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lactin during pregnancy, and levels rise after exer-

cise, meals, and stimulation of the chest wall. Phys-

ical and psychological stress increases the secretion

of prolactin, but the level rarely exceeds 40 g per

liter. Breast examination is infrequently associated

with elevation of the prolactin level.

12

Metoclopramide, phenothiazines, and butyro-phenones antagonize lactotroph dopamine recep-

tors, leading to prolactin levels that exceed 100 g

per liter.

13

Risperidone causes a similar elevation,

and monoamine oxidase inhibitors and tricyclic

antidepressants raise prolactin levels through ef-

fects on the delivery of dopamine to the portal ves-

sels.

13,14

Serotonin-reuptake inhibitors may cause

hyperprolactinemia, but the prolactin levels rarely

exceed the normal range.

15

Nearly 10 percent of

patients taking verapamil have elevated prolactin

levels, but other calcium-channel blockers are not

associated with hyperprolactinemia.

16

Less com-

monly used antihypertensive agents that are asso-ciated with hyperprolactinemia include reserpine

and methyldopa.

17

Prolactin levels may also be mild-

ly elevated after the administration of estrogen.

18

The magnitude of medication-induced elevations

in the prolactin level is variable, and the level re-

turns to normal within days after the cessation of

therapy.

19

In general, medication-induced hyper-

prolactinemia is associated with levels of prolactin

in the range of 25 to 100 g per liter.

Craniopharyngioma, acromegaly, granuloma-

tous infiltration of the hypothalamus, severe head

trauma, and large nonfunctioning pituitary tumors

may also lead to hyperprolactinemia. In patientswith acromegaly, prolactin may be secreted along

with growth hormone. The development of large

nonfunctioning pituitary tumors can compress the

pituitary stalk and lead to prolactin levels in the

range of 25 to 200 g per liter, with increases to

levels of less than 100 g per liter in most cases.

20

In some patients with primary hypothyroidism, mild

hyperprolactinemia develops owing to the increased

synthesis of thyrotropin-releasing hormone.

21

Pro-

lactin levels are elevated in patients with chronic

renal failure because of decreased clearance of the

hormone.

22

When no cause of hyperprolactinemia can be

identified, the diagnosis is idiopathic hyperpro-

lactinemia. A prolactinoma may be present but may

be too small to be detected radiographically. In one

third of patients with idiopathic hyperprolactine-

mia, the level of prolactin later returns to the normal

range, and in nearly half, it remains unchanged.

2,23

In one study, only 10 percent of patients with idio-

pathic hyperprolactinemia had radiographic evi-

dence of a pituitary tumor during a follow-up peri-

od of six years.

23

diagnostic studies

A single measurement of the prolactin level in a

blood sample obtained at any time of the day is usu-

ally adequate to document hyperprolactinemia. Be-

cause of the pulsatile nature of prolactin secretion

and the effect of stress, a test that shows a level of

25 to 40 g per liter should be repeated before hy-

perprolactinemia is diagnosed. Most causes of hy-

perprolactinemia can be ruled out on the basis of

the history and physical examination, a pregnancy

test, and assessments of thyroid function and renal

function. Provocative tests with the use of insulin-

induced hypoglycemia, levodopa, and thyrotropin-releasing hormone are not helpful in the evaluation

of patients for hyperprolactinemia.

When other causes of hyperprolactinemia have

been ruled out, the diagnosis of a prolactinoma is

confirmed by gadolinium-enhanced MRI. Comput-

ed tomography with intravenous contrast enhance-

ment is an alternative, but MRI is more effective in

revealing small adenomas and the extension of large

tumors.

24

Prolactinomas are classified as micro-

adenomas if they are less than 10 mm in diameter

(Fig. 1A) and as macroadenomas if they are 10 mm

or greater in diameter (Fig. 1B). Patients with mac-

roadenomas that extend beyond the sella should un-dergo visual-field examination and testing of ante-

rior pituitary function.

