1、高泌乳激素血症高泌乳激素血症(Hyperprolactinemia)白永河白永河內分泌暨新陳代謝科內分泌暨新陳代謝科彰化基督教醫院彰化基督教醫院PRLuRegulated by the hypothalamus主要是主要是 tonic inhibitionuHypothalamus 分泌分泌 2 種種 hypothalamic factors- PIF (PRL-inhibiting factor)Dopamine- PRF (PRL-releasing factor)TRH, VIPPRLuStimulate breast developmentuInitiate and maintain
2、lactation uPRL receptor- alveolar surface of mammary cell- liver, kidney- ovary, testes, prostateuEstrogen- synergistic in promoting breast development- antagonize in effect of lactationBreast developmentu須要多種須要多種 hormone 的的 coordinated action 包括包括 major stimuli: estrogen progesterone prolactin GHpl
3、acental mammotropic H minor stmuli: insulin cortisol thyroid hormoneBreast developmentuDuct growth: estrogenuLobuloalveolar development: PRL+progesteroneuLactation: PRL + oxytocinGalactorrhea需要需要 PRL + Gonadal steroid 才會出現才會出現 not necessarily seen in all prolactinomas和和 serum PRL level 無關無關Galactorr
4、hea 的的 incidence 差異很大差異很大 女性女性 30-80% 男性常男性常 no galactorrhea即使有即使有 galactorrhea, 其中其中50%病人的病人的 PRL 可能正常可能正常反之，即使反之，即使 PRL 100ng/ml, 也可能也可能 no galactorrhea Galactorrhea 為為 poor marker of hyperprolactinemiaPRLu1928discovered in extract of bovine pituitaryu1970sensitive bioassayu1971RIA (Friesen, Fourn
5、ier, Desjardians)secreted by the erythrosinophilic subtype of chromophobic cells in the adenohypophysisPRLuA stress hormoneuSecreted in a pulsatile fashionhighest in the early morning (睡醒之前睡醒之前)lower in the afternoonuphysiologic PRL - pain- nipple stimulation- fondling (women only)- pregnancy (可達 20
6、0-500 ng/ml)- pelvic examination- exercise- sleepPRLuDaily secretion rate: 400 g/天天uMetabolic clearance: 40 ml/m2/minuClearance pathway: 25% kidney 75% liveruPlasma T1/2: 50 minuPlasma level: 300 ng/ml umbilical PRL maternal PRLuPituitary PRL: 100 g per pituitary PRLuPRL value 和和 prolactinoma tumor
7、size 成正比成正比uPRL 1000 ng/ml tumor extension into cavernous sinus 150 ng/ml 幾乎一定就是幾乎一定就是 prolactinoma 100-150 ng/ml: (1) prolactinoma (2) pseudoprolactinoma (3) drug-induced 20-100 ng/ml: 須須 repeat 檢查檢查 ( pulsatile secretion)(1) stress of vein puncture (pain) (2) stress or physical examination(3) brea
8、st examination(4) pelvic examination PRLuBlood sampling 須注意事項須注意事項-indwelling venous cannula-at least 2 hr resting-20 minutes interval 3-6 次-sampling time usually not criticalHyperprolactinemiauBasic mechanisms ()- Hypothalamic dopamine deficiencylhypothalamic tumorlAV malformationlinflammatory proc
9、essldrugs: methyldopa (Aldomet) reserpine-Defective transport mechanismslpituitary or stalk tumorlhead injurylsection of pituitary stalkHyperprolactinemiauBasic mechanisms ()-Lactotroph insensitivity to dopamineldopamine receptor blocking agents- phenothiazine (chlorpromazine)- butyrophenones (halop
10、eridol)- benzamide: metoclopamide sulpiride domperidone-Stimulation of lactotrophslHypothyroidismlTRHlEstrogenlChest wall injury: herpes zoster, surgerylPRL-producing tumorPituitary tumoru約佔約佔 brain tumor 的的 10% 左右左右-Prolactinoma40-50%-Non-functioning adenoma30%-Gonadotroph cell adenoma10-15%-Acrome
11、galy10%-Cushings disease-TSH-secreting adenomaProlactinomauGeneral population 中可能中可能5-10%有有 prolactinoma- 這其中只有 5-10% come to clinical attension2/3 microadenoma1/3 macroadenomauAutopsy study- 6.5-27% (11%) 有 pituitary adenoma- no antemortem endocrine dysfunction- 40-50% (+) for PRL by immunocytochem
