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Biomedical subjects

Ashley B Grossman

Publications and source records attributed to Ashley B Grossman.

At least 19 recordsLinked to original sources
PubMed2007

Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients.

BACKGROUND: The effect of GH replacement on thyroid function in hypopituitary patients has hitherto been studied in small groups of children and adults with conflicting results. OBJECTIVE: We aimed to define the effect and clinical significance of adult GH replacement on thyroid status in a large cohort of GH-deficient patients. PATIENTS AND METHOD: We studied 243 patients with severe GH deficiency due to various hypothalamo-pituitary disorders. Before GH treatment, 159 patients had treated central hypothyroidism (treated group) while 84 patients were considered euthyroid (untreated group). GH dose was titrated over 3 months to achieve serum IGF-1 concentration in the upper half of the age-adjusted normal range. Serial measurements of serum T4, T3, TSH and quality of life were made at baseline and at 3 and 6 months after commencing GH replacement. RESULTS: In the untreated group, we observed a significant reduction in serum T4 concentration without a significant increase in serum T3 or TSH concentration; 30/84 patients (36%) became hypothyroid and needed initiation of T4 therapy. Similar but lesser changes were seen in the treated group, 25 of whom (16%) required an increase in T4 dose. Patients who became hypothyroid after GH replacement had lower baseline serum T4 concentration, were more likely to have multiple pituitary hormone deficiencies and showed less improvement in quality of life compared with patients who remained euthyroid. CONCLUSION: GH deficiency masks central hypothyroidism in a significant proportion of hypopituitary patients and this is exposed after GH replacement. We recommend that hypopituitary patients with GH deficiency and low normal serum T4 concentration should be considered for T4 replacement prior to commencement of GH in order to provide a robust baseline from which to judge the clinical effects of GH replacement.

Adolescent↗
PubMed2006

Insulinomas may present with normoglycemia after prolonged fasting but glucose-stimulated hypoglycemia.

BACKGROUND: Insulinomas are rare but are the most common cause of hyperinsulinemic hypoglycemia in the adult population. Diagnosis of this pathology relies on clinical features along with laboratory tests and imaging investigations to aid in localization. One of the most robust standard tests used for establishing a biochemical diagnosis is the prolonged (72 h) fast. Currently, it is recommended that a prolonged supervised fast be performed, at least for 48 h if not for 72 h, and many would take the absence of hypoglycemia after a 72-h fast as evidence excluding the diagnosis. METHODS: We employed prolonged fasts and standard glucose tolerance tests, plus imaging studies and surgical pathology, in two patients with suspected insulinomas. RESULTS: The prolonged 72-h fast was normal in both the patients, whereas in both cases a prolonged oral glucose tolerance test clearly demonstrated the induction of severe hyperinsulinemia followed by significant hypoglycemia. Surgical removal confirmed the presence of insulinomas in each case. CONCLUSIONS: Although the sensitivity of the 72-h fast is high and still plays an important role in the diagnosis of an insulinoma, we suggest that a "normal" test result should be interpreted in the light of clinical symptoms.

Adult↗
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

Cushing's syndrome.

Cushing's syndrome results from lengthy and inappropriate exposure to excessive glucocorticoids. Untreated, it has significant morbidity and mortality. The syndrome remains a challenge to diagnose and manage. Here, we review the current understanding of pathogenesis, clinical features, diagnostic, and differential diagnostic approaches. We provide diagnostic algorithms and recommendations for management.

Adrenocorticotropic Hormone↗
PubMed2006

Expanding role of AMPK in endocrinology.

Adenosine 5' monophosphate-activated protein kinase (AMPK) is a regulator of cellular and systemic energy homeostasis. It mediates some of the effects of peripheral hormones such as leptin, ghrelin and adiponectin, and it is involved in the insulin-sensitizing role of the antidiabetic drug metformin. There is increasing evidence that AMPK has a central role in mediating the appetite-modulating and metabolic effects of many other hormones and substances, including the cannabinoids. Recent studies have illustrated the interaction between hormones and AMPK, and highlighted AMPK as a potential target for the development of tissue-specific AMPK modulators in the treatment of obesity and the metabolic syndrome.