In general, serum prolactin levels parallel tumor

size fairly closely. Macroadenomas are typically as-

sociated with levels of over 250 g per liter, and in

some cases the level exceeds 1000 g per liter. Care

must be taken in interpreting a moderate elevation

of the prolactin level (

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nadal dysfunction, and the patients desires with

respect to fertility. The primary therapy for all pro-

lactinomas is a dopamine agonist. Transsphenoi-

dal surgery does not reliably lead to a long-term

cure,

26,27

and a recurrence of hyperprolactinemia

is common.

28,29

The dopamine agonists approved

for use in the United States are bromocriptine and

cabergoline. Bromocriptine is an ergot derivative

that has been used for two decades and is now off

patent. Cabergoline is a nonergot agonist with ahigh affinity for lactotroph dopamine receptors.

Microadenomas

Both bromocriptine and cabergoline decrease pro-

lactin secretion and reduce the size of tumors,

30

but

on the basis of its safety record in pregnancy, bro-

mocriptine is the treatment of choice when resto-

ration of fertility is the patients goal. Bromocrip-

tine normalizes the secretion of prolactin in 82

percent of women with microadenomas and re-

stores menses and fertility in over 90 percent.

30

Therapy is initiated with a dose of 0.625 mg ad-

ministered at bedtime with a snack. After one week,

a morning dose of 1.25 mg is added to the regimen.

At weekly intervals, the dose is increased by 1.25 mg,

for a total dose of 5.0 mg, and the immunoradiomet-

ric assay for prolactin is repeated after one month.

A daily dose of 5.0 to 7.5 mg is usually required to

restore menses and normalize the level of prolac-

tin, and for maximal effect, the drug should be ad-

ministered twice daily. Side effects, including nau-

sea, orthostatic hypotension, and depression, are

minimized if the therapy is initiated at night. Intra-

vaginal administration is associated with dimin-

ished gastrointestinal side effects, and the effect of

the drug lasts for 24 hours.

31,32

Some vaginal irri-

tation may occur, but, in general, this approach is

well tolerated.

31,32

In most women, a regimen of 2.5

to 5.0 mg daily is necessary to normalize the level ofprolactin.

Women should be advised to use a mechanical

form of contraception until two regular menstrual

periods have occurred, and bromocriptine should

be stopped when one menstrual cycle has been

missed. Used in this fashion, bromocriptine has

not been associated with an increased incidence

of spontaneous abortion, ectopic pregnancy, or con-

genital malformation.

33

Among infants of moth-

ers who conceived after taking cabergoline, the in-

cidence of congenital malformations is no higher

than that in the general population, but the num-

ber of pregnancies studied has been small.

34,35

Un-

til there is more information about cabergoline-

induced pregnancy, cabergoline should not be used

as a therapy for infertility.

The risk of symptomatic enlargement of a mi-

croadenoma during pregnancy is about 1 percent.

Formal visual-field testing is not necessary during

Figure 1. Gadolinium-Enhanced, T

1

-Weighted Coronal MRI Scans Showing a Microadenoma and a Macroadenoma.

The microadenoma (arrow, Panel A) is a hypodense intrasellar mass, 4 mm in diameter. The macroadenoma (arrow,Panel B) is a mass, 1 cm in diameter, with extension toward the optic chiasm.

BA

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2038

pregnancy,

33

nor is serial measurement of prolac-

tin levels, because increased levels do not correlate

reliably with tumor enlargement. Lactation is not

associated with tumor growth. Women wishing to

breast-feed their infants should not be given bro-

mocriptine.

Transsphenoidal surgery is an option in an in-fertile patient who cannot tolerate bromocriptine

or in whom bromocriptine is ineffective. Surgery

for microadenomas has a success rate of 74 per-

cent,

36

but higher rates have been achieved among

carefully selected patients with prolactin levels that

were lower than 200 g per liter, small tumors, and

a short duration of amenorrhea.

