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Hyperprolactinemia

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Hyperprolactinemia Hyperprolactinemia Presentation Transcript

  • 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 inhibition
    • Hypothalamus 分泌 2 種 hypothalamic factors
      • PIF (PRL-inhibiting factor)
      • Dopamine
      • PRF (PRL-releasing factor)
      • TRH, VIP
  • PRL
    • Stimulate breast development
    • Initiate and maintain lactation
    • PRL receptor
      • alveolar surface of mammary cell
      • liver, kidney
      • ovary, testes, prostate
    • Estrogen
      • synergistic in promoting breast development
      • antagonize in effect of lactation
  • Breast development
    • 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
    • Duct growth: estrogen
    • Lobuloalveolar development: PRL+progesterone
    • Lactation: 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
    • 1928 discovered in extract of bovine pituitary
    • 1970 sensitive bioassay
    • 1971 RIA (Friesen, Fournier, Desjardians)
    • secreted by the erythrosinophilic subtype
    • of chromophobic cells in the adenohypophysis
  • PRL
    • A stress hormone
    • Secreted in a pulsatile fashion
    • highest in the early morning ( 睡醒之前 )
    • lower in the afternoon
    • physiologic PRL ↑
      • pain
      • nipple stimulation
      • fondling (women only)
      • pregnancy ( 可達 200-500 ng/ml)
      • pelvic examination
      • exercise
      • sleep
  • PRL
    • Daily secretion rate: 400 μ g/ 天
    • Metabolic clearance: 40 ml/m 2 /min
    • Clearance pathway: 25% kidney
    • 75% liver
    • Plasma T 1/2 : 50 min
    • Plasma level: < 15 ng/ml
    • ♂ :5 ng/ml (3-10)
    • ♀ :8 ng/ml (5-15)
    • fetal PRL > 300 ng/ml
    • umbilical PRL > maternal PRL
    • Pituitary PRL: 100 μ 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) 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
    • Blood 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
    • Basic mechanisms ( Ⅰ )
      • Hypothalamic dopamine deficiency
        • hypothalamic tumor
        • AV malformation
        • inflammatory process
        • drugs: methyldopa (Aldomet)
        • reserpine
      • Defective transport mechanisms
        • pituitary or stalk tumor
        • head injury
        • section of pituitary stalk
  • Hyperprolactinemia
    • Basic mechanisms ( Ⅱ )
      • Lactotroph insensitivity to dopamine
        • dopamine receptor blocking agents
          • phenothiazine (chlorpromazine)
          • butyrophenones (haloperidol)
          • benzamide: metoclopamide
          • sulpiride
          • domperidone
      • Stimulation of lactotrophs
        • Hypothyroidism
        • TRH
        • Estrogen
        • Chest wall injury: herpes zoster, surgery
        • PRL-producing tumor
  • Pituitary tumor
    • 約佔 brain tumor 的 10% 左右
      • Prolactinoma 40-50%
      • Non-functioning adenoma 30%
      • Gonadotroph cell adenoma 10-15%
      • Acromegaly 10%
      • Cushing's disease
      • TSH-secreting adenoma
  • Prolactinoma
    • General 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
    • Autopsy 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
    • Grow slowly over years
    • Large tumor -> hypopituitarism
    • (singly or incombination) GH deficiency 最常見
    • Impaired pulsatile gonadotropin (LH, FSH)
    • (via alteration in hypothalamic LHRH secretion) (increased endogenous opiate tone)
    • BMD ↓
  • Prolactinoma
    • Grade Ⅰ : microadenoma (s suprasellar extension)
    • Grade Ⅱ : macroadenoma (c or s suprasellar extension)
    • Grade Ⅲ : localized boney destruction
    • Grade Ⅳ : diffuse boney destruction
    _ _ _
  • Pituitary capillary
    • Capillary 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
    • Etiology: unclear
    • ? Arise de novo
    • ? Estrogen-induced
    • ? Abnormality of hypothalamic regulation
    • ? Monoclonal in origin
  • Causes of hyperprolactinemia ( Ⅰ )
    • Hypothalamic disease
      • Tumor: metastatic ca
      • carniopharyngioma
      • germinoma
      • cyst, hamartoma
      • glioma
      • Infiltrative disease
      • sarcoidosis
      • tbc
      • histiocytosis
      • granuloma
      • Pseudotumor cerebri
      • Cranial irradiation
  • Causes of hyperprolactinemia ( Ⅱ )
    • Pituitary disease
      • Prolactinoma
      • Acromegaly
