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Migraine headaches have a complex pathophysiology; both vascular and neuronal mechanisms have been proposed. One possible scenario begins with brain-initiated events evolving to cortical spreading depression (CSD), which in turn activates the trigeminal nerve to cause headaches. Experimental evidence supports a relationship between CSD as a cause of migraine aura as well as CSD as a cause of trigeminal activation. Susceptibility to CSD and to migraine appears to be genetically determined. In some migraine subtypes, genes controlling translocation of calcium, sodium and potassium have been implicated, perhaps altering the susceptibility to CSD. This chapter briefly reviews current knowledge pertaining to migraine pathophysiology with emphasis on current notions linking disturbances in ion flux to the genesis of headache.

Object: The Photon Radiosurgery System (PRS) is a miniature x-ray generator that can stereotactically irradiate intracranial tumors by using low-energy photons. Treatment with the PRS typically occurs in conjunction with stereotactic biopsy, thereby providing diagnosis and treatment in one procedure. The authors review the treatment of patients with brain metastases with the aid of the PRS and discuss the indications, advantages, and limitations of this technique., Methods: Clinical characteristics, treatment parameters, neuroimaging-confirmed outcome, and survival were reviewed in all patients with histologically verified brain metastases who were treated with the PRS at the Massachusetts General Hospital between December 1992 and November 2000. Local control of lesions was defined as either stabilization or diminution in the size of the treated tumor as confirmed by Gd-enhanced magnetic resonance imaging. Between December 1992 and November 2000, 72 intracranial metastatic lesions in 60 patients were treated with the PRS. Primary tumors included lung (33 patients), melanoma (15 patients), renal cell (five patients), breast (two patients), esophageal (two patients), colon (one patient), and Merkle cell (one patient) cancers, and malignant fibrous histiocytoma (one patient). Supratentorial metastases were distributed throughout the cerebrum, with only one cerebellar metastasis. The lesions ranged in diameter from 6 to 40 mm and were treated with a minimal peripheral dose of 16 Gy (range 10-20 Gy). At the last follow-up examination (median 6 months), local disease control had been achieved in 48 (81%) of 59 tumors. An actuarial analysis demonstrated that the survival rates at 6 and 12 months were 63 and 34%, respectively. Patients with a single brain metastasis survived a mean of 11 months. Complications included four patients with postoperative seizures, three with symptomatic cerebral edema, two with hemorrhagic events, and three with symptomatic radiation necrosis requiring surgery., Conclusions: Stereotactic interstitial radiosurgery performed using the PRS can obtain local control of cerebral metastases at rates that are comparable to those achieved through open resection and external stereotactic radiosurgery. The major advantage of using the PRS is that effective treatment can be accomplished at the time of stereotactic biopsy.

The authors describe the case of a 36-year-old man who presented with bitemporal hemianopsia and a serum prolactin concentration of 1440 ng/ml. Magnetic resonance imaging of the pituitary revealed a presumed macroadenoma with suprasellar and temporal lobe extension. Although the patient's prolactin level was lowered to 55 ng/ml by bromocriptine therapy, no tumor shrinkage occurred. Fourteen months later, progression of visual field defects necessitated transsphenoidal resection, which was incomplete. Immunocytochemical analysis of the biopsy tissue was positive for prolactin and, in view of the clinical picture, more detailed analysis was not performed. External-beam radiotherapy was given 2 years later because of enlargement of residual tumor. Subsequently, despite a fall in the serum prolactin concentration to less than 20 ng/ml in response to the course of bromocriptine, the mass displayed further extension into the temporal lobe. Nine years after the patient's initial presentation, he underwent transfrontal craniotomy for sudden deterioration in visual acuity caused by hemorrhage into the mass. No adenohypophyseal tissue was identified in the resected tissue. The mass was composed of dysplastic neurons that were strongly immunoreactive for synaptophysin and neurofilament (indicating neural differentiation) and prolactin. Review of the original biopsy specimen indicated that the prolactin-positive cells had striking neuronal morphological characteristics. The final diagnosis in this case is prolactin-secreting gangliocytoma. Although exceedingly rare, this disease must be added to the differential diagnosis in cases of "prolactinoma" when bromocriptine therapy is followed by a marked decline in serum prolactin that is not accompanied by significant tumor shrinkage. Furthermore, in such instances, consideration should be given to "obtaining a biopsy sample prior to electing for radiotherapy.

Background: Untreated Cushing disease historically has a high mortality rate, but the long-term survival of patients with Cushing disease after transsphenoidal surgery has not been reported., Objective: To determine long-term mortality rate in patients who are treated for Cushing disease with current management techniques., Design: Retrospective case series., Setting: Tertiary care center., Patients: 161 patients (32 men and 129 women; mean age, 38 years) who were treated for Cushing disease between 1978 and 1996., Intervention: Transsphenoidal adenomectomy and as-needed adjunctive therapy., Measurement: Record review with follow-up interview., Results: The cure rate for patients with microadenomas who had no previous therapy was 90% (123 of 137). No perioperative deaths occurred (0 of 193 procedures [95% CI, 0.0% to 1.9%]). Follow-up data (mean, 8.7 years) were obtained for 99% of patients (159 of 161). Six patients died. The 5- and 10-year survival rates were 99% (CI, 97% to 100%) and 93% (CI, 88% to 99%), respectively. Survival was similar to that seen in an age- and sex-matched sample that was based on U.S. population data (standardized mortality ratio, 0.98 [CI, 0.44 to 2.2]; P > 0.2)., Conclusion: Survival of patients treated for Cushing disease with current management techniques between 1978 and 1996 was better than the poor survival historically associated with this disorder.

The authors present the case of a patient in whom intradural metastasis from renal cell carcinoma spread to the cauda equina. To the authors' knowledge, this is only the second report of its kind. This male patient had undergone nephrectomy for the treatment of renal cell carcinoma for 5 years and was diagnosed as having metastatic lung disease 1 year prior to admission. The patient presented with lower back pain that radiated to both legs, but he exhibited no sensorimotor deficits. The majority of cauda equina tumors are primary tumors, and metastases are very rare. The literature is reviewed with reference to current molecular genetic paradigms of metastatic renal cell carcinoma.

