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Show ]. Clin. Neuro-ophthalmol. 3: 229-237, 1983. Pituitary Adenomas An Update on Their Management with an Emphasis on the Role of Bromocriptine DANIEL L. BARROW, MD. GEORGE T. TINDALL, MD. Abstract This article reviews the advances in neurosurgery, neuroradiology, and neuroendocrinology that have altered the management of patients with pituitary adenomas. These benign tumors can produce significant morbidity including loss of vision. Morbidity may be avoided or corrected if available diagnostic and therapeutic options are instituted appropriately. Introduction Progress in neurosurgery, neuroradiology, neuroendocrinology, and neuropharmacology has changed the diagnostic and therapeutic approach to patients with pituitary tumors. Because of these rapid advances, periodic assessments of management must be made to increase the accuracy of diagnosis, minimize patient risk and cost, and utilize available treatment options appropriately. These significant advances have had an impact in several areas. For instance, the widespread employment of computerized tomography (CT) has obviated the need for most other neurodiagnostic studies in patients with pituitary tumors. Also, the refinement of microsurgical techniques has made transsphenoidal surgery the procedure of choice for the vast majority of pituitary neoplasms, including those large lesions producing mass effect. Furthermore the advent of the dopamine agonist, bromocriptine, has had a major influence on the treatment of certain endocrine-active pituitary tumors both as primary and adjunctive therapy. This publication will focus on new developments in the treatment of pituitary adenomas and changes in management that have come about as a result of the introduction of bromocriptine, with particular attention to large tumors that would be of neuroophthalmological interest. Pathology and Clinical Presentation Classically, pituitary tumors were differentiated histologically as chromophobe, acidophil (eosino- From the Division of Neurosurgery, Emory University Hospital and Clinic, Atlanta, Georgia. December 1983 philic), or basophil, depending on their stammg characteristics with hematoxylin and eosin (H&E). While somewhat useful, this classification suffered from the lack of good correlation between the secretory characteristics of the tumors and their H&E pathology. Kovacs and Horvath l have developed a classification of pituitary adenomas based on cytogenesis with attempts to correlate the morphological features of the tumor cells with their secretory activities, the clinical history, symptomatology, and biochemical findings. This classification consists of eight subgroups: 1) human growth hormone (hGH) cell adenoma; 2) prolactin cell adenoma; 3) mixed hGH cell-prolactin cell adenoma; 4) acidophil stem cell adenoma; 5) corticotroph cell adenoma; 6) thyrotroph cell adenoma; 7) gonadotroph cell adenoma; and 8) undifferentiated cell adenoma, including oncocytoma. We and most authorities believe that this is the most practical classification in use today because of the close correlation between function and ultrastructure. Pituitary tumors are also divided arbitrarily on the basis of size into microadenomas (largest diameter < 10 mm) and macroadenomas (> 10 mm). We believe a third category, the invasive adenoma, should be recognized. This includes all tumors that invade the cavernous sinus, middle cranial fossa, or walls of the third ventricle and are, therefore, unable to be totally removed. Pituitary tumors can present clinically as either an endocrinopathy due to hypersecretion of one or more hormones or as mass effects resulting from their size. Endocrinopathy Endocrinopathy results from excessive hormone secretion by a pituitary adenoma. Prolactin adenomas (prolactinomas), the most frequently occurring type, are associated with the clinical syndrome of menstrual irregularities and infertility with or without galactorrhea2 - 4 (Forbes-Albright, Amenorrhea- galactorrhea, A-G syndrome). loss of libido and dyspareunia may also be complaints. Prolactinomas tend to be larger in men than in women at the time they come to medical