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PubMed2006

Myopathy in horses with pituitary pars intermedia dysfunction (Cushing's disease).

Fifteen horses with pituitary pars intermedia dysfunction were studied. The horses were of various breeds and between 15 and 28 years of age. Control horses matched for breed and age were studied for comparison. Evaluations included complete blood cell count and serum biochemical analysis, electromyography, and gluteus medius muscle biopsies for histochemical, morphometric, and ultrastructural analysis. No differences were found between groups of horses on routine laboratory analysis or electromyography. We demonstrated that muscle wasting in diseased horses was the result of atrophy of types 2A and 2B muscle fibers and loss of type 2B myofibers. Mild non-specific non-inflammatory myopathic alterations such as myofiber size variation, internal nuclei, perimysial, endomysial and sarcoplasmic fat accumulation were observed. At the ultrastructural level, subsarcolemmal mitochondrial accumulation and increased lipid droplets were evident. Similar to other species, this study confirmed atrophy of type 2 fibers as the cause of muscle mass loss in horses with Cushing's disease.

Animals↗
PubMed2002

Pituitary pars intermedia dysfunction: equine Cushing's disease.

PPID in older equids has become a major health concern of horse owners. In response, equine practitioners have made greater efforts at understanding, diagnosing, and treating this disorder. Although PPID is recognized to be a different form of pituitary-dependent hyperadrenocorticism than is seen in canine or human patients, relatively little is known about the pathophysiology and natural progression of the disease. At present, the diagnosis is best supported by manifestation of characteristic clinical signs and endocrinologic test results, preferably a supportive DST result. Treatment must focus on improving overall health care, including body clipping, dentistry, and nutrition. As the condition progresses, administration of pergolide or a combination of pergolide and cyproheptadine is currently considered the best medical treatment. The time point at which medication should be added to improved health care and management changes is not currently known, but loss of body condition and development of hyperglycemia suggest more advanced PPID that would likely benefit from drug therapy. Whether medical treatment needs to be continuous or could be intermittent is also unknown. As the demand for treatment of affected equids continues to increase, clinical response and endocrinologic testing data as well as pharmacologic data for currently used drugs and other agents should be expected. Similarly, novel medical, and perhaps surgical, treatment strategies for this condition should also be anticipated in the future.

Adrenocorticotropic Hormone↗
PubMed2006

Difficulty in the diagnosis of Cushing disease.

BACKGROUND: A 48-year-old woman presented to our clinic 1 year after hypertension was discovered on a routine screening visit. During the previous year, she had noticed weight gain in the face and abdomen, easy bruising, oligomenorrhea and facial and periareolar hair growth. On presentation, she reported no weakness, fracture, back pain, depression, irritability, problem with cognition or memory, increased appetite, hot flashes or altered sleep. Previous medication history included 2.5 mg lisinopril daily and 25.0 mg hydrochlorothiazide daily for 12 months. INVESTIGATIONS: Measurement of urine glucocorticoid excretion, evening plasma and salivary cortisol levels, and basal and corticotropin-releasing-hormone-stimulated adrenocorticotropic hormone and cortisol levels. An overnight 8 mg dexamethasone suppression test, pituitary MRI, inferior-petrosal-sinus sampling, cavernous sinus and jugular venous sampling were performed. DIAGNOSIS: Cushing disease. MANAGEMENT: The patient underwent trans-sphenoidal resection, assessment of remission and subsequent treatment with hydrocortisone.

17-Hydroxycorticosteroids↗
PubMed2006

A cross-sectional study to investigate long-term cognitive function in people with treated pituitary Cushing's disease.