      • Cushing's disease
      • Pituitary stalk section
      • Empty sella syndrome
      • Metastatic ca
      • Meningioma
      • Intrasella germinoma
      • Infiltrative disease
        • sarcoidosis
        • tbc
        • giant cell granuloma
  • Cause of hyperprolactinemia ( Ⅲ )
    • Drug-induced
      • Monoamine inhibitor (catecholamine depletor)
      • ( 在 hypothalamus 抑制 dopamine)
        • Aldomet
        • Reserpine
      • Dopamine receptor antagonist
      • ( 在 pituitary 抑制 dopamine)
        • Chlorpromazine (wintermin)
        • Fluphenazine (wintermin)
        • Perphenazine
        • Promazine
        • Butyrophenone (haloperidol)
        • Motoclopramide (primperan)
        • Domperidone (motilium)
        • Sulpiride (dogmatyl)
  • Causes of hyperprolactinemia ( Ⅳ )
    • Drug-induced
      • Lactotroph stimulator
        • Estrogen
        • TRH
      • Narcotics
        • Morphine
        • Enkephalin
        • Codeine
        • Methadone
      • Amphetamine
      • H2-receptor blocker
        • Cimetidine (Tagamet)
        • Ranitidine (Zantac)
  • Causes of hyperprolactinemia ( Ⅴ )
    • Major systemic disease
      • 1 ° hypothyroidism
      • CRF
      • Liver cirrhosis
      • Seizure
    • Neurogenic
      • breast manipulation
      • chest wall lesion
        • burn
        • herpes zoster
        • mastectomy
    • Stress: ‧ physical (pain)
      • ‧ psychologic
    • PCO
    • Idiopathic
  • Symptoms and Signs (Female)
    • Delayed menarche
    • Disturbance of menstrual function (60-90%)
    • amenorrhea
    • oligomenorrhea
    • regular mens c infertility
    • Galactorrhea (30-80%)
    • 和 duration of gonadal dysfunction 有關
    • amenorrhea 愈久,較不會有 galactorrhea
    • Estrogen deficiency
      • libido ↓ hirsutism
      • vaginal dryness (DHEA by adrenal ↑ )
      • dyspareunia (free testosterone ↑ )
    _
  • Symptoms and Signs (male)
    • 男性和 postmenopausal 女性較常以 mass effect 表現
    • Headache (63%)
    • Visual abnormality
      • visual acuity ↓
      • ophthalmoplegia
      • visual field defect
      • ( 先 bitemporal upper quadrant anopia)
      • ( 再 bitemporal hemianopia)
    • Hypogonadism
      • libido ↓ (83%) adiposity (70%)
      • impotence galactorrhea (14-33%)
      • infertility gynecomastia ( 少見 )
  • Mass effect
    • Suprasellar extension: bitemporal hemianopia
    • Extends posteriorly
      • homonymous visual field defect
    • Lateral extension (into the cavernous sinus)
      • compress cranial nerve 3, 4, 5, 6
    • Extend into the temporal lobe : seizure
  • Hyperprolactinemia
    • 干擾 hypothalamic-pituitary-ovarian axis
    • at 3 locations
      • hypothalamic level
        • interfer tonic or cyclic release of GnRH (LHRH)
      • pituitary level
        • desensitize gonadotropin response to GnRH
      • ovarian level
        • impaires progesterone production
        • (by ovarian granulosa cell)
  • PRL
    • PRL function in male: unclear
      • sperm production
      • prostate citrate production
    • PRL ↑-> 5 α -reductase ↓
    Spermatogenesis testosterone dihydrotestosterone (biologically active) 5 α -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 adenoma
    • craniopharyngioma
    • tuberculum sella meningioma
    • aneurysm
  • Normoprolactinemic galactorrhea
    • enhanced sensitivity of breast to PRL
    • 常見於 persistence of postpartum galactorrhea
    • after discontinuation of oral pills
  • Pregnancy with prolactinoma
    • Microadenoma
    • 5% progress to macroadenoma
    • Macroadenoma
    • 25% expand and produce symptoms
    • (15-35%)
  • Primary hypothyroidism
    • 常有 breast tenderness, 偶而 galactorrhea
    • PRL 大部份正常
    • 但也可能上昇,通常 < 100 ng /ml
    • long-standing hypothyroidism 時
    • 可能出現 sellar enlargement
    • 如果又加上 PRL ↑ ,易誤為 prolactinoma
    • PRL response to TRH ↑
  • CRF
    • PRL ↑ in 60-70% ( < 150ng/ml)
    • PRL response to TRH ↓
    • receptor or postreceptor defect in the lactotroph
    • not altered by HD
    • reversed by renal transplantation
  • D.D. of hyperprolactinemia
    • Prolactinoma
    • Primary hypothyroidism (TSH)
    • CRF (BUN/Cr)
    • Liver cirrhosis (GOT/GPT, A/G)
    • Cushing's syndrome (cortisol)
    • Acromegaly (GH)
    • Drug-induced (history taking)
    • Pregnancy ( β -HCG)
    • Pseudoprolactinoma
    • Physiologic hyperprolactinemia
  • Treatment of microadenoma