To analyze the long term outcome after multimodality therapy for acromegaly, a retrospective review was performed on 162 patients who underwent transsphenoidal surgery at Massachusetts General Hospital between 1978 and 1996. The surgical cure rate for microadenomas was 91%, that for macroadenomas was 48%, and it was 57% overall. The surgical cure rate was significantly dependent on tumor size, but was not dependent on age or sex. An improvement in the surgical cure rate was noted over the course of the review, from 45% before 1987 to 73% since 1991. Long term follow-up was obtained in 99% of U.S. residents (149 of 151), with a mean follow-up period of 7.8 yr. Adjuvant radiation and/or pharmacological therapy was given to 61 patients. Of the entire group, 83% (124 of 149) were in biochemical remission as determined by normalization of serum insulin-like growth factor I levels or by GH suppression after oral glucose tolerance testing at last contact or at death. The recurrence rate was 6% at 10 yr and 10% at 15 yr after surgery in those patients who initially met the criteria for surgical cure. The 10-yr survival rate was 88%, and there were 12 deaths at postoperative intervals of 2-12 yr, with the most common cause of death being cardiovascular disease. A Cox proportional hazards model showed that patient-years with persistent disease carried a 3.5-fold [95% confidence interval (CI), 1.0-12; P = 0.02] relative mortality risk compared to those patient-years in remission. A Poisson person-years regression analysis showed no significant difference in survival between those 86 patients cured at operation and an age- and sex-matched sample from the U.S. population [standardized mortality ratio (SMR), 0.84; 95% CI, 0.3-2.2; P = 0.35]. A similar analysis on the entire group of 149 patients showed no significant difference in survival from that in a control sample (SMR, 1.16; 95% CI, 0.66-2.0; P = 0.3). Mortality risk for patient-years with persistent active disease after unsuccessful treatment vs. that in the U.S. population sample remained increased (SMR, 1.8; 95% CI, 0.9-3.6; P = .05). This analysis suggests that the decreased survival previously reported to be associated with acromegaly can be normalized by successful surgical and adjunctive therapy.

Introduction: A mobile computed tomographic scanner has been developed in which the scan plane is selected by means of gantry translation, rather than by translation of the patient table. This permits computed tomographic scanning in situ of any patient who is positioned on a radiolucent surface that fits within the inner diameter of the gantry. We report the design of and initial experience with this scanner as used with adapters for intraoperative and bedside computed tomography (CT)., Methods: The scanner is equipped with wheels, draws power from wall outlets (120 V, 20 A) in combination with batteries, and has a translating gantry. Preclinical studies of image quality were performed with phantoms. An operating table adapter was built for use with a radiolucent cranial fixation device. A bedside adapter was built that holds the head and shoulders of a patient in the intensive care unit., Results: The preclinical phantom studies showed satisfactory image spatial resolution (0.8 mm) and low-contrast resolution signal-to-noise relative standard deviation (0.37%). Experience to date with 12 patients has confirmed the feasibility of intraoperative CT on demand. Experience to date with 26 patients has confirmed the feasibility of routine bedside CT in the intensive care unit., Conclusion: With these adaptations, mobile CT may increase the efficiency of intraoperative scanning by making it available to multiple operating rooms without committing it to any room for an entire operation and may increase the efficiency and safety of CT of critically ill patients who currently need to leave the intensive care unit to travel to a fixed CT installation and back.

The majority of cases of Cushing's disease are due to an underlying pituitary corticotroph microadenoma (< or = 10 mm). Corticotroph macroadenomas (> 10 mm) are a less common cause of Cushing's disease, and little is known about specific clinical and biochemical findings in such patients. To define further the clinical characteristics of patients with corticotroph macroadenomas, we performed a retrospective review of Cushing's disease due to macroadenomas seen at Massachusetts General Hospital between 1979 and 1995. Of 531 patients identified with a diagnostic code of Cushing's syndrome, 20 were determined to have Cushing's disease due to a macroadenoma based on radiographic evidence of pituitary adenoma greater than 10 mm and pathological confirmation of a pituitary adenoma. A comparison review of charts of 24 patients with Cushing's disease due to corticotroph microadenomas identified on the basis of radiographic evidence of a normal pituitary gland or a pituitary adenoma 10 mm or less in diameter was also performed. The mean ages of the patients (+/- SD) with macroadenomas and microadenomas were similar (39 +/- 12 and 38 +/- 14 yr, respectively). The baseline median 24-h urine free cortisol (UFC) excretion was 1341 nmol/day (range, 304-69,033 nmol/day) and 877 nmol/day (range, 293-2,558 nmol/day) for macroadenoma and microadenoma patients, respectively (P = 0.058). After the 48-h high dose dexamethasone suppression test, UFC decreased by 77 +/- 19% (mean +/- SD) and 91 +/- 7% in macroadenoma and microadenoma subjects, respectively (P = 0.04). Fifty-six percent of macroadenoma patients and 92% of microadenoma patients had greater than 80% suppression of UFC after high dose dexamethasone administration (P = 0.03). The baseline median 24-h urinary 17-hydroxysteroid (17-OHCS) excretion was 52 mumol/day (range, 25-786 mumol/day) and 44 mumol/day (range, 17-86 mumol/day) for macroadenoma and microadenoma subjects, respectively (P = 0.09). After the standard high dose dexamethasone suppression test, 17-OHCS excretion decreased by 46 +/- 33% and 72 +/- 22% for macroadenoma and microadenoma subjects, respectively (P = 0.02). Fifty-three percent of patients with macroadenomas and 86% of patients with microadenomas had greater than 50% suppression of 17-OHCS after high dose dexamethasone administration (P = 0.02). Baseline plasma ACTH values were above the normal range in 83.3% of macroadenoma patients and in 45% of microadenoma subjects (P = 0.05). Tumors were immunostained with the MIB-1 antibody for Ki-67 to investigate proliferation in the adenomas. There was a trend for a higher Ki-67 labeling index in corticotroph macroadenomas, and seven (44%) macroadenomas vs. three (18%) microadenomas had labeling indexes greater than 3%, but this was not statistically significant. In summary, corticotroph macroadenomas are often associated with less glucocorticoid suppressibility than the more frequently occurring microadenomas. Therefore, the lack of suppression of UFC or 17-OHCS after the administration of high dose dexamethasone in a patient with Cushing's disease does not necessarily imply the presence of ACTH-independent Cushing's syndrome and is more commonly seen in patients with corticotroph macroadenomas than in those with microadenomas. Increased plasma ACTH concentrations are typical of patients with corticotroph macroadenomas and may be a more sensitive indicator of neoplastic corticotrophs than the UFC or 17-OHCS response to standard high dose dexamethasone testing.