attention. This may be related to the fact that the tumors are detected earlier in females due to their more apparent c1in- 229 Pituitary Adenomas ical symptoms resulting from the endocrinopathy. Since the tumors are usually larger in males at the time of presentation, the clinical picture is often dominated by symptoms resulting from mass effect (see below). The symptoms of amenorrhea and/or galactorrhea resulting from prolactinomas in females are due to the resultant hyperprolactinemia and are indistinguishable from hyperprolactinemia caused by other mechanisms. Unlike the other pituitary hormones, prolactin is under a predominantly inhibitory control by the hypothalamus. A prolactin inhibitory factor (PIF), believed to be dopamine, is released by the hypothalamus to prevent an unrestrained release of prolactin by the normal pituitary. In practice there are three major causes for sustained hyperprolactinemia: 1) ingestion of certain drugs, particularly phenothiazines, which are dopamine antagonists; 2) primary hypothyroidism; and 3) pituitary tumors. Elevated serum prolactin levels (>25 ng/ml) in patients with pituitary tumors occur as a result of one of two mechanisms. The first relates to the fact that certain tumors, either partly or entirely free of hypothalamic control, autonomously secrete excessive quantities of prolactin (i.e., true prolactinomas). The other possible mechanism is through impingement on the hypothalamus and/or stalk in such a manner as to diminish the delivery of PIF, resulting in unrestrained overproduction of prolactin by normal, nontumorous cells in the adenohypophysis. In patients with pituitary tumors, it is difficult to identify the underlying mechanism for elevated prolactin levels when the values are only moderately elevated (i.e., <150 ng/ml). Elevations of this magnitude can result from either of the above mechanisms. Thus, a lesion such as an intrasellar craniopharyngioma, aneurysm, or nonfunctional pituitary adenoma could cause modest elevations of prolactin by stalk compression. Conversely, whenever the level of serum prolactin exceeds 150 ng/ml, it almost certainly indicates that the mechanism for the hyperprolactinemia is autonomous secretion by a prolactinoma. Growth hormone-secreting adenomas and mixed hGH cell-prolactin adenomas are associated with the clinical syndrome of gigantism or acromegaly. Gigantism only occurs when the tumor causes elevated hGH levels prior to fusion of epiphyseal bone plates about the time of puberty. After puberty the characteristic clinical features of acromegaly are produced. This includes overgrowth of the head, hands, and feet (especially thickening of the heel pads), prognathism, arthritic manifestations, acroparesthesia (including the carpal tunnel syndrome), impairment in glucose tolerance with clinically manifest diabetes mellitus in 10-15% of patients, cardiomyopathy, and hyperhidrosis. It has been reported that acromegaly re- 230 duces life expectancy by at least 5 years and that most of the relatively early deaths occur from arteriosclerotic heart disease. 5 The corticotroph cell adenoma is responsible for hypersecretion of ACTH which causes both Cushing's disease6 and Nelson's syndrome.7 The latter syndrome results from a pituitary adenoma that develops in a number of patients who have undergone bilateral adrenalectomy for Cushing's disease. The tumors associated with Nelson's syndrome are usually biologically aggressive. A melanocyte stimulating hormone (MSH)-like activity of the excessive ACTH causes a deep skin pigmentation. The clinical features of Cushing's disease include the "moon facies," "buffalo hump," hypertension, thin skin, purple striae, ecchymoses, osteoporosis, glucose intolerance, emotional disorders and (in women) also amenorrhea and hirsutism. Cushing's disease reduces life expectancy and causes considerable morbidity. Many patients are emotionally labile and easily irritated. Common causes of death in Cushing's disease include pyogenic infections, hypertensive-arteriosclerotic cardiovascular disease, and suicide.6 Thyrotroph cell adenoma, a rare tumor, causes a clinical syndrome of thyrotoxicosis due to its secretion of