Endocrine Abstracts

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3) is a potent antiproliferative agent with putative applications in the treatment of common cancers. However, doses of 1,25D3 required to achieve tangible anticancer responses also stimulate unwanted calciotropic effects. Data suggest that this is due, in part, to acquired resistance to 1,25D3 in cancer cells, particularly in more aggressive tumours. To investigate this fu...

Introduction:Hepatic IGF-I is generally believed to be regulated by pituitary-derived GH. However recent studies have emphasized the importance of paracrine/autocrine IGF-I in normal growth and development, as well as some malignancies. However, it remains unclear how locally produced IGF-I is regulated. The aim of this project was to investigate IGF-I expression in different tissues from the growth hormone receptor knock-out (GHR-KO) mouse.<p class=...

Adiponectin has been shown to modulate angiogenesis and tumour cell behaviour. Breast and endometrial cancer patients have significantly decreased serum adiponectin levels, which may be important in such hormone-dependent cancers. Prostate cancer is another hormone-dependent cancer. Adiponectin orchestrates its actions by activating two seven-transmembrane receptors, adiponectin-R1 (adipo-R1) and adiponectin-R2 (adipo-R2). In this study we aim to determine adipo-R1/R2 expressi...

The meningioma is a tumour that arises from cells that form a fibrous membrane, covering the brain. They account for around 15percent of intracranial tumours and about 7percent of all people dying from brain tumours. These tumours occur more frequently in women than in men and this has lead to the suggestion that oestrogens have a role in their development and growth. Studies a decade ago with antioestrogens have proved inconclusive and therefore a medical therapy based on ant...

Introduction: The GH/IGF-I axis has been implicated in the pathogenesis of breast cancer and development of tamoxifen resistance. We have previously used siRNA to successfully silence the IGF-I receptor (IGF-IR) in MCF-7 breast cancer cells. To further characterize the growth changes that occur when elements of the GH/IGF-I axis are disrupted we investigated the use of siRNA to cause long term silencing of IGF-IR.Methods: MCF-7 cells were cultured in phe...

The cell cycle occupies a pivotal role in the control of cellular proliferation, a critical point being activation of CyclinE which is held in check by the inhibitor p27. CyclinE is targeted for degradation by the F-box protein Archipelago (Ago/Fbw7/cdc4), while p27 is exported out of the nucleus by Jun activation domain-binding protein 1 (Jab1). Over-expression of CyclinE has been reported in breast cancer. We have now explored the role of Jab1 and Ago in mediating changes in...

Somatostatin and its analogues negatively regulate the growth of multiple epithelial cell types. This anti-proliferative effect occurs through multiple mechanisms, one of which is cell cycle arrest at the G0/G1 phase. p27, a cyclin-dependent kinase inhibitor, has a negative influence on cell cycle progression, and there are recent data suggesting that somatostatin increases p27 levels. We have previously shown that pituitary adenoma cells contain less p27 protein than normal p...

Objective: Because the altered expression of superoxide dismutases, CuZn (SOD1) and Mn (SOD2) have been shown to constitute the basis of either resistance or susceptibility to the cytotoxic effect of various cytostatics and nucleoside drugs, we tested whether in human uterin cervix carcinoma cells (HeLaS3) the cytotoxic effect of cytostatics adriamycin (Adr), and cis-platinum (CP) or nucleoside drug, tiazofurin (TF) were involved in the activity of SOD1 and SOD2. Methods: Cyto...

Introduction: In endocrine tumours, such as that of the breast, the protein survivin has emerged as a unique regulator of cell death. We have previously shown that bFGF regulates survivin expression through the MAP kinase cascade. The transcriptional complex myc/max is an oncogene that lies downstream of the MAP kinase pathway suggesting a possible role in survivin's regulation.Aim: To determine if bFGF can mediate survivin expression by signalling throu...

In breast cancer associations between p160 co-activator proteins and the development of resistance to endocrine treatment have been shown. We hypothesized that nuclear co-regulatory proteins may interact with non-steroid receptors. We investigated the effect of silencing the co-activator, SRC-1, on tumour cell growth in vitro. We also examined the MAPK activated transcription factors, Ets, as possible interaction proteins of the co-activator SRC-1 in human breast cancer. The e...

Background: Tamoxifen is a partial estrogen agonist used to treat estrogen receptor positive breast cancer. It has been discovered however that resistance to tamoxifen develops in some cancers. In order to investigate the mechanisms underlying the development of resistance we have created a tamoxifen resistant breast cancer cell line.Aims: To develop a breast cancer cell line that is resistant to the anti-growth effects of tamoxifen.<p class="abstext...

Background: Multiple Endocrine Neoplasia (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreas and pituitary. Recent consensus guidelines have recommended screening of MEN1 gene mutations in patients who have at least two of the parathyroid hyperplasia, pancreatic endocrine tumour or pituitary adenoma, or are suspicious of having MEN1 (multiple parathyroid tumours before age 30, recurrent hyperparathyroidism, gastrinoma or multiple isl...

