Prolactin
1. ÇÕ¼º
weakly homologous to GH and hPL
ÀÌ´Â 6¹ø ¿°»öü¿¡ ÀÖ´Â common GH-PRL-hPL precursor geneÀ» °øÀ¯Çϱ⠶§¹®ÀÌ´Ù.
prolactinÀº lactotrope¿¡¼ ÇÕ¼ºµÇ¸ç ÀÌ´Â ant. pituitary cellÀÇ 20%¸¦ Â÷ÁöÇÑ´Ù.
cf. somatotrope = 50%
lactotrope & somatotropeÀº °°Àº precursor cell¿¡¼ ¹ß»ýÇϹǷΠPRL & GH µÑ´Ù ºÐºñÇÏ´Â
Á¾¾çÀ» ÀÏÀ¸Å°±âµµ ÇÑ´Ù.
ÀÓ½ÅÁß 2nd trimester, 3rd trimester, ºÐ¸¸ÈÄ Ã¹ ¼ö°³¿ù°£ marked lactotrope cell
hyperplasia°¡ »ý±â´Âµ¥ estrogenÀÇ ¿µÇâ ¶§¹®ÀÌ´Ù.
2. ºÐºñ
normal adult serum prolactin levels : 10-25 ug/L(women), 10-20 ug/L(men)
prolactin secretionÀº ¹Úµ¿¼ºÀÌ¸ç ¼ö¸éÁß¿¡´Â REM¶§ highest secretory peak°¡ ÀϾ°í
30 ug/LÀÌ»óÀÇ peak serum prolactin levelÀº »õº® 4½Ã-6½Ã »çÀÌ¿¡ ÀϾ¸ç ¹Ý°¨±â´Â 50ºÐ
ÀÌ´Ù.
prolactinÀÇ predominant central control mechanismÀº inhibitory mxÀÌ´Ù.
: dopamine-mediated suppression of PRL release
pituitary¿¡¼ dopamine type 2(D2) receptors´Â prolactinÀ» inhibition½ÃŲ´Ù.
D2 receptor activationÀº cAMP pathway¸¦ ¾ïÁ¦ÇÏ¿© membrane hyperpolarization½Ã۰í
voltage-gated calcium channelÀ» ´Ý°Ô ÇÏ¿© intracellular free calciumÀ» °¨¼Ò½ÃÄÑ
secretory granule exocytosis¸¦ blockÇÑ´Ù.
ÀÌ·¯ÇÑ dopamineÀÇ potent PRL inhibitory effect ¶§¹®¿¡ dopamine agonist´Â
hyperprolactinemic disorderÀÇ Ä¡·á¿¡ Áß½ÉÀû ¿ªÇÒÀ» ÇÑ´Ù.
TRH ÁÖ»çÈÄ 15-30ºÐ ³»¿¡ prolactinÀÌ ºÐºñµÇ´Âµ¥ TRH¿Í prolactin°úÀÇ »ý¸®Àû °ü·Ã¼ºÀº
ºÐ¸íÄ¡ ¾Ê´Ù. VIP¶ÇÇÑ PRL release½ÃŲ´Ù.
¹Ý¸é glucocorticoid & thyroid hormoneÀº PRL secretionÀ» ¾ïÁ¦ÇÑ´Ù.
serum PRL level˼ exercise, meals, sexual intercourse, minor surgical procedures,
general anesthesia, acute MI, other acute stressµî¿¡¼ Áõ°¡µÈ´Ù.
<Á¤¸®>
PRL Áõ°¡ : TRH, VIP
exercise, meals, sexual intercourse, minor surgical procedures, general anesthesia,
acute MI, other acute stressµî
PRL °¨¼Ò : dopamine, glucocorticoid, thyroid hormone
3. ÀÛ¿ë
PRL receptor : type I cytokine receptor family(GH, IL-6 receptor)¿¡ ¼ÓÇÔ
-> Janus kinase(JAK) pathway¸¦ ÅëÇØ STAT family phosphorylation
-> STAT family´Â ÇÙÀ¸·Î À̵¿ÇÏ¿© target gene¿¡ transcription factor·Î ÀÛ¿ë.
