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¸¦ °üÂûÇÏ¸é¼ °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¤»óȵǰí IGF-I level
Àº 3-4Àϳ» Á¤»óȵȴÙ.
¡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