Hyperprolactinemia is caused by increased levels of the hormone prolactin, which is regulated by the hypothalamus. Elevated prolactin levels can be caused by hypothalamic or pituitary tumors, systemic diseases, or certain drugs. Common symptoms of hyperprolactinemia in females include menstrual irregularities and galactorrhea, while males commonly experience symptoms related to mass effects of pituitary tumors such as headaches and visual abnormalities. Treatment options for hyperprolactinemia depend on the size and invasiveness of any pituitary tumors, and may involve dopamine agonists such as bromocriptine or surgery.

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 200-500 ng/ml) pelvic examination exercise sleep

9. 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

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 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

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 Grade Ⅰ : microadenoma (s suprasellar extension) Grade Ⅱ : macroadenoma (c or s suprasellar extension) Grade Ⅲ : localized boney destruction Grade Ⅳ : diffuse boney destruction _ _ _

18. 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

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 sperm production prostate citrate production PRL ↑-> 5 α -reductase ↓ Spermatogenesis testosterone dihydrotestosterone (biologically active) 5 α -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 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 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

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 205-502 (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 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

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 -> 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

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 Surgical success rate Microadenoma ↓ Macroadenoma ↑ Preoperation bromocriptine therapy:

51. 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)

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