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1、高泌乳激素血症(Hyperprolactinemia),白永河內分泌暨新陳代謝科彰化基督教醫院,PRL,Regulated by the hypothalamus主要是 tonic inhibitionHypothalamus 分泌 2 種 hypothalamic factorsPIF (PRL-inhibiting factor)DopaminePRF (PRL-releasing factor)TRH, VIP,PRL,Stimulate breast developmentInitiate and maintain lactation PRL receptoralveolar surf
2、ace of mammary cellliver, kidneyovary, testes, prostateEstrogensynergistic in promoting breast developmentantagonize in effect of lactation,Breast development,須要多種 hormone 的 coordinated action 包括 major stimuli: estrogen progesterone prolactin GHplacental mammotropic H minor stmuli: insulin cortisol
3、thyroid hormone,Breast development,Duct growth: estrogenLobuloalveolar development: PRL+progesteroneLactation: PRL + oxytocin,Galactorrhea,需要 PRL + Gonadal steroid 才會出現 not necessarily seen in all prolactinomas和 serum PRL level 無關Galactorrhea 的 incidence 差異很大 女性 30-80% 男性常 no galactorrhea即使有 galacto
4、rrhea, 其中50%病人的 PRL 可能正常反之，即使 PRL 100ng/ml, 也可能 no galactorrhea Galactorrhea 為 poor marker of hyperprolactinemia,PRL,1928discovered in extract of bovine pituitary1970sensitive bioassay1971RIA (Friesen, Fournier, Desjardians)secreted by the erythrosinophilic subtype of chromophobic cells in the adeno
5、hypophysis,PRL,A stress hormoneSecreted in a pulsatile fashionhighest in the early morning (睡醒之前)lower in the afternoonphysiologic PRLpainnipple stimulationfondling (women only)pregnancy (可達 200-500 ng/ml)pelvic examinationexercisesleep,PRL,Daily secretion rate: 400g/天Metabolic clearance: 40 ml/m2/m
6、inClearance pathway: 25% kidney 75% liverPlasma T1/2: 50 minPlasma level: 300 ng/ml umbilical PRL maternal PRLPituitary PRL: 100 g per pituitary,PRL,PRL value 和 prolactinoma tumor size 成正比PRL 1000 ng/ml tumor extension into cavernous sinus 150 ng/ml 幾乎一定就是 prolactinoma 100-150 ng/ml: (1) prolactinom
7、a (2) pseudoprolactinoma (3) drug-induced 20-100 ng/ml: 須 repeat 檢查 ( pulsatile secretion)(1) stress of vein puncture (pain) (2) stress or physical examination(3) breast examination(4) pelvic examination,PRL,Blood sampling 須注意事項indwelling venous cannulaat least 2 hr resting20 minutes interval 3-6 次s
8、ampling time usually not critical,Hyperprolactinemia,Basic mechanisms ()Hypothalamic dopamine deficiencyhypothalamic tumorAV malformationinflammatory processdrugs: methyldopa (Aldomet) reserpineDefective transport mechanismspituitary or stalk tumorhead injurysection of pituitary stalk,Hyperprolactin
9、emia,Basic mechanisms ()Lactotroph insensitivity to dopaminedopamine receptor blocking agentsphenothiazine (chlorpromazine)butyrophenones (haloperidol)benzamide: metoclopamide sulpiride domperidoneStimulation of lactotrophsHypothyroidismTRHEstrogenChest wall injury: herpes zoster, surgeryPRL-produci
10、ng tumor,Pituitary tumor,約佔 brain tumor 的 10% 左右Prolactinoma40-50%Non-functioning adenoma30%Gonadotroph cell adenoma10-15%Acromegaly10%Cushings diseaseTSH-secreting adenoma,Prolactinoma,General population 中可能5-10%有 prolactinoma這其中只有 5-10% come to clinical attension2/3 microadenoma1/3 macroadenomaAut
11、opsy study6.5-27% (11%) 有 pituitary adenomano antemortem endocrine dysfunction40-50% (+) for PRL by immunocytochemical stain幾乎全部為 microadenoma,Prolactinoma,Grow slowly over yearsLarge tumor hypopituitarism (singly or incombination) GH deficiency 最常見Impaired pulsatile gonadotropin (LH, FSH)(via alter
12、ation in hypothalamic LHRH secretion)(increased endogenous opiate tone)BMD ,Prolactinoma,Grade: microadenoma (s suprasellar extension)Grade: macroadenoma (c or s suprasellar extension)Grade: localized boney destructionGrade: diffuse boney destruction,_,_,_,Pituitary capillary,Capillary in pituitaryn
13、ormal62 capillaries/0.1mm2microadenoma51.1macroadenoma 9.3由於 capillary number 減少 less inhibited by PRL-inhibiting factorserum PRL 和 tumor size 成正比,Prolactinoma,Etiology: unclear? Arise de novo? Estrogen-induced? Abnormality of hypothalamic regulation? Monoclonal in origin,Causes of hyperprolactinemi
