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The 38-year-old man called our clinic because of
progressive enlargement of bilateral breasts with discharge
for one month. He had been otherwise healthy until one year
earlier before the visiting when he began to note decreased
libido. Eretile dysfunction and impotence also developed at
that time. However, he attributed it to work stress and had
never visited outside clinics for evaluation. This was the
first time that he sought medical attention due to unusual
bresat enlargement with discharge. Bilateral atrophic testes
and sparse pubic and axillary hair were found. Under the
impression of gonad failure, he was admitted for further
evaluation. There was no visual deficit or headache. He denied
having taken any medication or herb over the past one year
prior to onset of symptoms. Otherwise, he denied to have
smoking, drug abuse, alcohol consumption, or operation. There
was no family history of endocrine disorders.
On admission, his consciousness was clear, his height was
162 cm and weight was 74 kg. The body temperature was 36.6°C,
pulse rate was 88 /min, respiratory rate was 20/min and the
blood pressure was 136/80 mmHg. The nose was not enlarged and
the mandible was not protruding. The conjunctivae were pink,
sclerae were anicteric and the pupils were isocoric with
prompt light reflex. The neck was supple without a goiter. No
neck or axillary lymphadenopathy was palpated but the axillary
and pubic hair was sparse. Discharge from the nipple was noted
while pressing the breast. Chest, heart, abdomen and back were
normal. The extremities were freely movable without edema.
Neurological examinations, including visual fields, were
unremarkable.
The laboratory investigations disclosed normal renal and
liver function. Baseline serum hormone levels showed
hyperprolactinemia and hypogonadotropic hypogonadism (tables).
Hyperprolactinemia-related gynecomastia and hypogonadism were
suspected. Magnetic resonance imaging (MRI) of the brain
showed a tumor, measuring 1.8 x 1.6 x 1.5 cm in size, inside
the pituitary gland without invasion to the suprasellar optic
chiasma (figure). The cavernous sinus and posterior lobe of
the pituitary gland were not involved. He received
testosterone enanthate depot administered monthly and
bromocriptine 2.5 mg QD initially under the diagnosis of
prolactinoma. The dose of bromocriptine was increased to 2.5
mg tid gradually. Follow-up prolactin level decreased to 18
ng/ml and androgen supplement was tappered. Sexual activity
improved and gynecomastia regressed during his regular
follow-up at our hospital.
<Laboratory
data>
1. Results of
baseline biochemistry
| Lab test |
BUN |
Cr |
Na |
K |
ALT |
T-bil |
| Reference value |
<24 mg/dL |
<1.3 mg/dL |
135-145 mmol/L |
3.5-5.3 mmol/L |
<37 U/L |
0.2-1.0 mg/dL |
| |
26.5 |
0.8 |
142 |
3.6 |
29 |
0.3 | 2. Results of the baseline endocrine tests
| FSH |
LH |
DHEA-S |
Androstenedione |
Testosterone |
Estradiol |
Progesterone |
3.5-10.5
mIU/mL |
1.5-8.3
mIU/mL |
4.8-15.6
μmol/L |
1.75-8.7 nM |
10-50 ng/mL |
73.6-368
pg/mL |
0.3-1.5
ng/mL |
| 0.49 |
＜ 0.8 |
＜ 0.8 |
＜ 0.2 |
＜ 0.2 |
22.5 |
＜ 0.2 |
| TSH |
FT4 |
ACTH |
Cortisol |
hGH |
Prolactin |
| 0.4- 4 μIU/mL |
0.60-1.75 ng/dL |
10-65 pg/mL |
5-25 μg/dL |
0.06-5 ng/mL |
1.4-24.2 ng/mL |
| 0.65 |
1.4 |
11 |
21 |
0.08 |
239 |
**Follicle-stimulating hormone＝FSH,
luteinizing
hormone＝LH,
DHEA-S＝dehydroepiandrosterone sulfate,
thyroid-stimulating hormone＝TSH,
free thyroxine＝FT4,
corticotropin＝ACTH,
growth hormone＝hGH.
