hyperprolactinemia & prolactinoma - medkorat.in.th [read...objective • hypothalamic-pituitary...

Hyperprolactinemia &

Prolactinoma

นายแพทย์อดุมศกัดิ� เลศิสทุธิพร

โรงพยาบาลมหาราชนครราชสีมา

30/09/2557

Objective

• Hypothalamic-pituitary target organ axes

• Prolactin

– Type, level, hook effect

• Hyperprolactinemia

– Symptom

• Prolactinoma

– Symptom

– Treatment

Hypothalamic-pituitary-target organ

axis

Hypo

thalamic

-

pituitary-

prolactin

axis

Hypo

thalamic

-

pituitary-

prolactin

axis

Prolactin1

• Monomeric prolactin – 23 kDa 65-85%

• Dimeric prolactin – 45-60 kDa 10-20%

• Macroprolactin – 150-170 kDa <10 %

– Bind IgG

– Decrease Bioequivalent

– Decrease renal excretion2

1.Fahie-Wilson M,Smith TP. Determination of prolactin: the macroprolactin problem. Best Pract Res Clin Endocrinol Metab 2013;27:725-42

2.Shimatsu A, Hattori N. Macroprolactinemia: diagnotic, clinical, and pathogenetic significance. Clin Dev Immunol 2012;2012:167132.

Prolactin

• >25 : hyperprolactinemia

• <100 : drug

• <150 : stalk effect

• >200 , >250 : prolactinoma2

• >500 : macroprolactinoma3

2. Melmed S, et al. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical

practice guildeline. J Clin Endocrinol Metab 2011;96:273-88

3.Donadio F, et al. Patients with macroprolactinoma: clinical and radiological feature. Eur J Clin

Invest 2007;37:552-7

Prolactin

• Increase

– Sucking

– Breast stimulation

– Stress

– Serotonin

– Norepinephrine

– Histamine

– Endogenous opioid

– somatostatin

• Decrease

– Dopamine

• Acetylcholine

• Angiotensin II

• Vasopressine

– Negative feed back

William endocrine 12nd

Prolactin

• Breast

• Milk

• Inhibit GnRH, LH, FHS secretion – anovalation

• Postpartum prolactin 8x

• No breast feeding normalize 7 day

Tyson JE, Hwang P, Guyda H, Friesen HG, studies of prolactin secretion in human pregnancy. AmJ Obstet Gynecol 1972;113:14-20

Hook effect


Hook effect Macroprolactinemia

•polyethylene glycol precipitation


Symptoms of Hyperprolactinemia

• Menstrual irregularities

• sexual dysfunction

• galactorrhea1

• osteopenia 2

1Kleinberg DL, Noel GL, and Frantz AG: Galactorrhea: a study of 235 cases including 48 with pituitary tumors. N Engl J Med 1977; 296: pp. 589-600

2Klibanski A, Neer RM, Beitins IZ, et al: Decreased bone density in hyperprolactinemic women. N Engl J Med 1980; 303: pp. 1511-1514

Menstrual irregularities

sexual dysfunctionHigh PRL

– inhibits ovarian and testicular function

– short-loop feedback : inhibits GnRH 1

• Women may present with – primary or secondary amenorrhea

– oligomenorrhea, menorrhagia, delayed menarche, or regular menses

– Infertility: short luteal phase

– changes in libido and vaginal dryness

• Men – loos or decrease in libido, impotence,

– premature ejaculation or intracoital erection loss, oligospermia, or azospermia 2

1Milenkovic L, D’Angelo G, Kelly PA, and Weiner RI: Inhibition of gonadotropin hormone-releasing hormone release by prolactin from GT1 neuronal cell lines through prolactin receptors. Proc Natl Acad Sci USA 1994; 91: pp. 1244-1247

2 Ciccarelli A, Guerra E, De Rosa M, et al: PRL secreting adenomas in male patients. Pituitary 2005; 8: pp. 39-42

• Galactorrhea

– 50% of women, 35% of men 1

• Bone density may decrease

– hyperprolactinemia-induced sex steroid deficiency 2

1.Thorner MO, Vance ML, Laws ER, et al: The anterior pituitary. In Wilson JD, Foster DW, (eds) Philadelphia: Saunders, 1998, pp. 249-340

2.Klibanski A, Biller BMK, Rosenthal DI, and Saxe V: Effects of prolactin and estrogen deficiency in amenorrheic bone loss. J Clin Endocrinol Metab 1988; 67: pp. 124-130