AMP-Activated Protein Kinases↗
PubMed2006

Cushing's syndrome caused by an occult source: difficulties in diagnosis and management.

BACKGROUND: A 24-year-old woman presented with a 12.5 kg weight gain over 6 months (mostly abdominal), hirsutism, acne, ankle edema, polydipsia, nocturia, back pain, pigmentation, poor libido and lightened menses to our hospital in May 1986. She had been treated for the previous 2 years with furosemide and spironolactone for peripheral edema, and had stopped the combined oral contraceptive 2 months previously. She did not take tobacco, recreational drugs or alcohol. Upon physical examination she was grossly Cushingoid with florid clinical manifestations. INVESTIGATIONS: Serum potassium and bicarbonate, circadian rhythm of cortisol, low-dose and high-dose dexamethasone suppression tests, plasma adrenocorticotropic hormone (ACTH), corticotropin releasing-hormone stimulation test, CT scan of the pituitary, plain chest radiology, CT scan of the chest and abdomen, trans-sphenoidal pituitary biopsy and histology, CT scan and MRI of the thorax, MRI of the pituitary, octreotide scintigraphy, gastroscopy, colonoscopy, gut peptides, tumor markers, urine 5-hydroxyl-indole-acetic acid, resection, histology, immunocytochemistry and in situ hybridization. DIAGNOSIS: Occult ectopic ACTH syndrome from a presumed appendiceal neuroendocrine tumor. The tumor was only identified some 20 years from initial presentation. MANAGEMENT: Adrenolytic therapy before bilateral adrenalectomy to cure Cushing's syndrome, glucocorticoid and mineralocorticoid replacement therapy, and then repeated surveillance over 20 years to locate the ectopic source of ACTH. This was finally identified by CT scan and excised at laparotomy.

ACTH Syndrome, Ectopic↗
PubMed2006

The management of differentiated thyroid cancer using 123I for imaging to assess the need for 131I therapy.

BACKGROUND: Follow-up of 131I whole-body scanning after 131I ablation is associated with potential stunning. Previous studies have suggested that, for scanning, 123I is more sensitive than 131I in identifying thyroid tissue, but its specificity when positive is less certain. AIM: The use of 123I as an imaging agent in place of serial 131I imaging has been evaluated in the surveillance and treatment of differentiated thyroid carcinoma. RESULTS: A total of 186 studies in 136 patients with differentiated thyroid carcinoma were evaluated after total or near total thyroidectomy followed by 131I ablation. In 125 studies 123I scanning was negative and no 131I therapy was given; four patients were positive on 123I scanning but for other reasons no 131I therapy was given. In 48/49 patients a positive 123I scan was followed by positive 131I therapeutic uptake. Only one patient failed to show positive uptake of I when first treated and she subsequently demonstrated uptake on a second therapy. CONCLUSION: High-dose 123I imaging is the correct predictor of the 131I post-therapy scan findings in most cases, at an administered activity that avoids stunning. As a diagnostic agent it is preferable to 131I in differentiated thyroid carcinoma.

Adolescent↗
PubMed2006

PPAR-gamma expression in pituitary tumours and the functional activity of the glitazones: evidence that any anti-proliferative effect of the glitazones is independent of the PPAR-gamma receptor.