12、ical stain- 幾乎全部為 microadenomaProlactinomauGrow slowly over yearsuLarge tumor hypopituitarism (singly or incombination) GH deficiency 最常見最常見uImpaired pulsatile gonadotropin (LH, FSH)(via alteration in hypothalamic LHRH secretion)(increased endogenous opiate tone)uBMD ProlactinomauGrade : microadenom
13、a (s suprasellar extension)uGrade : macroadenoma (c or s suprasellar extension)uGrade: localized boney destructionuGrade: diffuse boney destruction_Pituitary capillaryuCapillary in pituitarynormal62 capillaries/0.1mm2microadenoma51.1macroadenoma 9.3由於由於 capillary number 減少減少 less inhibited by PRL-in
14、hibiting factorserum PRL 和和 tumor size 成正比成正比ProlactinomauEtiology: unclear? Arise de novo? Estrogen-induced? Abnormality of hypothalamic regulation? Monoclonal in originCauses of hyperprolactinemia ()uHypothalamic disease- Tumor: metastatic ca carniopharyngioma germinoma cyst, hamartoma glioma- Inf
15、iltrative disease sarcoidosis tbc histiocytosis granuloma- Pseudotumor cerebri- Cranial irradiation Causes of hyperprolactinemia ()uPituitary disease- Prolactinoma- Acromegaly- Cushings disease- Pituitary stalk section- Empty sella syndrome- Metastatic ca- Meningioma- Intrasella germinoma- Infiltrat
16、ive diseaselsarcoidosisltbclgiant cell granulomaCause of hyperprolactinemia ()uDrug-induced- Monoamine inhibitor (catecholamine depletor) (在 hypothalamus 抑制 dopamine)lAldometlReserpine- Dopamine receptor antagonist (在 pituitary 抑制 dopamine)lChlorpromazine (wintermin)lFluphenazine (wintermin)lPerphen
17、azinelPromazinelButyrophenone (haloperidol)lMotoclopramide (primperan)lDomperidone (motilium)lSulpiride (dogmatyl)Causes of hyperprolactinemia ()uDrug-induced- Lactotroph stimulatorlEstrogenlTRH- NarcoticslMorphinelEnkephalinlCodeine lMethadone- Amphetamine- H2-receptor blockerlCimetidine (Tagamet)l
18、Ranitidine (Zantac)Causes of hyperprolactinemia ()uMajor systemic disease- 1hypothyroidism- CRF- Liver cirrhosis- SeizureuNeurogenic- breast manipulation- chest wall lesionlburnlherpes zosterlmastectomyuStress: physical (pain) psychologic uPCOuIdiopathicSymptoms and Signs (Female)uDelayed menarcheuD
19、isturbance of menstrual function (60-90%)amenorrheaoligomenorrhearegular mens c infertilityuGalactorrhea (30-80%)和和 duration of gonadal dysfunction 有關有關amenorrhea 愈久，較不會有愈久，較不會有 galactorrheauEstrogen deficiencylibidohirsutism vaginal dryness(DHEA by adrenal )dyspareunia(free testosterone )_Symptoms
20、and Signs (male)u男性和男性和 postmenopausal 女性較常以女性較常以mass effect 表現表現uHeadache (63%)uVisual abnormality- visual acuity- ophthalmoplegia- visual field defect (先 bitemporal upper quadrant anopia) (再 bitemporal hemianopia)uHypogonadism- libido (83%)adiposity (70%)- impotencegalactorrhea (14-33%)- infertili
21、tygynecomastia (少見)Mass effectuSuprasellar extension: bitemporal hemianopiauExtends posteriorly- homonymous visual field defectuLateral extension (into the cavernous sinus)- compress cranial nerve 3, 4, 5, 6uExtend into the temporal lobe : seizureHyperprolactinemiau干擾干擾 hypothalamic-pituitary-ovaria
22、n axis at 3 locations- hypothalamic levellinterfer tonic or cyclic release of GnRH (LHRH)- pituitary levelldesensitize gonadotropin response to GnRH- ovarian levellimpaires progesterone production (by ovarian granulosa cell)PRLuPRL function in male: unclear- sperm production- prostate citrate produc
23、tionuPRL 5-reductase Spermatogenesistestosterone dihydrotestosterone(biologically active) 5-reductasePseudoprolactinomau任何任何 intrasellar or parasellar tumor (non-PRL-secreting pituitary adenoma) pituitary stalk compression interfer with PIF delivery (Dopamine) PRL (很少很少 150 ng/ml)例如例如:non-functionin
