Dopamine agonists and pituitary tumor shrinkage.

0163-769X/92/1302-0220$03.00/0 Endocrine Reviews Copyright © 1992 by The Endocrine Society

Vol. 13, No. 2 Printed in U.S.A.

Dopamine Agonists and Pituitary Tumor Shrinkage JOHN S. BEVAN, JONATHAN WEBSTER, CHRISTOPHER W. BURKE, AND MAURICE F. SCANLON Division of Endocrinology, Diabetes and Metabolism, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, Wales, UK; and Department of Endocrinology (C. W.B.), Radcliffe Infirmary, Oxford 0X2 6HE, England, UK

I. The Problem of the Large Pituitary Tumor II. Macroprolactinomas A. Cellular mechanisms of dopamine agonist shrinkage B. Clinical aspects of macroprolactinoma shrinkage 1. Patients reviewed 2. Cardiff-Oxford macroprolactinoma survey 3. Meta-analysis of 271 tumors a. shrinkage rates b. Time course of shrinkage c. c. Amount of shrinkage d. Effects on serum PRL e. Effects on pituitary function f. Dopamine agonist resistance g. Dopamine agonist withdrawal h. Nonshrinking prolactinomas 4. New dopamine agonists 5. Prolactinomas and pregnancy 6. Management strategies III. Nonfunctioning Tumors A. Tumor biology B. Responses to dopamine agonists: clinical aspects C. Possible reasons for nonshrinkage D. Treatment recommendations for NFTs IV. Other Pituitary Tumor Types A. GH-secreting adenomas B. TSH-secreting adenomas C. ACTH-secreting adenomas V. Summary

failure is diagnosed (2). A variety of other tumor mass effects may occur: extreme suprasellar extension may block the foramen of Monro and result in hydrocephalus, lateral extension into the temporal lobe may cause fits, and anterior extension into the frontal lobes may produce personality change (3). Local invasion or compression of cavernous sinuses may lead to cranial nerve palsies, particularly of the third and sixth nerves, although this occurs mainly in the context of pituitary apoplexy (4). Rarely, macroadenomas metastasize within the central nervous system (5) or extend outside the skull (6, 7). The tumor types that produce these clinical syndromes most commonly are macroprolactinomas and the so-called nonfunctioning tumors (3). GH-secreting tumors grow to large size less frequently and ACTH-secreting adenomas are usually confined to the sella. TSH-secreting adenomas are often large at the time of presentation but are uncommon tumors (8). Large pituitary tumors may compromise anterior pituitary function either by direct compression of pituitary tissue or by interference with hypothalamic control mechanisms. This is particularly common with nonfunctioning tumors, probably reflecting the fact that, as a group, they comprise the largest pituitary tumors (9). The hypogonadism frequently present has a number of interrelated components. First, there may be direct interference with gonadotropin release due to pressure effects on the hypothalamus or pituitary (10). Second, hyperprolactinemia, whether from hypothalamo-pituitary disconnection ("stalk compression") or tumor secretion, inhibits gonadotropin pulsatility probably by an action on the hypothalamic GnRH pulse generator (10, 11). Third, PRL excess may inhibit ovarian, but probably not testicular, steroidogenesis, though this remains controversial (12). Tumor decompression is needed most urgently when a patient presents with a large pituitary tumor, particularly if vision is impaired. Until recently, this was achieved by transcranial surgery which, although producing a good

I. The Problem of the Large Pituitary Tumor

P

ATIENTS with large pituitary tumors may present with a variety of problems related to space occupation or endocrine dysfunction. The most frequent complication is upward extension with compression of the visual pathways, classically producing a bitemporal field loss, although visual loss may be markedly asymmetrical in up to one third of patients (1). There is frequently a delay of many months before the cause of the visual Address requests for reprints to: J. S. Bevan, M.D., M.R.C.P., Department of Endocrinology, Aberdeen Royal Infirmary (Ward 47), Foresterhill, Aberdeen AB9 2ZB, Scotland, UK.

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DOPAMINE AGONISTS AND PITUITARY TUMORS

visual result (13,14), carried a significant morbidity and an appreciable mortality, particularly in earlier series [10% overall mortality in the series of Elkington and McKissock (13)]. Furthermore, large tumors are virtually never cured by transcranial surgery alone (15), making external radiotherapy essential with high probability of eventual hypopituitarism. Even with this combination, tumor recurrence occurred in as many as 8% (13). Over the past 2 decades it has become apparent that tumors with large suprasellar extensions can be satisfactorily decompressed via the transsphenoidal route (3, 9,16,17), though in fact this was well recognized by Harvey Cushing in the 1920s (18). Transsphenoidal surgery alone, although less traumatic for the patient, seldom cures the large pituitary tumor (9, 15, 19, 20), and radiotherapy is frequently applied for long-term tumor control. Many physicians would regard radiotherapy to be unsuitable as sole therapy for the large pituitary tumor, although it may be used if the patient is unfit for surgery or if the tumor is inoperable. Although tumor mass is reduced by radiation in the long-term (21) the effect is too slow for those presenting with visual failure. With prolactinomas serum PRL concentrations take many years to fall and rarely reach normal (22-25). Furthermore, radiationinduced hypothalamic damage may lead to increased PRL secretion from the normal pituitary and make serum PRL a poor marker of residual tumor mass (21, 26). Radiotherapy undoubtedly reduces the recurrence rate after surgery (24), but the possibility of eventual hypopituitarism necessitates repeated endocrine evaluation (26). Conventional therapies therefore had a number of disadvantages. The suggestion that bromocriptine (BC) might cause tumor regression of prolactinomas, as well as suppressing PRL secretion, came from case reports in the late 1970s which demonstrated visual improvement and bony remodeling of the sella during therapy (27-30). These were followed by early prospective studies of larger groups of patients (31-38) which showed clear radiological evidence of tumor shrinkage in more than one half of hyperprolactinemic patients with macroadenomas treated with dopamine agonists, usually BC. In a proportion of these medically treated patients it was unclear whether the hyperprolactinemia was due to tumor secretion or hypothalamo-pituitary disconnection, and a number of nonfunctioning tumors were probably misclassified as "BC-resistant prolactinomas." In tumors that were clearly PRL-secreting, BC-induced tumor shrinkage produced frequent improvement in visual failure (34) and, in contrast to the deleterious effects on anterior pituitary function of transcranial surgery and radiotherapy, dopamine agonist therapy occasionally produced improvement in pituitary function (33, 36), probably due