Pre-operative localisation of insulinomas is essential prior to resection. Many imaging modalities have been used. Angiography is well described for localising neuroendocrine tumours and the use of selective intrarterial calcium injection to stimulate insulin release with simultaneous sampling of insulin levels in the hepatic vein has been shown to allow localisation of the tumour to particular vascular territories, even when other modalities have not been helpful.<p class...

It is well established that external pituitary irradiation (EPI) effectively reduces serum growth hormone levels in acromegaly. However the effect of EPI in normalising serum insulin like growth factor-1 levels (IGF-1) remains disputed. We studied 60 patients between 1964 and 2004 who received EPI for acromegaly: 22 women, 38 men; mean age at diagnosis 38.5 years (range 14-68). Pituitary surgery was carried out in 50/60 patients; in 47 patients EPI was given after their last s...

BACKGROUND: Dopamine agonists are the treatment of choice in macroprolactinomas. A number of these tumours do not respond to the commonly used doses. In such cases the outcome after alternative approaches has not been clarified.AIM: To assess the response of macroprolactinomas to bromocriptine (BRC) or cabergoline (CAB) and the result of further interventions in resistant cases.PATIENTS AND METHODS: All records of the patients pres...

An important issue for all endocrinologists involved in management of non-functioning pituitary adenomas (NFAs) not treated surgically at initial presentation is the frequency and duration of follow-up neuroimaging. Previous studies have described tumour enlargement in less than 15% of microadenomas (<1cm diameter) with macroadenomas (1cm diameter or more) showing a greater propensity for growth. With improvements in neuroimaging techniques we felt that it was timely to rev...

Sporadic pituitary tumours are generally benign tumours in which the none of the oncogenes or tumour suppressor genes classically mutated in other cancers are commonly mutated, nor are there frequent changes in genes associated with genetic endocrine neoplasia syndromes. Such tumours are associated with excessive but not completely unregulated proliferation, implicating a possible abnormality in a cell signalling pathway in their pathogenesis. Recently, the serine/threonine ki...

Several studies suggest that mortality rates due to cardiovascular disease (CVD) are increased in patients with hypopituitarism. We retrospectively assessed the prevalence of known diabetes, treated hypertension and dyslipidemia, known risk factors for cardiovascular disease (CVD), in a large population (n:250) of patients with hypothalamic-pituitary disease. We then prospectively screened 90 such patients for the following CVD risk factors: obesity, diabetes mellitus, smoking...

It is now well established that unilateral autonomous aldosterone secreting tumour (AST) in contrast to bilateral adrenal hyperplasia (BAH) - are corrected by surgery. The optimal method of pre-operatively defining a unilateral autonomous AST still remains controversial. There is agreement that adrenal scanning techniques are often unreliable or misleading. The aim of the current study was to analyse if a random aldosterone:renin (AR) ratio (after stopping anti-hypertensive me...

Introduction: Growth hormone (GH) replacement is widely used in the management of patients with adult-onset (AO) GH deficiency (GHD). In most cases, AO-GHD arises as a result of pituitary/peri-pituitary tumours and/or their treatment. The aim of this study was to examine the effect of GH replacement on growth/recurrence of non-anterior pituitary parasellar tumours.Methods: Fifty consecutive patients (21 males; mean age 45.9) with severe AO-GHD (peak seru...

Aim: To audit the management and treatment outcomes of patients with acromegaly at Royal Devon and Exeter Hospital.Patients and methods: Hospital case records of 43 patients (21 male), presenting between 1982 and 2004 were reviewed retrospectively. Age at presentation ranged from 21 years to 77 years, with average follow-up being 11.2 years.Results: 9 (29 percent) of 31 patients had microadenomas at presentation while 22 (71 percen...

Background: There is a large agreement that most of the incidentally discovered, clinically mute adrenal masses are incidentalomas - non-functioning tumours, which have to be explored in order to differentiate the adrenal carcinoma.Material and methods: We studied the prevalence and characteristics of clinically mute adrenal tumours and the evolution of adrenal incidentalomas, with the approval of the local Ethical Committee, in 123 patients with adrenal...

Selective Parathyroid Venous Sampling in Patients with Complicated Primary HyperparathyroidismCM Ogilvie, PL Brown, M Matson, R Carpenter, WM Drake, PJ Jenkins, SL Chew, JP MonsonCentre for Endocrinology and Departments of Surgery and Radiology, St Bartholomew's Hospital, QMUL, London EC1A 7BEThe role of pre-operative localisation of abnormal parathyroid glands remains controversial but is particularly releva...