ÀÛ¿ë: lactationÀ¯Áö, reproductive function°¨¼Ò, sexual drive¾ïÁ¦
(hypothalamic GnRH, pituitary gonadotropin¾ïÁ¦, gonadal steroidogenesis¾ïÁ¦)
GI calciumÈí¼öÁõ°¡, bone calcium mobilization, bile acidÁõ°¡, pancreatic ¥â cell growth,
appetite stimulation, analgesia
¡Å bone loss & long-term development of osteoporosis risk¡è
4. Hyperprolactinemia
1) ¿øÀÎ Tab 328-8
PRL level>100 ug/LÀÇ most common cause = prolactinoma
microprolactinoma°¡ less pronounced PRL elevationÀ» ÀÏÀ¸Å³¼ö´Â ÀÖÀ¸³ª ÁߵÀÇ
PRL»ó½ÂÀº drugs, pituitary stalk compression, hypothyroidism, or ranal failure¿¡¼ ´õ
ÈçÇÏ°Ô º¼¼ö ÀÖ´Ù.
ÀӽŰú ¼öÀ¯°¡ hyperprolactinmeiaÀÇ °¡Àå Áß¿äÇÑ »ý¸®Àû ¿øÀÎÀÌ´Ù.
sleep, nipple stimulation, sexual orgasm, chest wall stimulation or trauma, CRF, primary
hypothyroidismµµ PRLÀ» Áõ°¡½ÃŲ´Ù.
hypothalamic-pituitary lesionÀÌ ÀÖÀ» ¶§ hypothalamic dopamine ÇÕ¼º°ú portal vessel
delivery, or lactotrope response¸¦ ¼Õ»ó½ÃÄÑ hyperprolactinemia¸¦ ÀÏÀ¸Å²´Ù. ±×·¯¹Ç·Î
hypothalamic tumors, cysts, infiltrative disorders, and radiation-induced damage´Â PRL
À» Áõ°¡½Ã۴µ¥ ÈçÈ÷ 30-100 ug/LÀÌ´Ù.
dopamine antagonistµµ hyperprolactinemia¸¦ ÀÏÀ¸Å°´Âµ¥ ¸¹Àº antipsychotics &
antidepressant°¡ ¿©±â ÇØ´çÇÑ´Ù. methyldopaµµ dopamineÇÕ¼ºÀ» ¾ïÁ¦Çϰí, verapamilÀº
dopamine À¯¸®¸¦ ¾ïÁ¦ÇÑ´Ù.
estrogen, antiandrogens, and TRH¿Í °°Àº hormonal agent°¡ PRLÀ» À¯µµÇÑ´Ù.
* Drug
i) dopamine receptor blocker: phenothiazine, chlorpromazine, haloperidol,
metoclopramide
ii) dopamine synthesis inhibitors: ¥á-methyldopa
iii) catecholamine depleter: reserpine
iv) opiate
v) H2 antagonist: cimetidine, ranitidine
vi) imipramine: amitriptyline, amoxapine
vii) SSRI: fluoxetine
viii) calcium channel blocker: verapamil
ix) hormone: estrogen, antiandrogens
2) Áõ»ó ¹× Áø´Ü
¿©ÀÚ¿¡¼ÀÇ hallmarks: amenorrhea, galactorrhea(80%), and infertility
hyperprolactinemia°¡ Áö¼ÓÇϸé bone mineral density°¡ °¨¼Ò
³²ÀÚ¿¡¼´Â libido°¨¼Ò, visual loss(optic nerve compression)
impotence, and oligospermia, ¿À·¡ Áö¼Ó½Ã osteopenia, reduced muscle mass,
and decreased beard growth
true galactorrhea´Â µå¹°´Ù.