INTRODUCTION: It has been proposed that exposure to high levels of endogenous steroids in untreated pituitary Cushing's disease damages hippocampal structures leading to impairment in learning and memory processes. We hypothesised that patients with treated pituitary Cushing's disease would perform significantly worse on tests of cognitive ability than those with nonfunctioning pituitary adenomas. DESIGN: Sixteen adults with pituitary Cushing's disease (PCD) and 16 adults with non-functioning pituitary adenomas (NFA) undertook the following comprehensive neuropsychological assessments: National Adult Reading Test (NART: premorbid abilities), California Verbal Learning Test (CVLT 2 UK: learning and recall), Stroop (executive functioning), Trail-Making Test (TMT: executive functioning and attention), Adult Memory and Information Processing Battery (AMIPB: Information Processing Speed and Story Recall subtests). RESULTS: There was no significant difference in premorbid IQ scores (NFA mean=101 SD=13; PCD mean=102, SD=13), in verbal learning nor any significant difference in the percentage of verbal material retained in story recall (AMIPB). Performance on higher executive tasks Stroop and TMT and on measures of information processing was similar. However, there were significant decrements between some mean scores for both groups and published normative data with a clear association between higher HADS depression scores and impaired objective memory and attention which was not specific to PCD. CONCLUSIONS: We found no difference in cognitive function between patients with PCD and NFA. The results suggest a discrepancy between patients' subjective perception of functional cognitive impairments and objective findings on psychometric testing and point to the influence of affective symptoms on cognitive performance, particularly in Cushing's disease.

Adult↗
PubMed2006

Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease.

Negative feedback regulation of the proopiomelanocortin (POMC) gene by the glucocorticoid (Gc) receptor (GR) is a critical feature of the hypothalamo-pituitary-adrenal axis, and it is in part exerted by trans-repression between GR and the orphan nuclear receptors related to NGFI-B. We now show that Brg1, the ATPase subunit of the Swi/Snf complex, is essential for this trans-repression and that Brg1 is required in vivo to stabilize interactions between GR and NGFI-B as well as between GR and HDAC2. Whereas Brg1 is constitutively present at the POMC promoter, recruitment of GR and HDAC2 is ligand-dependent and results in histone H4 deacetylation of the POMC locus. In addition, GR-dependent repression inhibits promoter clearance by RNA polymerase II. Thus, corecruitment of repressor and activator at the promoter and chromatin modification jointly contribute to trans-repression initiated by direct interactions between GR and NGFI-B. Loss of Brg1 or HDAC2 should therefore produce Gc resistance, and we show that approximately 50% of Gc-resistant human and dog corticotroph adenomas, which are the hallmark of Cushing disease, are deficient in nuclear expression of either protein. In addition to providing a molecular basis for Gc resistance, these deficiencies may also contribute to the tumorigenic process.

Animals↗
PubMed2005

Nitration and increased alpha-synuclein expression associated with dopaminergic neurodegeneration in equine pituitary pars intermedia dysfunction.

Equine pituitary pars intermedia dysfunction (PPID) is a spontaneously occurring progressive disease affecting aged horses and ponies. The pathogenesis of PPID is poorly understood, but the available evidence supports a loss of dopaminergic inhibition of the melanotropes of the pars intermedia. Horses with PPID have increased plasma concentrations of pars intermedia pro-opiomelanocortin-derived peptides that decrease in response to dopamine or dopamine agonist administration. Dopamine and dopamine metabolite concentrations are decreased in the pars intermedia of affected horses compared to age-matched control horses. Horses with disease that are treated with the dopamine agonist pergolide show improvement in clinical signs and normalisation of diagnostic test results. In the present study, immunohistochemical evaluation of pituitary and hypothalamic tissue demonstrated reduced tyrosine hydroxylase immunoreactivity in affected horses compared to age-matched and young controls, supporting the role of dopaminergic neurodegeneration in PPID. In addition, immunohistochemical evaluation revealed an increase in the oxidative stress marker, 3-nitrotyrosine and in nerve terminal protein, alpha-synuclein that colocalised in the pars intermedia of horses with disease. These findings suggest a role for nitration of overexpressed alpha-synuclein in the pathogenesis of neurodegeneration in PPID.

Animals↗
PubMed2006

Treatment of Cushing's disease: a retrospective clinical study of the latest 100 cases.

