39 mia a y Adenomas Pituitarios

8/6/2019 39 mia a y Adenomas Pituitarios

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Hyperprolactinemia,Galactorrhea, and Pituitary

AdenomasEtiology, Differential Diagnosis, Natural History, ManagementRogerio A. Lobo

39

KEY TERMS AND DEFINITIONS

Bromocriptine (2-Bromo--

Ergocryptine Mesylate). Semisyntheticergot alkaloid that is a dopamine receptoragonist used to treat hyperprolactinemia.

Cabergoline. A long-acting dopaminereceptor agonist that directly inhibitssecretion of prolactin from the pituitaryand is an effective treatment forhyperprolactinemia.

Computed Tomography (CT). Animaging technique for detecting soft tissueabnormalities that uses a computer tointegrate differences in X-ray beamattenuation resulting from varying densitiesin adjacent tissue.

Craniopharyngioma. A rare hypothalamictumor that can produce hyperprolactinemia.

Empty Sella Syndrome. An intrasellar

extension of the subarachnoid space

resulting in compression of the pituitarygland and an enlarged sella turcica that maybe associated with galactorrhea andhyperprolactinemia.

Galactorrhea. Nonpuerperal secretionfrom the breast of watery or milky fluid that

contains neither pus nor blood.

Hyperprolactinemia. Levels of circulatingprolactin above normal (>20 to 25 ng/mL)that can cause galactorrhea or amenorrhea orboth.

Hypocycloidal Tomography. Multipleradiographs of the sella turcica at intervalsof 2 to 3 mm with a hypocycloidalmovement.

Macroadenoma. An uncommon type ofprolactin-secreting pituitary adenoma(prolactinoma) greater than 1 cm in

diameter, usually with extrasellar extension.

Magnetic Resonance Imaging (MRI).

Technique for soft tissue imaging that usesresonance of hydrogen nuclei in a staticmagnetic field exposed to low-frequencyradiowaves.

Microadenoma. The common type ofprolactinoma less than 1 cm in diameter.

Prolactin. Polypeptide hormone secretedby anterior pituitary lactotrophs that hasmammotrophic and lactogenic functions.

Prolactin-Inhibiting Factor. Theneurotransmitter (believed to be dopamine)that inhibits prolactin synthesis andrelease.

Prolactinoma. The most commonpituitary tumor arising from chromophobiccells that secrete prolactin.

963

Prolactin (PRL) is a polypeptide hormone containing 198 aminoacids and having a molecular weight of 22,000 daltons. Itcirculates in different molecular sizes: a monomeric (small) form(mol wt 22,000 daltons), a polymeric (big) form (mol wt50,000 daltons), and an even larger polymeric (big-big) form(mol wt > 100,000 daltons). Big PRL is presumed to be a dimer,and big-big PRL may represent an aggregation of monomericmolecules. The larger forms also contain added sugar moieties(glycosylation) which decreases biologic activity. The small formis biologically active, and about 80% of the hormone is secreted

in this form. Most immunoassays measure both the small andlarge forms of PRL. As stated earlier, the polymeric forms havereduced biologic activity and reduced binding to mammarytissue membranes. Women have been identified with high levelsof PRL on routine immunoassay who are completely normaland have been found to have circulating polymeric forms on gelelectrophoresis.

PRL is synthesized and stored in the pituitary gland in chromo-phobe cells called lactotrophs, which are located mainly in thelateral areas of the gland. PRL is encoded by its gene (10 kb) onchromosome 6. At the molecular level, it is stimulated and

suppressed by multiple factors. The principal stimulating factoris thyroid-releasing hormone (TRH), and the major inhibitingfactor is dopamine. Estrogen also enhances PRL secretion byenhancing the effects of TRH and inhibiting the effects ofdopamine. A potential direct effect may also be mediated viagalanin. The principal receptor dopamine interacts with is D2,

which is the target for various dopamine agonists used in thetreatment of hyperprolactinemia.

In addition, PRL is synthesized in decidualized stroma ofendometrial tissue. From these tissues PRL is secreted into the

circulation and, in the event of pregnancy, into the amnioticfluid. The control of decidual PRL is different from that of thepituitary and does not respond to dopamine. PRL is normallypresent in measurable amounts in serum, with mean levels ofabout 8 ng/mL in adult women. It circulates in an unboundform, has a 20-minute half-life, and is cleared by the liver andkidney. The main function of PRL is to stimulate the growth ofmammary tissue as well as to produce and secrete milk into thealveoli; thus, it has both mammogenic and lactogenic functions.Specific receptors for PRL are present in the plasma membraneof mammary cells as well as many other tissues.


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64 REPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY

PHYSIOLOGY

PRL synthesis and release from the lactotrophs are controlledby central nervous system neurotransmitters, which act on thepituitary via the hypothalamus. The major control mechanismis inhibition, as pituitary stalk section results in increased PRLsecretion. It appears that the major physiologic inhibitor of PRLrelease is the neurotransmitter dopamine, which acts directlyon the pituitary gland. There are specific dopamine receptorson the lactotrophs, and dopamine inhibits PRL synthesis andrelease in pituitary cell cultures. Thus dopamine appears to bethe prolactin-inhibiting factor (PIF). Although a hypothalamicprolactin-releasing factor (PRF) has not been isolated, it isknown that both the neurotransmitter serotonin and thyrotropin-releasing factor stimulate PRL release. Since the latter stimulatesPRL release only minimally unless infused, it appears that sero-tonin is PRF or is responsible for its secretion. The rise in PRLlevels during sleep appears to be controlled by serotonin.

PRL is secreted episodically, and serum levels fluctuatethroughout the day and throughout the menstrual cycle, withpeak levels occurring at midcycle. Although changes in PRLlevels are not as marked as the pulsatile episodes of luteinizinghormone (LH), Bckstrm and colleagues reported a declinein both basal concentration and pulse frequency of PRL in theluteal phase of the cycle. Estrogen stimulates PRL productionand release. Under the influence of estrogen, PRL levels increasein females at the time of puberty.

During pregnancy, as estrogen levels increase, there is a con-comitant hypertrophy and hyperplasia of the lactotrophs. Thematernal increase in PRL occurs soon after implantation, con-comitant with the increase in circulating estrogen. Circulatinglevels of PRL steadily increase throughout pregnancy, reachingabout 200 ng/mL in the third trimester, and the rise is directlyrelated to the increase in circulating levels of estrogen. Despitethe elevated PRL levels during pregnancy, lactation does not

occur because estrogen inhibits the action of PRL on the breast,most likely blocking PRLs interaction with its receptor. A day ortwo following delivery of the placenta, both estrogen levels andPRL levels decline rapidly and lactation is initiated. PRL levelsreach basal levels in nonnursing women in 2 to 3 weeks. Althoughbasal levels of circulating PRL decline to the nonpregnant rangeabout 6 months after parturition in nursing women, followingeach act of suckling, PRL levels increase markedly and stimulatemilk production for the next feeding.

