高泌乳激素血症

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 uRegulated by the hypothalamus 主要是 tonic inhibition uHypothalamus 分泌 2 種 hypothalamic factors -PIF (PRL-inhibiting factor) Dopamine -PRF (PRL-releasing factor) TRH, VIP PRL uStimulate breast development uInitiate and maintain lactation uPRL receptor -alveolar surface of mammary cell -liver, kidney -ovary, testes, prostate uEstrogen -synergistic in promoting breast development -antagonize in effect of lactation Breast development u須要多種 hormone 的 coordinated action 包括 major stimuli: estrogen progesterone prolactin GH placental mammotropic H minor stmuli: insulin cortisol thyroid hormone Breast development uDuct growth: estrogen uLobuloalveolar development: PRL+progesterone uLactation: 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 galactorrhea, 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 u1928 discovered in extract of bovine pituitary u1970 sensitive bioassay u1971 RIA (Friesen, Fournier, Desjardians) secreted by the erythrosinophilic subtype of chromophobic cells in the adenohypophysis PRL uA stress hormone uSecreted in a pulsatile fashion highest in the early morning (睡醒之前 ) lower in the afternoon uphysiologic PRL -pain -nipple stimulation -fondling (women only) -pregnancy (可達 200-500 ng/ml) -pelvic examination -exercise -sleep PRL uDaily secretion rate: 400 g/天 uMetabolic clearance: 40 ml/m2/min uClearance pathway: 25% kidney 75% liver uPlasma T1/2: 50 min uPlasma level: 300 ng/ml umbilical PRL maternal PRL uPituitary PRL: 100 g per pituitary PRL uPRL value 和 prolactinoma tumor size 成正比 uPRL 1000 ng/ml tumor extension into cavernous sinus 150 ng/ml 幾乎一定就是 prolactinoma 100-150 ng/ml: (1) prolactinoma (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 uBlood sampling 須注意事項 -indwelling venous cannula -at least 2 hr resting -20 minutes interval 3-6 次 -sampling time usually not critical Hyperprolactinemia uBasic mechanisms ( ) - Hypothalamic dopamine deficiency lhypothalamic tumor lAV malformation linflammatory process ldrugs: methyldopa (Aldomet) reserpine -Defective transport mechanisms lpituitary or stalk tumor lhead injury lsection of pituitary stalk Hyperprolactinemia uBasic mechanisms ( ) -Lactotroph insensitivity to dopamine l dopamine receptor blocking agents -phenothiazine (chlorpromazine) -butyrophenones (haloperidol) -benzamide: metoclopamide sulpiride domperidone -Stimulation of lactotrophs l Hypothyroidism l TRH l Estrogen l Chest wall injury: herpes zoster, surgery l PRL-producing tumor Pituitary tumor u約佔 brain tumor 的 10% 左右 -Prolactinoma 40-50% -Non-functioning adenoma 30% -Gonadotroph cell adenoma10-15% -Acromegaly 10% -Cushings disease -TSH-secreting adenoma Prolactinoma uGeneral population 中可能 5-10% 有 prolactinoma - 這其中只有 5-10% come to clinical attension 2/3 microadenoma 1/3 macroadenoma uAutopsy study -6.5-27% (11%) 有 pituitary adenoma -no antemortem endocrine dysfunction -40-50% (+) for PRL by immunocytochemical stain - 幾乎全部為 microadenoma Prolactinoma uGrow slowly over years uLarge tumor hypopituitarism (singly or incombination) GH deficiency 最常見 uImpaired pulsatile gonadotropin (LH, FSH) (via alteration in hypothalamic LHRH secretion) (increased endogenous opiate tone) uBMD Prolactinoma uGrade : microadenoma (s suprasellar extension) uGrade : macroadenoma (c or s suprasellar extension) uGrade : localized boney destruction uGrade : diffuse boney destruction _ _ _ Pituitary capillary uCapillary in pituitary normal 62 capillaries/0.1mm2 microadenoma 51.1 macroadenoma 9.3 由於 capillary number 減少 less inhibited by PRL-inhibiting factor serum PRL 和 tumor size 成正比 Prolactinoma uEtiology: unclear ? Arise de novo ? Estrogen-induced ? Abnormality of hypothalamic regulation ? Monoclonal in origin Causes of hyperprolactinemia ( ) uHypothalamic disease -Tumor: metastatic ca carniopharyngioma germinoma cyst, hamartoma glioma -Infiltrative 