Prolactinoma (Caso Clínico)

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clinical practice

This

Journal

feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines,

when they exist. The article ends with the authors clinical recommendations.

Prolactinoma

Janet A. Schlechte, M.D.

From the Department of Internal Medicine,University of Iowa, Iowa City. Address re-print requests to Dr. Schlechte at the De-partment of Internal Medicine, 157 MRF,University of Iowa Hospitals and Clinics,200 Hawkins Dr., Iowa City, IA 52242, or [email protected].

N Engl J Med 2003;349:2035-41.

Copyright 2003 Massachusetts Medical Society.

A 22-year-old woman who wants to become pregnant has had no menses since shediscontinued the use of an oral contraceptive one year ago, and recently, galactorrheadeveloped. She takes no medications and has had no headaches, visual loss, dyspareu-nia, or decreased libido. Physical examination shows no abnormalities, except for thebilateral breast discharge. A test for serum human chorionic gonadotropin is nega-tive, the thyrotropin level is normal, and the serum prolactin level is 95 g per liter.Magnetic resonance imaging (MRI) reveals a mass, 3 mm in diameter, in the anteriorlobe of the pituitary. How should she be treated?

Prolactin-secreting tumors are benign neoplasms that account for about 40 percent ofall pituitary tumors. Over 90 percent are small, intrasellar tumors that rarely increase insize.

1-4

The primary action of prolactin is to stimulate lactation, but it is the effect ofprolactin on gonadal function that warrants clinical attention. Hypersecretion of pro-lactin leads to infertility and gonadal dysfunction by interrupting secretion of gonado-tropin-releasing hormone, inhibiting the release of luteinizing hormone and follicle-stimulating hormone, and impairing gonadal steroidogenesis.

5,6

clinical presentation

The most common symptoms of hyperprolactinemia in premenopausal women areamenorrhea and infertility. Galactorrhea occurs in about 80 percent of such women,and some women with prolactinomas have infrequent menstrual flow (oligomenor-rhea) or regular menses.

1

Hyperprolactinemia is often detected after discontinuationof the use of an oral contraceptive, but there is no apparent relation between the use oforal contraceptives and the formation of prolactinomas.

7

The majority of prolactinomasin women are small at the time of diagnosis, and headaches and neurologic deficits arerare.

1

In contrast, prolactinomas in men typically tend to be large at the time of diagno-sis and may cause cranial-nerve dysfunction, visual loss, and hypopituitarism.

8

In men,hyperprolactinemia leads to impotence, infertility, and decreased libido, but these arerarely the initial symptoms; galactorrhea and gynecomastia are uncommon.

8

In bothsexes, long-standing hyperprolactinemia leads to low bone density in the spine.

9-11

After prolactin has returned to the normal range, bone density will increase but doesnot reach normal values.

9-11

causes of hyperprolactinemia

The secretion and release of prolactin are mediated by dopamine, and any process thatdisrupts dopamine secretion or interferes with the delivery of dopamine to the portalvessels may cause hyperprolactinemia. Normal prolactin levels in women and men arebelow 25 g per liter and 20 g per liter, respectively. There is a 10-fold increase in pro-

the clinical problem

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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 secretionof prolactin, but the level rarely exceeds 40 g perliter. Breast examination is infrequently associatedwith elevation of the prolactin level.

12

Metoclopramide, phenothiazines, and butyro-phenones antagonize lactotroph dopamine recep-tors, leading to prolactin levels that exceed 100 gper liter.

13

Risperidone causes a similar elevation,and monoamine oxidase inhibitors and tricyclicantidepressants raise prolactin levels through ef-fects on the delivery of dopamine to the portal ves-sels.

13,14

Serotonin-reuptake inhibitors may causehyperprolactinemia, but the prolactin levels rarelyexceed the normal range.

15

Nearly 10 percent ofpatients taking verapamil have elevated prolactinlevels, but other calcium-channel blockers are notassociated with hyperprolactinemia.

16

Less com-monly used antihypertensive agents that are asso-ciated with hyperprolactinemia include reserpineand methyldopa.

17

Prolactin levels may also be mild-ly elevated after the administration of estrogen.

18

The magnitude of medication-induced elevationsin the prolactin level is variable, and the level re-turns to normal within days after the cessation oftherapy.

19

In general, medication-induced hyper-prolactinemia is associated with levels of prolactinin the range of 25 to 100 g per liter.

Craniopharyngioma, acromegaly, granuloma-tous infiltration of the hypothalamus, severe headtrauma, and large nonfunctioning pituitary tumorsmay also lead to hyperprolactinemia. In patientswith acromegaly, prolactin may be secreted alongwith growth hormone. The development of largenonfunctioning pituitary tumors can compress thepituitary stalk and lead to prolactin levels in therange of 25 to 200 g per liter, with increases tolevels of less than 100 g per liter in most cases.

20

In some patients with primary hypothyroidism, mildhyperprolactinemia develops owing to the increasedsynthesis of thyrotropin-releasing hormone.

21

Pro-lactin levels are elevated in patients with chronicrenal failure because of decreased clearance of thehormone.