This report offers a description of typical changes seen on gadolinium-enhanced magnetic resonance (MR) imaging of the entire spine that indicate spontaneous intracranial hypotension (SIH). To the authors' knowledge, this is the first report of its kind. They describe three cases of SIH that were accompanied by dural enhancement throughout the neuraxis on imaging, with the evolution of associated subdural and epidural fluid collections in the spine. Recognition of this disorder is important to be able to distinguish it from an infectious or neoplastic process in which surgical intervention might be warranted. Evaluation using gadolinium-enhanced cranial and spinal MR imaging in patients with postural headaches and an (111)In-labeled cerebrospinal fluid leak study are discussed. Treatment with an epidural blood patch is shown to be particularly effective, with resolution of the radiological and clinical findings.

Fas ligand (FasL) is involved in tumor evasion from the immune system. We analyzed 22 human gliomas for expression of FasL and its receptor, Fas. Positive FasL and Fas immunoreactivity was detected in 13 out of 22 tumors by Western blotting and in 15 out of 22 tumors by immunohistochemistry. Immunohistochemistry also showed that Fas and FasL expression was confined to tumor cells. Co-expression of these molecules was confirmed by Western blotting and immunohistochemistry in 4 of 7 glioma cell lines. Co-expression of FasL and Fas within tumor cells suggests that their contribution in vivo to the process of immune system evasion and tumor cell apoptosis is complex and probably involves additional factors.

Although phorbol esters, synthetic activators of protein kinase C (PKC), can stimulate large increases in the binding of cytosolic PKC to form membrane-bound PKC (PKCm, an indicator of PKC activation), the authors report that even small increases in PKCm induced by phorbol esters (8-12% of total PKC content) can be associated with significant PKC-mediated contractions in vitro (50-85% of maximum) in normal canine cerebral arteries. Increases in PKCm of similarly small magnitude were found in vitro when control artery segments were exposed to hemolysate, but only if the arterial smooth-muscle cells were first slightly depolarized by increased extracellular potassium to values of membrane potential similar to those observed in canine cerebral arteries during chronic cerebral vasospasm. These increases in PKCm (6-8% of total PKC content) coincided with a greatly augmented contractile response to hemolysate. These results show that the previous observation of only a small increase in PKCm (approximately 7% of total PKC content) after experimental subarachnoid hemorrhage in the canine model does not preclude a potentially important role for PKC-mediated contraction in the pathogenesis of cerebral vasospasm.

Objective: We report the design and initial characterization of the dosimetry and radiobiology of a novel device for interstitial stereotactic radiosurgery., Instrumentation: The device is lightweight, handheld, and battery-powered, and it emits x-ray radiation from the tip of a probe 3 mm in diameter by 10 cm in length., Methods: The dosimetry was characterized by two independent methods: thermoluminescent dosimeters and radiochromic film. The radiobiology was characterized by in vivo irradiation of rat liver, dog liver, and dog brain. The animals were killed at varying intervals of time, and histological examinations were performed. Heat transfer from the probe to dog brain was studied in vivo by placing thermocouple sensors around the probe tip before irradiating., Results: Both dosimetric methods showed a steep dose-distance fall-off relationship (proportional to the reciprocal of the cube of the distance from the probe tip). Rats and dogs that were killed weeks to months after liver irradiation tended to have sharply demarcated lesions. Liver enzyme levels, measured serially in the dogs, did not give evidence of chronic inflammation. Histological examination of the brains of dogs that were killed acutely after irradiation did not show evidence of inflammation, edema, or hemorrhage. The tissue temperature elevation 1 cm from the tip never exceeded 0.5 degree C, thereby excluding hyperthermia as a significant contributor to the formation of lesions., Conclusions: Because this device requires relatively few supporting resources, has sharp dosimetric properties, and seems to be safe, it may be useful as a clinical tool for interstitial stereotactic radiosurgery.

Objective: This report describes the clinical evaluation of a novel stereotactic radiosurgical device for interstitial irradiation of malignant brain tumors., Methods: Fourteen patients with cerebral lesions less than 3.5 cm in greatest diameter were treated with a single fraction of stereotactic interstitial irradiation (average, 12.5 Gy). Clinical evaluation, Karnofsky Performance Scale ratings, and neuroimaging studies were obtained at 6-week intervals postoperatively to assess treatment response. Reduction or stabilization of tumor size on follow-up imaging was accepted as local control, whereas tumor enlargement indicated local failure., Instrumentation: This battery-powered miniature x-ray generator device produces low-energy x-ray photons that are attenuated rapidly within tissue. A dose decline rate proportional to 1/r3 yields extremely sharp dose fall-off curves with minimal exposure to surrounding tissue. Dose rates of 200 cGy per minute are possible, allowing for the administration of 12.5 Gy to a lesion 3 cm in diameter in less than 1 hour., Results: Local control (stabilization or reduction in lesion size) was obtained in 10 of the 13 patients with tumors with follow-up of 1.5 to 36 months (mean, 12 mo). Of three patients with radiographic progression, recurrence was symptomatic in only one. All patients tolerated the procedure well, and most patients were discharged home the day after treatment. No new neurological deficits were noted after biopsy and irradiation., Conclusions: Preliminary experience with this novel radiosurgical device has demonstrated its feasibility and safety. Clinical efficacy of this technique is now under investigation in an international multicenter study.

Objective: To evaluate the safety and any potential effect of cyclosporine A (CycA) in preventing cerebral vasospasm., Methods: Nine patients with Fisher Grade 3 subarachnoid hemorrhages were studied. After a loading dose of 7.5 mg/kg of CycA was administered every 12 hours for two doses, enteral treatment with CycA was started within 72 hours of the onset of the subarachnoid hemorrhage. Whole blood CycA levels were titrated to maintain levels of 50 to 400 ng/kg. Transcranial doppler ultrasonography was performed daily. Middle cerebral artery velocities were used to assess the degree of vasospasm. Angiography was performed to confirm the vasospasm in symptomatic patients, or it was performed if transcranial doppler ultrasonograms were unobtainable. Patients were treated with a standard pharmacological regimen of nimodipine. Induced hypertension, hemodilution, and hypervolemia were instituted at the discretion of the neurosurgical team. Intra-arterial papaverine was infused into the vasospastic vessels of three recalcitrant patients. Outcome was assessed at 6 months with the Glasgow Outcome Scale., Results: All the patients displayed evidence of vessel narrowing, which was disclosed by transcranial doppler ultrasonography or angiography. Five patients developed ischemic deficits, two were treated with intra-arterial papaverine, and three died of complications secondary to vasospasm. No significant hepatic, renal, or infectious complication developed as a result of the administration of CycA., Conclusions: CycA proved safe to use but failed to prevent the development of cerebral vasospasm or delayed ischemic deficits in patients considered at high risk.