3) Lab
basal, fasting morning PRL level Á¤»óÄ¡ <20 ug/L
hyperprolactinemia°¡ ÀÖÀ»¶© hypothyroidism(TSH, T4ÃøÁ¤)À» ¹èÁ¦ÇØ¾ß ÇÑ´Ù.
4) Ä¡·á
¿øÀÎÀ» Ä¡·áÇÑ´Ù. ¿øÀÎÀÌ ¹«¾ùÀÌµç °£¿¡ PRLÀ» Á¤»óȽÃÄÑ¾ß Çϴµ¥ dopamine agonist´Â
È¿°úÀûÀÌ´Ù.
hyperprolactinemiaÀÇ 30%(with or without a visible pituitary microadenoma)´Â ÀúÀý·Î
ȸº¹µÈ´Ù.
5. Prolactinoma
1) ¿øÀÎ
microadenoma < 1cm, not usually invase the parasellar region
macroadenoma > 1cm, locally invasion
F : M = 20 : 1(microadenoma), 1:1(macroadenoma)
tumor size´Â PRL ³óµµ¿Í ºñ·ÊÇÑ´Ù.
Àå±âÃßÀû°üÂû¿¡¼ microadenoma´Â 5%¿¡¼ macroadenoma·Î ÁøÇàÇÑ´Ù.
microadenomaÀÇ 30%¿¡¼´Â ÀúÀý·Î hyperprolactinemia°¡ ȸº¹µÈ´Ù.
2) Áõ»ó ¹× Áø´Ü
¿©ÀÚ : amenorrhea, infertility & galactorrhea
³²ÀÚ : impotence, loss of libido, infertility, central CNS compression sign(headache,
visual defect)
PRL level > 100 ug/L´Â ´ëü·Î macroadenoma, <100 ug/L´Â ´ëü·Î microadenoma,
other sellar lesions, or nonneoplastic causes
ÀÌ·± ÀÌÀ¯·Î ÇØ¼ hyperprolactinemiaÀÇ ¸ðµç ȯÀÚ¿¡°Ô¼ MRI¸¦ ½ÃÇàÇØ¾ß ÇÑ´Ù.
nonlactotrope lesionÀÇ mass effect¿¡ ÀÇÇØ hyperprolactinemia°¡ »ý±ä °æ¿ì¿¡µµ
dopamine agonist·Î Ä¡·áÇϸé hyperprolactinemia°¡ ±³Á¤µÈ´Ù. ±×·¯¹Ç·Î dopamine
agonist¿¡ ÀÇÇØ PRL suppressionµÇ¾ú´Ù°í ÇØ¼ ¹Ýµå½Ã prolactinoma¸¦ ÀǹÌÇÏ´Â °ÍÀº
¾Æ´ÔÀ» ±â¾ïÇØ¾ß ÇÑ´Ù.
3) Ä¡·á
i) microadenoma´Â macroadenoma·Î °ÅÀÇ ÁøÇàÇÏÁö ¾ÊÀ¸¹Ç·Î ÀÓ½ÅÀ» ¿øÇÏÁö ¾Ê´Â´Ù¸é
Ä¡·á°¡ ÇÊ¿ä¾ø´Ù.
bone loss¿Í hypoestrogenemiaÀÇ ¿µÇâÀ» ¿¹¹æÇϱâ À§ÇØ estrogen replacementÀÇ ÀûÀÀÀÌ
µÇ³ª, À̰ÍÀÌ tumor size¸¦ Áõ°¡½Ãų À§ÇèÀº ¾ø¾î º¸ÀδÙ. ÀÌ·± ȯÀÚ´Â regular serial PRL
& MRI¸¦ checkÇÑ´Ù.