thyrotropin. Many pituitary tumors are nonsecretory and almost all are benign, slowgrowing lesions. Mass Effects Mass effects are most commonly expressed by disturbances in visual acuity, visual field defects, headaches, hypopituitarism, and more rarely other cranial nerve palsies (III, IV, V, VI), hypothalamic dysfunction, or hydrocephalus. Because of the intimate relationship of the optic chiasm to the diaphragm sella, pituitary macroadenomas (>10 mm) characteristically cause a bitemporal hemianopia.M In a typical case, the superior temporal quadrants are affected initially, followed thereafter by the inferior temporal quadrants. Continued tumor growth will result in progressive chiasmal compression and loss of the inferior nasal followed by the superior nasal quadrants and blindness. In the early stages of chiasmal compression, the field defect may be so subtle as to be easily missed by "gross visual field testing" and requires formal examination by perimetry. Meticulous visual field testing to small red isopters, with targets presented bilaterally, may assist in the detection of early changes since deficits to red color testing may precede detectable abnormalities with white or other colored targets. Extraocular muscle paralysis is a relatively uncommon manifestation of pituitary adenomas. The oculomotor nerve is the most commonly involved, followed next by the abducens and then the troch- Journal of Clinical Neuro-ophthalmology Barrow, Tindall Figures la and lb. (a) Coronal CT scan through the sella shows an 8-mm microadenoma (arrow) with erosion of the sella floor below. (b) Coronal CT shows a macroadenoma with suprasellar extension (arrows). lear nerve. Proptosis is a rare finding of pituitary adenomas and occurs secondary to tumor extending into the cavernous sinus, with resultant vascular congestion. Microadenomas «10 mm) usually produce symptoms only as a result of hypersecretion of hormones and are rarely seen by the ophthalmologist. Conversely, macroadenomas are frequently seen by ophthalmologists due to the visual disturbances they produce. Nonfunctional pituitary tumors most frequently present with mass effects. Prolactin-secreting adenomas, especially in a male, will often become macroadenomas. Growth hormone- secreting tumors will occasionally produce visual disturbances and ACTH secreting adenoma rarely become large enough to do so. Neuroradiological Diagnosis Neurodiagnostic studies have undergone considerable evolution in recent years. The test that has had the greatest impact in this area has been computerized tomography (CT scan)-an impact seen in diagnosis, planning, and executing surgery and in postoperative follow-up for early identification of recurrent tumor. In our opinion, a high-resolution coronal CT scan is the only neurodiagnostic test required in the vast majority of cases (Figs. la and Ib). The diagnostic accuracy of the scanner, while not perfect, is superior to multidirectional December 1983 polytomography and pneumoencephalography and has replaced these tests. Polytomography has proven to be unreliable in predicting the presence of an intrasellar mass. Erosion of the sella floor, once used a criterion for the diagnosis of a pituitary tumor, occurs in many normal sellas.9 ,10 In addition, polytomography exposes the patient to a greater dose of radiation and provides less information than CT. In our opinion, cerebral angiography is usually not indicated in the neurodiagnostic evaluation, particularly when the serum prolactin is 150 ngj ml or there is endocrinologic evidence for a growth hormone or ACTH-secreting tumor. However, when such evidence is lacking, the serum prolactin level is <150 ngjml and there is a possibility of an intracranial aneurysm with intrasellar extension, visualization of the intracranial circulation becomes important. The newer technique of intravenous digital subtraction angiography will confirm or eliminate the presence of an aneurysm and avoid the arterial catheterization of conventional angiography. Medical Therapy Although cyproheptadine has been used in the treatment of Cushing's disease, ACTH-secreting pituitary adenomas are rarely seen by the ophthalmologist due