Over the last 30 years, perfluorocarbons (PFCs) have been extensively investigated as oxygen carriers. Early studies indicated that these compounds could be used as blood substitutes or protective agents against ischemia. Adverse characteristics such as instability, short intravascular half-life, and uncertainties concerning possible toxicity precluded wide clinical application. However, advances in PFC technology have led to the development of improved second-generation oxygen carriers that incorporate well-tolerated emulsifiers (egg-yolk phospholipids). The authors review recent developments in this field and consider the potential role of PFCs in future neurosurgical practice. Diagnostic applications could include their use to assess cerebral blood flow, local oxygen tension, and brain metabolism or to achieve enhanced imaging and precise staging of inflammatory, neoplastic, or vascular disease processes by means of computerized tomography, ultrasonography, and magnetic resonance studies. Therapeutic applications could include cerebral protection, an adjunctive role in radiotherapy of malignant brain tumors, protection against air embolism, the preservation of organs for transplantation, and ventilatory support in head-injured patients with compromised lung function. In addition, PFCs have been used successfully as a tool in ophthalmic microsurgery and potentially they could fulfill a similar role in microneurosurgery.

The techniques of two experimental surgical operations on the trigeminal nerve are described, namely, excision of the trigeminal ganglion (ganglionectomy) and division of the trigeminal root (rhizotomy), in the cat. These techniques have been developed with the specific aims of achieving the trigeminal lesion and also preserving a satisfactory postoperative quality of life for the animal in order to make it possible to study the long-term effects of trigeminal dennervation. To the best of our knowledge, a detailed description of such a surgical methodology is lacking; reporting of these procedures may facilitate future research on the trigeminal nerve.

It remains unknown what proportion of delayed arterial narrowing after subarachnoid hemorrhage depends on ongoing metabolic activity within arterial smooth muscle cells versus changes in the passive structural properties of the arterial wall. To determine this, vasospasm was induced by the double subarachnoid hemorrhage model. Anterior spinal artery segments were harvested from control dogs and from dogs with vasospasm. The segments were suspended in a force transducer and stretched to an optimal length for contraction. The difference in tension between 37 and 0 degrees C was defined as the intrinsic tone, and the residual tension at 0 degrees C was defined as the passive tension. The segments taken from dogs with vasospasm had increased intrinsic tone and passive tension (the differences were 3.8 kN/m2 [P < 0.05] and 14.8 kN/m2 [P < 0.025], respectively). Hence, the passive component accounted for 79.6% of the increased tension in vasospastic arterial segments. The intracellular calcium concentration was measured in these segments, using the luminescent calcium indicator, aequorin. The vasospastic segments had increased basal intracellular calcium concentration (398 versus 258 nmol/L, P < 0.025). In parallel experiments, control and vasospastic vessels were immediately excised when the animals were killed, and the vessels were quick-frozen. Subsequently, using two-dimensional gel electrophoresis to measure percent myosin light chain phosphorylation, vasospastic vessels were found to have increased myosin light chain phosphorylation (37 versus 2%, P < 0.05). The increased intracellular calcium concentration and increased percent myosin light chain phosphorylation in vasospastic segments implicate a role for the Ca(2+)-dependent pathway of smooth muscle cell contraction in vasospasm.

Activin, a member of the transforming growth factor-beta (TGF beta) cytokine family, acts as a pituitary cell mitogen via a novel family of receptor-linked serine/threonine (Ser/Thr) kinases. Pituitary tumors synthesize activin subunits, and the autocrine action of these growth factors may modulate tumor proliferation. We, therefore, investigated the expression of activin/TGF beta type I receptor messenger ribonucleic acids (mRNAs), designated ALK1 through ALK5 (ALK = activin receptor-like kinase), and type II receptor mRNAs using RT-PCR in 34 human pituitary adenomas of all phenotypes and normal pituitary tissue. ALK2 and ALK5, specific mediators of activin and TGF beta signals, respectively, were found to be expressed only in tumor and not in normal pituitary cells, and ALK2 expression was found only in tumors of a mammosomatotroph cell lineage. ALK1, ALK3, and ALK4 mRNAs were found in both normal and neoplastic pituitary cells. The alternatively spliced cytoplasmic domain of ALK4 consists of 11 kinase subdomains, that are critical for modulating receptor function and intracellular signaling. Truncated forms of the ALK4 cytoplasmic domain lacking these subdomains may attenuate activin signal transduction and affect both tumor phenotype and proliferation via the formation of inactive type I/type II complexes. Three truncated ALK4 receptor mRNAs generated by alternate splicing of the cytoplasmic Ser/Thr kinase domain were found to be tumor specific. One of these truncated receptor mRNAs, ALK4-5, is a novel splice variant that has not been previously described. Expression of the ActRII and T beta RII type II receptor mRNAs, which specifically bind activin and TGF beta, respectively, was highly prevalent among all tumor subtypes and normal pituitary tissue. However, ActRIIB, an activin-specific type II receptor that displays a 3- to 4-fold higher affinity for ligand than ActRII, was expressed in 94% of tumors, but was not prevalent in normal tissue. These data are the first to demonstrate tumor-specific expression of Ser/Thr kinase receptors mRNAs and their splice variants in human pituitary adenomas.

Symptomatic herniation of the spinal cord through the dura is an uncommon clinical problem. Since 1989, we have encountered three patients who each presented with an unexplained, longstanding Brown-Sequard syndrome and were found to have idiopathic herniation of the thoracic spinal cord. This report describes the clinical, radiographic, and surgical findings in these three patients and reviews the five previously reported patients with this syndrome. Idiopathic herniation of the spinal cord is a treatable cause of the Brown-Sequard syndrome that may be more common than is currently recognized and should be known to all surgeons managing spinal disorders.