ii) symptomatic microadenoma
Ä¡·áÀÇ ¸ñÀûÀº hyperprolactinemia¸¦ controlÇϰí, tumor size¸¦ °¨¼Ò½Ã۸ç, menses &
fertility¸¦ ȸº¹Çϰí, galactosemia¸¦ È£Àü½Ã۴µ¥ ÀÖ´Ù. À̸¦ À§ÇØ dopamine agonist°¡
»ç¿ëµÈ´Ù.
prolactinÀÌ Á¤»óȵǾú´Ù°í ÇØ¼ tumor size°¡ °¨¼ÒµÇ¾ú´Ù°í È®½ÅÇÒ¼ö ¾øÁö¸¸, prolactin
levelÀÌ °¨¼ÒÇÏÁö ¾Ê´Â ȯÀÚ¿¡°Ô¼ tumor shrinkage´Â ÈçÄ¡ ¾Ê´Ù.
iii) macroadenoma
dopamine agonist·Î Ä¡·á¸¦ ½ÃÀÛÇϱâ Àü¿¡ formal visual field test¸¦ ½ÃÇàÇÑ´Ù.
mass shrinkage & maximum size reductionÀÌ ÀϾ¶§±îÁö MRI & visual field¸¦ 6-12
°³¿ù °£°ÝÀ¸·Î Æò°¡ÇÑ´Ù.
(1) Medical: oral dopamine agonist(cabergoline or bromocriptine)°¡ micro- or
macroadenomaÄ¡·áÀÇ ±âº»ÀÌ´Ù. dopamine agonist´Â lactotrope cell
proliferation ¹× prolactin secretion & synthesis¸¦ ¾ïÁ¦ÇÑ´Ù.
¨ç Bromocriptine : dopamine agonist·Î lactotrope D2 dopamine receptor¿¡ Á÷Á¢ ÀÛ¿ë
ÇÏ¿© prolactin secretionÀ» ¾ïÁ¦Çϸç, micro- and macroadenomaÀÇ
initial tx·Î »ç¿ëÇÑ´Ù.
microadenoma¿¡¼ ºü¸£°Ô serum prolactinÁ¤»óÈ(70%), tumor size°¨¼Ò, gonadal
functionȸº¹
macroadenoma¿ª½Ã 70%¿¡¼ prolactin levelÁ¤»óÈ, 50%ÀÌ»óÀÇ tumor mass
shrinkage(¡40%),
mass effect sxÀº ¼öÀϳ» dramaticÇÏ°Ô ÁÁ¾ÆÁü. sexual functionȸº¹(¼öÁÖ ¼Ò¿ä)
¾àÁߴܽà recurrent hyperprolactinemia & tumor expansionÀÌ ÀϾ ¼ö ÀÖ°í
visual compromise À§ÇèÀÌ ÀÖ´Ù.
initial prolactin level controlÈÄ¿¡ ÃÖ¼ÒÇÑÀÇ À¯Áö¿ë·®À¸·Î °¨·®ÇÑ´Ù.
¡5% : ȸº¹µÇ¾î Àç¹ßÇÏÁö ¾Ê´Â´Ù.
low dose(0.625- 1.25 mg) at bedtime with a snack ->Á¡Â÷ Áõ·®ÇÏ¿© ¡Â7.5mg(2.5mg tid
±îÁö)
20%´Â resistant
* S/E : nausea, vomiting, postural hypotension with faintness(initial doseÈÄ) ¡25%
other S/E : constipation, nasal stuffiness, dry mouth, nightmare, insomnia &
vertigo
-> °¨·®
15%´Â °á±¹ tolerableÇÏÁö ¸øÇѵ¥ intravaginal adminstrationÀÌ Á¾Á¾ È¿°úÀûÀÌ´Ù.
auditory hallucinations, delusions, and mood swings(5%)
rare report : leukopenia, thrombocytopenia, pleural fibrosis, cardiac arrhythmia,
hepatitis
¨è Cabergoline : ergoline derivative
long-acting dopamine agonist with high D2 receptor affinity
Åõ¿© 14ÀÏÈÄ¿¡ prolactin suppression, prolactinoma shrinkage(in most patient)
0.5-1.0 mg ÁÖ 2ȸ
i) microadenoma : normoprolactinemia & normal gonadal functionȸº¹(¡80%)
galactorrheaÈ£Àü(-90%)
ii) macroadenoma : 70%¿¡¼ prolactin Á¤»óÈ, tumor shrinkage
bromocriptine¿¡ resistantÇÑ È¯ÀÚµµ È¿°úÀûÀÌ´Ù.