    • Disadvantage of untreated microadenoma
      • loss of libido
      • dyspareunia, hypogonadism
      • BMD ↓
      • premature CAD
      • enlargement of tumor mass
  • Microadenoma
    • Indication of treatment
      • desire of becoming pregnant
      • 須 eliminate galactorrhea
      • 須 relieve symptoms of hypogonadism
    • 如果上述 concern 不存在
      • periodically follow up 即可
  • Prolactinoma
    • Therapeutic decision making
      • Microadenoma
        • desire for pregnancy (-) -> periodically follow up
        • desire for pregnancy (+) -> surgery
        • recurrent after surgery -> pharmacotherapy
      • Macroadenoma
        • Ⅰ : PRL 200-500 ng/ml, invasiveness (-): surgery
        • Ⅱ : PRL 500-1000 ng/ml, 或 invasiveness (+)
        • pharmacotherapy or surgery
        • Ⅲ : PRL > 1000 ng/ml, invasiveness (+)
        • pharmacotherapy
  • Pharmacotherapy of prolactinoma
    • Ergot preparation
      • Bromocriptin (approved by FDA)
      • Lisuride
      • Pergolide
      • Metergoline
      • Terguride (greater pituitary selectivity)
      • Cabergoline (longer duration of action)
    • non-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
    • the only FDA approved drug in the USA
    • initial 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 mg
    • standard dose: 2.5 mg tid
    • maintain dose: 2.5 mg bid
    _
  • Bromocriptine therapy
    • Drug efficacy in reducing PRL doesn't 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
    • Short treatment period -> w ithdrawl
    • -> 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
    • Intolerate to oral therapy 時,可改用 vaginal administration (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 cycles
    • Not teratogenic in human
    • fetal loss
    • congenital malformation
    • Injectable form available in Europe
    • effective for 4-6 wk
    : not increased ]
  • Bromocriptine therapy
    • 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 2 ° hyperprolactinemia
    • (pseudoprolactinoma)
    • Bromocriptine Rx Prolactinoma Pseudoprolactinoma
    • PRL ↓ ↓
    • tumor size ↓ ( -)
  • Bromocriptine therapy
    • Tumor most likely to response
      • highest PRL
      • not combined PRL + GH secreting tumor
    • Visual field 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 effect
      • GI upset : nausea, vomiting
      • abdominal fullness
      • abdominal cramping
      • constipation
      • Dizziness (orthostatic hypotension)
      • Headache
      • Fatigue
      • Nasal stuff
      • CSF rhinorrhea
      • Hallucination and psychosis (1.3%)
  • Transsphenoid hypophysectomy
    • Indication of surgical therapy
      • intolerate to pharmacologic agent
      • inadequate to pharmacologic agent
        • poor compliance
        • irregular follow up
      • desire of becoming pregnant
      • cystic tumor
      • tumor apoplexy
  • Surgical therapy
    • cure rate recurrent rate
    • Microadenoma 70-90% 15-50%
    • Macroadenoma 20-30% 70-80%
    Varies with p't selection and surgical technique OP 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 cure
      • total removal of tumor mass
      • normalization of PRL
      • resumption of ovulatory menstruation
      • restore infertility
      • no evidence of recurrence over 5 years
    • Criteria of recurrence
      • reappearance of hyper PRL over 5-yr period
  • Surgical therapy
    • Surgical success rate
    • Microadenoma ↓
    • Macroadenoma ↑
    Preoperation bromocriptine therapy:
  • Surgical therapy
    • Surgical success rate
    • bromocriptine-treated 44%
    • no bromocriptine 78%
    • fibrosis induced by bromocriptine
    • shrinkage of tumor cell
      • enlargement of the extracellar & perivascular space
      • filled by the collagen deposition
      • more dense consistency of the adenoma
    • shrunken tumor adhere to adjacent normal pituitary tissue
    Preoperation bromocriptine in microadenoma (Landolt, 1982)
  • Radiotherapy
    • some effectiveness in reducing PRL
    • more slowly
    • less completely
    • alternative therapy (generally not recomnend as primary therapy)
    • indication: postoperation recurrence
  • When to check PRL
    • Amenorrhea, oligomenorrhea
    • Galactorrhea
    • Sexual dysfunction
      • loss of libido
      • dyspareunia ( ♀ )
      • impotence ( ♂ )
    • Infertility
    • Visual field defect
    • Headache