26,27

In 95 percent of patients with microadenomas,

the tumors do not progressively increase in size,

2-4

so that suppression of tumor growth is not an in-

dication for therapy. When pregnancy is not an is-

sue, either bromocriptine or cabergoline will restore

menses and eliminate galactorrhea. Bromocrip-tine is less expensive but requires administration

twice daily; about 5 percent of patients cannot tol-

erate bromocriptine, and in 10 percent it is not ef-

fective.

33

Cabergoline appears to be more effective

in decreasing prolactin secretion and restoring ovu-

latory cycles; it is effective in 70 percent of patients

who do not have a response to bromocriptine and

is associated with fewer side effects.

37,38

Caber-

goline therapy is begun at a dose of 0.25 mg ad-

ministered twice weekly, and the dose is increased

monthly until prolactin secretion normalizes, to a

maximal dose of 1 mg twice weekly; doses ranging

from 0.25 to 0.5 mg twice weekly are usually suffi-cient to normalize the prolactin level.

37

The use of a dopamine agonist should be con-

tinued unless the patient becomes pregnant, and

the prolactin level should be checked yearly. In some

patients, the drug may ultimately be discontinued.

In approximately 25 percent of women treated with

bromocriptine for at least 24 months, the prolactin

level remains normal after the discontinuation of

therapy.

39,40

If the prolactin level does not return to

the normal range with therapy, or if the patient can-

not tolerate the first dopamine agonist, changing

to the other drug may be effective.

When fertility is not a concern, another option

is to treat microadenomas with an oral contracep-

tive that contains estrogen and a progestin. This

therapy will not normalize bone density, but it may

prevent progressive bone loss. Although estrogen

can induce lactotroph hyperplasia, short-term use

of oral contraceptives in women with microadeno-

mas does not appear to be associated with tumor

growth.

41,42

A woman with a microadenoma who

is taking estrogen will need to have her prolactin lev-

els measured yearly. MRI should be repeated if clin-

ical signs of tumor expansion appear or if the pro-

lactin level exceeds 250 g per liter.

Macroadenomas

Because of the large potential for growth, a mac-

roadenoma is an absolute indication for therapy.

Treatment should be initiated with a dopamine ago-

nist and should be managed by an endocrinologist.

Both of the dopamine agonists that are currently

available provide effective therapy for macroade-

nomas,

37,43

but, as in patients with microadeno-

mas, bromocriptine should be used when fertility

is the goal of treatment.

A macroadenoma that is confined to the sella is

not likely to enlarge sufficiently during pregnancy

to cause clinically serious complications, and pa-tients with intrasellar macroadenomas who wish to

become pregnant should be followed in the same

way as patients with microadenomas. When supra-

sellar extension of a macroadenoma is detected in

a patient who wishes to become pregnant, there is

a 15 to 35 percent risk of tumor enlargement dur-

ing gestation.

33

These tumors should be surgically

debulked before pregnancy, and after surgery, ther-

apy with bromocriptine should be initiated. Bro-

mocriptine has been used throughout pregnancy

in a small number of patients, without major com-

plications or fetal abnormalities,

44

and its use is

probably less harmful than surgical interventionduring pregnancy.

45

Visual-field testing should be

performed at least once every three months during

pregnancy, and MRI should be repeated if symp-

toms of tumor enlargement develop.

Hypogonadism

When fertility is not an issue, the goals of treatment

are restoration of gonadal function and reduction

of the size of the tumor. Either dopamine agonist

can be used, but cabergoline may be more effective

in reducing the prolactin levels, decreasing the size

of the tumor, and eliminating visual-field abnor-

malities.

46

There have been no studies that directly

compared the efficacy of cabergoline with that of

bromocriptine for the treatment of macroadeno-

mas, but cabergoline has been shown to be effective

for bromocriptine-resistant tumors.