3.Figure
legend:
Magnetic
resonance T1-weighted contrast-enhancing imaging coronal view
showed an adenoma, as an inhomogenously hypo-enhancing area in
the left side of the adenohypophysis.
<病例解析>
男性女乳症( gynecomastia)
的因素有很多,分為生理及病理方面。生理性方面，包括：嬰兒時期、青春期時或之前、及老年男人。至於病理性方面，則須先利用觸診確定有沒有乳房結構的問題。若有懷疑便需進一步安排乳房攝影或超音波。排除掉乳房病灶的可能，接下來需幫病人檢測血中荷爾蒙的濃度。人體內的泌乳素(prolactin)高、動情素(estrogen)高、及男性素(testosterone)低等等都會造成男性女乳症，而在排除掉內分泌相關的問題後，找不到病因的男性女乳症高達25%。我們的病人在此呈現的是一高泌乳素血症(
hyperprolactinemia)造成的男性女乳症。在未懷孕的女性血中prolactin值＞25
ng/ml、男性血中prolactin值> 20 ng/ml時,
便稱為泌乳素過高症。泌乳激素的合成與儲存主要是位於腦下腺之前葉(即腦垂體腺性部,
adenohypophysis)的後側部的chromophobe cells稱之為lactotropes，之後在肝和腎臟代謝
清除。Prolactin的製造和分泌是受到中樞神經系統和神經性傳導物質所控制，它是經由下視丘（hypothalamus）作用在腦下腺。PIF(
Prolactin-inhibiting factor)可抑制其分泌:
其中dopamine能直接作用在腦下腺細胞的Dopamine接受體，來抑制prolactin 的製造和分泌 ；另外，
Serotonin和 thyrotropin-releasing hormone (TRH)
能促進prolactin的分泌。泌乳素過高症的臨床表現，包括：gynecomastia、溢乳(galactorrhea)、不孕(infertility)；在女性會無月經(amenorrhea),
在男性會性欲減低。因為過高的 prolactin會影響正常gonadotropin releasing
hormone（GnRH）的波動性釋放(pulsatility)，進而影響了FSH和LH的分泌造成男、女性的hypogonadism。不過，來門診就診時的主訴，女性多因無月經，
且較易有乳房的症狀；而男性往往在之前將減低性欲(decreased
libido)及陽萎（impotence）歸因於其他因素而延誤就醫，致使就診時腺瘤皆已長得很大而表現主要以視力模糊及頭痛等腫瘤壓迫症狀為主。泌乳素過高症的原因，包括：生理性及病理性。生理性狀況下造成泌乳素上升的原因有：懷孕、乳房和乳頭的刺激、運動、睡眠、壓力、吃東西、性交等都會引起上升。因此在一天中prolactin的起伏很大，增加最大的時候是睡覺時，下午初期也會有小幅上升；所以最適當的
prolactin測量是在早晨空腹時抽取血液檢查，並且是在同一個安靜、沒有壓力的環境下，否則即使病人沒有病理性問題，也會得到一個不正常的昇高值。至於病理性原因,
常見的有：甲狀腺機能過低症(因 TRH增加)、慢性肝腎疾病(
因代謝降低)、慢性乳部神經受到刺激(如胸部手術、胸部創傷、胸部帶狀包疹等)。另外，很多藥物會造成泌乳素升高：如麻醉藥、嗎啡類止痛藥、精神科用藥(如抗憂鬱藥)、荷爾蒙製劑(如避孕藥)、降血壓藥(如α-methyldopa、reserpine)、胃腸科的胃潰瘍用藥(如
histamine 2 receptor blockers:
cimetidine)及止吐藥(sulpiride、metoclopramide)等皆會。至於下視丘問題則少見。排除上述原因之後，最重要就是要考慮到腦下腺的問題。分泌prolactin的腦下腺腺瘤稱為prolactinoma。在診斷方面，除了典型的症狀，還要加上血中乳促素濃度和核磁共振攝影。當血中乳促素大於200
ng/mL，乳促素瘤而且是巨大腺瘤的可能性很大(但有可能是服用藥物,