to their small size. Bromocriptine, a 231 Pituitary Adenomas Figure 1 (cant.). dopamine agonist, is a potent inhibitor of the synthesis and release of prolactin by the pituitary gland. This drug has been shown to produce significant shrinkage of prolactinomas. ll , 12 The effect of bromocriptine upon pituitary adenomas other than prolactinomas is uncertain, Reports have indicated that some nonfunctional pituitary adenomas as well as those secreting growth hormone may undergo size reduction following use of the drug, Evidence for a tumor inhibitory effect of dopamine agonists has come from clinical as well as experimental observations, There have been several reports of improvement in visual fields12-I~ and improvement in extraocular movementsI", 19 during dopamine agonist therapy of patients with prolactinomas, Restoration of normal endocrine function by bromocriptine with maintenance of normal function after drug discontinuation has been cited as evidence for an antitumor effect. 14 Radiographic shrinkage of pituitary tumors has been shown by pneumoencephalographi",21-2:3 and computerized tomography (CT), 12, 24-2~ Experimental data have supported the clinical observations, Inhibition of prolactin secretion and tumor regression have both been observed in rodentsn ,28 A reversal of the estrogen-induced increase in mitotic index and DNA turnover has been demonstrated in rat pituitary in situ after treatment with dopamine agonist drugs,29, :J() Animal studies suggest that bromocriptine affects the process of exocytosis and reduces prolactin granule release from the cell. Many investigators, including our- 232 (b) selves, believe that bromocriptine lacks a cytotoxic effect and produces tumor shrinkage without curative properties, Rapid changes occur in prolactinoma volume after withdrawal and reinstitution of bromocriptine, 12,:31 In prolactinomas removed surgically from patients treated with bromocriptine, Rengechary et al. 32 and we:31, 33 have observed pathological changes consisting of a reduction of cytoplasmic volume due to reduction and involution of ribosomes, rough endoplasmic reticulum, and Colgi complexes, This was interpreted as a reversible inhibition of the protein-synthetic machinery of the neoplastic cell. These changes were not identified by Rengechary and his group in a growth hormone-secreting tumor treated with bromocriptine for 6 weeks,:32 These changes were also not seen in tumors of two of our patients who discontinued bromocriptine 1 and 2 weeks prior to surgery where CT had shown dramatic reduction of tumor volume, while on the drug and rapid return of size after discontinuation,31,33 Our observation of absence of widespread cellular necrosis, infarction, or vascular damage in the presence of significant changes in cell size indicate that bromocriptine may selectively inhibit protein and hormone synthesis in prolactinoma cells rather than have a direct vascular or cytotoxic effect. The enthusiasm among some clinicians over the initial results with bromocriptine therapy of prolactinomas has led to the suggestion that the drug can be used as primary treatment for these neo- Journal of Clinical Neuro-ophthalmology Barrow, Tindall Figures 2a and 2b. (a) Coronal CT scan through sella shows a large invasive mass with extension into the cavernous sinuses. the sphenoid sinus. and with suprasellar extension. Arrow points to right carotid artery within the cavernous sinus. This patient presented with a bitemporal hemianopia and serum prolactin of 2,400. (b) CT scan of same patient after treatment with bromocriptine for 2 months. Both the suprasellar and cavernous sinus extensions have diminished in size. The visual fields returned to normal following institution of bromocriptine therapy. plasms, reserving surgery for the therapeutic failures. Some investigators proposed bromocriptine as initial therapy for growth hormone-secreting tumors as well. 18, :3.5 In our opinion, this approach is not sound, as there is currently not sufficient data to support the notion that either prolactinomas or growth hormone secreting tumors can be cured by bromocriptine, Our aim in this section is to attempt to put into perspective the uses of bromocriptine in the management of pituitary tumors. Despite the lack of available evidence of a cytotoxic effect of bromocriptine, we do believe that its use is indicated in certain situations. Our studies3 1, 33 and others32 have supported the contention that dopamine agonist agents act preferentially on the prolactin synthetic mechanism of cells. We have found that bromocriptine has no effect on nonfunctional ~ituitary tumors, either clinically or pathologically.' 