46

Patients with macroadenomas generally require

higher doses of bromocriptine (usual range, 7.5 to




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2039

10.0 mg daily) or cabergoline (usual range, 0.5 to

1.5 mg twice weekly) than do patients with micro-

adenomas. With both dopamine agonists, a de-

crease in prolactin levels occurs within two to three

weeks after treatment begins and usually precedes

a decrease in the size of the tumor and the restora-

tion of anterior pituitary function.

43

The length oftime necessary to achieve a reduction in tumor size

ranges from weeks to years.

43,47-49

Visual-field test-

ing should be repeated one month after the initia-

tion of therapy, and MRI should be repeated after

six months of treatment. Prolactin levels should be

measured yearly.

When the prolactin level has been normal for

two years and the size of the tumor has decreased

by at least 50 percent, the dose of cabergoline or

bromocriptine can be gradually decreased, with

close follow-up to rule out tumor enlargement. Af-

ter two years of uninterrupted therapy, even low

doses of these medications inhibit prolactin secre-tion and control tumor growth.

48

In patients with

macroadenomas, discontinuation of the drug usu-

ally leads to renewed expansion of the tumor and

to a recurrence of hyperprolactinemia and should

therefore be undertaken with extreme caution.

Given the potential for growth of macroadeno-

mas, the use of estrogen is generally discouraged. If

a macroadenoma does not respond to medical ther-

apy, transsphenoidal surgery should be undertak-en. Surgery is rarely curative, however, and therapy

with a dopamine agonist will be necessary after-

ward to normalize prolactin secretion. External ra-

diation may be required if substantial tumor tissue

remains after surgery. The major side effects of ra-

diation therapy are hypopituitarism, damage to the

optic nerve, and neurologic dysfunction.

There is limited information regarding the effects

of the discontinuation of therapy for prolactinoma.

Studies of patients with microadenomas or mac-roadenomas that were treated with bromocriptine

over a period of 24 to 48 months have shown that

areas of un cert ai n t y

Figure 2. Management of Prolactinoma in Women.

Hyperprolactinemia

Rule out secondary causes

MRI

Intrasellar Suprasellar

Microadenoma

Infertility Amenorrhea


BromocriptineDopamine

agonist


Bromocriptine,surgery, or both

Dopamineagonist, surgery,

or both

Regularmenses

Macroadenoma

BromocriptineNo treatmentDopamineagonist orestrogen

progesterone




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15.

Urban RJ, Veldhuis JD. A selective sero-

tonin reuptake inhibitor, fluoxetine hydro-

chloride, modulates the pulsatile release of

prolactin in postmenopausal women. Am

J Ob stet Gynecol 1991;164:147-52.

16.

Fearrington E, Rand CH Jr, Rose JD. Hy-

perprolactinemia-galactorrhea induced by

verapamil. Am J Cardiol 1983;51:1466-7.

17.

Steiner J, Cassar J, Mashiter K, Dawes I,

Fraser TR, Breckinridge A. Effects of meth-

yldopa on prolactin and growth hormone.

Br Med J 1976;1:1186-8.

18.

Yen SS, Ehara Y, Siler TM. Augmenta-

tion of prolactin secretion by estrogen in hy-

pogonadal women. J Clin Invest 1974;53:

652-5.

19.

Rivera JL, Lal S, Ettigi P, Hontela S, Muller

HF, Friesen HG. Effect of acute and chronic

neuroleptic therapy on serum prolactin levels

in men and women of different age groups.

Clin Endocrinol 1976;5:273-82.

20.

Arafah MB, Nekl KE, Gold RS, Selman

WR. Dynamics of prolactin secretion in pa-

tients with hypopituitarism and pituitary

macroadenomas. J Clin Endocrinol Metab

1995;80:3507-12.

21.