Nipple and breast stimulation also increase PRL levels in thenonpregnant female. Other physiologic stimuli that increasePRL release are exercise, sleep, and stress. In addition, PRL levelsnormally rise following ingestion of the noonday meal. Forthese reasons PRL levels normally fluctuate throughout the day,

with maximal levels observed during nighttime while asleep anda smaller increase occurring in the early afternoon (Fig. 39-1).When the amount measured in the circulation in the nonpreg-nant woman exceeds a certain level, usually 20 to 25 ng/mL, thecondition is called hyperprolactinemia. The optimal time toobtain a blood sample for assay to diagnose hyperprolactinemiais during the midmorning hours. Increases in PRL levels abovethe normal range can occur without a pathologic condition ifthe serum sample is drawn from a patient who has recentlyawakened, has exercised, or has had recent breast stimulation,such as breast palpation, during a physical examination.

The most frequent cause of slightly elevated PRL levels isstress, particularly the stress caused by visiting the physiciansoffice. An excellent study demonstrating that most mildly ele-vated PRL levels are not caused by pathologic hyperprolactinemia

was performed by Muneyyirci-Delale and coworkers. These in-vestigators studied 50 women without radiologic evidence of aprolactinoma who had elevated PRL levels (23 to 156 ng/mL)measured in two consecutive blood samples obtained 1 to 2 weeksapart. When these women had serial blood sampling subse-quently performed in a quiet room, 20 had normal PRL levelsin the 1-hour blood sample (Fig. 39-2). The initial PRL levelsin these 20 women ranged from 26 to 69 ng/mL. The results ofthis study indicate that stress-related hyperprolactinemia is acommon cause of a mild increase in PRL. All women with initial

PRL levels less than 70 ng/mL should have subsequent samplesdrawn 60 minutes after resting in a quiet room to determinewhether true pathologic hyperprolactinemia is present.

Hyperprolactinemia can produce disorders of gonadotropinsex steroid function, resulting in menstrual cycle derangement(oligomenorrhea and amenorrhea) and anovulation, as well asinappropriate lactation or galactorrhea. The mechanism wherebyelevated PRL levels interfere with gonadotropin release appearsto be related to abnormal gonadotropin-releasing hormone(GnRH) release. Women with hyperprolactinemia have abnor-malities in the frequency and amplitude of LH pulsations, with

DIURNAL VARIATION OF PROLACTIN

Females (N= 5)

Males (N= 5)

Hours

Prolactin(ng/mL)

35

30

25

20

15

10

5

0

0

1100 1900 0300 1100 1900 0300

20

15

10

5

Figure 39-1. Hour-to-hour variation of serum prolactin concentration innormal women and men studied throughout 48 consecutive hours. (FromKletzky OA, Davajan V: Hyperprolactinemia: Diagnosis and treatment. InMishell DR Jr, Davajan V: Infertility, Contraception and ReproductiveEndocrinology, 4th ed. Copyright 1997 by Blackwell Scientific Publications,Malden, MA. All rights reserved. Reproduced with permission.)


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HYPERPROLACTINEMIA, GALACTORRHEA, AND PITUITARY ADENOMAS

a normal or increased gonadotropin response following GnRHinfusion.

This abnormality of GnRH cyclicity thus inhibits gonado-tropin release but not its synthesis. The reason for this abnormalsecretion of GnRH is an inhibitory effect of dopamine opioidpeptides at the level of the hypothalamus. In addition, elevatedPRL levels have been shown to interfere with the positive

estrogen effect on midcycle LH release. It has also been shownthat elevated levels of PRL directly inhibit basal as well asgonadotropin-stimulated ovarian secretion of both estradiol andprogesterone. However, this mechanism is probably not theprimary cause of anovulation, because women with hyper-prolactinemia can have ovulation induced with various agents,including pulsatile GnRH. Some women with moderate hyper-prolactinemia as determined by radioimmunoassay have a greaterthan normal proportion of the big-big forms. Because of thereduced bioactivity of this form of PRL, these individuals canhave normal pituitary and ovarian function.

The clinician should measure serum PRL levels in all women with galactorrhea, as well as those with oligomenorrhea andamenorrhea without the presence of an elevated level of follicle-

stimulating hormone (FSH). Hyperprolactinemia has been re-ported to be present in 15% of all anovulatory women and 20%of women with amenorrhea of undetermined cause. Galactorrheais defined as the nonpuerperal secretion from the breast of

watery or milky fluid that contains neither pus nor blood. Thefluid may appear spontaneously or after palpation. To determineif galactorrhea is present, the clinician should palpate the breast,moving from the periphery toward the nipple in an attemptto express any secretion. The diagnosis of galactorrhea can beconfirmed by observing multiple fat droplets in the fluid whenit is examined under low-power magnification (Fig. 39-3). The

incidence of galactorrhea in women with hyperprolactinemiahas been reported to range from 30% to 80%, and these differ-ences probably reflect variations in the techniques used to detectmammary excretion. Unless there has been continued breaststimulation after a pregnancy, the presence of galactorrhea

serves as a biologic indicator that the PRL level is abnormallyelevated. Davajan and associates reported that 62% of women with galactorrhea have hyperprolactinemia. Some individualswith galactorrhea and normal immunoassayable PRL levels mayhave elevated biologically active PRL. The incidence of hyper-prolactinemia is higher (88%) in those women with galactorrhea

who have amenorrhea and low estrogen levels than in those women with galactorrhea and normal estrogen levels (49%),regardless of menstrual status.

ETIOLOGY

Pathologic causes of hyperprolactinemia, in addition to a

PRL-secreting pituitary adenoma (prolactinoma) and other pitui-tary tumors that produce acromegaly and Cushings disease,include hypothalamic disease, various pharmacologic agents,hypothyroidism, chronic renal disease, or any chronic type ofbreast nerve stimulation, such as may occur with thoracic opera-tion, herpes zoster, or chest trauma. The following box providesa list of the various causes of hyperprolactinemia.

One of the most frequent causes of galactorrhea and hyper-prolactinemia is the ingestion of pharmacologic agents, partic-ularly tranquilizers, narcotics, and antihypertensive agents (seethe following box ). Of the tranquilizers, the phenothiazines and

*

**

*

Figure 39-2. Mean plus or minus standard error ( SE) serum prolactin levelsin women with prolactinoma (N= 20) and idiopathic (N= 30) and stress-related (N= 20) hyperprolactinemia before (pretest I and II) and during

hyperprolactinemia test. Differences (*p < 0.01) are in relation to time zerovalues. (Mean prolactin values among groups were also significantly different[p < 0.01] at all times.) (From Muneyyirci-Delale O, Goldstein D, Reyes FI,et al: Diagnosis of stress-related hyperprolactinemia: evaluation of thehyperprolactinemia rest test. NY State J Med 89:205, 1989.)

Figure 39-3. Fat droplets seen under microscope from a patient withgalactorrhea. (From Kletzky OA, Davajan V: Hyperprolactinemia: Diagnosisand treatment. In Mishell DR, Davajan V, Lobo RA [eds]: Infertility,Contraception and Reproductive Endocrinology, 3rd ed. Cambridge, MA,Blackwell Scientific Publications, 1991.)