14、a (),Hypothalamic diseaseTumor: metastatic ca carniopharyngioma germinoma cyst, hamartoma gliomaInfiltrative disease sarcoidosis tbc histiocytosis granulomaPseudotumor cerebriCranial irradiation,Causes of hyperprolactinemia (),Pituitary diseaseProlactinomaAcromegalyCushings diseasePituitary stalk se
15、ctionEmpty sella syndromeMetastatic caMeningiomaIntrasella germinomaInfiltrative diseasesarcoidosistbcgiant cell granuloma,Cause of hyperprolactinemia (),Drug-inducedMonoamine inhibitor (catecholamine depletor) (在 hypothalamus 抑制 dopamine)AldometReserpineDopamine receptor antagonist (在 pituitary 抑制
16、dopamine)Chlorpromazine (wintermin)Fluphenazine (wintermin)PerphenazinePromazineButyrophenone (haloperidol)Motoclopramide (primperan)Domperidone (motilium)Sulpiride (dogmatyl),Causes of hyperprolactinemia (),Drug-inducedLactotroph stimulatorEstrogenTRHNarcoticsMorphineEnkephalinCodeine MethadoneAmph
17、etamineH2-receptor blockerCimetidine (Tagamet)Ranitidine (Zantac),Causes of hyperprolactinemia (),Major systemic disease1hypothyroidismCRFLiver cirrhosisSeizureNeurogenicbreast manipulationchest wall lesionburnherpes zostermastectomyStress: physical (pain) psychologic PCOIdiopathic,Symptoms and Sign
18、s (Female),Delayed menarcheDisturbance of menstrual function (60-90%)amenorrheaoligomenorrhearegular mens c infertilityGalactorrhea (30-80%)和 duration of gonadal dysfunction 有關amenorrhea 愈久，較不會有 galactorrheaEstrogen deficiencylibidohirsutism vaginal dryness(DHEA by adrenal )dyspareunia(free testoste
19、rone ),_,Symptoms and Signs (male),男性和 postmenopausal 女性較常以mass effect 表現Headache (63%)Visual abnormalityvisual acuityophthalmoplegiavisual field defect (先 bitemporal upper quadrant anopia) (再 bitemporal hemianopia)Hypogonadismlibido (83%)adiposity (70%)impotencegalactorrhea (14-33%)infertilitygynec
20、omastia (少見),Mass effect,Suprasellar extension: bitemporal hemianopiaExtends posteriorlyhomonymous visual field defectLateral extension (into the cavernous sinus)compress cranial nerve 3, 4, 5, 6Extend into the temporal lobe : seizure,Hyperprolactinemia,干擾 hypothalamic-pituitary-ovarian axis at 3 lo
21、cationshypothalamic levelinterfer tonic or cyclic release of GnRH (LHRH)pituitary leveldesensitize gonadotropin response to GnRHovarian levelimpaires progesterone production (by ovarian granulosa cell),PRL,PRL function in male: unclearsperm productionprostate citrate productionPRL 5-reductase ,Sperm
22、atogenesistestosterone dihydrotestosterone(biologically active),5-reductase,Pseudoprolactinoma,任何 intrasellar or parasellar tumor (non-PRL-secreting pituitary adenoma) pituitary stalk compression interfer with PIF delivery (Dopamine) PRL (很少 150 ng/ml)例如:non-functioning pituitary adenomacraniopharyn
23、giomatuberculum sella meningiomaaneurysm,Normoprolactinemic galactorrhea,enhanced sensitivity of breast to PRL 常見於 persistence of postpartum galactorrhea after discontinuation of oral pills,Pregnancy with prolactinoma,Microadenoma5% progress to macroadenomaMacroadenoma25% expand and produce symptoms
24、 (15-35%),Primary hypothyroidism,常有 breast tenderness, 偶而 galactorrheaPRL 大部份正常但也可能上昇，通常 100 ng /mllong-standing hypothyroidism 時可能出現 sellar enlargement如果又加上 PRL，易誤為 prolactinomaPRL response to TRH,CRF,PRLin 60-70% ( 150ng/ml)PRL response to TRH receptor or postreceptor defect in the lactotrophnot a
25、ltered by HDreversed by renal transplantation,D.D. of hyperprolactinemia,ProlactinomaPrimary hypothyroidism (TSH)CRF (BUN/Cr)Liver cirrhosis (GOT/GPT, A/G)Cushings syndrome (cortisol)Acromegaly (GH)Drug-induced (history taking)Pregnancy (-HCG)PseudoprolactinomaPhysiologic hyperprolactinemia,Treatmen
26、t of microadenoma,Disadvantage of untreated microadenomaloss of libidodyspareunia, hypogonadismBMD premature CADenlargement of tumor mass,Microadenoma,Indication of treatmentdesire of becoming pregnant須 eliminate galactorrhea須 relieve symptoms of hypogonadism如果上述 concern 不存在periodically follow up 即可