Sixteen dogs were entered into a study of the double subarachnoid hemorrhage (SAH) model of cerebral vasospasm. Six animals were sacrificed 72 hours after the first experimental SAH, and the remaining 10 animals were killed 72 hours after the second experimental SAH; ten additional animals served as controls. Basilar arteries were rapidly excised from the dogs and frozen. Multiple segments of the frozen arteries were analyzed independently for total protein and 1,2-diacylglycerol (DAG) content, which averaged 3.17 (+/- 0.27 standard error of the mean; SEM) pmol DAG/microgram protein for all 25 arteries analyzed. A slight decreasing trend in DAG content relative to that of control vessels was found in vessels chronically constricted in situ by subarachnoid blood clot; however, this trend did not attain statistical significance. Two segments of the same vessels were assayed independently for protein kinase C (PKC) activity, which averaged 1.21 (+/- 0.08 SEM) pmol phosphate incorporation per minute per microgram protein for all 24 arteries analyzed. A small decrease in PKC content was noted in vessels that experienced a single SAH; however, PKC returned to near control value in vessels subjected to double SAH. The ratio of particulate (membrane bound) to soluble PKC activity, an indicator of PKC translocation to the membrane and hence PKC activation, showed a small but statistically significant trend to increase with experimental SAH.

A causal or supportive relationship between 1,2-diacylglycerol (DAG) content and the maintenance of tonic vasoconstriction was sought in canine basilar arteries treated in vitro with various agents reported to increase DAG levels in other tissues (platelet-derived growth factor, vasopressin, angiotensin II, and endothelin-1) and, conversely, with agents known to activate sustained constriction (high K+, phorbol ester, hemolysate, and endothelin-1). Multiple segments from individual isolated arteries were prepared. Some segments were immediately frozen as controls and others incubated in physiological saline solution at 37 degrees C for either 5 minutes or 30 minutes in the presence or absence of different concentrations of the test materials. Segments were then quickly frozen until homogenized for lipid extraction and DAG assay. The DAG content of samples incubated up to 2 hours in physiological saline solution alone did not significantly differ from that of immediately frozen control samples. Resting DAG content expressed relative to total protein measured in each sample averaged 3.82 +/- 0.26 (standard error of the mean) pmol DAG/microgram of protein (74 samples from 37 arteries). Endothelin at 2 x 10(-7) mol/L led to a statistically significant increase in DAG content of approximately 40% of basal content at 5 and 30 minutes. A smaller increase in DAG attributable to hemolysate (approximately 25%) was statistically significant at 30 minutes, whereas vasopressin provoked a notable decrease in DAG content. The other agents had no effect. No differences in these results were noted between normal canine basilar arteries and arteries constricted in vivo by subarachnoid blood clot before isolation.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatostatin (SRIF) exerts its diverse biological effects through a family of membrane receptors. In addition to inhibiting GH secretion, SRIF has antiproliferative effects and has been used clinically in the treatment of pituitary tumors. SRIF receptor (SSTR) expression has recently been identified in pituitary adenomas, and it is unknown whether differential expression of SSTR subtypes predicts clinical responses to SRIF analogs. We therefore determined which SSTR subtype messenger RNAs (mRNAs) are expressed in pituitary adenoma phenotypes and in normal human pituitary tissue using reverse transcriptase-polymerase chain reaction and tested whether expression of specific SSTR subtype mRNA is necessary for SRIF inhibition of GH secretion in human somatotroph adenomas in vitro. Expression of SSTR subtypes 1, 2, and 5 mRNA was identified in all pituitary adenoma types and normal pituitary tissue. In contrast, SSTR3 mRNA was detected in only one somatotroph adenoma as well as in control insulinoma tissue, a tissue known to express SSTR3 mRNA, and was not detected in normal pituitary tissue. SSTR4 mRNA was not detected in any human pituitary tissue. To determine whether specific SSTR subtype mRNA expression is required for SRIF inhibition of GH secretion, five somatotroph adenomas were treated with 10(-7) mol/L SRIF in vitro, and significant inhibition of GH release occurred in all adenomas. All five tumors expressed SSTR2 mRNA and SSTR5 mRNA, and three expressed SSTR1 mRNA. The absence of SSTR1 mRNA expression did not affect the ability of SRIF to suppress GH secretion. We conclude that: 1) human pituitary adenomas and normal pituitary express multiple SSTR gene transcripts; 2) SSTR5 mRNA, which has not been reported in other human endocrine tumor types, is expressed in neoplastic and normal pituitary tissue; and 3) SSTR2 mRNA, SSTR5 mRNA, and variable SSTR1 mRNA are expressed in GH-secreting tumors, which are responsive to SRIF in vitro. Further understanding of SSTR gene expression in pituitary adenomas will facilitate our understanding of the pathogenetic mechanisms of tumorigenesis and may provide a rationale for the use of specific SRIF analogs for clinical application.

Vasodilation of rabbit carotid arteries induced by a pulsed-eye laser was studied in vitro to clarify the underlying mechanism. Artery segments were double cannulated in a pressure-perfusion apparatus which, under physiological conditions, allows for differential application of various solutions, pharmacological agents, and pulsed-dye laser light. Vasoconstriction was activated using both pharmacological and nonpharmacological agonists. Laser energy at a wavelength of either 480 or 575 nm was applied intraluminally in 1-microseconds pulses, which caused dilation of the arteries if hemoglobin was present in the lumen at sufficient concentration. Induced vasodilation did not specifically require the presence of hemoglobin; the same phenomenon could be repeated using an inert dye such as Evans blue as an optical absorber of laser energy. The optical density of the absorber, the number of applied laser pulses, and total amount of applied energy directly influenced the vasodilatory response. Laser-induced vasodilation was possible in both normal vessels and vessels denuded of endothelium. Pulsed-dye laser-induced vasodilation is therefore not a phenomenon mediated through chemical processes, but is rather a purely physical process initiated by the optical absorption of laser energy by the intraluminal medium, which probably induces cavitation bubble formation and collapse, resulting in the vasodilatory response of the vessel.

Meningiomas are thought to arise from arachnoid cap or meningothelial cells that not only cluster on the surface of pacchionian granulations but also can cover the arachnoid membrane in other locations. This frequent apposition to the dura mater probably accounts for the usual attachment of the neoplasm to this layer. We report a deep sylvian fissure meningioma without dural attachments in the right hemisphere of an adult patient. The patient initially presented with simple partial seizures. Magnetic resonance imaging revealed a contrast-enhancing circular mass in the superior aspect of the insular region, deep to the inferior parietal lobule. Surgical exploration confirmed the absence of dural attachments. Microscopically, the tumor was found to be a sparsely cellular meningioma with an extensive collagenous matrix. A survey of the literature reveals that the majority of cases of meningiomas without dural attachments occur either in children or below the tentorium. Extremely rare cases of supratentorial meningiomas without dural attachment have been described in adults. The uncommon locations of these tumors at sites distant from the dura mater is postulated to reflect the rare occurrence of arachnoidal cap cells in the Virchow-Robin spaces along the cerebral vasculature or in pial layers distant from the dura mater.