OBJECTIVE: It has been reported that both normal pituitary and pituitary tumours express PPAR-gamma, a nuclear hormone receptor, the expression being more abundant in pituitary tumours, and that this is the basis for the reported antiproliferative effects of the thiazolidinedione, rosiglitazone, in animal models. However, the mechanisms for the responsivity to rosiglitazone have remained unclear. DESIGN AND MEASUREMENTS: To investigate this further, 'real-time' PCR was used to assess PPAR-gamma mRNA expression, and Western blotting and immunohistochemistry to study its protein expression, in 46 human pituitary tumours and normal pituitary tissue. Cell proliferation of the GH3 pituitary cell line was assessed by [3H]-thymidine-incorporation after 48 h rosiglitazone and pioglitazone (10(-4) M- 10(-10) M) treatment alone, or rosiglitazone in combination with the PPAR-gamma antagonist GW9662. RESULTS: PPAR-gamma mRNA and protein was found to be expressed in normal pituitary and was variably expressed in pituitary tumours, but were increased specifically in nonfunctioning pituitary adenomas. However, very little staining was observed with immunohistochemistry, with only occasional cell nuclei stained, and no difference was detectable between controls and tumours. Rosiglitazone at 10(-4) M and 10(-5) M concentrations inhibited cell proliferation (10(-4) M 14.0% +/- 1.5% and 10(-5) M 67% +/- 4%[mean +/- SEM]vs Control 100% +/- 3%, P < 0.0001) while lower concentrations showed no significant effect. Following withdrawal of rosiglitazone 10(-5) M, the cells fully recovered at a further 48 h, while lower doses showed a 'rebound' of stimulation. Pioglitazone was of similar potency to rosiglitazone in inhibiting proliferation. The PPAR-gamma antagonist did not show a significant reversal of the antiproliferative effect of rosiglitazone, and indeed suppressed proliferation on its own. CONCLUSIONS: Our data suggest that the antiproliferative action of rosiglitazone is probably not via PPAR-gamma.

Adenoma↗
PubMed2006

Ectopic ACTH syndrome.

Ectopic adrenocorticotropin secretion (EAS) accounts for 10-15% of cases of Cushing's syndrome and comprises a spectrum of tumours from undetectable isolated lesions to widespread metastatic and aggressive malignancies. EAS is often associated with severe hypercortisolaemia causing hypokalaemia, diabetes, generalized infections, hypertension and psychotic reactions. Surgical resection of the primary lesion, achievable with a curative intent in about 40% of patients with EAS, is associated with complete remission in up to 80% of such cases. It is therefore mandatory to localize the source of ectopic ACTH hypersecretion in order to stage the disease and adopt optimal treatment modalities. Modern cross-sectional imaging techniques can identify the majority of the ACTH secreting lesions, either initially or at follow-up reassessment. However, in approximately 10-20% of patients with EAS, the source of ACTH hypersecretion remains occult in spite of extensive investigation and prolonged followup. In such cases, control of the hypercortisolemia can be achieved with long-term adrenolytic medication. When conditions require a prompt and definitive resolution of the hypercortisolaemia (i.e. as in pregnancy), bilateral adrenalectomy remains an alternative option. This review focuses on the clinical features, diagnostic pitfalls, management and long-term followup of the EAS based on the extensive experience of major referral centres.

ACTH Syndrome, Ectopic↗
PubMed2006

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours.

OBJECTIVES: Somatostatin (SST) analogues play an important role in the medical management of somatotroph pituitary adenomas and new agonists have the potential to be effective in a wider group of pituitary and other tumours. The anti-proliferative effect of SST occurs through multiple mechanisms, one of which is cell-cycle arrest, where p27, a cyclin-dependent kinase inhibitor, is an important regulator. We hypothesised that SST may upregulate p27 protein levels and downregulate the MAP kinase pathway in these tumours. METHODS: Human pituitary adenoma cells and rat pituitary cell line (GH3) were cultured and treated in vitro with octreotide and the broad-spectrum SST agonist SOM230 (pasireotide). Immunoblotting for p27 and phospho-ERK (pERK) was performed and proliferation assessed by [3H]-thymidine incorporation. Histological samples from acromegalic patients treated with octreotide before surgery were immunostained for p27 and compared to samples from untreated patients matched for sex, age, tumour size, extension and invasiveness. RESULTS: We detected upregulation of p27 protein levels with SST analogue treatment in vitro in human pituitary adenoma samples. pERK1/2 was inhibited by SST analogues in both the human samples and GH3 cells. SST and its analogues inhibited the proliferation of GH3 cells. p27 immunostaining was stronger in samples from patients with longer preoperative octreotide treatment (more than 6 months) than in samples from patients with shorter treatment periods. CONCLUSIONS: This study demonstrates that SST-mediated growth inhibition is associated with the downregulation of pERK and upregulation of p27. More potent and broader-spectrum SST analogues are likely to play an increasing role in the treatment of tumours, where the MAP kinase pathway is overactivated.