2, 33 As stated above, others have found some therapeutic benefit of bromocriptine on some growth hormone-secreting tumors. December 1983 Indications for Treatment with Bromocriptine One such indication is in the patient with the AG syndrome and hyperprolactinemia in whom no tumor can be demonstrated by CT. If there is no readily indentifiable source of the elevated serum prolactin, one option is to treat those patients desiring pregnancy with bromocriptine. This will lower serum prolactin levels regardless of the etiology and usually the female patient will resume menstruation and galactorrhea will cease. On occasion we have explored patients in this category if special endocrine stimulation testing (i.e., chlorpromazine stimulation) has indicated the presence of a tumor. We have usually found either a small pituitary adenoma or hyperplasia. This decision is made after extensive discussion with the patient and influenced by the desire of an individual patient. Another indication for primary treatment of a prolactinoma with bromocriptine, in our opinion, 233 Pituitary Adenomas (h) Figure 2 (con!.). is the unusual patient that presents with definite CT evidence of an invasive pituitary adenoma (e.g., tumor surrounds carotids, extends into third ventricle or middle fossa) associated with a markedly elevated serum prolactin (i.e., > 1,000 ng/ml). This is indicative of invasion of the cavernous sinus and leaves no doubt as to the diagnosis as virtually no other pathologic entity will cause such a high serum prolactin. We believe little is to be gained by putting these patients through an operative procedure, and have treated them initially with longterm bromocriptine. Figures 2a and 2b illustrate such a case. Although bromocriptine is not tumoricidal, its ability to produce dramatic reductions in size of prolactinomas can be utilized as a preoperative adjunct to possibly make excision of large tumors not only easier, but more certain. We have tested this hypothesis in a small number of patients with macroadenomas, both prolactin- and nonprolactinsecreting.~ l A 6-week course of bromocriptine effected measurable reduction in the size of all tumors that proved pathologically to be prolactinomas by immunocytochemistry and failed to reduce the size of tumors that ultimately proved to be nonfunctional. Figure 3 illustrates a case in which bromocriptine was used as a preoperative adjunct to reduce the mass before attempted excision. Although our preliminary results are encouraging, a word of caution has been sounded by Landolt and coworkers. They have reported that in their experience, the use of bromocriptine may actually reduce the chance of a surgical cure should one choose the latter option after treatment with bromocriptineY6 This may be related to the duration of bromocriptine treatment prior to surgery with the induction of fibrosis occurring after long-term treatment. 37 Obviously, this issue requires further investigation as it has major clinical implications. Even if bromocriptine is used to achieve a preoperative shrinkage, there will still be patients in whom a surgical cure will prove impossible, especially those with tumor involvement of the cavernous sinus. It appears reasonable to attempt a surgical excision after maximal shrinkage with bromocriptine in responsive tumors. Patients with responsive tumors in whom total surgical excision is impossible may be maintained on bromocriptine as an alternative to radiation therapy. Another cause for postoperative hyperprolactinemia besides residual or recurrent tumor is damage to the pituitary stalk by tumor and/or surgery, thus interfering with the delivery of PIF and resulting in uninhibited release of