We evaluate the current role of microsurgery for Cushing's disease (CD) and the efficacy of adjuvant treatment modalities. The standard treatment for primary CD remains transsphenoidal surgery followed by adjuvant therapy in cases with persisting hypercortisolism. Moderately severe cases are treated with radiotherapy, while in the very severe adrenalectomy is performed. In our series of primary CD (March 1997 to September 2004, mean observation period 18.8 months) adenomas were confirmed intraoperatively in 84.0% of the cases. Remission was achieved in 75.0% and recurrence was observed in 4.8% of the patients. Complications occurred in 2.0% of the cases and all resolved without resulting in permanent morbidity. In the literature, the rates of intraoperative confirmation of an adenoma vary between 59.1 and 100%, remission rates between 42 and 100%, and recurrence rates between 3.0 and 63.2% depending on the experience of the surgeon and on the definition of remission. These rates have not improved significantly over the years. In experienced hands selective adenomectomy remains the least damaging and most effective treatment modality since it results in rapid clinical improvement if performed successfully. Therefore, it remains the treatment of choice. Patients not cured by surgery alone benefited from a combination of adjuvant treatment tailored to their specific needs using medications, radiation and/or adrenalectomy. In this fashion, we achieved normalization of cortisol levels in 79% and improvement in another 18% of the patients. We expect these rates to increase further once patients treated with radiotherapy begin to experience its full effect within the next few years.

Adolescent↗
PubMed2006

Stereotactic radiosurgery for pituitary adenomas: a review of the literature and our experience.

Pituitary adenomas are not just one of the most common intracranial tumors but also one of the most difficult to cure. Neurosurgeons have adapted their tools to include precise ionizing radiation in the form of the gamma knife to treat pituitary adenomas. The use of the gamma knife in the management of pituitary adenomas following microsurgery or in selected cases as a primary treatment is safe. The combined application of transsphenoidal surgery and Gamma Knife surgery is beneficial in many difficult cases. However in some patients, optimal control of tumor growth and normalization of hypersecretory states are not achieved. Innovative improvements in operative and radiosurgical techniques are required to avoid pituitary insufficiency and to reduce the number of the cases in which optimal radiosurgery is not feasible because of close tumor proximity to the optic pathways.

Acromegaly↗
PubMed2006

Anesthetic and critical care management of patients undergoing pituitary surgery.

Patients with tumors of the pituitary gland represent a heterogeneous yet commonly encountered neurosurgical population. Optimal anesthetic care requires an understanding of the complex pathophysiology secondary to each patient's endocrinological disease. Although patients presenting with Cushing's disease and acromegaly have unique manifestations of endocrine dysfunction, all patients with tumors of the pituitary gland require meticulous preoperative evaluation and screening. There are many acceptable strategies for optimal intraoperative anesthetic management; however, the selection of anesthetic agents should be tailored to facilitate surgical exposure, preserve cerebral perfusion and oxygenation, and provide for rapid emergence and neurological assessment. A rapid emergence from anesthesia is particularly important, as an early neurological assessment is necessary to evaluate cranial nerve integrity. In the postoperative period, careful monitoring of fluid balance and serum sodium is essential to the early diagnosis of diabetes insipidus (DI) and the syndrome of inappropriate anti-diuretic hormone (SIADH) secretion. DI is most often transient, but can require medical therapy. SIADH has a number of treatment options and decisions should be based upon the patient's status. A thorough understanding of the preoperative assessment, intraoperative management, and potential complications is fundamental to successful perioperative patient care and avoidance of morbidity and mortality.

Acromegaly↗
PubMed2006

Growth hormone deficiency and replacement in patients with treated Cushing's Disease, prolactinomas and non-functioning pituitary adenomas: effects on body composition, glucose metabolism, lipid status and bone mineral density.