Pituitary adenomas have been shown to be clonal in origin, indicating that one or more somatic mutations underlie tumor pathogenesis. Mutated oncogenic forms of ras protein have been identified in a number of human neoplasms, including thyroid adenomas and carcinomas. However, the potential role of activated ras in the development of specific human pituitary tumor phenotypes has not been determined. Although ras mutations were not found in glycoprotein hormone-secreting or somatotroph adenomas, we recently identified a mutation in the H-ras gene (Gly-Val) at codon 12 in a highly invasive prolactinoma. These data raise the possibility that ras mutations might play a role in the pathogenesis of PRL-secreting pituitary tumors and/or may be a marker for tumor invasiveness and malignant transformation. Therefore, we investigated 78 pituitary tumors (59 prolactinomas, 13 invasive prolactinomas, and 6 pituitary carcinomas) for activating point mutation in the three ras genes using oligonucleotide-specific hybridization. In contrast to the relatively high frequency of ras mutations in many different tumor types, no ras mutations were identified in either prolactinomas or pituitary carcinomas. Our data indicate that ras mutations are rare in prolactinomas and pituitary carcinomas.

Background and Purpose: Perfluorocarbons (PFCs) are considered promising cerebral protection agents because they could combine the beneficial effects of decreased blood viscosity with enhanced oxygen-carrying capacity and oxygen tissue delivery, but trials of PFCs as hemodilutants have been very limited. We evaluated fluoromethyloadamantane (FMA), a new perfluorocarbon compound, as an isovolemic hemodilutant and compared it with low-molecular-weight dextran 40 (D40) and a control group., Methods: Through a transorbital craniectomy, the internal carotid, anterior, and middle cerebral arteries were coagulated to create a cerebral infarction in anesthetized, mechanically ventilated rabbits. No other experimental procedure was performed in control animals. In the two other groups, hemodilution was commenced 30 minutes after the arterial occlusion with either D40 or FMA. Hemodynamic parameters and brain and systemic temperature were monitored throughout the experiments. All animals were killed 6 hours after the arterial occlusion., Results: Hemodynamic and metabolic parameters and blood oxygen content were not affected by the infusion of either FMA or D40. Brain and systemic temperature remained constant. The ratio of infarct volume to the hemispheric volume was 19.6 +/- 3.7% in the FMA group (n = 17), 19.9 +/- 4.6% in the D40 group (n = 16), and 40.3 +/- 5.7% in the control group (n = 17). The difference in infarct volume of both FMA and D40 animals compared with controls was statistically significant (P < .01) when tested with Student's t test. There was no significant difference between FMA and D40 groups., Conclusions: These results suggest that FMA has cerebral protective properties and should be purified, optimized, and further tested experimentally to develop a stable, efficient, and safe oxygen carrier, potentially suitable for clinical trials.

A lecithin-emulsified "Pluronic F-68"-free perfluorochemical compound, named F-1,3-DMA, was tested as a new agent in the prevention of central nervous tissue ischemia. A permanent ischemia leading to cerebral infarction was induced after microsurgical exposure and occlusion of the internal carotid, anterior, and middle cerebral arteries in the rabbit. Following arterial occlusion, F-1,3-DMA was administered intravenously, in a solution rendered isotonic to plasma, over a 30 minute period. The F-1,3-DMA was well tolerated. Hemodynamic, cardiovascular and metabolic parameters were not affected by the infusion of F-1,3-DMA. Although PO2 remained virtually unchanged, animals treated with F-1,3-DMA (n = 9), had smaller infarct volume by 61 percent as compared to the control (n = 8) group (P < 0.04, Student's t-test). Histopathology did not reveal any F-1,3-DMA related damage in the non-infarcted brain. These results suggest that F-1,3-DMA has nervous tissue ischemia protective properties possibly because of microflow effects although O2 transport to "local" tissue may be enhanced as well. We believe that further research is necessary in order to make clinical trials of F-1,3-DMA possible.

The recurrence rate of pituitary adenomas has been reported to be as high as 10% to 35% despite their generally benign nature. A monoclonal antibody directed against proliferating cell nuclear antigen (PCNA) was used to investigate whether the proliferative index might help to predict adenoma recurrence. This antigen is a nuclear protein identified as the auxiliary protein of deoxyribonucleic acid polymerase delta, and its gene expression correlates with cell proliferation. The authors studied 30 patients with recurrent pituitary adenomas, 32 with nonrecurrent adenomas, and seven normal pituitary tissue samples. The mean interval to recurrence ( +/- standard error of the mean) was 5.3 +/- 0.7 years. The age- and sex-matched nonrecurrent group had a mean follow-up period of 6.6 +/- 0.3 years without clinical recurrence. Mean percentages of PCNA-positive tumor nuclei in both the initial and the second surgical specimens of the recurrent adenomas (13.45% +/- 3.02% and 19.56% +/- 3.66%, respectively) were significantly higher than that of the nonrecurrent group (2.49% +/- 1.21%). In addition, recurrent tumors had a higher PCNA index than the initial tumors in the same patients. Normal anterior pituitary gland tissue had a significantly lower mean PCNA index (0.12% +/- 0.11%) than either patient group. Stepwise multivariate regression analysis indicated that factors which collectively correlated significantly with recurrence were: high PCNA index, large tumor size, extrasellar extension, and incomplete surgical excision. The PCNA nuclear count was not associated with age, sex, or hormone hypersecretion, but was higher in macro- than in microadenomas, in tumors with extrasellar extension, and in those incompletely excised. A higher PCNA index also correlated with a shorter disease-free interval. The authors conclude that evaluation of the PCNA index assists in predicting the likelihood of pituitary adenoma recurrence.

It is unclear whether Cushing's disease results from a primary pituitary disorder or arises in response to abnormal hypothalamic control of the pituitary gland. Clonal analysis can provide information as to whether neoplastic tissue is derived from a monoclonal proliferation of a genetically altered cell or from a polyclonal expansion of a group of cells affected by a common stimulus. We used X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase, hypoxanthine phosphoribosyltransferase, and DXS255 loci in 11 women with biochemically and pathologically confirmed Cushing's disease to determine the clonal origins of corticotroph adenomas and corticotroph hyperplasia. Tumor tissue from all 10 women with morphologically and immunohistochemically confirmed ACTH-secreting pituitary microadenomas demonstrated a monoclonal pattern. Pathologically confirmed corticotroph hyperplasia in a patient with a CRH-secreting bronchial carcinoid was found to be polyclonal. We conclude that corticotroph microadenomas in Cushing's disease are monoclonal, supporting the theory that a spontaneous somatic mutation is the primary pathogenetic mechanism in this disorder. In addition, the demonstration of polyclonality in corticotroph hyperplasia implies that excess of hypothalamic hormones is an etiologic mechanism in cases of Cushing's syndrome associated with ectopic CRH-secreting tumors.