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Central Nervous System Disorders

Hypothalamic CausesDiseases of the hypothalamus that produce alterations in thenormal portal circulation of dopamine can result in hyper-prolactinemia. Such diseases include craniopharyngioma andinfiltration of the hypothalamus by sarcoidosis, histiocytosis,leukemia, or carcinoma. All these conditions are rare, with cranio-pharyngioma being the most common. These tumors arise from

remnants of Rathkes pouch along the pituitary stalk. Grosslythey can be cystic, solid, or mixed, and calcification is usuallyvisible on radiograph. They are most frequently diagnosedduring the second and third decades of life and usually resultin impairment of secretion of several pituitary hormones.

Pituitary CausesVarious types of pituitary tumors, lactotroph hyperplasia, andthe empty sella syndrome can be associated with hyperpro-lactinemia. It has been estimated that as many as 80% of allpituitary adenomas secrete PRL. The most common pituitarytumor associated with hyperprolactinemia is the prolactinoma,arbitrarily defined as a microadenoma if its diameter is less than1 cm and as a macroadenoma if it is larger. Hyperprolactinemiahas been reported to occur in about 25% of individuals withacromegaly and 10% of those with Cushings disease, indicatingthat these pituitary adenomas, which mainly secrete growthhormone (GH) and adrenocorticotropic hormone (ACTH),frequently also secrete PRL. Hyperplasia of lactotrophs has beenreported to occur in about 8% of pituitary glands examined atautopsy. Individuals with hyperplasia of the lactotrophs cannotbe distinguished from those having a microadenoma by anyclinical, laboratory, or radiologic method. It is a diagnosis thatcan be made only at the time of surgical exploration of the pitui-tary gland. Pituitary enlargement with suprasellar extensioncaused by lactotroph hyperplasia has been reported. Functionalhyperprolactinemia is the term used for the clinical diagnosis ofcases of elevated PRL levels without evidence of an adenoma.This condition may occur because of decreased dopamineinhibition or the presence of an adenoma that is too small tobe visualized.

Another cause of hyperprolactinemia is the primary emptysella syndrome. The termprimary empty sella syndromedescribesa clinical situation in which an intrasellar extension of the sub-arachnoid space results in compression of the pituitary gland and

an enlarged sella turcica. The cause is believed to result froma congenital or acquired (by radiation or surgery) defect in thesella diaphragm that allows the subarachnoid membrane toherniate into the sella turcica (Fig. 39-5). The syndrome isusually associated with normal pituitary function except forhyperprolactinemia. Although some individuals with primaryempty sella syndrome have a coexistent prolactinoma, Ghariband colleagues reported a series of 11 persons with an emptysella and hyperprolactinemia who had no histologic evidence ofa prolactinoma or hyperplasia of the lactotrophs. They statedthat about 5% of individuals with the empty sella have hyper-prolactinemia or amenorrheagalactorrhea or both. It is theo-rized that with this syndrome distortion of the infundibularstalk results in decreased levels of dopamine reaching the pituitary

to inhibit PRL. Serum PRL levels are usually less than 100 ng/mL with the empty sella syndrome, and some women with thissyndrome have galactorrhea with normal PRL levels. Kleinbergand coworkers reported that about 10% of all individuals withan enlarged sella turcica have the empty sella syndrome. The bestmodality for diagnosing this condition is magnetic resonanceimaging (MRI). Computed tomographic (CT) scanning withintrathecal injection of metrizamide can also be used. It is im-portant to establish the diagnosis because the syndrome has abenign course.

Pharmacologic Agents Affecting ProlactinConcentrations

Stimulators

Anesthetics including cocainePsychoactive

PhenothiazinesTricyclic antidepressantsOpiates

ChlordiazepoxideAmphetaminesDiazepamsHaloperidolFluphenazineChlorpromazineSSRIs

HormonesEstrogenOral-steroid contraceptivesThyrotropin-releasing hormone

Antihypertensives-MethyldopaReserpineVerapamil

Dopamine receptor antagonists

MetoclopramideAntiemetics

SulpridePromazinePerphenazine

OthersCimetidineCyproheptiadineProtease inhibitors

InhibitorsL-DopaDopamineBromocriptinePergolide

CabergolineDepot bromocriptine

SSRIs, selective serotonin reuptake inhibitors.From Shoupe D, Mishell DR Jr: Hyperprolactinemia: Diag-nosis and treatment. In Lobo RA, Mishell DR Jr, Paulson RJ,Shoupe D (eds): Mishells Textbook of Infertility, Contracep-tion and Reproductive Endocrinology, 4th ed. Cambridge,MA, Blackwell Scientific Publications, 1997.


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Prolactinomas

In an unselected series of 120 autopsies of persons who had hadno clinical evidence of pituitary disease, Burrow and associates

found pituitary microadenomas to be present in 32 (27%). Morerecently Molitch described that PRL incidentalomas occur in11% of subjects at autopsy. Abd El-Hamid and colleagues alsoreported that adenomas were found in 78 of 486 (16%) pitui-tary glands examined after unselected autopsies. In all seriesPRL was found in about half the glands, indicating that morethan 1 in 10 individuals in the general population have aprolactinoma.

Overall about 50% of women with hyperprolactinemia havea prolactinoma. The incidence is higher when the PRL levelsexceed 100 ng/mL, and nearly all individuals with PRL levelsgreater than 200 ng/mL have a prolactinoma. The vast majorityof prolactinomas in women are microadenomas. Kleinbergand coworkers reported that overall 20% of individuals with

galactorrhea and 35% of women with amenorrheagalactorrheahad radiologic evidence of pituitary tumors. Tumors are alsopresent in about 20% of women with hyperprolactinemia andmenstrual irregularities without galactorrhea. The incidenceof prolactinoma is greater in those individuals with a more pro-found disturbance of normal hypothalamicpituitaryovarianfunction. Davajan and associates reported that 70% of women

with hyperprolactinemia, galactorrhea, and secondary amenor-rhea with low estrogen levels had radiologic evidence of apituitary adenoma. Evidence of a tumor occurred in only 20%to 30% of those with hyperprolactinemia and normal menses,

oligomenorrhea, or secondary amenorrhea who had sufficientestrogen to undergo withdrawal bleeding after progesteroneadministration. In both these studies no evidence of tumor

was found in individuals with normal menses, galactorrhea, and

normal PRL levels. Therefore radiologic studies do not needto be performed if galactorrhea is present and PRL levels arenormal.

Figure 39-6 depicts various possible causes of prolactinomaformation. In the past it was firmly believed that adenomas orhyperplasia were the result of hypothalamic dopamine dys-regulation, which was either a functional defect or the result ofaltered blood supply. Current thinking is that adenomas arisefrom single cell mutations, with clonal proliferation occurringsubsequently. However, a search for mutations in oncogenes,the dopamine D2 or TRH receptor, signal transduction mecha-nisms or transcription factors have not been very rewardingto date. Prolactinomas that occur in 20% of patients withmultiple endocrine neoplasia type 1 (MEN-1) may be due to an

inactivating mutation of theMENINgene, although this specialcase is clearly different from the usual type of prolactinomas.It is also important to note that prolactinomas may also

secrete other hormones; GH is the most frequent combination.Also, up to 40% of GH-secreting adenomas also secrete PRL.Combinations of PRL and ACTH, PRL and TSH, and PRL andFSH have been described.