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to relief of pressure on the normal pituitary and to restoration of hypothalamic control. The effect of dopamine agonist therapy on the size of tumors other than prolactinomas was unclear from these early studies. Some reports suggested that a proportion of nonfunctioning tumors would shrink (38-40) whereas others described probable nonfunctioning tumors that had not regressed (31, 33). Similar uncertainty existed regarding GH-secreting tumors (31, 33, 38). It was also unclear whether dopamine agonist therapy alone provided a permanent cure of responsive tumors or whether adjunctive therapy, such as surgery or radiotherapy, was necessary for long-term tumor control. A related question was whether significant BC resistance would emerge during long-term medical therapy. The failure to shrink of a significant number of macroprolactinomas was also unexplained. This review seeks to clarify some of these issues and to evaluate critically the ability of dopamine agonists to reduce the size of different pituitary tumor types. It deals specifically with macroadenomas since it is in this group that tumor shrinkage is most desirable clinically. The major part comprises an analysis of 355 well-characterized macroadenomas studied during dopamine agonist therapy with modern computerized tomography (CT), 271 PRL-secreting and 84 nonfunctioning, and indicates those factors predictive of dopamine agonist-induced tumor shrinkage. Later sections consider GH, TSH, and ACTH-secreting macroadenomas and their tumor responsiveness to dopamine agonists. The review does not address shrinkage of microadenomas; neither does it consider feedback pituitary tumors or hyperplasia (41) or tumor shrinkage after apoplexy (42). II. Macroprolactinomas A. Cellular mechanisms of dopamine agonist shrinkage In addition to BC, other dopamine agonists including lisuride (34), pergolide (43), mesulergine (44), CV 205502 (45), and cabergoline (46) have been shown to shrink macroprolactinomas. When tumor shrinkage was first documented, in the late 1970s, the mechanism of this dopamine agonist-specific effect was obscure. The antimitotic action of BC had been known for some time (47) but, in slow-growing human pituitary tumors, this seemed an unlikely explanation for the rapid tumor regression. BC-induced tumor infarction was another early hypothesis, but patients improved without clinical evidence of apoplexy, and this theory has not been supported by subsequent histological studies (48, 49). A number of reports in 1982 suggested that tumor regression was due to lactotroph cell size reduction (37,50, 51), and subsequent ultrastructural studies have demonstrated a rapid involution of rough endoplasmic reticu-


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lum and Golgi apparatus (52), which was reversible after drug withdrawal (53). What is the mechanism of this dismantling of the protein synthetic machinery in the tumorous lactotroph? In BC-responsive macroprolactinoma patients serum PRL levels fall to 25% of the pretreatment values within 6 h of the first dose. This rapid effect on secretion has been similarly demonstrated in vitro; after 24 h exposure to BC, tumorous lactotrophs show a reduction in exocytosis and intracellular accumulation of PRL-immunoreactive granules but no reduction in cell size (54). It seems reasonable therefore to propose that the initial event in BC action is the inhibition of PRL release. The precise mechanisms by which intracellular messengers mediate these inhibitory effects remain controversial. The class D2 dopamine receptor in normal and tumorous lactotrophs is negatively coupled with adenylate cyclase, and reduction in intracellular cAMP levels is an important mechanism whereby dopamine and BC inhibit hormone release (55-57). Conversely, compounds that enhance adenylate cyclase activity promote lactotroph PRL secretion (55, 58, 59). Other regulators are also involved. Calcium has an important role in PRL secretion (58) and, in normal animal pituitary, dopamine inhibits phosphatidylinositol turnover, which in turn regulates intracellular calcium mobilization and protein kinase C activity (60). Exactly how these intracellular messengers interact with cAMP in the control of PRL secretion in the tumorous lactotroph is still not well understood. Accepting that a reduction in intracellular cAMP concentration is an important component of inhibition of PRL secretion by BC, how does this relate to subsequent changes in lactotroph cell size? In 1981 Brocas et al. (61) showed that BC administration to rats produced rapid suppression of serum PRL concentrations to undetectable levels at 24 h, followed by a delayed effect on PRL messenger RNA and PRL synthesis (50% reduction after 3 days). Furthermore, the inhibition of PRL mRNA synthesis could be reversed using long-acting analogs of cAMP (62). It is likely that BC-lowered cAMP levels have the immediate effect of preventing PRL release and the later effect of reducing gene transcription and PRL synthesis. Using biopsy material from prolactinoma patients given short-term preoperative BC, Landolt et al. (52) estimated a half-life of 3 days for the disappearance of lactotroph rough endoplasmic reticulum and Golgi apparatus. Presumably this involves a reduction in ribosomal protein and RNA synthesis, but the cause of this phenomenon, and whether it is directly related to the inhibition of PRL secretion, remain obscure. Serum PRL levels may be suppressed in some patients without tumor shrinkage, though the converse does not occur. BC not only reduces the synthesis and release of PRL

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but accelerates its lysosomal degradation within the lactotroph. De Marco et al. (63) have shown that the drug greatly increases lysosomal acid PRL proteolytic activity within 24 h of administration. This activity is probably due to the concerted actions of the cysteine proteases, cathepsins B and D. The overall increase in cellular lysosomal activity with increased autophagic vacuole formation may be one of the mechanisms responsible for the removal of rough endoplasmic reticulum and Golgi. Again, the intracellular signal for these changes is unknown. The occasional "complete disappearance" of giant prolactinomas during prolonged BC suggests that the drug may have an antimitotic action on some tumors (64, 65). However, hyperprolactinemia returned after drug withdrawal in even these cases (64), suggesting that at least some lactotrophs had escaped. Inhibitory effects of BC on lactotroph DNA synthesis (66) were presumably responsible for the cytostatic effects of the drug on human prolactinoma cells growing in soft agar, observed by Arafah et al. (67). B. Clinical aspects of macroprolactinoma

shrinkage

1. Patients reviewed. This section contains a detailed review of the individual responses of 271 macroprolactinomas to primary dopamine agonist therapy. Patients were included for analysis using the following criteria: 1) fully diluted pretreatment serum PRL concentration of greater than 167 /ig/liter (5000 mU/liter), thus virtually excluding the possibility of hyperprolactinemia due to hypothalamo-pituitary disconnection (68, 69); 2) pituitary macroadenoma on high-resolution computed tomography (CT) scan; 3) dopamine agonist therapy (mostly BC) for at least 4 weeks; 4) included in a prospective series of at least four patients studied with two or more high-resolution CT scans providing some quantification of tumor size. Isolated case reports describing particularly remarkable shrinkage (65) or nonshrinkage (70), resolution of cavernous sinus syndrome (71) or hydrocephalus (72), or development of cerebrospinal fluid rhinorrhea (73, 74) were excluded from analysis. The results obtained are therefore likely to be truly representative of the macroprolactinoma tumor group. The choice of stringent entry criteria meant that some large studies could not be analyzed in sufficient detail to enable inclusion. For example, the group data presented by Vance et al. (75) on 26 macroprolactinoma patients treated with CV 205-502 precluded individual analysis. Similarly, the series of Lesser et al. (76) and Davis et al. (7) do not contain sufficient CT data to enable estimation of tumor volume. "Useful" tumor shrinkage for the purpose of this review was defined arbitrarily as greater than 25% reduction in adenoma volume, in accord with common