Malformations of the diaphragma sellae may permit transdiaphragmatic cerebrospinal fluid pulsations that lead to expansion of the sella turcica. The purpose of this report is to describe an intrasellar arachnoid cyst observed during surgery being filled by the action of an apparent one-way valve.

There is increasing evidence that clinically nonfunctioning pituitary tumors produce and secrete glycoprotein hormone and/or free alpha- and beta-subunits. In addition, hypersecretion of free alpha-subunit occurs in up to 37% of patients with somatotroph adenomas. An understanding of glycoprotein hormone regulation is important in developing effective therapeutic strategies for patients with tumors associated with intact glycoprotein hormone and free subunit hypersecretion. We investigated glycoprotein hormone and free subunit secretion by somatostatin in primary dispersed cultures of pituitary tumor cells from 23 patients with pituitary adenomas. Fifteen tumors from patients with clinically nonfunctioning adenomas (group 1) and 8 tumors from patients with somatotroph adenomas and cosecretion of alpha-subunit (group 2) were studied. Cultures were incubated with control or somatostatin-supplemented media for 24 h. Media samples from group 1 tumors were assayed for intact glycoprotein hormones and free alpha- and beta-subunits secretion levels, while media samples from group 2 cultures were assayed for alpha-subunit and GH secretion levels. Significant (P less than 0.05-0.001) inhibition of secretion of 1 or more intact hormones and/or free subunits was found in 10 of the 15 group 1 tumors. SRIF[10(-7) M] suppressed intact gonadotropin secretion in 60% of FSH-producing tumors and 30% of LH-producing tumors. Media concentrations of FSH beta and LH beta were decreased in 31% and 50% of group 1 tumors, respectively, following somatostatin treatment in those tumors which secreted free beta-subunits. alpha-Subunit was secreted by 12 of the 15 tumors, but significant (P less than 0.02-0.01) inhibition by somatostatin was observed in only 2 tumors. In contrast, significant (P less than 0.05-0.001) inhibition of alpha-subunit in the somatotroph adenomas was found in 6 of the 8 tumors. Significant decreases in alpha-subunit were observed only in those tumors where GH was also significantly inhibited by somatostatin. We conclude that 1) somatostatin inhibits intact glycoprotein or free subunit secretion in the majority of clinically nonfunctioning pituitary tumors in vitro and 2) alpha-subunit secretion is suppressed in 17% and 69% of clinically nonfunctioning and somatotroph adenomas, respectively, consistent with a differential regulation of alpha-subunit by somatostatin in these two tumor types.

Laser energy at a wavelength of 480 nm was applied in 1-microseconds pulses of 3 to 10 mJ to two models of vasospasm. Rabbit common carotid arteries (CCA's) were constricted chronically by the application of human blood within a silicone sheath. Peak vasospasm developed 24 to 48 hours later, and persisted for up to 6 days. Endovascular laser treatment was delivered to 40 CCA's via a 200-microns diameter silica quartz fiber introduced through the femoral artery. The CCA caliber increased from 60% of the pre-vasospasm control diameter to a minimum post-laser diameter of 83% of control. No instances of laser-induced perforation or of arterial thrombosis were observed for up to 60 days after treatment. Prophylactic laser application to nine normal vessels was able to attenuate the development of vasospasm if blood was applied immediately thereafter (88% vs. 59% of control diameter, p less than 0.02), but not if blood was applied 7 days later. Studies in 16 normal CCA's established that there was a considerable margin between the laser energy required to induce dilatation and that which caused perforation, providing that the fiber remained relatively central within the artery. Morphological examination demonstrated focal loss of endothelial cells immediately after laser application, followed approximately 7 days later by the development of areas of intimal hyperplasia. Only minimal changes were observed in the medial or adventitial layers. In a second study, the basilar artery of seven dogs was constricted chronically by two intracisternal injections of autologous blood 3 days apart. Five dogs received endovascular laser treatment 7 or 10 days after the first injection, when basilar artery diameter was reduced to a mean of 61% and 77% of control, respectively. Immediately following treatment, basilar artery diameter increased to 104% and 102% of resting diameter, respectively. Both untreated and laser-treated arteries were smaller than the control diameter at 30 days (80% and 82%, respectively), but in each group the vasodilatory response to hypercapnia was preserved. These findings indicate that 1-microsecond laser pulses are well tolerated by systemic and cerebral arteries in two different animal models, and suggest that the 480-nm pulsed-dye laser may have an application for the treatment or prophylaxis of cerebral vasospasm.

Laser energy of 480 nm was applied in 1-microsecond pulses varying between 2.2 and 10 mJ to in vitro and in vivo models of cerebral vasospasm. First, the pulsed-dye laser was applied intravascularly via a 320-microns fiber to basilar artery segments from six dogs. The segments were mounted in a vessel-perfusion apparatus and constricted to, on average, 70% of resting diameter by superfusion with dog hemolysate. Immediate increase in basilar artery diameter occurred to a mean of 83% of control. In a second model, the basilar artery was exposed transclivally in the rabbit. In three normal animals, superfusion of the artery with rabbit hemolysate resulted in a reduction of mean vessel diameter to 81% of control. Following extravascular application of the laser, vessels returned to an average of 106% of the resting state. In six rabbits, the basilar artery was constricted by two intracisternal injections of autologous blood. 3 days apart. Two to 4 days after the second injection, the basilar artery was exposed. Extravascular laser treatment from a quartz fiber placed perpendicular to the vessel adventitia resulted in an immediate 53% average increase in caliber to an estimated 107% of control. No reconstriction was observed over a period of up to 5 hours. Morphologically, damage to the arterial wall was slight. This preliminary investigation suggests that the 1-microsecond pulsed-dye laser may be of benefit in the treatment of cerebral vasospasm.