如resperidol等)；血中乳促素介於100到200
ng/mL，通常係因乳促素瘤，可以是微腺瘤或巨大腺瘤；乳促素大於100
ng/mL的腺瘤通常可以在影像上清楚顯示；如果乳促素介於20至100 ng/mL之間，通常診斷較困難。腺瘤直徑小於1公分稱為
microadenoma，直徑大於1公分稱為 macroadenoma。大部份的 prolactinoma是
microadenoma。一般病史與物理檢查，須留意是否有頭痛，視覺障礙或神經功能異常等腫瘤壓迫症狀。影像學檢查方面，
MRI對soft tissue解像力佳，沒有放射線暴露問題，能精確地找出1
mm以上的microadenoma，因此是公認比CT更好的診斷工具。
所有的病人都應該接受治療以防腫瘤長大、骨質疏鬆、及性腺功能低下。治療包括內科治療、手術切除及放射線治療。對於微腺瘤通常建議以內科治療為主，可以用dopamine
agonist，可以直接抑制乳促素分泌，包括bromocriptine及cabergoline，前者副作用較多，包括頭暈、噁心、嘔吐、姿勢性低血壓，建議從低劑量開始；後者較長效（一星期一到兩次）、較有效且副作用較少。對於巨大腺瘤一般建議手術治療；但是，應該先使用內科治療，手術之後通常須輔以藥物治療甚至放射線治療。對於泌乳素過高症的處理，第一選擇是內科治療。內科治療對macroadenoma及microadenoma皆有好的效果，在沒有adenoma或合併有microadenoma的病人，90％
prolactin會回復正常，75 ％
microadenoma體積變小或消失。而對於macroadenoma的病人，80-90％會有效地縮小腫瘤的體積，如果有腫瘤壓迫造成的視覺或神經障礙，也會很快地改善。至於手術，則因術後復發率高，所以只在內科治療失敗，病人無法忍受藥物副作用，和大的macroadenoma(尤其是在懷孕的女性)
時，才考慮外科切除。另外，放射線治療由於可能會破壞腦下腺和視神經，故不常用。因此在macroadenoma不完全切除時，才考慮做為輔助性治療。內科治療的藥物，首推dopamine
agonists，屬於ergot的衍生物，它能直接促進dopamine
receptors，來抑制prolactin的分泌，如bromocriptine及cabergoline等。Bromocriptine的副作用較多，最常見的副作用是胃腸不適和姿態性低血壓，有一半的病人在開始時會發生，因此開始服用時，最好利用晚上睡覺前和食物一起服用且從低劑量開始；至於cabergoline則較長效（一星期一到兩次）、較有效且副作用較少。若bromocriptine無法承受時,
可考慮換成副作用較少的cabergoline，再不行就得考慮手術。因此，長期追蹤與評估是必要的；一般prolactin每半年檢查一次，磁振攝影每年檢查一次；而macroadenoma
尚需加作神經理學檢查及視野檢查，以評估藥物成效，同時必需評估是否繼續藥物治療或外科切除。
<參考文獻>
- Casanueva FF, et al.
Guidelines of the Pituitary Society for the diagnosis and
management of prolactinomas. Clin Endocrinol (Oxf).
2006;65:265-73.
- Gillam MP, et al. Advances
in the treatment of prolactinomas. Endocr Rev.
2006;27:485-534.
- Minniti G, et al.
Diagnosis and management of pituitary tumours in the
elderly: a review based on personal experience and evidence
of literature. Eur J Endocrinol. 2005;153:723-35.
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Case Discussion
繼續教育考題