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to pretreatment serum PRL concentration (Table 1). Overall, 79% of patients (215/271) showed more than 25% shrinkage, and 89% (241/271) shrank to some degree. The proportion of patients showing greater than 25% reduction in tumor volume in each group is shown in Fig. 2 in relation to pretreatment serum PRL, sex, size of tumor, and duration of dopamine agonist therapy. It is apparent that pretreatment serum PRL concentration is not a predictor of tumor shrinkage; 83% of patients in serum PRL groups more than 3333 and 167333 jug/liter showed more than 25% tumor shrinkage. No sex difference in relation to tumor shrinkage was apparent in any of the five PRL groups (Fig. 2). Of 102 macroprolactinomas large enough to produce chiasmal compression, 85% showed tumor shrinkage of more than 25% and of 115 patients treated for longer than 1 yr, 83% showed such shrinkage, with a 90% figure for those patients with initial serum PRL greater than 3333 ng/ liter. These shrinkage rates are higher than figures still quoted commonly in the endocrine literature: for example, 65% (95), "almost 70%" (96), and 78% (97), perhaps reflecting the fact that there has been no detailed analysis of a large group of definite macroprolactinomas. b. Time course of shrinkage. There has been some controversy regarding the time course of prolactinoma shrinkage. In a short-term study, Barrow et al. (48) found

clinical practice and as used in two large series previously reported (77, 78). 2. Cardiff-Oxford macroprolactinoma survey. A series of 30 macroprolactinoma patients treated with dopamine agonists in Cardiff or Oxford between 1981 and 1989 is summarized in Fig. 1 and illustrates the heterogeneity of responses to dopamine agonist therapy. Overall, 73% shrank by more than 25%, 80% shrank to some degree, and 20% did not regress at all. Patients 12 and 15 illustrate the most frequent pattern of response with early tumor shrinkage and suppression of serum PRL concentration. In contrast, patient 10 showed no change in tumor volume or vision after 1 month, despite suppression of serum PRL, and neither PRL nor tumor volume had altered in patient 26 after 1 month of BC. In patient 13, tumor regression was evident only after 18 months, in contrast to the majority of responsive tumors which shrank within 1-2 months of therapy. Vision improved in 16 of 17 patients whose tumors shrank but also improved in two of five patients whose CT scans did not reveal shrinkage. 3. Meta-analysis of 271 macroprolactinomas. a. Shrinkage rates. Two hundred and seventy one macroprolactinoma patients were selected for review as described above and divided into five groups according

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We have assumed that 1 ^g/liter is equivalent to 0.03 U/liter for conversion purposes. S = >25% shrinkage; NS = 0-25% shrinkage; BC, bromocriptine; L, lisuride; BC-LAR, depot BC (repeatable); CV, CV 205-502. "Thirty patients in the Cardiff/Oxford survey (1981-1989) described in this review (Fig. 1), which includes seven patients from Bevan et al. (9).

that responsive prolactinomas showed no further shrinkage on CT scans performed after 6 weeks of BC, compared to that observed after 3 weeks. In the long-term study of 38 macroprolactinomas reported by Liuzzi et al. (83) there was clear evidence of tumor size reduction within 3 months in all but three of the 29 tumors that shrank; in these three exceptions shrinkage was documented first after 8 (one case) and 36 (two cases) months. In this series, maximal shrinkage was seen within 3 to 8 months of therapy in all early responders, except in one who had further shrinkage during the third and fourth years. Nineteen of the 27 tumors described by Molitch et al. (77) showed maximal tumor reduction within 6

months or less, and 12 of 18 that shrank by more than 25% achieved most regression within the same time. In contrast, CT scans at 6 weeks showed no shrinkage in eight patients, and regression was demonstrated for the first time at 6 months, with further reduction during the following 6 months. Bevan et al. (9) found that most tumor shrinkage occurred after 4-6 weeks, with little further reduction after 3-6 months of BC. In the CardiffOxford series shown in Fig. 1, 13 patients were studied with three or more sequential CT scans; of the 11 tumors which shrank, 10 showed most size reduction within 3 months, with further minor shrinkage in three. Only one patient showed a late response, at 18 months. The series


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Pre-treatment serum prolactin >3333

1667-3333

667-1667

40 32 48 31

31 19 16 14

40 35 27 36

13 21

6 9

6 9

6 9

6 9

333-667

167-333

(jig/I)

100 n

FIG. 2. Summary of shrinkage (25% or more) seen in macroprolactinoma patients divided into five groups according to pretreatment PRL concentration. The first 2 bars in each group show the responses of all 271 patients according to sex. Si indicates the response of patients with tumors large enough to produce chiasmal compression. H shows patients treated with dopamine agonists for longer than 1 yr. The figure at the foot of each bar indicates the number of patients.

80 60 -

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reported by Sieck et al. (86) and Van't Verlaat (98) showed similar results. Overall, most would agree that rapid shrinkage occurs during the first 3 months of therapy in the majority of tumors and that reduction thereafter occurs at a much slower rate. For reasons that are unclear, a minority of tumors shrink only after several months of therapy and, if visual failure is present, many of these will be operated on early as medical failures. Some giant prolactinomas continue to shrink at an appreciable rate throughout several months of dopamine agonist therapy (64, 65) to a point of apparent "disappearance" (vide infra). c. Amount of shrinkage. How much tumor size reduction can be expected? This is of importance, since shrinkage of a large tumor by less than 25% may prompt consideration of additional treatment modalities. Table 2 contains a summary of the quantitative data from nine series. Thirty-eight percent of those treated for 1-3 months had already attained tumor shrinkage of 50% or more. Of those treated for 12 months or more, 86% showed such shrinkage. Van't Verlaat et al. (45, 84, 98) have described 20 patients treated for 1 yr or more, 19 of whom showed more than 50% shrinkage. Sixteen of these 19 had regressed by 75% or more, but data concerning tumor size in the other series do not permit analysis of a larger number of patients. d. Effects on serum PRL. Many investigators have noted that tumor shrinkage is preceded by suppression of serum PRL concentration. Of the 215 tumors that shrank by 25% or more, 58% attained a normal serum PRL level during the period of observation. Indeed, all responsive patients showed a fall in PRL of at least 50%, and 87% had a concentration less than 10% of the

pretreatment value. Improvement in vision is a common accompaniment of tumor size reduction in patients with chiasmal compression and may precede the radiological changes. This will not be considered in detail here since the neuro-ophthalmological aspects of tumor shrinkage have been recently reviewed elsewhere (99). Suffice it to say that visual field defects improve in about 90% of patients in whom they were abnormal before treatment (77). It is important to emphasize that although early visual improvement occurs frequently, it may be several months before maximum benefit accrues. Thus, persistence of a visual field defect is not an absolute indication to proceed to surgery. e. Effects on pituitary function. Early series suggested that recovery of impaired anterior pituitary function might accompany tumor shrinkage (33, 36). With regard to normalization of ACTH, TSH, and GH secretion, the literature provides few numerical data. Some have reported that the majority of those with ACTH deficiency recover function after tumor shrinkage (31, 84, 88, 100), whereas others have found only modest improvement (77, 90) or none at all (9, 78, 86). Variable results for TSH recovery have also been reported in these series. Since many clinicians leave patients on cortisol or T4 replacement once a clear deficiency has been demonstrated, it is impossible to make a definitive statement on the likelihood of pituitary function recovery. There is rather more information on gonadal status after dopamine agonist treatment. Figure 3 shows plasma testosterone concentrations before and after at least 3 months of BC in 34 men with macroprolactinomas drawn from the series in Table 1. Of the 20 who became normoprolactinemic, only nine had normal plasma testos-