Long-term studies of individuals with microadenomas demon-strate that enlargement is uncommon and that many of thesetumors regress spontaneously. In a longitudinal retrospectivestudy of 43 women with hyperprolactinemia and a radiologic

Figure 39-5. Diagrammatic representation ofempty sella syndrome.A, Normal anatomicrelationship. B, C, and D, Progression in

development of empty sella syndrome. Notethinning of floor and symmetrical enlargementof sella turcica. (From Kletzky OA, Davajan V:Hyperprolactinemia: Diagnosis and treatment.In Mishell DR, Davajan V, Lobo RA [eds]:Infertility, Contraception and ReproductiveEndocrinology, 3rd ed. Cambridge, MA,Blackwell Scientific Publications, 1991.)

Cerebrospinal fluid

Opticchiasma

Arachnoidmembrane

Pituitarydiaphragm

Pituitary gland

Defectivediaphragm

Arachnoidherniation

Completeherniation

Thinning of sella floor

Increasedherniation

Defectivediaphragm

C D

A B


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diagnosis of microadenoma, March and colleagues found that

only 2 women had evidence of enlargement of the adenoma, with a mean duration of follow-up of 5 years. Of these 43 women, 3 had spontaneous regression of their hyperprolac-tinemia and resumption of normal menses. Koppelman andcoworkers reported similar results. Of 25 women with prolacti-nomas (18 with microadenomas and 7 with minimally enlargedsella) followed up for a mean duration of 11 years withouttreatment, only 1 woman had slight progression of a sellaabnormality. None had visual field or other pituitary functionchanges, seven resumed normal menses spontaneously, andgalactorrhea spontaneously resolved in six.

The results of these retrospective studies have been confirmedby two prospective studies of untreated microprolactinomas.In a 3- to 7-year prospective longitudinal study of 30 hyper-prolactinemic women, Schlechte and associates found that of 13

women with initially abnormal radiographic findings, 4 becamenormal, 7 did not change, and 2 had evidence of tumor growth.Of 17 women with initially normal radiographic findings, 4became minimally abnormal. None of the 30 developed a macro-adenoma or pituitary hypofunction. In this study, as in the tworetrospective studies just reported, more sensitive radiographictechniques (tomograms, followed by CT) were used as thestudy progressed and could account for the minimal evidence oftumor growth. Sisam and colleagues overcame this problem byprospectively following a group of 38 women with hyperpro-lactinemia and microprolactinomas by serial CT scans for amean duration of 50 months. None of these women had evi-dence of tumor progression, even the 2 who had a marked in-crease in PRL levels. In this group, nine (25%) had spontaneousimprovement of their symptoms. Martin and coworkers fol-lowed the natural history of 41 women with idiopathic hyper-prolactinemia and amenorrheagalactorrhea for up to 11 years.During this time, 9 women conceived spontaneously, and 16have resumed spontaneous menses with cessation of galactorrhea.Only one woman developed a microadenoma. Thus, hyper-prolactinemia with or without a microadenoma follows a benignclinical course in most women, and therapy is unnecessary unlesspregnancy is desired or estrogen levels are low.

The combination of six studies in 139 women observed forat least 8 years without treatment showed that the progressionrate is only 6.5%. Several studies have reported that pregnancyis beneficial for women with functional hyperprolactinemia orPRL-secreting microadenomas. Following pregnancy, PRL levelsdecrease in about half the women. Crosignani and associatesreported that PRL levels became normal in about 30% of 176hyperprolactinemic women after pregnancy. PRL levels decreased

to normal in 36% of women with functional hyperprolactinemiaand 17% of those with adenomas. Therefore if women withhyperprolactinemia desire to become pregnant they should beencouraged to do so, as pregnancy is likely to result in normalor lowered PRL levels.

DIAGNOSTIC TECHNIQUES

Because most prolactinomas are microadenomas that do notcause enlargement of the sella turcica, the diagnosis usuallycannot be made by ordinary anteroposterior and lateral coned

X-ray examination of the sella turcica. With the development ofmore precise radiologic methods of detecting soft tissue pituitary

abnormalities, it is now possible to detect even small adenomas.Initially detection of microadenomas was accomplished byobtaining tomographic radiographic examination of the sellaturcica at intervals of 2 to 3 mm in the anteroposterior andlateral projections with a hypocycloidal movement. These arecalled hypocycloidal tomograms. Comparing the results of tomo-grams with the findings of microadenoma at autopsy, Burrowand coworkers found that the incidence of both false-positiveand false-negative tomographic findings was about 20% each,

with an overall accuracy rate of 61%. Furthermore, radiationexposure with polytomography may be in excess of 20 rads.

PATHOGENESIS OF PITUITARY TUMORS

HypothalamusNormal

Hyperplasia ortumor due tohypothalamicdysfunction

Tumorarising de novo

Pituitary

Pituitary hormone

HyperplasiaTumor

Tumor

Hypothalamus

Hypothalamus

Pituitary hormone

Pituitary hormone

Releasing factor(+)

Inhibiting factor()

Releasing factor(+)

Inhibiting factor()

Releasing factor(+)

Inhibiting factor()

Figure 39-6. Possible mechanisms leading to the formation of a prolactinoma.Top: normal regulation. Middle: tumors could arise because of an increase inPRL-releasing factor (PRF) or a decrease in PRL-inhibiting factor (dopamine).Bottom: tumors could arise de novo without hypothalamic influence. (FromMolitch ME: Clinical features and epidemiology of prolactinomas in women.In Olefsky JM, Robbins RJ [eds]: Prolactinomas: Practical Diagnosis andManagement. New York, Churchill Livingstone, 1986, pp 6795.)


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Current recommended techniques are to obtain a CT scan with IV contrast, or an MRI with gadolinium enhancement.The latter provides better soft tissue definition, and the CT scanprincipally shows bony structural abnormalities.

The MRI provides 1-mm resolution and thus should be ableto detect all microadenomas. Stein and associates comparedresults of CT and MRI in 22 individuals with suspected pitui-tary adenomas. MRI was found to be the superior diagnosticmodality because of its greater soft tissue contrast (Fig. 39-7).In addition the MRI does not have the radiation exposure of theCT scan (23 rads, 0.03 Gy).

Recommended Diagnostic Evaluation

It is currently recommended that PRL levels be measured in allwomen with galactorrhea, oligomenorrhea, or amenorrhea whodo not have an elevated FSH level. If PRL is elevated, a TSHassay should be performed to rule out the presence of primaryhypothyroidism. If TSH is elevated, T3 and T4 should bemeasured to rule out the rare possibility of a TSH-secretingpituitary adenoma. If TSH is elevated and hypothyroidism ispresent, appropriate thyroid replacement should begin, and thePRL level will usually return to normal. If TSH is normal andthe woman has a normal PRL level with galactorrhea, no furthertests are necessary if she has regular menses. Because some

women with galactorrhea, abnormal menstrual function, andnormal PRL levels have been found to have the empty sellasyndrome, an MRI or a CT scan should be obtained to establishthe diagnosis in women with these findings.