BACKGROUND/AIMS: This study was designed to determine whether previous Cushing's disease (CD) or prolactinoma (PRL) could exert adverse effects additional to those of growth hormone (GH) deficiency as a consequence of variable degrees of prior hypogonadism or hypercatabolism. We report the effects of 5 years GH treatment in 124 GH deficiency adults; 42 patients with non-functioning pituitary adenomas (NFPA), 43 with treated PRL and 39 with treated CD. METHODS: Fasting plasma glucose, HbA(1c), lipoprotein profile, anthropometry and bone mineral density (BMD) were measured at baseline, 6 months and annually up to 5 years. RESULTS: Mean body mass index remained unchanged in the PRL group and tended to increase in the NFPA group. In contrast, body mass index decreased in the CD group. Decreases in waist and waist/hip ratio were seen in all groups at 6 months. Decreases in total cholesterol and low-density lipoprotein cholesterol were seen in all groups and remained sustained at 5 years. Plasma glucose and HbA(1c) increased at 6 months. Subsequently, plasma glucose returned to baseline values at 5 years; in contrast, HbA(1c )remained unchanged at the end of the study. Baseline lumbar spine and hip BMD were lower in the PRL and CD groups than in the NFPA group, decreased over 1 year in all groups and subsequently increased by 2 years in NFPA with a subsequent increase in lumbar spine BMD in PRL and CD groups delayed to 3-5 years. CONCLUSIONS: Baseline characteristics and response to GH replacement are qualitatively similar in NFPA, PRL and CD patients. Because improvements in BMD occur later in PRL and CD patients, an extended trial of GH therapy may be indicated in those patients who were commenced on GH therapy as an additional treatment for reduced BMD.

Adenoma↗
PubMedDate not supplied

Cytopathologic features of pituitary carcinoma with cervical vertebral bone metastasis: a case report.

BACKGROUND: Pituitary carcinomas are extremely rare tumors of the adenohypophysis. The presence of craniospinal and/or systemic extracranial metastases is the only reliable criterion for the diagnosis of pituitary carcinoma. To date, only 2 cases have been reported correctly by fine needle aspiration biopsy (FNAB). We present an additional case of pituitary carcinoma with FNAB features. CASE: A 60-year-old woman presented with clinical features of Cushing's disease and a pituitary tumor. She underwent transsphenoidal resection of the tumor. The initial diagnosis was an adrenocorticotrophic hormone (ACTH)-producing invasive pituitary adenoma. The patient presented again with neck pain 6 years after the operation. Magnetic resonance imaging revealed metastatic tumor masses at the level of C5-C6 of the cervical vertebrae. Intraoperative fine needle aspiration and incomplete excision of metastatic tumors were performed. Cytologically, tumor cells were composed of a combination of loose groups and single cells. Neoplastic cells had a relatively monotonous appearance and displayed characteristic neuroendocrine tumor features. Immunocytochemistry from cell block sections revealed AE1/ AE3, synaptophysin chromogranin A and ACTH positivity in the tumor cells. CONCLUSION: Pituitary carcinoma with extracranial systemic metastases demonstrates typical neuroendocrine features on fine needle aspiration. In the differential diagnosis, metastatic neuroendocrine carcinomas should be kept in mind. In the absence of sufficient clinical data, these 2 entities cannot be distinguished correctly through the cytologic features.

Biopsy, Fine-Needle↗
PubMed2005

Inhibition of 11beta-hydroxysteroid dehydrogenase eliminates impaired glucocorticoid suppression and induces apoptosis in corticotroph tumor cells.

Cushing's disease is characterized by persistent ACTH secretion under hypercortisolemia. In an attempt to clarify the molecular mechanism, we examined the effect of 11beta-hydroxysteroid dehydrogenase (HSD) inhibition on glucocorticoid suppression of ACTH release using murine corticotroph tumor cells. We found that 11beta-HSD2, as well as -HSD1, was expressed in the cells and that its inhibition by carbenoxolone significantly improved the negative feedback effect of glucocorticoid. Carbenoxolone also enhanced apoptosis induced by cortisol. These effects are most likely attributable to inhibition of 11beta-HSD2 because only cortisol, a substrate of 11beta-HSD2, was present in these experimental conditions. We conclude that ectopic expression of 11beta-HSD2 is, at least in part, responsible for the impaired glucocorticoid suppression in corticotroph adenoma. Inhibition of 11beta-HSD2 may be applicable to the medical therapy for Cushing's disease.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2006

Retinoic acid as a novel medical therapy for Cushing's disease in dogs.