Adenoma↗
PubMed2005

The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up.

CONTEXT: There are few large series of patients with ectopic, nonpituitary, corticotropin (ACTH) secretion (EAS). OBJECTIVE: The objective of this study was to analyze the clinical, biochemical, and radiological features, management, and treatment outcome of patients with EAS. DESIGN: This was a retrospective case-record study. SETTING: The setting for this study was a tertiary referral hospital center. PATIENTS: Forty patients with EAS were studied. MAIN OUTCOME MEASURES: Clinical, biochemical, and radiological features and response to therapy and survival were measured. RESULTS: The median follow-up was 5 yr (range, 2-30 yr). None of the dynamic tests achieved 100% accuracy, but bilateral inferior petrosal sinus sampling showed an absent central gradient in all but one case (one of 12). Imaging correctly identified the lesion at first investigation in 65% of cases. Bronchial carcinoid tumors were the most common cause of EAS (n = 12; 30%), followed by other neuroendocrine tumors (n = 13, 32.5%). In 12.5% of patients, the source of EAS was never found. Octreotide scintigraphy and whole-body venous sampling were of limited value. Surgical attempt at curative resection was successful in 83% (10 of 12) of patients with bronchial carcinoid tumors; others responded generally well to adrenolytic therapy or bilateral adrenalectomy. Tumor histology and the presence of distant metastases were the main predictors of overall survival (P < 0.05). CONCLUSIONS: A variety of tests and imaging studies are necessary for the correct diagnosis of the EAS, but even then, up to 20% of cases present a covert or occult EAS syndrome. These cases require a prolonged follow-up, review, and repetition of diagnostic tests and scans.

ACTH Syndrome, Ectopic↗
PubMed2005

Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase.

Endocannabinoids and ghrelin are potent appetite stimulators and are known to interact at a hypothalamic level. However, both also have important peripheral actions, including beneficial effects on the ischemic heart and increasing adipose tissue deposition, while ghrelin has direct effects on carbohydrate metabolism. The AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that functions as a fuel sensor to regulate energy balance at both cellular and whole body levels, and it may mediate the action of anti-diabetic drugs such as metformin and peroxisome proliferator-activated receptor gamma agonists. Here we show that both cannabinoids and ghrelin stimulate AMPK activity in the hypothalamus and the heart, while inhibiting AMPK in liver and adipose tissue. These novel effects of cannabinoids on AMPK provide a mechanism for a number of their known actions, such as the reduction in infarct size in the myocardium, an increase in adipose tissue, and stimulation of appetite. The beneficial effects of ghrelin on heart function, including reduction of myocyte apoptosis, and its effects on lipogenesis and carbohydrate metabolism, can also be explained by its ability to activate AMPK. Our data demonstrate that AMPK not only links the orexigenic effects of endocannabinoids and ghrelin in the hypothalamus but also their effects on the metabolism of peripheral tissues.

AMP-Activated Protein Kinases↗
PubMed2005

Clinical and biochemical characteristics of adrenocorticotropin-secreting macroadenomas.