22

When no cause of hyperprolactinemia can beidentified, the diagnosis is idiopathic hyperpro-lactinemia. A prolactinoma may be present but maybe too small to be detected radiographically. In onethird of patients with idiopathic hyperprolactine-mia, the level of prolactin later returns to the normalrange, 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 ablood sample obtained at any time of the day is usu-ally adequate to document hyperprolactinemia. Be-cause of the pulsatile nature of prolactin secretionand the effect of stress, a test that shows a level of25 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 ofthe history and physical examination, a pregnancytest, and assessments of thyroid function and renalfunction. Provocative tests with the use of insulin-induced hypoglycemia, levodopa, and thyrotropin-releasing hormone are not helpful in the evaluationof patients for hyperprolactinemia.

When other causes of hyperprolactinemia havebeen ruled out, the diagnosis of a prolactinoma isconfirmed by gadolinium-enhanced MRI. Comput-ed tomography with intravenous contrast enhance-ment is an alternative, but MRI is more effective inrevealing small adenomas and the extension of largetumors.

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 mmor 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 tumorsize fairly closely. Macroadenomas are typically as-sociated with levels of over 250 g per liter, and insome cases the level exceeds 1000 g per liter. Caremust be taken in interpreting a moderate elevationof the prolactin level (

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nadal dysfunction, and the patients desires withrespect to fertility. The primary therapy for all pro-lactinomas is a dopamine agonist. Transsphenoi-dal surgery does not reliably lead to a long-termcure,

26,27

and a recurrence of hyperprolactinemiais common.

28,29

The dopamine agonists approvedfor use in the United States are bromocriptine andcabergoline. Bromocriptine is an ergot derivativethat has been used for two decades and is now offpatent. 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

buton 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 82percent 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 torestore 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, areminimized if the therapy is initiated at night. Intra-vaginal administration is associated with dimin-ished gastrointestinal side effects, and the effect ofthe drug lasts for 24 hours.

31,32

Some vaginal irri-tation may occur, but, in general, this approach iswell tolerated.

31,32

In most women, a regimen of 2.5to 5.0 mg daily is necessary to normalize the level ofprolactin.

Women should be advised to use a mechanicalform of contraception until two regular menstrualperiods have occurred, and bromocriptine shouldbe stopped when one menstrual cycle has beenmissed. Used in this fashion, bromocriptine hasnot been associated with an increased incidenceof 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 higherthan 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 usedas 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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pregnancy,

33

nor is serial measurement of prolac-tin levels, because increased levels do not correlatereliably with tumor enlargement. Lactation is notassociated with tumor growth. Women wishing tobreast-feed their infants should not be given bro-mocriptine.

Transsphenoidal surgery is an option in an in-fertile patient who cannot tolerate bromocriptineor in whom bromocriptine is ineffective. Surgeryfor microadenomas has a success rate of 74 per-cent,

36

but higher rates have been achieved amongcarefully selected patients with prolactin levels thatwere lower than 200 g per liter, small tumors, anda 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 restoremenses and eliminate galactorrhea. Bromocrip-tine is less expensive but requires administrationtwice 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 effectivein decreasing prolactin secretion and restoring ovu-latory cycles; it is effective in 70 percent of patientswho do not have a response to bromocriptine andis 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 increasedmonthly until prolactin secretion normalizes, to amaximal dose of 1 mg twice weekly; doses rangingfrom 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, andthe prolactin level should be checked yearly. In somepatients, the drug may ultimately be discontinued.In approximately 25 percent of women treated withbromocriptine for at least 24 months, the prolactinlevel remains normal after the discontinuation oftherapy.

39,40

If the prolactin level does not return tothe normal range with therapy, or if the patient can-not tolerate the first dopamine agonist, changingto the other drug may be effective.

When fertility is not a concern, another optionis to treat microadenomas with an oral contracep-tive that contains estrogen and a progestin. Thistherapy will not normalize bone density, but it mayprevent progressive bone loss. Although estrogencan induce lactotroph hyperplasia, short-term useof oral contraceptives in women with microadeno-

mas does not appear to be associated with tumorgrowth.

41,42

A woman with a microadenoma whois 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 currentlyavailable provide effective therapy for macroade-nomas,

37,43

but, as in patients with microadeno-mas, bromocriptine should be used when fertilityis the goal of treatment.

A macroadenoma that is confined to the sella isnot likely to enlarge sufficiently during pregnancyto cause clinically serious complications, and pa-tients with intrasellar macroadenomas who wish tobecome pregnant should be followed in the sameway as patients with microadenomas. When supra-sellar extension of a macroadenoma is detected ina patient who wishes to become pregnant, there isa 15 to 35 percent risk of tumor enlargement dur-ing gestation.

33

These tumors should be surgicallydebulked before pregnancy, and after surgery, ther-apy with bromocriptine should be initiated. Bro-mocriptine has been used throughout pregnancyin a small number of patients, without major com-plications or fetal abnormalities,

44

and its use isprobably less harmful than surgical interventionduring pregnancy.