24、g pituitary adenomacraniopharyngiomatuberculum sella meningiomaaneurysmNormoprolactinemic galactorrheauenhanced sensitivity of breast to PRL 常見於常見於 persistence of postpartum galactorrhea after discontinuation of oral pillsPregnancy with prolactinomauMicroadenoma5% progress to macroadenomauMacroadeno
25、ma25% expand and produce symptoms (15-35%)Primary hypothyroidismu常有常有 breast tenderness, 偶而偶而 galactorrheaPRL 大部份正常大部份正常但也可能上昇，通常但也可能上昇，通常 100 ng /mllong-standing hypothyroidism 時時可能出現可能出現 sellar enlargement如果又加上如果又加上 PRL ，易誤為，易誤為 prolactinomaPRL response to TRH CRFuPRLin 60-70% ( 1000 ng/ml, invasi
26、veness (+) pharmacotherapyPharmacotherapy of prolactinomauErgot preparation- Bromocriptin (approved by FDA)- Lisuride- Pergolide- Metergoline- Terguride (greater pituitary selectivity)- Cabergoline (longer duration of action)unon-Ergot preparation- CV 205-502 (Octahydrobenzquinolone)Bromocriptine Do
27、pamine agonist, 1971semisynthetic ergot alkaloidbinds to the dopamine receptoraffinity 為為 dopamine 的的 5-10X使使 PRL 恢復至恢復至 normal, in 64-100%改善改善 galactorrhea, 57-100%恢復恢復 mens and ovulation, 57-100%改善改善 visual field defect, 60-80%使使 tumor size reduction, 60-80%但無法改善但無法改善 loss of sleep-related PRL pul
28、satile secretionBromocriptine therapyuthe only FDA approved drug in the USAuinitial dose : 1.25 mg H.S.udose adjustment: 改換成改換成 1.25 mg QD ( c meal) 每隔每隔 3 天增加天增加 1.25 mgustandard dose: 2.5 mg tidumaintain dose: 2.5 mg bid_Bromocriptine therapyuDrug efficacy in reducing PRL doesnt necessarily predic
29、t tumor size reduction- 即使 PRL 沒有下降到正常，也可能有 tumor shrinkage- 即使 PRL 下降到正常，也不一定就有相等程度的 tumor size reductionuShort treatment period withdrawl rapid reexpansion of tumor size- therapeutic course 須持續幾年- long-term therapy 後才停藥，可能不會有 tumor reexpansion,但是 PRL 會再度上昇Bromocriptine therapyuIntolerate to oral t
30、herapy時，可改用時，可改用 vaginal administration (the same dosage)uPatient 必須被告知可能必須被告知可能 restore fertility 須事先使用須事先使用 mechanical contraception (否則會在服藥治療期間否則會在服藥治療期間 conception 而不自知而不自知) 直到直到 regular menstrual flow 3 cyclesuNot teratogenic in humanfetal losscongenital malformation uInjectable form available
31、in Europeeffective for 4-6 wk: not increasedBromocriptine therapyu對於對於 large pituitary tumor 如果如果 PRL 200 ng/ml，大部份是，大部份是 prolactinoma 如果如果 PRL 9 ng/ml 可能表示會可能表示會 recurrent Recurrent 時，再時，再 reoperation 的效果並不好的效果並不好Transsphenoid hypophysectomyuCriteria of cure- total removal of tumor mass- normalizat
32、ion of PRL- resumption of ovulatory menstruation- restore infertility- no evidence of recurrence over 5 yearsuCriteria of recurrence- reappearance of hyper PRL over 5-yr periodSurgical therapySurgical success rateMicroadenoma Macroadenoma Preoperation bromocriptine therapy:Surgical therapySurgical s
33、uccess ratebromocriptine-treated 44%no bromocriptine 78%ufibrosis induced by bromocriptineushrinkage of tumor cell- enlargement of the extracellar & perivascular space- filled by the collagen deposition- more dense consistency of the adenomaushrunken tumor adhere to adjacent normal pituitary tissueP
34、reoperation bromocriptine in microadenoma (Landolt, 1982)Radiotherapyusome effectiveness in reducing PRLumore slowlyuless completelyualternative therapy (generally not recomnend as primary therapy)uindication: postoperation recurrenceWhen to check PRLuAmenorrhea, oligomenorrheauGalactorrheauSexual dysfunction- loss of libido- dyspareunia ()- impotence ()uInfertilityuVisual field defectuHeadache
