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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¤»óÈ­½ÃÄÑ¾ß 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¤»óÈ­µÇ¾ú´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.