If PRL levels are elevated and the TSH is normal, an MRIif available or CT scan should be obtained to detect a micro-adenoma or macroadenoma. Macroadenomas are uncommonand rarely are present with a PRL level less than 100 ng/mL.If the PRL level is more than 100 ng/mL or the woman com-plains of headaches or visual changes, the likelihood of a tumorextending beyond the sella turcica is increased. Microadenomasare a common cause of hyperprolactinemia, but rarely enlarge.Neither pregnancy, oral contraceptives, nor hormone replace-ment therapy stimulates the growth of these small tumors, andtherapy is unnecessary unless ovulation induction is desired orhypoestrogenism is present.

Visual field determination and tests of ACTH and thyroidfunction are not necessary if a microadenoma is present, as thesesmall tumors do not interfere with overall pituitary functionand do not extend beyond the sella. However, these evalua-tions should be performed in individuals with macroadenomasbecause suprasellar extension of the tumor may exert pressure

on the optic chiasm, resulting in bitemporal visual field defectsand interference with vision. The size of these tumors may alsoaffect other aspects of pituitary function. Thus a test of ACTHreserve, such as insulin-induced hypoglycemia (insulin tolerancetest), as well as tests of thyroid function, should be performedon all individuals with a macroadenoma.

MANAGEMENT

Expectant Treatment

Women with radiologic evidence of a microadenoma or func-tional hyperprolactinemia who do not wish to conceive may

be followed without treatment by measuring PRL levels onceyearly. Many of these women have deficient estrogen, and lowestrogen levels in combination with hyperprolactinemia havebeen shown to be associated with the early onset of osteoporosis.If the woman has low estrogen levels, exogenous estrogen shouldbe administered. Either replacement estrogenprogestin therapy,as is used for postmenopausal women, or oral contraceptivescan be utilized. Corenblum and Donovan reported that a groupof women with both functional hyperprolactinemia and PRL-secreting pituitary microadenomas who were treated with eithercyclic estrogen and progestin or oral contraceptives for several

Figure 39-7. Images were selected to best demonstrate pathology and do notexactly correspond in level of section through sella turcica.A, CT scan (coronalsection) showing bony erosion of right sella turcica (arrowhead) with possiblesoft tissue extension into right cavernous sinus. Height of pituitary gland (notshown) is 9 mm. B, MRI (coronal section) showing soft tissue mass extendinginto right cavernous sinus near carotid artery(large arrowhead). Height ofpituitary gland is 9 mm. Normal optic chiasm is seen (small arrowhead). (FromStein AL, Levenick MN, Kletzky OA: Computer tomography versus magneticresonance imaging for the evaluation of suspected pituitary adenomas. ObstetGynecol 73:996, 1989.)

A

B


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years did not have an increase in the size of the adenomasor a marked increase in PRL levels. Mean PRL levels actuallydeclined with both treatment regimens. Testa reported that2 years of oral contraceptive use in a group of women with hyper-prolactinemia with microadenoma did not alter the size of theadenoma. Since side effects and cost are less and compliance isbetter with exogenous estrogen than with bromocriptine, it isnot necessary to use the latter agent unless ovulation and preg-nancy are desired. Individuals with hyperprolactinemia withor without microadenomas who have adequate estrogen levelsas shown by the presence of oligomenorrhea or amenorrhea

with follicular phase estradiol levels who do not wish to con-ceive should be treated with periodic progestin withdrawal(e.g., medroxyprogesterone acetate 510 mg/day for 10 dayseach month) or combination oral contraceptives to preventendometrial hyperplasia.

Medical Therapy

The initial treatment for macroadenomas, as well as for womenwith hyperprolactinemia who are anovulatory and wish to con-ceive, should be administration of a dopamine receptor agonist.Bromocriptine, pergolide, and cabergoline have been used

with success for treating hyperprolactinemia; bromocriptineand cabergoline are approved for use in the United States). Thegreatest amount of clinical experience has been with use ofbromocriptine (Fig. 39-8). This semisynthetic ergot alkaloid wasdeveloped in 1967 to inhibit PRL secretion. It directly stimu-lates dopamide 2 receptors, and as a dopamine receptor agonistit inhibits PRL secretion both in vitro and in vivo. Afteringestion, bromocriptine is rapidly absorbed, with blood levelsreaching a peak 1 to 3 hours later. Serum PRL levels remaindepressed for about 14 hours after ingestion of a single dose,after which time the drug is not detectable in the circulation.

For this reason the drug is usually given at least twice daily, withinitial therapy being started at one half of the 2.5-mg tabletto minimize side effects. The most frequent side effects areorthostatic hypotension (with an incidence of 15%), which canproduce fainting and dizziness as well as nausea and vomiting.To minimize these symptoms the initial dose should be takenin bed and with food at nighttime. Less frequent adverse symp-

toms include headache, nasal congestion, fatigue, constipation,and diarrhea. Most of these reactions are mild, occur early inthe course of treatment, and are transient. To reduce the adversesymptoms, the dose should be gradually increased every 1 to2 weeks until PRL levels fall to normal. The usual therapeuticdose is 2.5 mg twice or three times a day, but larger doses aresometimes used when a macroadenoma is present.

Adverse effects, such as nausea, vomiting, and nasal conges-tion, occur in about half the women taking oral bromocriptineand may cause them to discontinue treatment. Vermesh and col-leagues reported that the drug was very well absorbed vaginally

without the presence of side effects. Furthermore, when asingle tablet was placed deep in the posterior vaginal fornix,therapeutic blood levels persisted for more than 24 hours,during which time PRL levels remained suppressed (Fig. 39-9).Ginsburg and coworkers subsequently reported that this methodof bromocriptine administration was well accepted, effective,and well tolerated in a group of 31 hyperprolactinemic women,17 of whom could not tolerate oral bromocriptine. Minor side

effects occurred in only three women. The tablet is placeddigitally deep in the vagina nightly at bedtime. A single 2.5-mgdose reduced PRL concentrations in 90% of patients treatedand brought the levels to normal in one third of women. Higherdoses do not appear to be more effective. Ginsburg and co-

workers recommended that the drug be administered vaginallyinstead of orally for all women as a smaller dose of drug can be

Figure 39-8. Formula of bromocriptine.

Figure 39-9. Mean ( SEM) plasma levels of bromocriptine(blue circles) and prolactin (open circles) in a single study,extended to 48 hours, after vaginal bromocriptine (2.5 mg).(From Vermesh M, Fossum GT, Kletzky OA: Vaginalbromocriptine: Pharmacology and effect on serum prolactinin normal women. Obstet Gynecol 72:693, 1988.)


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used, once-daily administration is more convenient, and sideeffects are fewer.

Bromocriptine is approved for treatment of adverse symp-toms associated with hyperprolactinemia, such as galactorrhea,as well as anovulatory infertility with and without the presenceof a PRL-secreting adenoma. In hyperprolactinemic women

without adenomas, PRL levels return to normal in more than90%, fertility is restored in 80%, and galactorrhea is eradicatedin 60% with bromocriptine therapy. In women with hyper-prolactinemia and a microadenoma, similar rates of successhave been reported. Therefore, a dopamine agonist such as

bromocriptine or cabergoline is the treatment of choice forwomen with PRL-secreting microadenomas who wish to ovulateor are bothered by galactorrhea.