CONTEXT: Cushing's disease as a result of a pituitary macroadenoma is an uncommon cause of Cushing's syndrome, and reports in the published literature are few and of limited size. OBJECTIVE: Our objective was to establish the clinical and biochemical characteristics of macroadenomas associated with Cushing's disease compared with a large cohort of microadenomas and to assess their response to therapy. DESIGN: We conducted a retrospective case-records study for the years 1964-2001. SETTING: The study occurred at a tertiary referral hospital center. PATIENTS: Patients had Cushing's disease presenting with a pituitary macroadenoma, in comparison with a large group of microadenoma patients. INTERVENTIONS: Interventions included therapy with surgery and radiotherapy. MAIN OUTCOME MEASURES: Outcome measures included basal and dynamically responsive plasma ACTH and cortisol levels and response to treatment. RESULTS: We identified 18 patients with Cushing's disease secondary to a macroadenoma; basal 0900 h plasma ACTH was 135.8 +/- 32.5 and 45.0 +/- 4.3 ng/liter (mean +/- SEM), respectively, in macroadenomas and microadenomas (P = 0.013). Mean 0900 h serum cortisol was significantly increased in the macroadenomas (27.5 +/- 3.0 microg/dl, 759.6 +/- 82.6 nmol/liter, vs. 22.6 +/- 0.6 microg/dl, 624.7 +/- 16.4 nmol/liter) (P = 0.021). Testing with high-dose dexamethasone showed less suppression in the macroadenomas (57.6 +/- 8.7% vs. 74.4 +/- 2.1%; P = 0.02) and an attenuated ACTH response to CRH. For all biochemical variables there was considerable overlap between the two groups. Few patients with macroadenomas were cured by surgery. CONCLUSIONS: Pituitary macroadenomas causing Cushing's disease have biochemical features largely distinct from patients harboring microadenomas but represent one end of a continuum.

Adenoma↗
PubMed2005

A rapid method for analyzing serum pro-insulin-like growth factor-II in patients with non-islet cell tumor hypoglycemia.

CONTEXT: Non-islet cell tumor hypoglycemia (NICTH) results from the hypersecretion of pro-IGF-II by a large, usually mesenchymal tumor. Detection of pro-IGF-II in serum is a potential tumor marker in these patients. OBJECTIVE: The aim of this study was to validate a rapid and reliable method for determining serum pro-IGF-II. PATIENTS: Serum samples from 16 patients with NICTH were studied. MAIN OUTCOME MEASURE: The main outcome measure was serum concentration of pro-IGF-II determined by immunoblot analysis of pro-IGF-II and mature IGF-II after 16.5% tricine-SDS-PAGE, which was compared with pro-IGF-II measured by standard RIA after size-exclusion acid chromatography. RESULTS: The analyses of patients' sera by size-exclusion acid chromatography showed that 68 +/- 19% of IGF-II were present in the pro-IGF-II form, whereas only 18 +/- 4% corresponded to pro-IGF-II in controls. Scanning densitometry of immunoblots showed 67 +/- 16% in the bands corresponding to pro-IGF-II in patients' sera, compared with 27 +/- 9% in controls. The detection sensitivity of tricine-SDS-PAGE method was the same as for size-exclusion chromatography, but the tricine-SDS-PAGE method is quicker and requires smaller amounts of serum. CONCLUSION: Tricine-SDS-PAGE followed by IGF-II immunoblot analysis provides a rapid, reproducible, and sensitive method for the separation of serum pro-IGF-II from mature IGF-II and is a useful laboratory evaluation of patients with a clinical diagnosis of NICTH.

Adult↗
PubMed2005

Clinical review: Diagnosis and management of pituitary carcinomas.