Galactorrhea

• นํ %านมไหลผิดปกตใิน 1

– หญิง ไมไ่ด้ให้นมบตุร หรือ หยา่นม 1 ปี

– ชาย

• Incident 20-25% ของผู้หญิง 2

1.Huang W, Molitch ME. Evaluation and mangement of galactorrhea. Am Fam Physician 2012;85:1073-80

2.Kemmann E. Incidence of galactorrhea. JAMA 1976;236:2747

Physiologic

• Pregnancy - prolactin > 500 ng/ml

• Breast feeding / breast stimulation

• Witch’s milk : newborn

• Stress

• Heavy exercise


Drug

• Antipsychotic

– Typical

• Haloperidol, chlorpromazine, perphenazine, fluphenazine, promethazine

– Atypical

• Risperidol

• Antidepressant

– SSRI : Fluoxitine, citalopam, paroxetine

– TCA: amitriptyline, chlomipramine, desipramine

– MAO inhibitor : Pargyline, clorgyline


Drug

• GI

– Metoclopramide, domperidone, ranitidine, cimetidine

• CVS

– Verapamil, methyldopa, reserpine, labetalol

• CNS :phenotoin

• OC

• กญัชา ฝิ2 น โคเคน เฮโรอีน มอร์ฟีน

• สมนุไพร


Hypothalamus

• Sellar/supra sellar

• Stalk effect – Pituitary macroadenoma

– Germ cell tumor

– Craniopharyngioma

– Rathke’s cleft cyst

– Meningioma

– Sarcoidosis

– Langerhans cell histocytosis

– Lymphocytic hypophysiits

– Aneurysm

– Empty sellar

– radiotherapy


Pituitary tumor

• Prolactinoma

• Acromegaly 20-50% co-secretion with

hyperprolactinemia


other

• Tumor

– RCC, ovarian teratoma, non Hodgkin lymphoma

– Colorectal cancer

• Renal or liver failure

• PCOS 3-10%

• Adrenal insufficiency


PROLACTINOMA

Prolactinoma

• Microadenomas < 10 mm in diameter

• Macroadenomas > 10 mm in diameter

– impinge on parasellar structures


Prolactinoma

• Incidence 30 per 100,000 persons1

• microadenomas 11% of pituitaries

• 46% immunostain positively for PRL 2

• female-to-male – microprolactinomas is 20 : 1

– macroadenomas is 1 : 1

• PRL levels and tumor size usually correlated

• 7% to 14% of microadenomas continue to grow3

1.Fernandez A, Karavitaki N, Wass JA,et al

: Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf) 2009 Jul 24; Epub

2.Molitch ME: Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am 2008; 37: 151-171xi

3.Colao A, Di Sarno A, Cappabianca P,et al

: Withdrawal of long-term cabergoline therapy for tumoral and nontumoral hyperprolactinemia. N Engl J Med 2003; 349: 2023-2033

Prolactinoma

• 20% macroprolactinemia

• galactorrhea, oligomenorrhea or amenorrhea,

or erectile dysfunction and decreased libido

Donadio F, Barbieri A, Angioni R, et al: Patients with macroprolactinaemia: clinical and radiological features.

Eur J Clin Invest 2007; 37: pp. 552-557

• Macroprolactinomas have a greater

propensity to grow

• tumor size correlates

with serum PRL levels


Clinical Features

• associated

– hyperprolactinemia

– tumor size or invasiveness


Tumor Mass Effects


Tumor Mass Effects

• compressive effects on visual structures– bitemporal hemianopsia

– superior bitemporal defects

– decreased visual acuity

– Headaches

– seizures (a result of extension into the temporal lobe)

– Hydrocephalus are rare

– unilateral exophthalmos

– cavernous sinuses pituitary apoplexy

Zikel OM, Atkinson JL, Hurley DL,et al

: Prolactinoma manifesting with symptomatic hydrocephalus. Mayo Clin Proc 1999; 74: 475-477

Treatment

Microprolactinoma

• 90% no progression in 4-6 years

• Symptomatic

Schelechte J, Dolan K, et al. The natural history of untreated hyperprolactinemia: a

prospective analysis. J Clin Endocrinol Metab 1989;68:412-8

Microprolactinoma

งานประชมุโรคต่อมไร้ท่อในเวชปฏิบตั ิครั %งที2 29 พ.ศ. 2557

Macroprolactinoma

• Medication

• Surgery

• Pregnancy

• Non pregnancy


Medication indication

• Macroprolactinoma

• Microprolactinoma

– Increase size

– Infertile

– Galactorrhea

– Amenorrhea

– Acne hirsutism

– Gynocomastia

– Male sex hormone


medication

• Dopamine agonist– Ergot derivertive

• Bromocriptine

• Cabergoline

• Pergoline : withdraw

– Non ergot derivertive• Quinagoline : OD, 50% bromocritine resistant

• Lisuride : BID same quinagolide

• Tergulide :