Two types of artificial membranes, a medical-grade aliphatic polyurethane and a polysiloxane-carbonate block copolymer, were tested as substitutes for dura in 24 and 12 rabbits, respectively. The films were placed either epidurally, subdurally, or as dural grafts in equal subgroups of animals. The postoperative course was uneventful with no manifestations of convulsive disorder or cerebrospinal fluid leak. The animals were sacrificed 3, 6, or 9 months after implantation of the artificial membranes. Both types of artificial membranes were easily removed from the underlying nervous and the other surrounding tissues. The histological examination failed to reveal adhesions, neomembrane formations, or any type of foreign body reactions to the polyurethane film. The implantation of the polysiloxane-carbonate film caused no reaction when it was applied epidurally. As a dural graft, the polysiloxane-carbonate copolymer induced the formation of a thin neomembrane of one to two layers of fibroblasts which formed a watertight seal of the dural defect. A similar thin neomembrane was found to encase this artificial membrane in the group of animals in which it was implanted subdurally. There was no foreign body reaction to the polysiloxane-carbonate film. The authors conclude that these materials hold promise as dural substitutes or in the prevention of spinal dural scarring, and should be evaluated clinically.

A 6-year-old girl developed secondary sexual characteristics 5 months after severe closed head injury. Endocrinological tests confirmed a pubertal sexual condition; there was also diminution of serum melatonin and disruption of the diurnal pattern. Magnetic resonance imaging demonstrated focal hypothalamic injury; this is believed to be the first time such a posttraumatic lesion has been demonstrated by imaging techniques. The pathophysiology of this condition is discussed.

Clinically nonfunctioning pituitary adenomas are benign neoplasms comprising approximately 25-30% of pituitary tumors. Little is known about the pathogenesis of pituitary neoplasia. Clonal analysis allows one to make the important distinction between a polyclonal proliferation in response to a stimulatory factor versus a monoclonal expansion of a genetically aberrant cell. We investigated the clonal origin of pituitary tumors using X-linked restriction fragment length polymorphisms at the phosphoglycerate kinase and hypoxanthine phosphoribosyl-transferase genes. Restriction enzymes were used to distinguish maternal and paternal X-chromosomes, and combined with a methylation-sensitive restriction enzyme to analyze allelic X-inactivation patterns in six pituitary adenomas. All six tumors showed a monoclonal pattern of X-inactivation. These data indicate that nonfunctioning pituitary adenomas are unicellular in origin, a result consistent with the hypothesis that this tumor type is due to somatic mutation.

The short-term (less than or equal to 72-hour) cerebral vascular reaction to subarachnoid injectates of various specific blood components was determined by angiography in a canine model of cerebral vasospasm. Cell-free subarachnoid clots of autologous plasma in the basal cistern were found to produce no significant reaction of the basilar artery, while whole-blood clots induced a small (15%) chronic constriction after 24 hours. Because the plasma clots were not well retained in the basal cistern, however, small beads (dextran or latex) were added to stabilize them. Injection of beads and plasma led to moderate-to-severe chronic vasoconstriction (35% to 40%) with rapid onset. Control experiments demonstrated that these foreign bodies (beads) alone induced this vascular reaction. Histological examination showed that severe inflammation followed the introduction of subarachnoid beads. The experiments demonstrate that inflammation alone, in the absence of other processes associated with subarachnoid hemorrhage, may induce persistent and severe cerebroarterial constriction and raises the possibility that inflammation in response to subarachnoid blood may play a role in clinical vasospasm.

The short-term (less than or equal to 72-hour) reaction to subarachnoid injections of various blood components was determined in a canine model of cerebral vasospasm. Platelet-rich plasma (PRP) formed durable clots in the basal cistern surrounding the basilar artery and provoked no vascular reaction in 72 hours or more. Freshly isolated autologous erythrocytes resuspended in PRP likewise provoked no vasoconstriction in 72 hours although a second injection of fresh erythrocytes in PRP induced significant reaction, as in the conventional "double subarachnoid hemorrhage (SAH)" canine model. Hemolysate of fresh erythrocytes led to a severe immediate vascular reaction after introduction into the basal cistern using PRP as the carrier/clotting medium, as did the injection of intact erythrocytes incubated ex vivo for 72 hours. Resolution of the initial reaction was rapid for hemolysate, but slow and (depending on hematocrit) incomplete for intact "aged" erythrocytes. In vitro measurements of erythrocyte lysis in these media and histological examination indicate that the production of erythrocyte lysate was responsible for the vascular reaction observed, suggesting that the rate of lysis of erythrocytes in the subarachnoid clot is a major factor in the genesis of vasospasm after SAH.

This paper presents the results of transsphenoidal surgery in 41 consecutive patients with visual loss from pituitary adenomas. The most common pattern of loss was bitemporal hemianopia. Transsphenoidal decompression resulted in visual improvement in 78% of patients. If patients with optic atrophy and pre-operative complete blindness were excluded, improvement extended to 94% of patients. Because of its efficacy and low morbidity, transsphenoidal resection of pituitary tumours is the procedure of choice for most adenomas with extrasellar extension and visual field loss.

The factors responsible for the production of prolactin-secreting tumors are obscure. One hypothesis, that chronic loss of dopamine control from the hypothalamus may be associated with prolactinoma formation, was tested. Female adult Fischer 344 rats were subjected to ovariectomy and were then given subcutaneous implants of diethylstilbestrol (DES) Silastic capsules to produce lactotrophic hyperplasia. Sequential studies assessed the neuronal activity of the tuberoinfundibular dopaminergic neurons of the arcuate nucleus of the hypothalamus (A12) during and after this estrogen-induced pituitary growth. Immunocytochemical staining for tyrosine hydroxylase was used as a marker for dopamine synthesis, plasma radioimmunoassay provided plasma prolactin levels, and magnetic resonance imaging and histological studies were performed to examine the structural changes occurring in the pituitary gland. Animals were sacrificed from 3 to 67 days after DES implantation. To determine the reversibility of the estrogen-induced changes, rats were also sacrificed at different time intervals after the removal of 30-, 40-, or 60-day DES implants. After 30 days of DES treatment, plasma prolactin levels increased 40-fold and pituitary weight increased more than threefold. Tyrosine hydroxylase immunoreactivity diminished gradually and was almost completely depleted at 30 days. Pituitary histology revealed marked prolactin cell hyperplasia. These changes were completely reversible; removal of the capsule after 30 days resulted in eventual normalization of plasma prolactin levels and pituitary size and in restoration of tyrosine hydroxylase immunoreactivity in the A12 region. Sixty days of DES treatment produced large hemorrhagic tumors with sustained high plasma prolactin levels and an irreversibly distorted A12 area. These observations suggest that in these animals loss of dopamine regulation secondary to estrogen stimulation initially produces prolactin hyperplasia but that prolonged loss leads to adenoma formation.