Pituitary carcinomas are rare, making up some 0.2% of all pituitary tumors, but represent a particular challenge to clinical practice. The diagnosis of a pituitary carcinoma requires evidence of metastatic disease, either outside the central nervous system (CNS) or as separate noncontiguous foci within the CNS. They may present as typical pituitary adenomas, which reveal their malignant character only as time progresses, or as peculiarly aggressive tumors ab initio. Recent changes in histopathological classification have clarified many of the features of such tumors, including immunohistochemical staining for Ki-67 and p53, but to date none has been found to be pathognomonic. The majority of carcinomas are secretory, usually arising from corticotroph tumors or prolactinomas, but all histological types and secretory patterns are represented. Treatment is by surgery, transsphenoidal wherever possible, and conventional and stereotactic radiotherapy, but ultimately, a plethora of therapies may be required, including various attempts at medical therapy. Chemotherapy in some instances probably prolongs survival, but, in general, their progress from the diagnosis of carcinomatous changes is progressive and inexorable. However, we do not believe there will be any real prospect of long-term survival until the development and use of therapies targeted at specific molecular abnormalities.

Adrenocorticotropic Hormone↗
PubMed2005

Fasting and postprandial hyperghrelinemia in Prader-Willi syndrome is partially explained by hypoinsulinemia, and is not due to peptide YY3-36 deficiency or seen in hypothalamic obesity due to craniopharyngioma.

The cause of the unique elevation in fasting plasma levels of the orexigenic gastric hormone ghrelin in many patients with Prader-Willi syndrome (PWS) is unclear. We measured fasting and postprandial plasma ghrelin in nonobese (n = 16 fasting and n = 8 postprandial) and obese non-PWS adults (n = 16 and 9), adults with genetically confirmed PWS (n = 26 and 10), and patients with hypothalamic obesity from craniopharyngioma tumors (n = 9 and 6). We show that 1) plasma ghrelin levels decline normally after food consumption in PWS, but there is still fasting and postprandial hyperghrelinemia relative to the patient's obesity (2.0-fold higher fasting ghrelin, 1.8-fold higher postprandial ghrelin, adjusting for percentage of body fat); 2) the fasting and postprandial hyperghrelinemia in PWS appears to be at least partially, but possibly not solely, explained by the concurrent relative hypoinsulinemia and preserved insulin sensitivity for the patient's obesity (residual 1.3- to 1.6-fold higher fasting ghrelin, 1.2- to 1.5-fold higher postprandial ghrelin in PWS, adjusting for insulin levels or homeostasis model assessment of insulin resistance); 3) hyperghrelinemia and hypoinsulinemia are not found in craniopharyngioma patients with hypothalamic obesity, and indeed, these patients have relative hyperinsulinemia for their obesity; and 4) there is no deficiency of the anorexigenic intestinal hormone peptide YY(3-36) in PWS contributing to their hyperghrelinemia.

Adult↗
PubMed2005

Lymphoma metastasizing to the pituitary: an unusual presentation of a treatable disease.

Lymphoma involving the pituitary gland is particularly rare. We present two cases of patients with pituitary lymphoma, both of whom were symptomatic from pituitary dysfunction. The first patient demonstrated pituitary involvement on imaging, with mild biochemical diabetes insipidus but clear hypoadrenalism. Both adrenals were grossly enlarged on CT scanning and biopsy of one of the adrenal masses confirmed the diagnosis of diffuse large B cell lymphoma. The second patient presented with clinical diabetes insipidus but with no obvious abnormalities on pituitary imaging. CT scanning of abdomen and pelvis, however, revealed widespread lymphadenopathy. Lymph node biopsy revealed a T cell-rich B cell lymphoma. Review of the English-language literature of all published cases of pituitary lymphoma in the presence of generalised disease in immunocompetent patients revealed 13 cases. Most patients had large B cell non-Hodgkin's lymphoma. Involvement of the anterior lobe of the pituitary was more frequently seen than in patients developing pituitary metastases from solid tumour primaries. Patients with advanced lymphoma including the pituitary also appear to have a better prognosis than patients presenting with pituitary metastases. This is an important diagnosis to make as rapidly as possible to allow the early institution of effective therapy.

Diabetes Insipidus↗