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TABLE 2. Extent of prolactinoma shrinkage in relation to duration of dopamine agonist therapy Percentage of patients showing various reductions in Duration of therapy

Patients (n)

prolactinoma volume Tumor shrinkage

1-3 months 4-11 months >12 months

42 30 29

1-24% 17% 27% 7%

25-50% 45% 30% 7%

>50% 38% 43% 86%

Data compiled from Refs. 9, 45, 77, 78, 84, 88, 93, 94, and 98.

terone levels. An even smaller proportion of those who remained hyperprolactinemic, albeit to a much lesser degree, achieved normal gonadal function as assessed by testosterone. At least two thirds of men with successfully treated tumors will therefore require androgen supplements. It is worth mentioning the single patient reported by Prior and co-workers (101), in whom administration of testosterone appeared to accelerate growth of a macroprolactinoma, despite continued BC administration. The effect was thought to be due to aromatization of testosterone to estradiol, which is a known growth stimulator for some prolactinomas. However, there is no other such case described, and this seems to be a rare complication of testosterone replacement. Female gonadal status is more difficult to ascertain due to cyclical variation of sex steroids and the paucity of data detailing restoration of ovulation. Nevertheless, cyclical menses return in more than 90% of premenopausal women (77, 86). Reproductive potential is also restored by dopamine agonists in the majority of women with macroprolactinomas, and the effects of pregnancy on prolactinoma size are reviewed below. /. Dopamine agonist resistance. How frequently does BC resistance occur during long-term therapy ? Breidahl et al. (102) described a single tumor that enlarged during BC therapy, having responded initially with both tumor size reduction and PRL suppression. Tumor growth continued even when the dose was increased to 40 mg daily, and in vitro PRL secretion was refractory to BC in micromolar concentrations; it is possible that the cells dedifferentiated and lost dopamine receptors or acquired a postreceptor defect. BC resistance developed during therapy in the tumor described by Ahmed and Shalet (103), but it responded subsequently to another dopamine agonist, pergolide. Since the latter drug is an ergoline compound, not an ergopeptine, it is possible that a clone of cells with altered dopamine agonist binding sites might have emerged. Patient 3 in the Cardiff-Oxford series (Fig. 1) was completely resistant to BC, but serum PRL fell during treatment with pergolide; though neither drug induced tumor shrinkage. The macroprolactinoma

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described by Bannister and Sheridan (104) continued to grow despite an increase in BC dosage to 90 mg daily. One PRL-secreting pituitary carcinoma developed brain metastases during BC therapy (105). Poor compliance with therapy is probably the cause of some examples of apparent BC resistance (106) and, in one of the cases described by Dallabonzana et al. (107), increased clearance induced by concurrent therapy with spiramycin may have been responsible for BC losing its efficacy. Overall, the acquisition of dopamine agonist resistance appears to be rare, even during treatment periods extending to 10 or more years. g. Dopamine agonist withdrawal. Although prolactinoma cells usually remain sensitive to BC, the drug does not provide a definitive cure for macroprolactinomas. Immediate tumor reexpansion after drug withdrawal may occur after short [weeks (37)] or medium (1 yr (108)] term therapy. Early tumor reexpansion is less common after long-term treatment. Johnston et al. (81) withdrew therapy from 15 prolactinoma patients after a mean of 3.7 yr treatment (range 1.5-7). CT scans performed 539 weeks later showed no change in 13, further shrinkage in one and slight enlargement in one. However, hyperprolactinemia returned in 14, presumably signifying the continuing presence of tumorous lactotrophs and the failure of dopamine agonist therapy to effect cure. Van't Verlaat and Croughs (109) have recently reported studies of 15 macroprolactinoma patients after BC withdrawal with very similar findings. Prolactinoma fibrosis is likely to be responsible for the lack of early reexpansion (vide infra), and tumor enlargement would be predicted in the longterm. Studies of drug withdrawal for more prolonged periods are required, particularly of patients treated for longer than 5 or even 10 yr, before a definitive statement can be made regarding the curative potential of dopamine agonist therapy. An alternative treatment approach is to attempt to reduce the dose of dopamine agonist after initial tumor control has been achieved. Liuzzi et al. (83) studied the effect of maintenance dose reduction in 21 macroprolactinoma patients. No significant changes in serum PRL or tumor size were noted over 6 to 52 months with greatly reduced doses of dopamine agonist; in 13 patients the BC daily dose was 2.5 mg or less. However it was possible to withdraw the drug in only one patient. Persistent tumor control depends therefore on continual administration of dopamine agonist, albeit at very low dose, or the application of external radiotherapy, which will enable the eventual withdrawal of BC in most cases, but possibly at the expense of inducing hypopituitarism. h. Nonshrinking prolactinomas. A proportion of genuine macroprolactinomas fail to regress during dopamine agonist therapy, but the percentage is lower than stated in earlier reviews [for example, 30% of 274 patients reviewed by Benker et al. (96)]. In the present review,


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DOPAMINE AGONISTS AND PITUITARY TUMORS Normoprolactinaemia

30^-

FIG. 3. Plasma testosterone concentrations before (O) and after (•) at least 3 months of BC in 34 men with macroprolactinomas previously untreated with surgery or radiotherapy (from the series in Table 1). Normoprolactinemia occurred in 20, but a degree of hyperprolactinemia persisted in 14 (though 3333 1667-3333 667-1667 333-667 167-333 Total % patients

(n)

Figures in parentheses indicate patients with normal serum PRL concentrations (1 yr) BC therapy, and some may be inclined to debulk such tumors, before radiotherapy. However, Esiri et al. (49) showed that there was a direct correlation between prolactinoma fibrous tissue content and duration of BC treatment in macroadenomas shrunk by the drug before surgery. Furthermore, treatment for longer than 3 months produced a tough tumor consistency which hampered subsequent surgery and resulted in increased perioperative morbidity (9). Others have been less impressed by BC-induced fibrosis (144); however, their data suggest that interstitial fibrosis tends to occur more frequently in those receiving BC until the time of surgery. It is now clear that three-field external radiotherapy can be given safely to patients with persistent suprasellar disease (145), and anecdotal accounts of tumor swelling and visual deterioration following such treatment have assumed undeserved prominence. How-