• Somatostatin analogue : study

• Prolactin receptor antagonist : study


Bromocriptine

• semisynthetic ergot alkaloid dopamine agonist

• menstrual function in 80% - 90% 1

• shrinks prolactinomas, restores impaired sexual function, and improves galactorrhea 2

• visual field abnormalities 90% 3,4

1.Thorner MO, Martin WH, Rogol AD, et al. Rapid regression of pituitary prolactinomas during bromocriptine treatment. J Clin Endocrinol Metab. 1980;51:438-445.

2.Shimon I, Melmed S. Management of pituitary tumors. Ann Intern Med. 1998;129:472-483.

3.Colao A, Ferone D, Marzullo P, et al. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev. 2004;25:102-152.

4.Vance ML, Evans WS, Thorner MO. Drugs five years later: bromocriptine. Ann Intern Med. 1984;100:78-91.

Bromocriptine

• Perivascular fibrosis 1

• microsurgery for macroprolactinomas2

• largest tumors and highest PRL levels respond

well to 2.5 mg bromocriptine three times daily

• Higher doses often not more effective3

1.Landolt AM, Osterwalder V: Perivascular fibrosis in prolactinomas: is it increased by bromocriptine?. J Clin Endocrinol

Metab 1984; 58: 1179-1183

2.Tyrrell JB, Lamborn KR, Hannegan LT,et al

: Transsphenoidal microsurgical therapy of prolactinomas: initial outcomes and long-term results. Neurosurgery 1999;

44: 254-261

3.Fahlbusch R, Buchfelder M, Schrell U,et al

: Short-term preoperative treatment of macroprolactinomas by dopamine agonists. J Neurosurg 1987; 67: 807-815

• Drug withdrawal : rapid tumor expansion1

• Bromocriptine not enlarge after drug

withdrawal 2

• Very occasionally, lowers PRL but tumor

expansion 3

1.Thorner MO, Perryman RL, Rogol AD, et al. Rapid changes of prolactinoma volume after withdrawal and reinstitution of bromocriptine. J Clin

Endocrinol Metab. 1981;53:480-483.

2.Kovacs K, Stefaneanu L, Horvath E, et al. Effect of dopamine agonist medication on prolactin producing pituitary adenomas: a morphological

study including immunocytochemistry, electron microscopy and in situ hybridization. Virchows Arch A Pathol Anat Histopathol.

1991;418:439-446.

3 .Kupersmith MJ, Kleinberg DL, Warren A, et al. Growth of prolcactinoma despite lowering of serum prolactin by bromocriptine. Neurosurgery.

1989;24:417-423.

Bromocriptine

Cabergoline

• longer duration

• once or twice weekly

• high affinity for lactotroph D 2 receptors

DiSalle E, Ornati G, Giudici D,et al

: A comparison of the in vivo and in vitro duration of prolactin lowering effect in rats of FCE 21336, pergolide and bromocriptine. J Endocrinol Invest 1984; 7: 32

Administration

Bromocriptine

• starting doses 1.25 mg daily

cabergoline

• starting doses 0.25 mg cabergoline weekly

• food before bedtime

Kletzky OA, Vermesh M: Effectiveness of vaginal bromocriptine in treating women with hyperprolactinemia. Fertil Steril 1989; 51: 269-272

Adverse Effects of Dopamine Agonists

• Nausea 50%

• Nasal stuffiness

• Depression

• digital vasospasm

• Postural hypotension

• preexisting psychosis 1.3% : bromocriptine 1

1.Turner TH, Cookson JC, Wass JA,et al

: Psychotic reactions during treatment of pituitary tumours with dopamine agonists. Br Med J (Clin Res Ed) 1984; 289: 1101-1103


• CSF rhinorrhea 6.1% with macroadenomas 1,2

1.Suliman SG, Gurlek A, Byrne JV,et al

: Nonsurgical cerebrospinal fluid rhinorrhea in invasive macroprolactinoma: incidence, radiological, and clinicopathological

features. J Clin Endocrinol Metab 2007; 92: 3829-3835

2.Leong KS, Foy PM, Swift AC,et al

: CSF rhinorrhoea following treatment with dopamine agonists for massive invasive prolactinomas. Clin Endocrinol (Oxf) 2000; 52:

43-49


• High doses of dopamine agonists

with serotoninergic properties – Risk heart valve regurgitation 1

• 155 patients with Parkinson's disease – high doses of ergot-derived dopamine agonists

