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

2. 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

3. 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

4. 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

5. Breast development Duct growth: estrogen
Lobuloalveolar development: PRL+progesterone
Lactation: PRL + oxytocin

6. 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

7. 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

8. 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 ng/ml)
pelvic examination
exercise
sleep

9. PRL Daily secretion rate: 400μg/天 Metabolic clearance: 40 ml/m2/min
Clearance pathway: 25% kidney
75% liver
Plasma T1/2: 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 μg per pituitary

10. 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
ng/ml: (1) prolactinoma
(2) pseudoprolactinoma
(3) drug-induced
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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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 ↓

17. Prolactinoma GradeⅠ: microadenoma (s suprasellar extension)_
GradeⅠ: microadenoma (s suprasellar extension)
GradeⅡ: macroadenoma (c or s suprasellar extension)
GradeⅢ: localized boney destruction
GradeⅣ: diffuse boney destruction _ _

18. Pituitary capillary Capillary in pituitary
normal capillaries/0.1mm2
microadenoma 51.1
macroadenoma
由於 capillary number 減少
∴ less inhibited by PRL-inhibiting factor
serum PRL 和 tumor size 成正比

19. Prolactinoma Etiology: unclear ? Arise de novo ? Estrogen-induced
? Abnormality of hypothalamic regulation
? Monoclonal in origin

20. Causes of hyperprolactinemia (Ⅰ)
Hypothalamic disease
Tumor: metastatic ca
carniopharyngioma
germinoma
cyst, hamartoma
glioma
Infiltrative disease
sarcoidosis
tbc
histiocytosis
granuloma
Pseudotumor cerebri
Cranial irradiation

21. 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

22. 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)

23. Causes of hyperprolactinemia (Ⅳ)
Drug-induced
Lactotroph stimulator
Estrogen
TRH
Narcotics
Morphine
Enkephalin
Codeine
Methadone
Amphetamine
H2-receptor blocker
Cimetidine (Tagamet)
Ranitidine (Zantac)

24. 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

25. 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 ↑) _

26. 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)

27. 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

28. 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)

29. PRL PRL function in male: unclear PRL↑→ 5α-reductase ↓
sperm production
prostate citrate production
PRL↑→ 5α-reductase ↓
Spermatogenesis
testosterone dihydrotestosterone
(biologically active)
5α-reductase

30. 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

31. Normoprolactinemic galactorrhea
enhanced sensitivity of breast to PRL
常見於 persistence of postpartum galactorrhea
after discontinuation of oral pills

32. Pregnancy with prolactinoma
Microadenoma
5% progress to macroadenoma
Macroadenoma
25% expand and produce symptoms
(15-35%)

33. 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↑

34. 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

35. 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

36. Treatment of microadenoma
Disadvantage of untreated microadenoma
loss of libido
dyspareunia, hypogonadism
BMD ↓
premature CAD
enlargement of tumor mass

37. Microadenoma Indication of treatment 如果上述 concern 不存在
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

38. Prolactinoma Therapeutic decision making Microadenoma Macroadenoma
desire for pregnancy (-) → periodically follow up
desire for pregnancy (+) → surgery
recurrent after surgery → pharmacotherapy
Macroadenoma
Ⅰ: PRL ng/ml, invasiveness (-): surgery
Ⅱ: PRL ng/ml, 或 invasiveness (+)
pharmacotherapy or surgery
Ⅲ: PRL > 1000 ng/ml, invasiveness (+)
pharmacotherapy

39. 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 (Octahydrobenzquinolone)

40. 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 %
改善 galactorrhea, %
恢復 mens and ovulation, %
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

41. 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 _

42. 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 → 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

43. 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

44. 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 ↓ (－）

45. 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)

46. 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%)

47. 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

48. 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

49. 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

50. Surgical therapy Preoperation bromocriptine therapy:
Surgical success rate
Microadenoma ↓
Macroadenoma ↑

51. Surgical therapy Preoperation bromocriptine in microadenoma
(Landolt, 1982)
Surgical success rate
bromocriptine-treated %
no bromocriptine %
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

52. Radiotherapy some effectiveness in reducing PRL more slowly
less completely
alternative therapy (generally not recomnend as primary therapy)
indication: postoperation recurrence

53. When to check PRL Amenorrhea, oligomenorrhea Galactorrhea
Sexual dysfunction
loss of libido
dyspareunia (♀)
impotence (♂)
Infertility
Visual field defect
Headache