Cushing's disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing's disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing's disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and alpha-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and alpha-MSH, and also in the cortisol/creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing's disease.

Adenoma↗
PubMed2006

Surgical remission of pituitary adenomas confined to the neurohypophysis in Cushing's disease.

CONTEXT: Partial or total removal of the pituitary cures 60-80% of patients with Cushing's disease (CD) in whom an adenoma cannot be identified at surgery. Many patients who fail complete or partial hypophysectomy are cured by sellar and parasellar irradiation. DESIGN/PATIENTS: As part of a series of prospective studies of CD, we identified 12 patients (34.5 +/- 19.9 yr; 11 females; four children) with tumors located completely within the neurohypophysis among 730 patients undergoing surgery for CD. SETTING: The study was conducted at a tertiary referral center at a clinical research hospital. RESULTS: All 12 patients had clinical and biochemically defined CD. Tumor was visible at surgery in 11 patients; all 12 tumors were positive for ACTH by immunohistochemistry. Two tumors were excised at repeat surgery because of persistent hypercortisolism within 14 d of negative exploration of the adenohypophysis. There were no long-term complications. At follow-up of 71.9 +/- 34.2 months (range, 30-138 months), all patients are in remission of CD. Adult patients have had significant improvement in weight and body mass indices, with restoration of normal menses in all women. In the four pediatric patients, height, weight, and body mass indices have been restored toward normal by surgical remission of CD. Hypopituitarism or long-term neurohypophysial dysfunction has not occurred. CONCLUSION: We report a new subset of patients with CD, ACTH-secreting adenomas that arise wholly within the posterior lobe of the pituitary gland. In cases of CD in which an adenoma is not identified in the adenohypophysis and in patients with persistent hypercortisolism after complete or partial excision of the anterior lobe, tumor within the neurohypophysis should be considered; selective adenomectomy of a neurohypophyseal, ACTH-secreting tumor can produce long-term remission.

Adenoma↗
PubMed2006

High prevalence of pituitary adenomas: a cross-sectional study in the province of Liege, Belgium.

CONTEXT: Prevalence data are important for assessing the burden of disease on the health care system; data on pituitary adenoma prevalence are very scarce. OBJECTIVE: The objective of the study was to measure the prevalence of clinically relevant pituitary adenomas in a well-defined population. DESIGN: This was a cross-sectional, intensive, case-finding study performed in three regions of the province of Liège, Belgium, to measure pituitary adenoma prevalence as of September 30, 2005. SETTING: The study was conducted in specialist and general medical practitioner patient populations, referral hospitals, and investigational centers. METHODS: Three demographically and geographically distinct districts of the province of Liège were delineated precisely using postal codes. Medical practitioners in these districts were recruited, and patients with pituitary adenomas under their care were identified. Diagnoses were confirmed after retrieval of clinical, hormonal, radiological, and pathological data; full demographic and therapeutic follow-up data were collected in all cases. RESULTS: Sixty-eight patients with clinically relevant pituitary adenomas were identified in a population of 71,972 individuals; the mean (+/- sd) prevalence was 94 +/- 19.3 cases per 100,000 population (95% confidence interval, 72.2 to 115.8). The group was 67.6% female and had a mean age at diagnosis of 40.3 yr; 42.6% had macroadenomas and 55.9% underwent surgery. Prolactinomas comprised 66% of the group, with the rest having nonsecreting tumors (14.7%), somatotropinomas (13.2%), or Cushing's disease (5.9%); 20.6% had hypopituitarism. CONCLUSION: The prevalence of pituitary adenomas in the study population (one case in 1064 individuals) was more than 3.5-5 times that previously reported. This increased prevalence may have important implications when prioritizing funding for research and treatment of pituitary adenomas.

Adenoma↗