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ever, we recommend that BC be continued throughout the radiotherapy treatment period. Second, approximately 10% of macroprolactinomas do not shrink with dopamine agonists and may require surgery after BC failure; it is unknown whether their texture is affected adversely, but since many will be operated upon within 3 months of presentation, particularly if vision is compromised, this is an academic question. Last, it is possible that if short-term BC produces compact shrinkage resulting in an intrasellar tumor, uncommon with large adenomas, some of these patients may be curable by subsequent surgery. This remains unproven, but some have found that short-term BC (days to weeks) facilitates surgical removal of prolactinoma tissue (48, 146). Overall, it would seem prudent to limit the duration of preoperative BC to a maximum of 3 months, if surgery is to be performed. These management guidelines have been summarized recently (147). III. Nonfunctioning Tumors A. Tumor biology Approximately 25% of surgically removed pituitary adenomas are not associated with clinical or biochemical evidence of increased hormone production (148), a figure that rises to around 70% for large tumors causing visual failure (3). Some are "clinically silent" in which immunocytochemistry shows positive staining for one or more anterior pituitary hormones (148). A further group show oncocytic transformation with most cells containing large numbers of abnormal mitochondria (149). Kovacs et al. (150) proposed the term null cell adenoma for tumors lacking immunostaining for specific pituitary peptides or hormones; 56 tumors were so classified out of a surgical series of 343 adenomas. Of these, 46 showed completely negative immunostaining for anterior pituitary hormones and their subunits. The remaining 10 showed scattered cells with positive immunostaining for the glycoprotein hormones, a-subunit or PRL. Many null cell tumors may actually be poorly secreting rather than completely nonsecreting. Electron microscopy demonstrates secretory granules in the majority, though these are smaller than those present in functioning adenomas (150,151). Furthermore, a secretory granule-specific protein, chromogranin, is frequently identified in nonfunctioning pituitary tumors (NFT), as in functional tumors (152). Four of five NFTs with negative staining for anterior pituitary hormones showed positive immunostaining for chromogranin-A, and two of these patients had elevated serum concentrations of the protein (153). In cell culture, a large proportion of NFTs secrete pituitary hormones, most commonly gonadotropins and their subunits (154). Five oncocytomas studied by Asa et al. (155) also released glycoprotein hormones

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in vitro. However the rate of secretion by NFTs is often low (155-157), and up to 25% do not secrete any known anterior pituitary hormone (158). Whether all cells within these tumors are of gonadotroph lineage has been an area of controversy. First, gonadotropin immunostaining, if present, is invariably confined to scattered or small groups of cells, leaving the identity of most cells unknown (151, 156). Second, gonadotropin contents are much lower than those present in normal pituitary (159). Furthermore, serum gonadotropin concentrations are usually within the normal range, although differentiation of normal from abnormal gonadotropin secretion may be difficult in postmenopausal women (157). Serum a-subunit concentration may be a useful tumor marker in a proportion of patients with NFTs. Oppenheim et al. (160) demonstrated raised levels in 14 of 63 (22%) using a sensitive monoclonal antibody assay, and Ishibashi et al. (161) showed elevated concentrations in five of 32 (16%) NFT patients. Definite gonadotropinomas can be distinguished from null cell adenomas by the presence of elevated serum hormone or subunit concentrations, which may increase paradoxically after TRH (162), and positive immunostaining in the majority of tumor cells (163), ideally supported by in vitro secretion studies (164). Recent studies have shed further light on the pathobiology of NFT cells. Yamada et al. (165) compared functioning and nonfunctioning adenoma cells using the reverse hemolytic plaque assay. Only 0.1-3.3% of NFT cells formed plaques identified by antisera to /3LH, jSFSH, and a-subunit, and the plaques were much smaller than those formed by 16.1-46.2% of prolactinoma or somatotrophinoma cells, using antisera to PRL or GH. Furthermore, using quantitative in situ hybridization histochemistry to demonstrate anterior pituitary hormone mRNA species, Levy and Lightman (166) showed considerable variability of glycoprotein gene expression between cells from individual NFTs. The clonality of NFTs is of considerable interest in view of this heterogeneity of hormone secretion. This has been addressed by examining X-linked restriction fragment polymorphisms of the phosphoglycerate kinase and hypoxanthine phosphoribosyl-transferase genes in tumor genomic DNA from female patients presenting with NFTs . All eight tumors studied thus far have proved to be monoclonal (167, 168). The molecular explanation for the synthetic and secretory inertia of the majority of NFT cells therefore remains obscure. For the purpose of this review, a NFT is defined simply as a pituitary tumor not associated with hormonal hypersecretion and which most commonly has the laboratory characteristics of a null cell tumor. However, such a grouping undoubtedly embraces several biological subtypes of NFT. In this section we shall also consider the


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responses of "true" gonadotropinomas to dopamine agonists, since the balance of evidence favors most NFTs being derived from gonadotroph cells. B. Responses to dopamine agonists: clinical aspects

In the early 1980s there was uncertainty regarding the responses of NFTs to dopamine agonists, as indicated in section I. Wolleson et al. (40) reported reduction in tumor area on CT in nine of 11 patients, but the mean decrease of only 34% was measured using a scanner of relatively poor resolution. Since then, the responses of 84 patients with NFTs have been described in seven series (Table 4), chosen for review using criteria 1-4 in section II.B.I. Twenty-three patients had mild hyperprolactinaemia (highest 113 jig/liter) but none of the tumors immunostained for PRL. Overall, 76 of 84 NFTs showed no change and one an increase in size during dopamine agonist therapy. At least five patients' vision deteriorated during medical therapy, implying an increase in tumor volume too small to be revealed by CT. Seven patients with NFTs showed a small decrease in tumor size, but this was due to coincident apoplexy in at least one (169). Use of higher BC doses did not increase the proportion of patients with tumor volume reduction (Table 4). However, 15.4% of those treated for longer than 1 yr achieved shrinkage, compared with 8.3% for the whole group (Table 4). Furthermore, van Schaardenburg et al. (173) presented preliminary evidence to suggest that dopamine agonists may arrest or slow the growth of some NFTs, TABLE 4. Changes in size of 84 nonfunctioning tumors during dopamine agonist therapy Change in tumor size A II +

KSW

Rof

None Barrow et al. (1984) Grossman et al. (1985) Pullan et al. (1985) Verde et al. (1985) Zarate et al. (1985) Bevan et al. (1987) Van Schaardenburg et al. (1989)

(48) (169) (170) (171) (172) (9) (173)

Total > 7.5 mg BC (> 3 months) > 7.5 mg BC (> 1 yr) > 20 mg BC (> 6 months)

6 12 4 19* 7 8 20c

Increase — — — — — — 1

Decrease — 1° 1 1 — — 4

76

1

7

53 22 10

1 0 0

6 4 1

Seventy nine patients were treated with BC, four with mesulergine, and one with pergolide. The median BC dose was 8.1 mg daily (range 5-37.5) given for a median treatment period of 7.5 months (range 0.573). 0 Coincident apoplexy. 6 Includes four patients whose vision deteriorated during therapy. c Includes one patient whose vision deteriorated and one whose vision improved during therapy.

