HDL¡è

T-CHO, insulin levelÀº º¯È­¾ø´Ù.

¨ê ºÎÀÛ¿ë

30%¿¡¼­ dose-related fluid retention, joint pain, carpal tunnel syndrome°æÇè

40%´Â myalgia, paresthesia

ÇöÀç±îÁö potential side effects´Â º¸°íµÇÁö ¾Ê¾Ò´Ù.

7. Acromegaly

1) ¿øÀÎ Tab 328-11

mc = somatotrope adenoma

GH + PRL : acidophilic stem-cell adenoma

GHRH-mediated acromegalyÀÇ mc cause = chest or abdominal carcinoid tumor

2) ¹ßÇö ¹× Áø´Ü

GH & IGF-I hypersecretion

¼­¼­È÷ ÁøÇàÇϹǷΠ10³âÀÌ»ó ÀÓ»óÀûÀ¸·Î Áø´ÜµÇÁö ¾Ê´Â´Ù.

soft tissue swelling -> heel pad thickness

generalized visceromegaly : cardiomegaly, macroglossia, thyroid gland enlargment

ÀÓ»óÀûÀ¸·Î °¡Àå Áß¿äÇÑ ¹®Á¦´Â cardiovascular system(30%)

: coronary heart disease, cardiomyopathy with arrhythmia, LVH,

diastolic dysfunction, hypertension

upper airway obstruction with sleep apnea(60%)

DM(25%), ´ëºÎºÐ glucose intolerance

colon polyp(1/3) & colonic malignancy risk¡è

overall mortality : 3¹è¡è

¡ñ cardiovascular & cerebrovascular disorder, malignancy & respiratory disease·Î ÀÎÇÔ

GH levelÀ» control¸øÇÏ¸é ¼ö¸íÀº 10³â Á¤µµ °¨¼ÒÇÑ´Ù.

3) Lab

i) Glucose-induced GH suppression test(= glucose tolerance test)

Á¤»ó¿¡¼­ 75g loadÇϸé 1-2½Ã°£³» GH < 1ug/L

acromegaly¿¡¼± ÀÌ·± Á¤»óÀû ¾ïÁ¦°¡ º¸ÀÌÁö ¾ÊÀ½

¡­20%´Â paradoxical GH rise

ii) TRHÅõ¿©½Ã paradoxical response(60%)

iii) PRL¡è(¡­25%)

iv) thyroid fx, gonadotropin, sex steroid¡é(¡ñ tumor mass effect)

<14ÆÇ> 1,25(OH)2 vit D levelÁõ°¡·Î hypercalciuria´Â ÈçÇÏ´Ù. hypercalcemia°¡ ÀÖ´Ù¸é ÀÌ´Â

acromegaly¶§¹®ÀÌ ¾Æ´Ï¶ó MEN 1 syndromeÀÌ ÀÖÀ½À» ÀǹÌÇÑ´Ù.

4) Ä¡·á Fig 328-10

surgical resection - initial tx

somatostatin analogue - adjuvant tx

irradiation : late hypopituitarism risk¡è & slow rate of biochemical response(5-15yr)

¨ç surgery : transsphenoidal approach

cure = microadenoma(¡­70%), macroadenoma(<50%)

¼ö¼úÈÄ soft tissue swellingÀº Áï½Ã ÁÁ¾ÆÁö¸ç GH levelÀº 1½Ã°£³» Á¤»óÈ­µÇ°í IGF-I level

Àº 3-4Àϳ» Á¤»óÈ­µÈ´Ù.

¡­10%´Â ¼ö³âÈÄ Àç¹ßÇϸç hypopituitarismÀÌ 15%¿¡¼­ ¹ß»ýÇÑ´Ù.

<Âü°í> ¼ö¼úÈÄ Àç¹ßÀ» ¿¹ÃøÇÏ´Â °¡Àå ÁÁÀº ¹æ¹ý(14ÆÇ)

= TRH stimulation test

Ä¡·áÈÄ GH°¨¼Ò¿Í ÀÓ»óÁõ»óÀÇ È£ÀüÀº ÀÏÄ¡ÇÏÁö ¾Ê´Â´Ù.

Ä¡·á°¡ ¼º°øÀûÀÏ °æ¿ì soft tissue swellingÀº Áï½Ã ÁÁ¾ÆÁö³ª °ñ°Ý°è º¯È­´Â

ÁÁ¾ÆÁöÁö ¾Ê´Â´Ù.

¨è somatostatin analogues : octreotide acetate, lanreotide

SSTR2 & 5 receptor¿¡ ÀÛ¿ë

50 ug tid SC(ÃÖ´ë 1500 ug/d)

<10%´Â ¹ÝÀÀÀÌ ¾øÀ½

GH <5ug/L·Î ¾ïÁ¦(¡­70%) <2 ug/L·Î ¾ïÁ¦(60%)

IGF-I Á¤»óÈ­(¡­75%)

10³âÀÌ»ó Àå±â»ç¿ëÇÏ¿©µµ desensitizationÀÌ »ý±âÁö ¾Ê´Â´Ù.

headache & soft tissue swellingÀº ¼öÀÏ-¼öÁÖ³»¿¡ »¡¸® ÁÁ¾ÆÁø´Ù(¡­75%).

biochemical remissionº¸´Ù´Â ÁÖ°üÀûÀÎ Áõ»ó È£ÀüÀÌ ´õ ¸¹Àºµ¥, headache, perspiration,

obstructive apnea, cardiac failure°¡ È£ÀüµÈ´Ù.

modest tumor size reduction(40%) -> ±×·¯³ª Ä¡·áÁß´ÜÈÄ ´Ù½Ã reverse

* S/E : well tolerated

GB contractility°¨¼Ò·Î ÀÎÇÑ GB sludge & asymptomatic cholesterol gallstones

(¡­30%)

¨é dopamine agonist(bromocriptine)

high dose(¡Ã20 mg/d) #3-4

GH <5 ug/d(¡­20%)

IGF-I Á¤»óÈ­(10%)

octreotide¿Í º´Çսà ´Üµ¶º¸´Ù additive biochemical control

¨ê GH antagonist: ¿¬±¸Áß

¨ë radiation