– significant heart valve regurgitation (moderate to severe, grade3 to 4)

– pergolide (23.4%)

– cabergoline (28.6%)

– non–ergot-derived dopamine agonists (0%)2

1.Schade R, Andersohn F, Suissa S,et al

: Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007; 356: 29-38

2.Zanettini R, Antonini A, Gatto G,et al

: Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med 2007; 356: 39-46

Stop Dopamine agonist

• รักษานานกวา่ 2 ปี

• Prolactin ปกติ

• MRI ไมพ่บก้อน หรือ ลดลง > 50% หรือ

macroprolactinoma ที2น้อยกวา่ 1 cm

• Pregnancy

• amenorrhea

• Regular F/U


Prognosis

• Micro/macroprolactinoma

– Prolactin level increase 80% ใน 8 ปี [recurrent]

– F/U : Prolactin level q 3 mo � 1 yr q 1yr� 5yr


Follow up

• No medication– prolactin level q 1 yr

– MRI : increase prolactin, mass effect

• Dopamine agonist – Prolactin level After Tx 1 mo then q 3-6mo

– MRI 3mo then q 1yr

• VF defect – After Tx 2-4 weeks


surgery

• Prolactin ลด ใน 1-12 สปัดาห์

• อตัราการหาย

– Microprolactinoma : 75-90%

– Macroprolactinoma : 18-80%

• Post op.D1 prolactin < 10 ng/ml resolve


Surgery indication

• Pituitary apoplexy• Cerebrospinal fluid fistula หลงัการรักษา Dopamine

agonist

• Intolerant S/E

• Non respond to medication– Macroprolactinoma – Microprolactinoma ในผู้หญิงที2ต้องการมีบตุร– ก้อนขนาดใหญ่ขึ %น– VF ไมด่ีขึ %น– Cystic prolactinoma


Radiation Therapy

• takes years to achieve maximal effect

• radiation dose is 4500 to 4600 centigray (cGy)

– normalization of PRL in 18 of 36 patients at a mean of 7.3 years after such treatment 1

• side effect of irradiation.

– Hypopituitarism

– Five years after radiotherapy (3750 to 4250 cGy) 2

1.Tsagarakis S, Grossman A, Plowman PN,et al

: Megavoltage pituitary irradiation in the management of prolactinomas: long-term follow-up. Clin Endocrinol (Oxf) 1991; 34: 399-406

2.Littley MD, Shalet SM, Beardwell CG,et al

: Hypopituitarism following external radiotherapy for pituitary tumours in adults. Q J Med 1989; 70: 145-160

radiation

• Respond 30%

• Use control of tumor growth

• not as effective as dopamine agonists

• S/E

– Hypopituitary

– Optic nerve

– Tumor


Adverse Effects

• in 165 patients

– 100% GH deficient

– 91% gonadotrophin deficient

– 77%ACTH deficient

– 42% were TSH deficient

1.Tsagarakis S, Grossman A, Plowman PN,et al

: Megavoltage pituitary irradiation in the management of prolactinomas: long-term follow-up. Clin

Endocrinol (Oxf) 1991; 34: 399-406

Pregnancy

• หยดุ Bromocriptine – ยกเว้น macroprolactinoma ที2ยงัไม่ได้ รับการผ่าตดัหรือ ฉายแสง– รับประทานตลอดการตั %งครรถ์

• Macorprolactinoma 30%progress mass effectขณะตั %งครรภ์ 1

• Post surgery/radiation 3% progress mass effect ขณะตั %งครรภ์ 2

• F/U eye q 3 mo

• Mass effect : bromocriptine or high dose steroid

1.Gilam MP, el at. Advance of treatment prolactinomas. Endocr Rev 2006;27:485-534

2.Melmed S, el at. Diagnosis and treatment hyperprolactinemia: endocrine Society clinical practice guideline . J Clin EndocrinolMetb 2011;96:273-88

Dopamine agonist resistant

Prolactinoma

Micro 10% macro 18%

No normal prolactine level

• Bromocriptine 15 mg/day

• Carbergoline 1.5-2 mg/day

• >=3 mo.

Or

• High dose to tolerate and decrease size < 50%

Gilam MP, el at. Advance of treatment prolactinomas. Endocr Rev 2006;27:485-534

Management dopamine agonist

resistant prolactinoma

• Bromocritine � carbergoline

• ผา่ตดั

• ฉายแสง


hyperprolactinemia & prolactinoma - medkorat.in.th [read...objective • hypothalamic-pituitary...

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