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even though they do not induce dramatic shrinkage. A few recent case reports have suggested that occasional NFTs may respond acutely to dopamine agonists (174177). However, none showed major tumor size reduction, and surgery just before or just after dopamine agonist therapy in four patients obscured the long-term effects of drug treatment (174, 177). C. Possible reasons for nonshrinkage

NFTs do not shrink dramatically during BC therapy despite the fact that they clearly possess dopamine receptors that bind the drug (178). What is the explanation for this apparent discrepancy? The relatively low secretory activity of these cells may be responsible; if no secretory product accumulates within the tumor cells after BC then perhaps some negative feedback effects do not occur. As noted above, less than 5% of cells in most NFTs show secretory activity in vitro (165). What is known about the actions of dopamine agonists on "true" gonadotropinomas? In four single case reports (three FSH/a, one LH/a) gonadotropin and a-subunit concentrations were reduced by BC, but significant tumor shrinkage did not occur (179-182). Similarly, Klibanski et al (183) reported that dopamine reduced asubunit secretion and gene transcription in four a-subunit secreting tumors. However, only two of the four had shown a reduction in tumor size, described as "small," after 6 weeks of BC treatment. BC can suppress the in vitro secretion of gonadotropins and a-subunit from the majority of NFTs and gonadotropinomas (154,183,184). Kwekkeboom et al. (185) presented in vitro data which showed that during prolonged (4-6 weeks) incubation of adenoma cells with BC, the drug had a time-dependent increasing inhibitory effect on release and synthesis, which led eventually to decreased intracellular concentrations of glycoproteins. The shrinkage of NFTs after BC may therefore require prolonged dopamine receptor stimulation, clearly impracticable if the patient has significant visual failure. Another possible explanation for the failure of pituitary tumors, other than prolactinomas, to shrink is that the density of membrane-bound dopamine receptors may be too low. The number of dopaminergic binding sites in prolactinoma membranes is approximately 5 times that in NFT membranes, although receptor affinities are identical (178). It is possible that the distribution of dopamine receptors within NFTs is heterogeneous; in view of the disparity between the effects of dopamine agonists on hormone/subunit secretion and tumor growth, one may speculate that expression of the dopamine receptor gene may be confined to the minority of cells synthesizing and secreting gonadotropins. A third explanation for the failure of NFTs to shrink



May, 1992

is that they may possess post-dopamine receptor defects that render the cells unable to respond to receptor activation, in a manner analogous to the rat pituitary tumor 7315a (186). Little is known of postreceptor mechanisms in NFTs, but preliminary data presented by Spada et al. (187) suggest that dopaminergic receptor transduction may be abnormal in a proportion of NFTs; cells from one third of tumors showed a paradoxical rise in intracellular free calcium after exposure to dopamine, suggesting a possible G protein abnormality. This is currently an area of intensive research; to date no NFT has been shown to possess the Gas mutation found in one third of GH tumors, or the G«i2 mutation found in one third of ovarian and adrenal endocrine tumors (188). D. Treatment recommendations for NFTs Some principles have been discussed already in section H.B.6. If a patient with a pituitary lesion of more than 10 mm has a serum PRL of less than 83 /ig/liter, then surgery, most often transsphenoidal, is usually the best initial treatment. This will successfully decompress most tumors (9, 16, 17) and enable identification of lesions that are not pituitary adenomas (69). Some may elect for a trial of BC in patients without visual failure but surgery will be required to establish the correct diagnosis if the lesion does not shrink after 3 months. Dopamine agonists do not have a role in the primary management of patients with NFTs, as they do for those with prolactinomas. BC may arrest NFT growth in occasional patients with difficult recurrent tumors, in whom previous pituitary irradiation has been given and for whom further surgery is contraindicated, but this remains unproven (173). BC may also be tried in those who refuse surgery; such therapy is unlikely to do harm and may be beneficial for some patients. At present there is no effective medical treatment for NFTs, and early experience with somatostatin and GnRH analogs has not been encouraging (189, 190).

IV. Other Pituitary Tumor Types A. GH-secreting adenomas Only 25% of GH-secreting tumors are microadenomas, but approximately 70% are less than 20 mm in diameter (191, 192). Attempted selective adenomectomy is therefore the preferred initial treatment for most patients. Ross and Wilson (193) have recently reviewed data on a total of 1360 patients from 30 surgical series; of these, 60% showed early cure (defined as a fall in plasma GH to less than 5 ^g/liter, but not necessarily insulin-like growth factor I (IGF-I) normalization or abolition of paradoxical responses) with minor endocrine penalty and minimal morbidity. As with other tumor types, cure was

233

less common for adenomas more than 20 mm in diameter, particularly those with invasion (193). The GH-lowering effect of BC in acromegalics was described first by Liuzzi et al. (194) and subsequently confirmed by many investigators. Barkan (192) has reviewed the biochemical efficacy of BC in 514 acromegalics from 28 series; plasma GH was reduced to less than 5 /ug/liter in 21%, with normalization of IGF-I in only 8% of assessible patients. He similarly reviewed the responses of 377 acromegalics to octreotide and found equivalent figures of 55% and 51%, respectively. It is recognized that there is a discrepancy between the few acromegalics who achieve biochemical normalization and the majority who enjoy symptomatic benefit during dopamine agonist therapy. The effect of dopamine agonists on GH tumor size has not been extensively studied. Early studies produced conflicting results; some found no shrinkage (31), whereas others showed reduction in a proportion (33, 38, 40). In a more recent study, Oppizzi et al. (195) studied 19 patients with GH-secreting macroadenomas treated with either BC or lisuride. During 4-24 months of therapy, only two tumors shrank. In one of these patients, extremely high GH levels were almost normalized by BC 10 mg daily, and CT (EMI 1010) after 7 months showed a 30% reduction in extrasellar tumor; PRL was normal. No further shrinkage took place during 18 months additional treatment. In the other, who had undergone radiotherapy 6 yr previously, GH fell from 80 to 20 /u.g/liter during BC 5 mg daily; after 6 months CT (EMI 1010) showed a 40% reduction in extrasellar adenoma, but there was no further shrinkage thereafter. Of five patients with visual field defects none improved during dopamine agonist therapy. Dose may be important, and Gross et al. (196) found that BC doses of 3080 mg daily produced shrinkage of three out of seven GH adenomas. It is generally accepted, however, that BC doses of greater than 20 mg daily do not usually further improve biochemical or symptomatic control. In summary, dopamine agonists rarely induce major shrinkage of GH-secreting adenomas, despite some lowering of plasma GH in the majority of patients. However, marked suppression of plasma GH usually occurs in the minority of patients whose tumors shrink. There are no comprehensive data on whether tumors secreting PRL, in addition to GH, are more likely to shrink after dopamine agonists. Dopamine agonists other than BC do not seem to be more effective in inducing shrinkage but cabergoline, with its prolonged duration of action, warrants evaluation. As noted above, somatostatin analogs are more effective than dopamine agonists in lowering GH and IGF-I concentrations. They also induce tumor shrinkage in 30-50% of patients, but the reduction is much smaller than that seen in prolactinomas treated with dopamine agonists (197, 198). Correspondingly, tu-


BEVAN ET AL.