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 -Infiltrative disease l sarcoidosis l tbc l giant cell granuloma Cause of hyperprolactinemia ( ) uDrug-induced -Monoamine inhibitor (catecholamine depletor) (在 hypothalamus 抑制 dopamine) l Aldomet l Reserpine -Dopamine receptor antagonist (在 pituitary 抑制 dopamine) l Chlorpromazine (wintermin) l Fluphenazine (wintermin) l Perphenazine l Promazine l Butyrophenone (haloperidol) l Motoclopramide (primperan) l Domperidone (motilium) l Sulpiride (dogmatyl) Causes of hyperprolactinemia ( ) uDrug-induced -Lactotroph stimulator l Estrogen l TRH -Narcotics l Morphine l Enkephalin l Codeine l Methadone -Amphetamine -H2-receptor blocker l Cimetidine (Tagamet) l Ranitidine (Zantac) Causes of hyperprolactinemia ( ) uMajor systemic disease -1hypothyroidism -CRF -Liver cirrhosis -Seizure uNeurogenic -breast manipulation -chest wall lesion l burn l herpes zoster l mastectomy uStress: physical (pain) psychologic uPCO uIdiopathic Symptoms and Signs (Female) uDelayed menarche uDisturbance of menstrual function (60-90%) amenorrhea oligomenorrhea regular mens c infertility uGalactorrhea (30-80%) 和 duration of gonadal dysfunction 有關 amenorrhea 愈久，較不會有 galactorrhea uEstrogen deficiency libido hirsutism vaginal dryness (DHEA by adrenal ) dyspareunia (free testosterone ) _ Symptoms and Signs (male) u男性和 postmenopausal 女性較常以 mass effect 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%) -impotence galactorrhea (14-33%) -infertility gynecomastia (少見 ) Mass effect uSuprasellar extension: bitemporal hemianopia uExtends posteriorly -homonymous visual field defect uLateral extension (into the cavernous sinus) -compress cranial nerve 3, 4, 5, 6 uExtend into the temporal lobe : seizure Hyperprolactinemia u干擾 hypothalamic-pituitary-ovarian axis at 3 locations -hypothalamic level l interfer tonic or cyclic release of GnRH (LHRH) -pituitary level l desensitize gonadotropin response to GnRH -ovarian level l impaires progesterone production (by ovarian granulosa cell) PRL uPRL function in male: unclear -sperm production -prostate citrate production uPRL 5 -reductase Spermatogenesis testosterone dihydrotestosterone (biologically active) 5 -reductase Pseudoprolactinoma u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 adenoma craniopharyngioma tuberculum sella meningioma aneurysm Normoprolactinemic galactorrhea uenhanced sensitivity of breast to PRL 常見於 persistence of postpartum galactorrhea after discontinuation of oral pills Pregnancy with prolactinoma uMicroadenoma 5% progress to macroadenoma uMacroadenoma 25% expand and produce symptoms (15-35%) Primary hypothyroidism u常有 breast tenderness, 偶而 galactorrhea PRL 大部份正常 但也可能上昇，通常 1000 ng/ml, invasiveness (+) pharmacotherapy Pharmacotherapy of prolactinoma uErgot 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 Dopamine agonist, 1971 semisynthetic ergot alkaloid binds to the dopamine receptor affinity 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 secretion Bromocriptine therapy uthe only FDA approved drug in the USA uinitial dose : 1.25 mg H.S. udose adjustment: 改換成 1.25 mg QD ( c meal) 每隔 3 天增加 1.25 mg ustandard dose: 2.5 mg tid umaintain dose: 2.5 mg bid _ Bromocriptine therapy uDrug efficacy in reducing PRL doesnt necessarily predict 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 reduction uShort 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 therapy uIntolerate to oral therapy時，可改用 vaginal administration (the same dosage) uPatient 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 cycles uNot teratogenic in human fetal loss congenital malformation uInjectable form available in Europe effective for 4-6 wk : not increased Bromocriptine therapy u 對於 large pituitary tumor 如果 PRL 200 ng/ml， 大部份是 prolactinoma 如果 PRL 9 ng/ml 可能表示會 recurrent Recurrent 時，再 reoperation 的效果並不好 Transsphenoid hypophysectomy uCriteria of cure -total removal of tumor mass -normalization