Despite administration of up to 20 mg of bromocriptine perday orally, about 10% of individuals with microadenomas failto have PRL levels return to normal, probably because of indi-vidual differences in the sensitivity of lactotrophs to bromo-criptine. Nevertheless, despite the persistently elevated PRLlevels, many of these women ovulate and conceive (Fig. 39-10).

If pregnancy occurs after ovulation is induced with bromo-criptine, therapy is usually discontinued, although there is noevidence that the drug is teratogenic or adversely affects preg-nancy outcome. If pregnancy is not desired but bromocriptineis used to treat galactorrhea, therapy is usually continued for

at least 12 months, after which it should be discontinued for afew weeks. Most women with microadenomas have recurrenceof hyperprolactinemia, amenorrhea, and galactorrhea, althoughabout 10% to 20% have permanent remission after discontinu-ing bromocriptine treatment. Moriondo and associates reportedthat after 1 year of bromocriptine treatment, 11% of women

with microadenomas had persistent normalization of PRL,with return of regular menses after the drug was discontinued(Fig. 39-11). This incidence of permanent remission reached22% after 2 years of treatment. A higher rate of permanentremission occurred in women treated with 10 mg/day than with

lower dosages, but higher doses of drug increase the incidenceof adverse reactions and cause discontinuation of treatment.These investigators found that after bromocriptine was dis-continued, there was a 40% reduction in mean PRL levels inall women treated, and about 60% had a greater than 30%reduction from pretreatment PRL levels after the drug was dis-continued. Rasmussen and colleagues reported the results ofdiscontinuation of long-term (median of 2 years) bromocriptinetherapy in 75 hyperprolactinemic women. In about half the

women it was necessary to reinstate treatment because PRLlevels rose. However, in the other half further treatment was un-

necessary because mean PRL levels decreased more than 60%and either returned to normal or were only slightly elevated(Fig. 39-12). More than half of these 33 women resumed regularmenses without further treatment. These data indicate thatthe remissions were drug-related and not spontaneous. UsingCT scans before and during bromocriptine therapy, Bonnevilleand coworkers found that about 75% of individuals with micro-adenomas had reduction in tumor size during bromocriptinetreatment, and in 40% the tumor had disappeared (Fig. 39-13).To determine if permanent remission has occurred, the PRLlevel should be measured about 6 weeks after discontinuationof treatment because the levels plateau at this time.

Bromocriptine treatment has also been shown to reduce tumormass in 80% to 90% of individuals with macroadenomas. In

addition, visual disturbances, if present, are usually promptlyrelieved. Following subsequent surgical removal of thesebromocriptine-treated tumors, histologic examination revealeda reduction of tumor cell size, with shrinkage of the cytoplasmbeing greater than the nucleus. In addition, there are modifica-tions of cell structure and morphology as compared with tumorsremoved without prior medical treatment. The organelles respon-sible for PRL synthesis shrink, indicating that bromocriptineimpairs PRL synthesis as well as release. The reduction in sizeof macroadenomas usually occurs rapidly, within a few weeksafter starting treatment, but following withdrawal of drug the

Figure 39-10. Mean serum prolactin response tobromocriptine therapy in five patients with radiographicevidence of pituitary adenoma and residual hyperprolactinemia.

All five ovulated, and four conceived. (From Kletzky OA, MarrsRP, Davajan V: Management of patients with hyper-prolactinemia and normal or abnormal tomograms. Am JObstet Gynecol 147:528, 1983.)


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tumor size may increase just as rapidly; thus the drug should bewithdrawn cautiously. In contrast to the frequent occurrence ofpituitary insufficiency, including diabetes insipidus, after surgicalor radiologic treatment of large tumors, bromocriptine treatmentis not accompanied by any type of pituitary insufficiency.

Because permanent remission rarely occurs following with-drawal of bromocriptine treatment from individuals with large

tumors, long-term treatment is usually necessary. The drug hasbeen administered in some individuals for up to 12 years with-out problems, and once biochemical, radiologic, and clinicalresponses to treatment are established, they are generally main-tained over a long-term period. Bromocriptine has also beensuccessfully used to treat individuals with failure of, or recur-rence after, operation or irradiation therapy.

Figure 39-11. Serum prolactin levels in four patientswho had persistently normal prolactin levels afterbromocriptine (BRC) treatment for 12 months. P,Pregnancy. (From Moriondo P, Travaglini P, Nissim M,et al: Bromocriptine treatment of microprolactinomas:Evidence of stable prolactin decrease after drug

withdrawal. J Clin Endocrinol Metab 60:764, 1985. Copyright 1985 by The Endocrine Society.)

Figure 39-12. Geometric mean serum prolactin levels before andafter discontinuation of bromocriptine treatment in 33 women withhyperprolactinemic amenorrhea. (Reprinted from Fertility and Sterility, 48,Rasmussen C, Bergh T, Wide L, Prolactin secretion and menstrual functionafter long-term bromocriptine treatment, 550. Copyright 1987, withpermission from The American Society for Reproductive Medicine.)

Figure 39-13. Coronal CT scan of a woman with microadenoma 4 monthsafter bromocriptine therapy (5 mg per day). Clinical and biologic results wereexcellent; pituitary gland is nearly normal, with reconstruction of sellar floor.(From Bonneville JF, Poulignot D, Cattin F, et al: Computed tomographicdemonstration of the effects of bromocriptine on pituitary microadenoma size.Radiology 143:451, 1982.)


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Molitch and associates reported the results of a 1-yearprospective multicenter study of the use of bromocriptine asprimary therapy for PRL-secreting macroadenomas in 27 indi-viduals. Bromocriptine dosage ranged from 5 to 12.5 mg daily,

with 7.5 mg being the most frequent dose. PRL levels fell inall individuals, and to 11% or less of pretreatment values in allbut one. Of this group, two thirds had PRL levels decreaseto normal during treatment. Tumor shrinkage was observed inall individuals, being reduced by more than 50% in half thepatients and by about 50% in an additional 20% of the studygroup. Visual field impairment disappeared in 9 of the 10 indi-viduals with abnormalities. In two thirds of the individualsreduction in tumor size occurred by 6 weeks, but in one thirdit was not evident until 6 months, indicating there were bothrapid and slow responses of tumor to drug treatment. Thereforeat least a 6-month trial of medical therapy is warranted forindividuals with a macroadenoma.

Because of these excellent results, the poor initial results ofoperation, and the high recurrence rates, these investigatorsconcluded that bromocriptine should be used as the initialmanagement of individuals with PRL-secreting macroadenomas.

After maximal shrinkage of tumor, medical therapy can becontinued or operative treatment used. The cost of continuingbromocriptine treatment is considerable; it is inconvenient totake medication several times a day, and some individuals haveunpleasant side effects with the higher dosages that may benecessary. Therefore some individuals prefer operative treatment.If they elect to have an operation, the drug should be continueduntil the time of operation to prevent tumor expansion. Therates of success after operation are no different among indi-viduals who received or did not receive bromocriptine before theoperation.