27、,Prolactinoma,Therapeutic decision makingMicroadenomadesire for pregnancy (-) periodically follow updesire for pregnancy (+) surgeryrecurrent after surgery pharmacotherapyMacroadenoma: PRL 200-500 ng/ml, invasiveness (-): surgery: PRL 500-1000 ng/ml, 或 invasiveness (+) pharmacotherapy or surgery: PR
28、L 1000 ng/ml, invasiveness (+) pharmacotherapy,Pharmacotherapy of prolactinoma,Ergot preparationBromocriptin (approved by FDA)LisuridePergolideMetergolineTerguride (greater pituitary selectivity)Cabergoline (longer duration of action)non-Ergot preparationCV 205-502 (Octahydrobenzquinolone),Bromocrip
29、tine,Dopamine agonist, 1971semisynthetic ergot alkaloidbinds to the dopamine receptoraffinity 為 dopamine 的 5-10X使 PRL 恢復至 normal, in 64-100%改善 galactorrhea, 57-100%恢復 mens and ovulation, 57-100%改善 visual field defect, 60-80%使 tumor size reduction, 60-80%但無法改善 loss of sleep-related PRL pulsatile secr
30、etion,Bromocriptine therapy,the only FDA approved drug in the USAinitial dose : 1.25 mg H.S.dose adjustment: 改換成 1.25 mg QD ( c meal) 每隔 3 天增加 1.25 mgstandard dose: 2.5 mg tidmaintain dose: 2.5 mg bid,_,Bromocriptine therapy,Drug efficacy in reducing PRL doesnt necessarily predict tumor size reducti
31、on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 reductionShort treatment period withdrawl rapid reexpansion of tumor sizetherapeutic 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 therapy,Intolerate to oral therapy時，可改用 vaginal administ
32、ration (the same dosage)Patient 必須被告知可能 restore fertility須事先使用 mechanical contraception (否則會在服藥治療期間 conception 而不自知) 直到 regular menstrual flow 3 cyclesNot teratogenic in humanfetal losscongenital malformation Injectable form available in Europeeffective for 4-6 wk,: not increased,Bromocriptine thera
33、py,對於 large pituitary tumor 如果 PRL 200 ng/ml，大部份是 prolactinoma 如果 PRL 200 ng/ml，可能是 2hyperprolactinemia (pseudoprolactinoma),Bromocriptine Rx ProlactinomaPseudoprolactinoma PRL tumor size (）,Bromocriptine therapy,Tumor most likely to responsehighest PRLnot combined PRL + GH secreting tumorVisual fie
34、ld defect 的改善，往往在 pituitary MRI 看到 tumor size reduction 之前 (表示仔細的 monitorning of visual acuity 和 visual field 為 more sensitive indicator of tumor response than image study),Bromocriptine therapy,Side effectGI upset : nausea, vomiting abdominal fullness abdominal cramping constipationDizziness (ortho
35、static hypotension)HeadacheFatigueNasal stuffCSF rhinorrheaHallucination and psychosis (1.3%),Transsphenoid hypophysectomy,Indication of surgical therapyintolerate to pharmacologic agentinadequate to pharmacologic agentpoor complianceirregular follow updesire of becoming pregnantcystic tumortumor ap
36、oplexy,Surgical therapy,cure raterecurrent rateMicroadenoma70-90%15-50%Macroadenoma20-30%70-80%,Varies with pt selection and surgical techniqueOP 後若 PRL 9 ng/ml 可能表示會 recurrent Recurrent 時，再 reoperation 的效果並不好,Transsphenoid hypophysectomy,Criteria of curetotal removal of tumor massnormalization of P
37、RLresumption of ovulatory menstruationrestore infertilityno evidence of recurrence over 5 yearsCriteria of recurrencereappearance of hyper PRL over 5-yr period,Surgical therapy,Surgical success rateMicroadenoma Macroadenoma ,Preoperation bromocriptine therapy:,Surgical therapy,Surgical success rateb
38、romocriptine-treated 44%no bromocriptine 78%,fibrosis induced by bromocriptineshrinkage of tumor cellenlargement of the extracellar & perivascular spacefilled by the collagen depositionmore dense consistency of the adenomashrunken tumor adhere to adjacent normal pituitary tissue,Preoperation bromocr
39、iptine in microadenoma (Landolt, 1982),Radiotherapy,some effectiveness in reducing PRLmore slowlyless completelyalternative therapy (generally not recomnend as primary therapy)indication: postoperation recurrence,When to check PRL,Amenorrhea, oligomenorrheaGalactorrheaSexual dysfunctionloss of libidodyspareunia ()impotence ()InfertilityVisual field defectHeadache,