45

Visual-field testing should beperformed at least once every three months duringpregnancy, and MRI should be repeated if symp-toms of tumor enlargement develop.

Hypogonadism

When fertility is not an issue, the goals of treatmentare restoration of gonadal function and reductionof the size of the tumor. Either dopamine agonistcan be used, but cabergoline may be more effectivein reducing the prolactin levels, decreasing the sizeof the tumor, and eliminating visual-field abnor-malities.

46

There have been no studies that directlycompared the efficacy of cabergoline with that ofbromocriptine for the treatment of macroadeno-mas, but cabergoline has been shown to be effectivefor bromocriptine-resistant tumors.

46

Patients with macroadenomas generally requirehigher doses of bromocriptine (usual range, 7.5 to


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10.0 mg daily) or cabergoline (usual range, 0.5 to1.5 mg twice weekly) than do patients with micro-adenomas. With both dopamine agonists, a de-crease in prolactin levels occurs within two to threeweeks after treatment begins and usually precedesa 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 sizeranges 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 aftersix months of treatment. Prolactin levels should bemeasured yearly.

When the prolactin level has been normal fortwo years and the size of the tumor has decreasedby at least 50 percent, the dose of cabergoline orbromocriptine can be gradually decreased, withclose follow-up to rule out tumor enlargement. Af-ter two years of uninterrupted therapy, even lowdoses of these medications inhibit prolactin secre-tion and control tumor growth.

48

In patients withmacroadenomas, discontinuation of the drug usu-

ally leads to renewed expansion of the tumor andto a recurrence of hyperprolactinemia and shouldtherefore be undertaken with extreme caution.

Given the potential for growth of macroadeno-mas, the use of estrogen is generally discouraged. Ifa macroadenoma does not respond to medical ther-apy, transsphenoidal surgery should be undertak-en. Surgery is rarely curative, however, and therapywith a dopamine agonist will be necessary after-ward to normalize prolactin secretion. External ra-diation may be required if substantial tumor tissueremains after surgery. The major side effects of ra-diation therapy are hypopituitarism, damage to theoptic nerve, and neurologic dysfunction.

There is limited information regarding the effectsof the discontinuation of therapy for prolactinoma.Studies of patients with microadenomas or mac-roadenomas that were treated with bromocriptineover a period of 24 to 48 months have shown that

areas of uncertainty

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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in 6 to 37 percent of patients, prolactin levels re-main normal after the withdrawal of bromocrip-tine.

40,47-53

Elsewhere in this issue of the

Journal,

Colao et al. report that prolactin levels remainednormal in over 60 percent of patients after the with-drawal of cabergoline.

54

Although there are no pre-cise criteria for predicting whether drug withdraw-al will be successful, this prospective analysis ofcabergoline withdrawal and the retrospective stud-ies conducted with bromocriptine suggest that life-long treatment of hyperprolactinemia may not beinevitable. Possible explanations for the persistenceof normal prolactin levels after drug withdrawal in-clude a cytocidal effect of the dopamine agonist andthe natural history of the tumor.

39,40,55

There are no formal guidelines for the managementof prolactinoma.

The diagnosis of a prolactinoma is established onthe basis of a sustained elevation of serum levels ofprolactin and radiographic evidence of a pituitaryadenoma after other causes of hyperprolactinemiahave been ruled out. The indications for therapy in-clude infertility, the presence of a macroadenoma,and hypogonadism. The primary therapy for all pro-lactinomas is a dopamine agonist. Bromocriptineand cabergoline are both effective in reducing thesize of the tumor and restoring gonadal function,

but bromocriptine should be used when pregnancyis the goal (Fig. 2). Cabergoline is more expensivethan bromocriptine but easier to administer, usuallybetter tolerated, and effective in patients who do nothave a response to bromocriptine. Surgery is rarelycurative in patients with prolactinomas and shouldbe recommended only when medical therapy is in-effective. Although discontinuation of drug therapyfor macroadenomas usually leads to recurrent hy-perprolactinemia and expansion of the tumor, thedose of the medication can often be decreased af-ter two years or more of therapy. My approach is totaper the medication at three-month intervals (re-ducing the weekly dose of cabergoline by 0.25 mgor the daily dose of bromocriptine by 2.5 mg), checkthe prolactin level after each dose reduction, and ob-tain an MRI scan six months after the initiation oftapering, in order to rule out tumor enlargement.

The young woman described in the vignettehas a prolactin-secreting microadenoma. There isno indication to test for anterior pituitary dysfunc-tion or to perform formal visual-field testing. Sheshould be treated with bromocriptine and shoulduse mechanical contraception until regular men-strual cycles have been established. When she be-comes pregnant, the bromocriptine should be dis-continued, though the medication is likely to beneeded again, after pregnancy and lactation. For pa-tients who have been receiving drug therapy fortwo years or more, I would attempt to discontinuethe medication, with reassessment of prolactin lev-els, to determine whether there is an ongoing needfor treatment.

guidelines

conclusionsand recommendations

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Copyright 2003 Massachusetts Medical Society.


Prolactinoma (Caso Clínico)

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