Cabergoline is a long-acting dopamine receptor agonist. Thisagent directly inhibits pituitary lactotrophs, thereby decreasingPRL secretion. It is given orally in doses of 0.251.0 mg twice

a week. The initial dose is half a 0.5-mg tablet twice a week.Peak plasma levels occur in 2 to 3 hours, and this drug has ahalf-life of 65 hours. Its slow elimination and long half-lifeproduces a prolonged PRL-lowering effect. The initial dose is0.25 mg twice weekly and the dosage may be increased at inter-vals of 4 weeks to achieve a satisfactory response. In a random-ized trial with bromocryptine, cabergoline lowered PRL levelsto normal in 83% of women, induced ovulation in 72%, andeliminated galactorrhea in 90%. The effectiveness of cabergoline

was greater than that of bromocryptine. Adverse effects, partic-ularly nausea, headaches, and dizziness, occurred with bothagents but were less frequent, less severe, and of shorter duration

with cabergoline. Therefore cabergoline is better tolerated thanbromocryptine and has higher continuation rates. Recent evi-

dence suggests that cabergoline is more effective in lowering PRLthan bromocryptine. Even in patients who had been treatedpreviously with bromocryptine, cabergoline has been found tobe effective (Table 39-1).

Cabergoline has been compared with other agents in effective-ness for reducing tumor size (see Table 39-1). It may be concludedthat in women who have never been treated, cabergoline iscurrently the agent of choice for reducing PRL levels and effectingtumor shrinkage. It is recommended that after serum PRL levelshave remained normal for 6 months cabergoline be discontinuedto determine if the PRL levels stay low without therapy.

Operative Approaches

Transsphenoidal microsurgical resection of prolactinoma hasbeen widely used for therapy, and numerous reports of largeseries of individuals treated by this technique have been pub-lished. In general, transsphenoidal operations have minimalrisk, with a mortality of less than 0.5%; however, the majority ofdeaths have been reported to occur after treatment of macro-adenomas. The risk of temporary postoperative diabetes insipidusis 10% to 40%, but the risk of permanent diabetes insipidusand iatrogenic hypopituitarism is less than 2%. The initial curerate, with normalization of PRL levels and return of ovulation,is relatively high for microadenomas (65% to 85%) and less so

with macroadenomas (20% to 40%). Vision can return to normalin 85% of patients with loss of acuity and visual field defects.

The initial cure rate is related to the pretreatment PRL levels.Those tumors with levels less than 100 ng/mL have an excellentprognosis (85%), and those with levels greater than 200 ng/mLhave a poor prognosis (35%). Operative treatment of tumors

in individuals older than 26 with amenorrhea for more than6 months carries a poorer prognosis than tumors in younger women with a shorter duration of amenorrhea. Nevertheless,long-term follow-up of patients after operation indicates thatlate recurrence of hyperprolactinemia is common. Serri and col-leagues followed 28 women with microadenomas and 16 withmacroadenomas for 6 years after operation. Although PRL levelsnormalized and menses resumed in 24 (85%) of those withmicroadenomas and 5 (31%) of those with macroadenomas whohad a good initial postoperative response, hyperprolactinemiarecurred in half of those with microadenoma and 4 of the5 with macroadenomas after a mean period of 4 and 2.5 years,respectively (Fig. 39-14). There was no significant differencein recurrence rates for those who conceived and those who

did not. Rodman and coworkers reported a lower postoperativerecurrence rate (about 20% for both microadenomas andmacroadenomas) following initial cure rates of 85% and 37%,respectively. The risk of recurrence in both series appeared to berelated to the immediate postoperative PRL levels, being greaterin persons with a PRL level greater than 10 ng/mL.

Overall it can be concluded that after surgery, recurrencerates for micro- or macroadenoma are similar (21% and 19.8%,respectively). Long-term surgical cure rates are 58% of micro-adenomas and only 26% macroadenomas using a normal PRLlevel as a criterion.

Table 39-1 Comparison of Efficacy of Dopamine

Agonists in Affecting Tumor Size Reduction*

TUMOR SIZE REDUCTION

Dopamine Number NoAgonist of Cases >50% 25%50%


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Because of the good results with medical therapy, surgery isrecommended only for women with macroadenoma who failto respond to medical therapy or have poor compliance with thisregimen. It is best to reduce the size of macroadenomas maxi-mally with bromocriptine before surgical removal of theseextrasellar tumors.

Radiation Therapy

External radiation with cobalt, proton beam, or heavy-particletherapy and brachytherapy with yttrium-90 rods implanted inthe pituitary have all been used to treat macroadenomas butare not the primary mode of treatment. Results of such therapy

have been inconsistent, and there is a delay of several monthsbetween treatment and resumption of ovulation. Furthermore,damage to normal pituitary tissue occurs, frequently leading toabnormal anterior pituitary function as well as diabetes insipidus.Damage to the optic nerves may also occur. Thus radiationtherapy should be used only as adjunctive management followingincomplete operative removal of large tumors.

Pregnancy

Many women with hyperprolactinemia with or withoutadenomas wish to become pregnant. A small percentage of these

women conceive spontaneously, but most require treatment

to induce ovulation. Barbieri and Ryan compiled a literaturereview of the pregnancy courses of 275 women with adenomas,the majority of whose conceptions had been induced by bromo-criptine. They reported that of 215 women with microprolac-tinomas, less than 1% had changes in visual fields, radiologicevidence of tumor enlargement, or neurologic signs. About5% developed headaches during pregnancy. Of 60 women withmacroprolactinomas, 20% developed adverse changes in visualfields and polytomographic or neurologic signs during preg-nancy, and some of them required bromocriptine or operativetreatment during pregnancy or shortly postpartum. Overall,

although only 1.4% of women with microadenomas have symp-toms during pregnancy, 24.4% of women with macroadenomashave symptoms. However, only about 3% of women withmacroadenomas have symptoms if they are treated prior topregnancy. For this reason excision of macroprolactinomasbefore pregnancy has been recommended in some cases. Never-theless, because pituitary function is usually diminished afteroperation, induction of ovulation must be performed with com-plicated and expensive gonadotropin treatment. Bromocriptinetreatment does not interfere with pituitary function and is thusthe therapy of choice for women with macroadenomas who wishto conceive. Continuous bromocriptine treatment throughoutpregnancy for women with macroadenomas has been recom-mended by some, because with this therapy visual disturbancesare rare. Despite a lowering of PRL levels, there is no effect onplacental hormone production, and pregnancy outcome doesnot appear to be affected.