BACKGROUND: Acromegaly is a chronic debilitating disease, which can also affect calcium metabolism. Hypercalciuria is a common finding but hypercalcaemia is rare and has been reported in 0-10% of cases in various studies involving small number of patients.AIM: To investigate the prevalence and aetiology of hypercalcaemia among patients with acromegaly.PATIENTS AND METHODS: The medical records of 145 patients who presented to our De...

Renal resistance to vasopressin has been demonstrated in type 1 diabetes, and in type 2 diabetes with nephropathy. However, renal response to vasopressin in type 2 diabetes without nephropathy, has not been studied.We studied 10 subjects with poorly controlled type 2 diabetes (PCDS, HbA1c > 9 %), 10 subjects with well-controlled type 2 diabetes (WCDS, HbA1c < 7 %), and 10 matched non-diabetic control subjects (NDCS), during a euglycaemic 8-hour wat...

Background: Untreated adult growth hormone deficiency (AGHD) is associated with hypertension, obesity and hyperleptinemia. Leptin is linked to obesity related hypertension, is secreted in a circadian rhythm and may contribute to the regulation of BP circadian rhythmicity.Methods: We studied the relationship between plasma leptin (half hourly samples), ambulatory systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP) over a 24-h period in ...

Background: Rathke cleft cysts (RCC) are benign, epithelial-lined cystic lesions arising from remnants of Rathke's pouch. Although reported in 13-22% of normal autopsies, they are rarely symptomatic. Their outcome after surgery remains unclear.Aim: To analyse the clinical/laboratory features and treatment outcome of patients who presented to the Departments of Endocrinology and Neurosurgery with symptomatic RCC (histologically confirmed) between 1977-200...

We have reported that serum DHEAS increases in growth hormone deficient (GHD) adults with intact ACTH reserve during GH replacement (GHR) in contrast with persisting low levels in ACTH-deficient GHD patients (Isidori et al. Clin Endo 2003:58:601). This was associated with a lower GH dose requirement in ACTH sufficient patients suggesting that DHEA may augment IGF-I generation. We have examined this hypothesis in a double blind placebo controlled trial of 30 hypopituitary femal...

Hyponatraemia is a well-recognised neurosurgical complication, but the incidence and complications are unknown.Objective : We aimed to define the incidence, pathophysiology and effects of significant hyponatraemia following neurosurgical admissions.Methods: All neurosurgical patients with significant hyponatraemia (plasma sodium <130 millimol per litre) between January 2002 and September 2003 were identified from computerised la...

Endocrine sequelae occur following cancer therapy. The majority of studies focus on childhood survivors of common cancers, in particular brain tumours, and isolated growth hormone deficiency (GHD) following radiotherapy is well recognised. The need for endocrine follow up in adults or following treatment of less common cancers with lower survival rates is often overlooked. Survival following treatment for nasopharyngeal cancer is improving. Although therapy options are changin...

INTRODUCTION: Although IGF-I is considered to reflect the daily GH secretion, its value in establishing the diagnosis of adult growth hormone deficiency (GHD) and in predicting the presence of further anterior pituitary deficits has not been elucidated in a large series.AIM: To evaluate the diagnostic utility of a subnormal IGF-I in patients with GHD and to investigate whether a low IGF-I is associated with the presence of further anterior pituitary defi...

Cortisol profiling at 20-min intervals over 24 hours during the fed state and in the last 24 hours of a 33-hr fast were undertaken in 34 ACTH-replete adult cancer survivors irradiated for non-pituitary brain tumours and 33 matched normal controls. Compared with normals, patients had significantly higher (mean ± SEM) minimum (nadir) cortisol concentration (37.8 ± 2.5 vs. 29.7 ± 2.9 nmol/L, p = 0.03), maximum cortisol concentration (547 ± 18 vs. 495 &...

We have used a sensitive chemiluminescence GH assay to analyse 24-hour GH profiles (20 minute sampling) from 11 adult cancer survivors with severe GH deficiency acquired following brain irradiation in childhood for non-pituitary brain tumours and 30 matched healthy normal volunteers. Cluster analysis revealed that the area under the curve for GH (AUCGH), absolute (maximum) GH peak height, mean peak height, maximum pulse area, mean pulse area, absolute (minimum) nadi...

Hyponatraemia occurs in 25-40% of patients with subarachnoid haemorrhage (SAH) but the pathogenesis is unclear.Objective: We aimed to establish the incidence, pathophysiology and consequences of hyponatraemia following SAH.Methods: A retrospective case note analysis of all patients with radiologically-proven SAH admitted to Beaumont Hospital between Jan 2002 and September 2003. Of 580 patients coded as SAH on HIPE records, 316 were...

Hypopituitarism has been reported in 28-65% of long-term survivors of traumatic brain injury (TBI). We attempted to define the natural history of post-traumatic hypopituitarism in order to devise guidelines for the optimal timing of patient assessment and hormone replacement.Fifty consecutive patients with severe or moderate TBI were enrolled in a prospective study of pituitary function during the acute phase, at 6 months and, at 12 months following TBI....