prolactin by the normal spared gland. This is an ideal situation for the use of bromocriptine if the hyperprolactinemia in producing unwanted symptoms (e.g., amenorrhea and galactorrhea). Transsphenoidal Surgery We currently believe that transsphenoidal microsurgery is the most appropriate primary treatment for the vast majority of pituitary tumors. The indications for surgery in patients with pituitary tumors at our institution are shown in Table 1. The Journal of Clinical Neuro-ophthalmolog) majority of patients with an endocrinopathy from a hypersecreting tumor will have a microadenoma, and it is with these patients that surgery achieves the best results. The macroadenoma, particularly one with suprasellar extension, but without other criteria of invasiveness, should (in our opinion) be treated surgically. The lesion has already demonstrated that it has growth potential, and while medical therapy will shrink some of the lesions, it does not eradicate it. Therefore surgery, in our opinion, remains the only method with a reasonable chance to cure the tumor. The technical details of the exposure along the nasal septum, entry into the sphenoid sinus and floor of the sella turcica, and the method of tumor removal have been discussed and illustrated in other publications.,34 Low operative mortality and morbidity rates and the ability to remove tumor and spare the normal pituitary gland in the majority of patients are the primary advantages of modern transsphenoidal microsurgery. It is recommended in all patients with pituitary tumors in whom operation is to be done, except in the following circumstances: 1) Extrasellar extension of the tumor into the anterior and/or middle fossa as determined by CT scan or other reliable neurodiagnostic tests. Conversely, suprasellar extension of tumor directly above the sella turcica, even in cases in which the extrasellar extension reaches 2 or 3 em, can be managed by the transsphenoidal technique. 2) Presence of a suprasellar tumor with a normal or only slightly abnormal sella turcica. This is likely to be the unusual "collar button" type of extension in which tumor extends through a relatively small opening in the diaphragm sella and then expands into a larger suprasellar component. In both of the aforementioned situations in which the transsphenoidal operation is relatively contraindicated, the lesion is best exposed and managed by craniotomy. Patients as well as physicians often question the safety of transsphenoidal microsurgery. In an effort to provide an answer, several neurosurgeons with considerable transsphenoidal experience were polled as to their mortality and morbidity rates in their series. Any patient that died within 30 days of surgery were counted as an operative mortality. Complications included CSF rhinorrhea that required reoperation (i.e., leaks that did not stop spontaneously or following one or more lumbar punctures, meningitis, and nonfatal arterial injUry). The data obtained from a poll of eight neurosurgeons are shown in Table 2. A total of 4,876 transsphenoidal operations for pituitary tumors were performed by these eight neurosurgeons with an operative mortality of only 0.4%. In the group of 19 patients who died as a result of or in association with the operation, there were extenuating circumstances in nearly every case. For instance, some patients had undergone previous therapies December 1983 Barrow, Tindall Figure 3. Top: Coronal CT scan through the sella shows a large pituitary adenoma with significant suprasellar extension. Center: Coronal CT scan in same patient after 3 weeks of treatment with bromocriptine. There has been dramatic reduction in the size of the tumor. Bottom: Metrizamide cisternogram performed after 6 weeks of treatment with bromocriptine. Metrizamide fills the suprasellar cistern proving that there has been size reduction of the tumor rather than interference with tumor enhancement on CT. TABLE 1. Indications for Surgery in Patients with Pituitary Tumors Verified prolactinoma causing AC svndrome- and infertility in women who de-sire pregnancy Verified pituitary tumor causing Cushing's disease, Nelson's syndrome, or acromegaly Macroadenoma (particularly with extrasellar extension) Pituitary tumor causing mass effect Visual loss Pituitary insufficiency Pituitary tumor associated with pituitary apoplexy 235 Pituitary Adenomas TABLE 2. Mortality and Complication Rate from Transsphenoidal Surgery on Pituitary Tumors· No. of No. of No. of Series Cases with Cases Mortalities Complications Collins 410 3 8 Hardy 912 4 19 Wilson 942 2 20 Laws 896 4 28 Tindall 437 1 II Ciric 290 0 6 Weiss 559 2 4 van Gilder 430 3 14 Total 4,876 19 (0.4%) 110 (2.3%) • Includes all adenomas (functional and nonfunctional microadenomas and macroadenomas). These data were obtained in lune 1982. (such as craniotomy), had extremely large tumors, were in marginal health, etc. It is significant that none of the eight neurosurgeons had an operative mortality in a patient with a microadenoma. The complication rate of only 2.3% is acceptably low. Summary Pituitary neoplasms present a wide range of clinical syndromes. Most tumors, even those producing visual impairment, can be treated and the majority cured. New developments in both the medical and surgical management of pituitary tumors have given the clinician options in treating some of these lesions. Both the patient and treating physician must be informed of those options in order to choose the most appropriate course in an individual case. References 1. Kovacs, K., and Horvath, E.: Pathology of pituitary adenomas. BulJ. Los Angeles Neurol. Soc. 42: 92110, 1979. 2. Boyar, R. M., Kapen, 5., Weitzman, E. D., et al.: Pituitary microadenoma and hyperprolactinemia: A cause of unexplained amenorrhea. N. Engl. ]. Med. 294: 263, 1976. 3. Child, D. F., Nader,S., Mashiter, K., et al.: Prolactin studies in "functionless" pituitary tumors. Br. Med. ]. 1: 604, 1975. 4. Turkington, R. W.: Secretion of prolactin by patients with pituitary and hypothalamic tumors. ]. Clin. Endocrinol. Metabol. 34: 159, 1972. 5. Wright, A. D., Hill, D. M., lowy, C, et al.: Mortality in acromegaly. Q. ]. Med. 39: 1-16, 1970. 6. liddle, G. W., and Melmon, K. l.: The adrenJls. In Textbook of Endocrinology, R. H. Williams, Ed. W. B. Saunders Co., Philadelphia, 1974, pp. 233-283. 7. Nelson, D. H., Meakin, j. W., and Thorn, G. W.: ACTH-producing pituitary tumors follOWing adre-nalectomy for Cushing's syndrome. Ann. Intern. Med. 52: 560-569, 1960. 8. Newman, M.: The chiasmal syndrome. Int. Ophthal. Clin. 7: 857, 1967. 9. Swanson, H. A., and duBoulay, G.: Borderline variants of the normal pituitary fossa. Br. ]. Radiol. 48: 366-369, 1975. 10. Burrow, G. N., Wortzman, G., Rewcastle, N. B., Holgate, R. C, and Kovacs, K.: Microadenomas of the pituitary and abnormal sellar tomograms in an unselected autopsy series. N. Engl. ]. Med. 304: 156158, 1981. 11. Thorner, M. 0., Perryman, R. l., Rogol, A. D., Conway, B. P., Macleod, R. M., login, I. S., and Morris, j. l.: Rapid changes of prolactinoma volume after withdrawal and reinstitution of bromocriptine. ]. Clin. Endocrinol. Metab. 53: 480-483, 1981. 12. Thorner, M. 0., Martin, W. H., Rogol, A. D., et al.: Rapid regression of pituitary prolactinomas during bromocriptine treatment.]. Clin. Endocrinol. Metab. 51: 438-445, 1980. 13. Corenblum, B., Webster, B. R., Mortimer, C B., et al.: Possible anti-tumor effect of 2 bromo-ergocryptine (CB-154 Sandoz) in 2 patients with large prolactin- secreting pituitary adenomas. (Abstract.) Clin. Res. 23: 614A, 1975. 14. Bergh, T., Nillius, S. j., lundberg, P.O., et al.: Bromocriptine treatment of prolactinomas. (letter.) N. Engl. ]. Med. 300: 1391, 1979. 15. Ezrin, C, Kovacs, K., and Horvath, E.: Hyperprolactinemia: Morphologic and clinical considerations. Med. Clin. North Am. 62: 393-408, 1978. 16. Vaidya, R., Aloorkar, S., and Sheth, A.: Therapeutic regression of putative pituitary hyperplasia and/or microadenoma with CB-154. (Abstract.) Fertil. Steril. 28: 363-364, 1977. 17. Vaidya, R. A., Aloorkar, S. D., Rege, N. R., et al.: Normalization of visual fields following bromocriptine treatment in hyperprolactinemic patients with visual field constriction. Fertil. Steri/. 29: 632-636, 1978. 18. Wass, j. A. H., Thorner, M. 0., Morris, D. V., Rees, l. H., Mason, A. S., jones, A. E., and Besser G. M.: long-term treatment of acromegaly with bromocriptine. Br. Med.]