Nevertheless, since bromocriptine crosses the placenta andsuppresses fetal PRL levels, its long-term effects on the newbornare unknown. Therefore it is now advised that women withmacroadenomas discontinue the drug after conception (as is thecase for those with microadenomas) and have therapy reinitiatedif and when symptoms of visual disturbance or severe headachesoccur. Most women who conceive after bromocriptine treat-ment have ingested the drug for a few weeks after conception.In a review of 1410 such pregnancies compiled by Turkalj andassociates there was a spontaneous abortion rate of 11%, ectopicpregnancy rate of 0.7%, and twin pregnancy rate of 1.8%. Theincidence of minor (2.5%) and major (1%) congenital defects

was similar to pregnancy outcomes in untreated populationsof women. The mean amount of drug ingested and durationof postconception treatment were similar in mothers who hadnormal children and those with defects. Thus ingestion ofbromocriptine during pregnancy does not appear to increase therisk of congenital abnormalities, spontaneous abortion, or multi-

ple gestation. Postnatal surveillance of more than 200 childrenborn in this series has revealed no adverse effects to date.Ruiz-Velasco and Tolis compiled the obstetric histories of

nearly 2000 pregnancies occurring in hyperprolactinemic womenthat have been reported in the literature. Most of these preg-nancies were induced with bromocriptine. There was a full-termdelivery rate of 85%, an abortion rate of 11%, a prematurityrate of 2%, and a multiple pregnancy rate of 1.2%. AlthoughPRL levels increased during pregnancy, after delivery the levelsreturned to pretreatment values in about 85%. A postpartumincrease over pretreatment levels was uncommon (3%), and PRLlevels returned to normal in 13%. Likewise, among women whohad postpartum radiologic sellar examination, 84% showedno change, 9% improved, and 7% worsened. Thus stopping

treatment during pregnancy only occasionally results in tumorgrowth. It is advised that women with macroadenomas havemonthly visual field examination and neurologic testing duringpregnancy, but this is probably unnecessary for women withmicroadenomas unless they develop symptoms of headache orvisual disturbances.

Following delivery, breast-feeding may be initiated withoutadverse effects on the tumors. Godo and associates reportedthat use of bromocriptine before conception and during preg-nancy did not affect the incidence of persistent lactation fol-lowing discontinuation of nursing. The incidence of menstrual

Figure 39-14. Cumulative recurrence rate in patients with microprolactinoma(group 1) or macroprolactinoma (group 2) after initially successful operation.Figures in parentheses indicate numbers of patients who were seen at eachyearly interval. (From Serri O, Rasio E, Beauregard H, et al: Recurrence ofhyperprolactinemia after selective transsphenoidal adenomectomy in women

with prolactinoma. N Engl J Med 309:280, 1983. Copyright 1983Massachusetts Medical Society. All rights reserved.)


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abnormalities and degree of galactorrhea were usually similar tothe state that existed before starting bromocriptine therapy.Therefore, following completion of nursing, as well as for

women who do not breast-feed at all, bromocriptine should beingested for 2 to 3 weeks and then discontinued. At that timeserum PRL measurement should be performed and treatmentreinstituted according to the findings.

Women with Hyperprolactinemia Who Do Not Wishto Conceive

For women who do not wish to conceive and for whomgalactorrhea is not a problem, no therapy is necessary unlessestrogen levels are low. Thus, to prevent osteoporosis in thisclinical situation, estrogenprogestin hormone replacement or

oral contraceptives should be given regardless of whether anadenoma is present. Long-term evaluation of all women withhyperprolactinemia should be performed. Unless a macro-adenoma is present, measurement of PRL levels once a year isadvisable. Repeat imaging studies are unnecessary unless symp-toms of headaches or visual disturbances occur or PRL levelsincrease substantially. If bromocriptine therapy is used, tempo-rary discontinuation of medication every year is advisable, withPRL measurement 6 weeks later. If the level is normal, repeatPRL measurements should be made semiannually. If the level isincreased, therapy may be reinitiated. During medical treatmentof macroadenomas, MRI or CT and visual field examinationshould be performed every 6 months to determine the effectof medication on the tumor. At these intervals a decision canbe made about whether to continue long-term bromocriptinetreatment or to remove the tumor surgically.

Estrogen stimulates PRL release but blocks its action at the

receptor in the breast. Physiologic stimuli for PRL release include breast and

nipple palpation, exercise, stress, sleep, and the noondaymeal.

The main symptoms of hyperprolactinemia are galactorrheaand amenorrhea, the latter caused by alterations in normalgonadotropin-releasing hormone (GnRH) release.

Hyperprolactinemia is present in 15% of all anovulatorywomen and 20% of women with amenorrhea of undeter-mined cause.

About 60% of all women with galactorrhea have hyper-prolactinemia, but almost 90% of women with galactorrhea,amenorrhea, and low estrogen levels have hyperpro-lactinemia.

Pathologic causes of hyperprolactinemia include pharma-cologic agents (tranquilizers, narcotics, and antihyperten-sive drugs), hypothyroidism, chronic renal disease, chronicneurostimulation of the breast, hypothalamic disease, andpituitary tumors (prolactinoma, acromegaly, Cushingsdisease).

About 3% to 5% of individuals with hyperprolactinemiahave hypothyroidism.

About 80% of all pituitary tumors secrete PRL. About 25% of individuals with acromegaly and 10% of

those with Cushings disease have hyperprolactinemia. About 10% of individuals with an enlarged sella have the

empty sella syndrome. Autopsy studies reveal that prolactinomas are present in

about 10% of the population. About 50% of women with hyperprolactinemia will have

a prolactinoma, as will nearly all of those with PRL levelsgreater than 200 ng/mL.

About 20% of women with galactorrhea and 35% of thosewith amenorrhea and galactorrhea have prolactinomas.

About 70% of women with hyperprolactinemia, galactor-rhea, and amenorrhea with low estrogen levels will have aprolactinoma.

Women with regular menses, galactorrhea, and normal PRL

levels do not have prolactinomas. About 13% of women with prolactinomas do not have

galactorrhea. Most macroadenomas enlarge with time; nearly all micro-

denomas do not. The initial operative cure rate for microadenomas is about

80% and for macroadenomas 30%, but the long-termrecurrence rate is at least 20% for each.

Most frequent side effects of bromocriptine are orthostatichypotension, nausea, and vomiting.

In women with hyperprolactinemia and no macroadenoma,bromocriptine treatment returns PRL levels to normal in90%, induces ovulatory cycles in 80%, and eradicatesgalactorrhea in 60%.

After 1 year of bromocriptine treatment, PRL levels remainnormal in 11% of women with microadenomas; after2 years permanent remission reaches 22%. After longer use,remissions of 50% have been reported.

Bromocriptine shrinks 80% to 90% of macroadenomas. When pregnancy occurs in women with microadenomas,

less than 1% have visual field changes, tumor enlargement,or neurologic signs; about 20% of women with macro-adenomas have such adverse changes.

Pregnancy increases the likelihood that PRL levels willdecrease or become normal over time.

Estrogen replacement therapy or oral contraceptives willnot stimulate growth of PRL-secreting microadenomas andcan be used for therapy of hyperprolactinemia and hypo-estrogenism.

Bromocriptine induction of pregnancy is not associated withan increased risk of congenital abnormalities, spontaneousabortion, or multiple gestation.

About 85% of patients with prolactinomas have no changein PRL levels or tumor size after delivery, 10% improve, and5% worsen.

The most frequent cause of mildly elevated PRL levels isstress.

KEY POINTS


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The best modality to diagnose pituitary adenomas or emptysella syndrome is MRI.

The natural history of nearly all microprolactinomas is tostay the same size, with adverse menstrual problems resolvingspontaneously in about one fourth of patients.

Surgical treatment of prolactinomas is recommended onlyfor patients who fail to respond or do not comply withmedical management.

For women who develop side effects with oral bromocriptine,vaginal administration usually alleviates the problem.

Cabergoline appears to be more effective and better toleratedthan bromocriptine.

KEY POINTS Continued

B I B L I O G R A P H Y

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39 mia a y Adenomas Pituitarios