IntroductionWe have previously shown that patients with pituitary Cushing's have impaired quality of life vs. other pituitary tumour groups. Whether this is related to direct neural effects of excess ACTH or cortisol is uncertain. In order to address this, we compared patients who had undergone definitive treatment for pituitary vs adrenal Cushings.DesignWe assessed 14 patients with biochemically cured pituit...

The insulin tolerance test (ITT) is used to determine the integrity of the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-somatotroph (GH) axes in patients suspected of ACTH and GH deficiency. In adults a cortisol response <500nmol/L is considered pathological and a GH peak <9mU/L is consistent with severe GH deficiency. Exercise is an alternative stimulus to GH release which may be used to diagnose GH deficiency during childhood but is rarely used during adult li...

Clinic based studies have shown that patients with Addison's disease have relatively high rates of depression and anxiety symptoms compared with population-based reference samples. Addison's disease results in deficiency of dehydroepiandrosterone (DHEA) and DHEA-sulphate in addition to glucocorticoids and mineralocorticoids. DHEA is thought to have beneficial effects on energy level and mood, independent of circulating testosterone levels. Thus there may be a direct link betwe...

BACKGROUND: Lymphocytic hypophysitis (LHy) is an uncommon inflammatory disorder of the pituitary with features mimicking those of sellar tumours, thereby often being misdiagnosed. However, no long-term follow-up studies have been published.OBJECT: To evaluate the clinical/radiological characteristics and the prognosis of patients with LHy.PATIENTS-METHODS: The records of the patients who presented to the Department of Endocrinology...

Adult-onset Langerhans Cell Histiocytosis (LCH) is a rare disease characterised by the abnormal proliferation of Langerhans cells, and has a distinct phenotype to that of childhood-onset LCH. Diabetes Insipidus (DI) is a well-recognised manifestation of LCH, caused by infiltration of the hypothalamo-pituitary axis (HPA). Anterior pituitary dysfunction is an uncommon complication of LCH, which has been shown to be associated with DI. However, this association has previously onl...

Relaxin-3 (INSL-7) is a recently discovered member of the insulin superfamily, a group of structurally related hormones whose precursors have a domain arrangement similar to that of pro-insulin. Relaxin-3 mRNA is expressed in the nucleus incertus of the brainstem which has projections to the hypothalamus, an area important in appetite regulation. Relaxin-3 binds with high affinity to the recently discovered previously orphan G-protein-coupled receptor, GPCR135, which is expres...

Oestrogen is an important regulator of the pituitary hormone prolactin (PRL) in vivo, although the regulation mechanism is poorly understood. Liganded oestrogen receptor (ER) synergises with the pituitary specific factor Pit-1 on the rat PRL promoter to facilitate chromatin looping and increased transcription; however, no such mechanism has been reported for the human PRL promoter, in which the ERE sequence is altered.In pituitary GH3 cells stably transf...

The hypothalamic-pituitary-adrenal axis is a major regulation of inflammation via the release of adrenal glucocorticoids. We recently showed that anaphylatoxin C3a receptors are expressed throughout the anterior pituitary gland and that immune-derived complement C3a and its less active derivative, C3adesR (loss of C-terminal arginine) are potent stimuli for pituitary hormones.In this study we investigated the expression of the anaphylatoxin receptor C5a ...

Annexin-1 (Anx-1), a 37kDa protein, is a member of the super-family of Ca2+- and phospholipid-binding annexin proteins and acts as a mediator of glucocorticoid (GC) action in the host defence and neuroendocrine systems. In the anterior pituitary Anx-1 is expressed mainly by folliculostellate (FS) cells and mediates the early delayed feedback inhibition exerted by GCs on the release of ACTH and other pituitary hormones.The role of Anx-1 in the ...

Peptide YY(3-36) (PYY(3-36)) is secreted from endocrine L-cells of the gastrointestinal tract and is thought to induce post-prandial satiety by inhibiting the release of neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus via the hypothalamic neuropeptide Y2 receptor (Y2R). NPY mRNA expression in the hypothalamus is markedly increased with fasting. Therefore, we investigated the effect of intraperitoneal (i.p.) injections of PYY(3-36) (120ug/kg) on food intake vers...

During early embryogenesis, the olfactory axons and gonadotrophin-releasing hormone(GnRH)-secreting neurons undergo dynamic processes of differentiation, migration and proliferation, regulated by a complex network of molecular and cellular mechanisms responding to various hormonal and developmental signals. Mutations in anosmin-1 and FGFR1 disrupt this pathway, causing Kallmann's syndrome(KS), a human hereditary disorder with GnRH deficiency and inability to smell. A primary n...