234

mor cells from octreotide-treated patients show an increased number of GH granules, in contrast to the marked reduction in PRL granules seen in lactotrophs exposed to dopamine agonists (192,199). B. TSH-secreting adenomas TSH-secreting pituitary tumors are uncommon, but most are macroadenomas, often associated with chiasmal compression (8). Of 24 previously reported cases challenged acutely with dopamine agonists, 20 showed no significant fall in serum TSH concentration (200). Such tumors showed little or no dopaminergic inhibition of TSH in vitro (200-202), and radioligand binding assay of membranes from two revealed complete absence of D2 dopaminergic binding sites, suggesting a mechanism for the BC resistance of thyrotropinomas (200). Long-term BC has been given to very few patients and, even in these cases, it is difficult to dissociate BC effects from those of additional surgical and radiotherapeutic treatments. During BC therapy (up to 50 mg daily) patients have shown either no fall (40, 203, 204) or a minimal reduction in serum TSH (205, 206). There are virtually no data on tumor shrinkage: Wolleson et al. (40) found minimal shrinkage and McLellan et al. (206) none at all, in two single cases. The virtually complete BC resistance of most tumors and the absence of membrane-bound dopamine receptors suggest that dopamine agonists have little role to play in the management of these tumors. Octreotide successfully reduces TSH hypersecretion in the majority of patients with thyrotropinomas but, as with GH tumors, this is accompanied by little or no tumor shrinkage (207, 208). Surgery remains the primary treatment modality for these tumors. C. ACTH-secreting adenomas The majority of ACTH-secreting pituitary tumors are microadenomas (209). Control of hypercortisolism is therefore a more important treatment goal than tumor size reduction, and up to 90% of patients may be cured by pituitary microsurgery (210). Pituitary tumors associated with Nelson's syndrome, however, may be aggressive and rapidly growing, and an effective medical treatment to inhibit tumor growth would be of value. Data on the effect of chronic dopamine agonist therapy on the size of ACTH-secreting adenomas are limited and largely confined to isolated case reports and very small series of patients (211). A preliminary report by Loli et al. (212) showed that none of five "large" adenomas shrank after 3-6 months of BC. Lamberts et al (213) proposed that a subset of ACTH-secreting tumors in Cushing's disease patients were of neurointermediate lobe origin and characterized by BC responsiveness, hyperprolactinemia, and relative insensitivity to dexamethasone suppression. The

Vol. 13, No. 2

existence of this type of tumor remains controversial, and other groups have presented histological evidence that does not support the hypothesis (214). Some ACTHsecreting adenomas show a clear biochemical response to dopamine agonists (215, 216), although control may be lost during more prolonged therapy (217, 218); such patients are exceptional however. Whitehead et al. (219) examined the acute effects of BC on the 24 h ACTH profiles of 12 adrenalectomized patients with Cushing's disease. There was a small fall, but this was significant at only five of 13 sampling points. The BC-responsive patient reported by Hale et al. (216) was said to be the only such example in 24 consecutive patients with Cushing's disease, 15 of whom had been treated with BC or lisuride for a median duration of 6 weeks; no tumor volume data were quoted. V. Summary The primary aim of this review has been to clarify the tumor shrinking effects of dopamine agonists on pituitary macroadenomas of different cell types. Shrinkage is most dramatic for macroprolactinomas and is due to cell size reduction. Seventy-nine percent of 271 definite macroprolactinomas were reduced in size by at least 25%, and 89% shrank to some degree. Most shrinkage occurs during the first 3 months of treatment, although in a minority shrinkage is delayed. Dopamine agonist resistance during long-term therapy is exceptional. Drug withdrawal nearly always leads to a return of hyperprolactinemia, even after several years treatment, although early tumor reexpansion is unusual. About 10% of true macroprolactinomas do not shrink with dopamine agonists; the molecular mechanisms of such resistance have yet to be determined. Alternative formulations of BC and new dopamine agonists (CV 205-502 and cabergoline) are useful for the minority of patients unable to tolerate oral BC, but do not seem to further improve overall shrinkage rates. The risks of pregnancy have probably been overstated, and BC is suitable primary treatment for women with prolactinomas of all sizes; the drug can be used safely during pregnancy in the event of clinically relevant tumor expansion. The interpretation of different degrees of hyperprolactinemia is discussed and management strategies suggested. Most patients with macroprolactinomas now avoid surgery, but drug-induced, time-dependent tumor fibrosis should be remembered if surgery is contemplated. Nonfunctioning pituitary tumors are mostly of gonadotroph cell origin and may be associated with significant disconnection hyperprolactinaemia. Seventy-six of 84 well-characterized tumors showed no tumor shrinkage during dopamine agonist therapy. Possible explanations include abnormalities of dopamine receptor number and


May, 1992


function. Preliminary evidence suggests that dopamine agonists may restrain the growth of some functionless tumors; most of these tumors, however, can be satisfactorily debulked using transsphenoidal surgery. In contrast to macroprolactinomas, other functioning pituitary tumors (GH-, TSH-, and ACTH-secreting) rarely shrink during dopamine agonist therapy, although the number of tumors studied is small.

Acknowledgements We are grateful to Professor Reg Hall for his constant encouragement and critical reading of this manuscript. We thank Dr Margaret Esiri for the photomicrograph in Fig. 4.