Snyder PJ, Jacobs LS, Utiger RD, Daugh-

aday WH. Thyroid hormone inhibition of the

prolactin response to thyrotropin-releasing

hormone. J Clin Invest 1973;52:2324-9.

22.

Sievertsen GD, Lim VS, Nakawatase C,

Frohman LA. Metabolic clearance and secre-

tion rates of human prolactin in normal

subjects and in patients with chronic renal

failure. J Clin Endocrinol Metab 1980;50:

846-52.

23.

Sluijmer AV, Lappohn RE. Clinical his-

tory and outcome of 59 patients with idio-

pathic hyperprolactinemia. Fertil Steril 1992;

58:72-7.

24.

Naidich MJ, Russell EJ. Current ap-

proaches to imaging of the sellar region and

pituitary. Endocrinol Metab Clin North Am

1999;28:45-79.

25.

St-Jean E, Blain F, Comtois R. High pro-

lactin levels may be missed by immunora-

diometric assay in patients with macropro-

lactinomas. Clin Endocrinol (Oxf ) 1996;44:

305-9.

26.

Aron DC, Tyrrell JB, Wilson CB. Pituitary

tumors: current concepts in diagnosis and

management. World J Med 1995;162:340-

52.

27.

Losa M, Mortini P, Barzaghi R, Gioia L,

Giovanelli M. Surgical treatment of prolac-

tin-secreting pituitary adenomas: early re-

sults and long-term outcome. J Clin Endo-

crinol Metab 2002;87:3180-6.

28.

Serri O, Rasio E, Beauregard H, Hardy J,

Somma M. Recurrence of hyperprolactine-

mia after selective transsphenoidal adeno-

mectomy in women with prolactinoma.

N Engl J Med 1983;309:280-3.

29.

Schlechte JA, Sherman BM, Chapler FK,

VanGilder J. Long-term follow-up of women

with surgically treated prolactin-secreting

pituitary tumors. J Clin Endocrinol Metab

1986;62:1296-301.

30.

Bevan JS, Webster J, Burke CW, Scanlon

MF. Dopamine agonists and pituitary tumor

shrinkage. Endocr Rev 1992;13:220-40.

31.

Jasonni VM, Raffeilli R, de March A,

Frank G, Flamigni C. Vaginal bromocriptine

in hyperprolactinemic patients and puerper-

al women. Acta Obstet Gynecol Scand 1991;

70:493-5.

32.

Kletzky OA, Vermesh M. Effectiveness

of vaginal bromocriptine in treating women

with hyperprolactinemia. Fertil Steril 1989;

51:269-72.

33.

Molitch M. Pregnancy and the hyper-

prolactinemic woman. N Engl J Med 1985;

23:1364-70.

34.

Robert E, Musatti L, Piscitelli G, Ferrari

CI. Pregnancy outcome after treatment with

the ergot derivative, cabergoline. Reprod Tox-

icol 1996;10:333-7.

35.

Ricci E, Parazzini F, Motta T, et al. Preg-

nancy outcome after cabergoline treatment

in early weeks of gestation. Reprod Toxicol

2002;16:791-3.

36.

Molitch M. Prolactinomas. In: Melmed

S, ed. The pituitary. 2nd ed. Malden, Mass.:

Blackwell, 2002:455-95.

37.

Webster J, Piscitelli G, Polli A, Ferrari CI,

Ismail I, Scanlon MF. A comparison of ca-

bergoline and bromocriptine in the treatment

of hyperprolactinemic amenorrhea. N Engl

J Med 1994;331:904-9.

38.

Colao A, DiSarno A, Sarnacchiaro S, et

al. Prolactinomas resistant to standard do-

pamine agonists respond to chronic caber-

goline treatment. J Clin Endocrinol Metab

1997;82:876-83.

39.

Jeffcoate WJ, Pound N, Sturrock ND,

Lambourne J. Long-term follow-up of pa-

tients with hyperprolactinaemia. Clin Endo-

crinol (Oxf) 1996;45:299-303.