ºÎÀÛ¿ë ¹× drug intolerance´Â bromocriptineº¸´Ù ´ú ÈçÇÏ´Ù.
¨é other dopaminergic agonist
pergolide mesylate, lisuride, guinagolide
(2) Surgery
Ix i) dopamine resistance or intolerance
ii) invasive macroadenoma with compromised vision : drug tx·Î ºü¸¥ È£Àü ¾øÀ» ¶§
¼ö¼úÈÄ microadenomaÀÇ 70%¿¡¼ prolactin normalization, macroadenoma´Â 30%¿¡¼
¸¸ Á¤»óÈ
hyperprolactinemiaÀç¹ßÀº ù 1³â°¿¡ ¡20%, long-term recurrence rate´Â
macroadenomaÀÇ °æ¿ì 50%ÀÌ»ó
(3) Radiotherapy
maximally tolerated dopamine agonist and/or surgery¿¡ ¹ÝÀÀÇÏÁö ¾Ê´Â aggressive
tumor¿¡ ´ëÇØ ¸¶Áö¸· Ä¡·á·Î »ç¿ë
4) Pregnancy
ÀÓ½ÅÁß¿¡´Â size°¡ Áõ°¡ÇÑ´Ù. ¡ñ estrogen ¹× other growth factorÀÇ ÀÚ±ØÀ¸·Î ÀÎÇÏ¿©
microadenomaÀÇ 5%, macroadenomaÀÇ 15-30%¿¡¼ À¯ÀÇÇÏ°Ô Å©±â Áõ°¡.
hyperprolactinemia¸¦ °¡Áø 25¼¼ ÀÌ»ó ¿©¼º¿¡¼ fertilityÀÇ È¸º¹À» À§Çؼ bromocriptineÀ»
»ç¿ëÇÑ´Ù(teratogenic effect¡¿). ±×·¯³ª ´ëºÎºÐÀÇ ÀúÀÚµéÀº fetal exposure¸¦ ÃÖ¼ÒÈÇÒ °Í
À» ±ÇÇÑ´Ù.
ÀÓ½ÅÀ» ¿øÇÏ´Â bromocriptine Åõ¿©¿©¼ºÀº mechanical contraceptionÀ» ÇØ¾ß ÇÑ´Ù.
ÀÓ½ÅÀÌ µÇ¸é bromocriptineÀ» Áß´ÜÇϰí prolactine levelÀ» Á¤±âÀûÀ¸·Î F/UÇϰí headache
& visual symptomÀÌ ¹ß»ýÇÏ´ÂÁö °üÂûÇÑ´Ù. macroadenomaÀÇ °æ¿ì¿£ regular visual field
testµµ Çϵµ·Ï ÇÑ´Ù.
tumor growth°¡ ³ªÅ¸³ª¸é bromocriptineÀ» ´Ù½Ã »ç¿ëÇϵµ·Ï ÇÑ´Ù.
pituitary MRI°¡ ¾ÈÀüÇϱä ÇÏÁö¸¸ severe headache and/or visual field detect¸¦ °¡Áø Áõ»ó
ÀÖ´Â ¿©¼º¿¡¼ ½ÃÇàÅä·Ï ÇÑ´Ù. ½Ã·Â¼Õ»óÀÌ À§Çù¹ÞÀ»¶© ¼ö¼úÇϵµ·Ï ÇÑ´Ù.