. 1: 875-878, 1977. 19. Friesen, H., and Tolis G.: The use of bromocriptine in the galactorrhoea-amenorrhoea syndromes: The Canadian Cooperative Study. Clin. Endocrinol. (Oxford) (Suppl.) 6: 91s-99s, 1977. 20. landolt, A. M.: Progress in pituitary adenoma biology: Results of research and clinical applications. In Advances and Technical Standards in Neurosurgery, H. Krayenbi.ihl, j. Brihaye, F. loew, V. logue, S. Mingrino, B. Pertuiset, l. Symon, H. Troupp, and M. G. Yasargil, Eds. Springer-Verlag, New York. 1978, pp. 1-49. 21. Corenblum, B.: Bromocriptine in pituitary tumours. (letter.) Lancet 2: 786, 1978. 22. George, S. R., Burrow, G. N., Zinman, B., et al.: Regression of pituitary tumors, a possible effect of bromergocryptine. Am. ]. Med. 66: 697-702, 1979. 23. Sobrinho, l. G., Nunes, M. C P., Santos, M. A., et al.: Radiological evidence for regression of prolactinoma after treatment with bromocriptine, (letter.) lancet 2: 257-258, 1978. journJI of Clinical Neuro-ophthalmology 24. landolt, A M., Wuthrich, R., and Fellmann, H.: Regression of pituitary prolactinoma after treatment with bromocriptine. (letter.) lancet 1: 1082-1083, 1979. 25. Matsumura, S., Mori, S., and Uozumi, T.: Size reduction of a large prolactinoma by bromergocryptine (CB-154) treatment. In Pituitary Adenomas: Biology, Physiopathology, and Treatment, P. J. Derome, C. P. Jedynak, and F. Peillon, Eds. Second European Workshop, la Pitie-Salpetriere, Paris, Asc1epios, 1980, p. 336. 26. McGregor, A M., Scanlon, M. F., Hall, K., et al.: Reduction in size of a pituitary tumor by bromocriptine therapy. N. Eng/. f. Med. 300: 291-293, 1979. 27. Macleod, R. M., and lehmeyer, J. E.: Suppression of pituitary tumor growth and function by ergot alkaloids. Cancer Res. 33: 849-855, 1973. 28. Quadri, S. K., lu, K. H., and Meites, J.: Ergot-induced inhibition of pituitary tumor growth in rats. Science 176: 417-418, 1972. 29. Davies, c., Jacobi, J., Lloyd, H. M., et al.: DNA synthesis and the secretion of prolactin and growth hormone by the pituitary gland of the male rat: Effects of diethylstilboestrol and a-bromo-ergocryptine methanesulphonate. f. Endocrinol. 61: 411-417, 1974. 30. Lloyd, H. M., Meares, J. D., and Jacobi, J.: Effects of oestrogen and bromocryptine on in vivo secretion and mitosis in prolactin cells. Nature 255: 497-498, 1975. 31. Barrow, D. L., Tindall, G. T., Kovacs, K., Thorner, M. 0., Horvath, E., and Hoffman, ]. c., lr.: Clinical and pathological effects of bromocriptine on prolactin- secreting and other pituitary tumors. f. Neurosurg. (In press.) December 1983 Barrow, Tindall 32. Rengachary, S. S., Tomita, T., Jefferies, B. F., et al.: Structural changes in human pituitary tumor after bromocriptine therapy. Neurosurgery 10: 242-251, 1982. 33. Tindall, G. T., Kovacs, K., Horvath, E., et al.: Human prolactin producing adenomas and bromocriptine: A histological immunocytochemical, ultrastructural and morphometric study. f. Clin. Endocrinol. Metab. 55: 1178-1183, 1982. 34. Tindall, G. T., Collins, W. F., Jr., and Kirchner, J. A: Unilateral septal technique for transsphenoidal microsurgical approach to the sella turcica. Technical note. f. Neurosurg. 49: 138-142, 1978. 35. Wass, J. A H., Moult, P. J. A., Thorner, M. 0., Dacie, J. E., Charlesworth, M., Jones, A E., and Besser, G. M.: Reduction of pituitary tumor size in patients with prolactinomas and acromegaly treated with bromocriptine with or without radiotherapy. Lancet 2: 66-69, 1979. 36. landolt, A. M., Keller, P. J., Froesch, E. R., and Mueller, ].: Bromocriptine: Does it jeopardise the result of later surgery for prolactinomas? (Letter.) Lancet 2: 657-658, 1982. 37. Tramu, G., Beauvillain, J. c., Mazzuca, M., et al.: Time dependent evolution of pituitary prolactin adenomas under bromocriptine therapy. In Pituitary Adenomas: Biology, Physiopathology and Treatment, P. J. Derome, C. P. Jedynak, and F. Peillon, Eds. Second European Workshop, la Pitie-Salpetriere, Paris, Asclepios, 1980, p. 343. Write for reprints to: Daniel L. Barrow, M.D., Division of Neurosurgery, Emory University Clinic, 1365 Clifton Road, N. E., Atlanta, Georgia 30322. 237 |