40.

Passos VQ, Souza JJ, Musolino NR, Bron-

stein MD. Long-term follow-up of prolacti-

nomas: normoprolactinemia after bromo-

criptine withdrawal. J Clin Endocrinol Metab

2002;87:3578-82.

41.

Corenblum B, Donovan L. The safety of

physiological estrogen plus progestin re-

placement therapy and with oral contracep-

tive therapy in women with pathological

hyperprolactinemia. Fertil Steril 1993;59:

671-3.

42.

Fahy UM, Foster PA, Torode HW, Har-

tog M, Hull MG. The effect of combined es-

trogen/progestogen treatment in women

with hyperprolactinemic amenorrhea. Gy-

necol Endocrinol 1992;6:183-8.

43.

Molitch ME, Elton RL, Blackwell RE, et

al. Bromocriptine as primary therapy for pro-

lactin-secreting macroadenomas: results of

a prospective multicenter study. J Clin Endo-

crinol Metab 1985;60:698-705.

44.

Konopka P, Raymond JP, Merceron RE,

Seneze J. Continuous administration of bro-

mocriptine in the prevention of neurological

complications in pregnant women with pro-

lactinomas. Am J Obstet Gynecol 1983;146:

935-8.

45.

Brodsky JB, Cohen EN, Brown BW Jr,

Wu ML, Whitcher C. Surgery during preg-

nancy and fetal outcome. Am J Obstet Gy-

necol 1980;138:1165-7.

46.

Verhelst J, Abs R, Maiter D, et al. Caber-

goline in the treatment of hyperprolactine-

mia: a study in 455 patients. J Clin Endocrinol

Metab 1999;84:2518-22.

47.

Warfield A, Finkel DM, Schatz NJ, Savi-

no PJ, Snyder PJ. Bromocriptine treatment of

prolactin-secreting pituitary adenomas may

restore pituitary function. Ann Intern Med

1984;101:783-5.

48.

Liuzzi A, Dallabonzana D, Oppizzi G, et

al. Low doses of dopamine agonists in the

long-term treatment of macroprolactinomas.

N Engl J Med 1985;313:656-9.

49. Rasmussen C, Bergh T, Wide L. Prolactin

secretion and menstrual function after long-

term bromocriptine treatment. Fertil Steril

1987;48:550-4.

50. Vant Verlaat JW, Croughs RJ. Withdraw-

al of bromocriptine after long-term therapy

for macroprolactinomas: effect on plasma

prolactin and tumor size. Clin Endocrinol

1991;34:175-8.

51. Johnston DG, Hall K, Kendall-Taylor P,

Patrick D, Watson M, Cook DB. Effect of do-

pamine agonist withdrawal after long-term

therapy in prolactinomas: studies with high-

definition computerised tomography. Lan-

cet 1984;2:187-92.

52. Wang C, Lam KS, Ma JT, Chan T, Liu MY,

Yeung RT. Long-term treatment of hyper-

prolactinaemia with bromocriptine: effect

of drug withdrawal. Clin Endocrinol (Oxf)

1987;27:363-71.

53. Zarate A, Canales ES, Cano C, Pilonieta

CJ. Follow-up of patients with prolactino-

mas after discontinuation of long-term ther-

apy with bromocriptine. Acta Endocrinol

(Copenh) 1983;104:139-42.

54. Colao A, Di Sarno A, Cappabianca P,

Di Somma C, Pivonello R, Lombardi G. With-

drawal of long-term cabergoline therapy for

tumoral and nontumoral hyperprolactine-

mia. N Engl J Med 2003;349:2021-31.

55. Gen M, Uozumi T, Ohta M, Ito A, Kaji-

wara H, Mori S. Necrotic changes in prolac-

tinomas after long term administration of

bromocriptine. J Clin Endocrinol Metab

1984;59:463-70.

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