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19. Randall RV, Laws ER, Abboud CF, Ebersold MJ, Kao PC, Scheithauer BW 1983 Transsphenoidal microsurgical treatment of prolactin-secreting pituitary adenomas, results in 100 patients. Mayo Clin Proc 58:108 20. Scanlon MF, Peters JR, Thomas JP, Richards SH, Morton WH, Howell S, Williams ED, Hourihan M, Hall R 1985 Management of selected patients with hyperprolactinaemia by partial hypophysectomy. Br Med J 291:1547 21. Johnston DG, Hall K, Kendall-Taylor P, Ross WM, Crombie AL, Cook DB, Watson MJ 1986 The long-term effects of megavoltage radiotherapy as sole or combined therapy for large prolactinomas: studies with high definition computerized tomography. Clin Endocrinol (Oxf) 24:675 22. Gomez F, Reyes FI, Faiman C 1977 Nonpuerperal galactorrhea and hyperprolactinemia. Am J Med 62:648 23. Kelly WF, Mashiter K, Doyle FH, Banks LM, Joplin GF 1978 Treatment of prolactin-secreting pituitary tumours in young women by needle implantation of radioactive yttrium. Q J Med 47:473 24. Sheline GE 1981 Pituitary tumors: radiation therapy. In: Beardwell C, Robertson GL (eds) The Pituitary. Butterworths, London, p 106 25. Grossman A, Cohen BL, Charlesworth M, Plowman PN, Rees LH, Wass JAH, Jones AE, Besser GM 1984 Treatment of prolactinomas with megavoltage radiotherapy. Br Med J 288:1105 26. Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Applegate G, Sutton ML 1989 Hypopituitarism following external radiotherapy for pituitary tumours in adults. Q J Med New Series 70:145 27. Corenblum B, Webster BR, Mortimer CB, Ezrin C 1975 Possible antitumour effect of 2 bromoergocryptine (CB154, Sandoz) in 2 patients with large prolactin-secreting pituitary adenomas. Clin Res 23:614A (Abstract) 28. Nillius SJ, Bergh T, Lundberg PO, Stahle J, Wide L 1978 Regression of a prolactin-secreting pituitary tumor during long-term treatment with bromocriptine. Fertil Steril 30:710 29. Landolt AM, Wuthrich R, Fellmann H 1979 Regression of pituitary prolactinoma after treatment with bromocriptine (letter). Lancet 1:1082 30. McGregor AM, Scanlon MF, Hall K, Cook DB, Hall R 1979 Reduction in size of a pituitary tumor by bromocriptine therapy. N Engl J Med 300:291 31. McGregor AM, Scanlon MF, Hall R, Hall K 1979 Effects of bromocriptine on pituitary tumour size. Br Med J 2:700 32. Wass JAH, Moult PJA, Thorner MO, Dacie JE, Charlesworth M, Jones AE, Besser GM 1979 Reduction of pituitary-tumour size in patients with prolactinomas and acromegaly treated with bromocriptine with or without radiotherapy. Lancet 2:66 33. Wass JAH, Williams J, Charlesworth M, Kingsley DPE, Halliday AM, Doniach I, Rees LH, McDonald WI, Besser GM 1982 Bromocriptine in management of large pituitary tumours. Br Med J 284:1908 34. Chiodini P, Liuzzi A, Cozzi R, Verde G, Oppizzi G, Dallabonzana D, Spelta B, Silvestrini F, Borghi G, Luccarelli G, Rainer E, Horowski R 1981 Size reduction of macroprolactinomas by bromocriptine or lisuride treatment. J Clin Endocrinol Metab 53:737 35. Sobrinho LG, Nunes MC, Calhaz-Jorge C, Mauricio JC, Santos MA 1981 Effect of treatment with bromocriptine on the size and activity of prolactin producing pituitary tumours. Acta Endocrinol (Copenh) 96:24 36. Prescott RWG, Johnston DG, Kendall-Taylor P, Crombie A, Hall K, McGregor A, Hall R 1982 Hyperprolactinaemia in m e n response to bromocriptine therapy. Lancet 1:245 37. Nissim M, Ambrosi B, Bernasconi V, Giannattasio G, Giovanelli MA, Bassetti M, Vaccari U, Moriondo P, Spada A, Travaglini P, Faglia G 1982 Bromocriptine treatment of macroprolactinomas: studies on the time course of tumor shrinkage and morphology. J Endocrinol Invest 5:409 38. Spark RF, Baker R, Bienfang DC, Bergland R1982 Bromocriptine reduces pituitary tumor size and hypersecretion. Requiem for pituitary surgery? JAMA 247:311 39. Johnston DG, Hall K, MacGregor A, Ross WM, Kendall-Taylor


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ing's disease and Nelson's syndrome. Excerpta Medica (7th International Congress of Endocrinology), Amsterdam, Abstract 1440 Lamberts SWJ, De Lange SA, Stefanko SZ 1982 Adrenocorticotropin-secreting pituitary adenomas originate from the anterior or the intermediate lobe in Cushing's disease: differences in the regulation of hormone secretion. J Clin Endocrinol Metab 54:286 McNicol AM, Teasdale GM, Beastall GH 1986 A study of corticotroph adenomas in Cushing's disease: no evidence of intermediate lobe origin. Clin Endocrinol (Oxf) 24:715 Atkinson AB, Kennedy AL, Sheridan B 1985 Six year remission of ACTH-dependent Cushing's syndrome using bromocriptine. Postgrad Med J 61:239 Hale AC, Coates PJ, Doniach I, Howlett TA, Grossman A, Rees LH, Besser GM 1988 A bromocriptine-responsive corticotroph adenoma secreting alpha-MSH in a patient with Cushing's disease. Clin Endocrinol (Oxf) 28:215 Kennedy AL, Sheridan B, Montgomery DAD 1978 ACTH and cortisol response to bromocriptine, and results of long-term therapy, in Cushing's disease. Acta Endocrinol (Copenh) 89:461 Croughs RJM, Koppeschaar HPF, Van't Verlaat JW, McNicol AM 1989 Bromocriptine-responsive Cushing's disease associated with anterior pituitary corticotroph hyperplasia or normal pituitary gland. J Clin Endocrinol Metab 68:495 Whitehead HM, Beacom DR, Sheridan B, Atkinson AB 1990 The effect of cyproheptadine and/or bromocriptine on plasma ACTH levels in patients cured of Cushing's disease by bilateral adrenalectomy. Clin Endocrinol (Oxf) 32:193

International Symposium "Molecular and Cellular Biology of Thyroid Disease". Pisa, Italy September 7-8, 1992 Topics: 1. Effects of Iodine and Selenium Deficiency on Thyroid Hormone Synthesis and Metabolism. 2. Defects in Thyroid Hormone Transport and Action. 3. Cross-talks of Lymphocytes and Thyrocytes: Adhesion Molecules, Cytokines and Growth Factors. 4. Molecular Biology, Biochemistry and Immunology of the TSH Receptor. 5. Molecular and Cellular Biology of Thyroid Cancer. 6. Relevance of Animal Models to Human Thyroid Pathology. 7. Applications of Molecular and Cellular Biology Techniques to Clinical Thyroidology Correspondence: Dr. Stefano Mariotti, Istituto di Endocrinologia, University of Pisa, Viale del Tirreno 64, 1-56018 TirreniaPisa, Italy. Tel.: +39-50-32590/33274, Fax: +39-50-33433 Organizing Secretariat: D.G.M.P. Via A. Ceci, 54 1-56125 Pisa Italy. Tel.: +39-50-21531/26359. Fax: +39-50-28584


Lower prolactin levels during cabergoline treatment are associated to tumor shrinkage in prolactin secreting pituitary adenoma.

Dopamine receptor agonists: selectivity and dopamine D1 receptor efficacy.

Prolactinomas and resistance to dopamine agonists.

Dopamine, the dopamine D2 receptor and pituitary tumours.

Dopamine agonists for negative symptoms in schizophrenia.

Allergy to ergot-derived dopamine agonists.

Centrally acting dopamine D2 receptor ligands: agonists.

Dopamine D3 receptor agonists as pharmacological tools.

Dopamine receptor agonists for Parkinson's disease.

Modification of ethanol intoxication by dopamine agonists and antagonists.

Potency and efficacy of dopamine agonists in mouse strains differing in dopamine cell and receptor number.

Publicity and reports of behavioral addictions associated with dopamine agonists.

Suppression of prolactin by dopamine agonists in schizophrenics and controls.

Dopamine agonists and cobalt-induced epilepsy in the rat.

Synthesis and pharmacology of some 2-aminotetralins. Dopamine receptor agonists.

Dopamine receptor agonists and antagonists enhance ATP-activated currents.

Dopamine auto- and postsynaptic receptors: electrophysiological evidence for differential sensitivity to dopamine agonists.

Guanine nucleotides regulate anterior pituitary dopamine receptors.

Differential effects of dopamine agonists upon stimulated limbic and striatal dopamine release: in vivo voltammetric data.

Effects of estrogens on pituitary cell and pituitary tumor growth.

Transnasal pituitary tumor surgery.

Exploiting tumor shrinkage through temporal optimization of radiotherapy.

Latent inhibition is unaffected by direct dopamine agonists.

Functionally selective dopamine D₂, D₃ receptor partial agonists.