Endocrine Abstracts

Primary hyperparathyroidism (HPT) is most frequently encountered as a non-familial disorder, but 10% of patients with primary HPT will have a hereditary form, which may occur as an isolated endocrinopathy or as part of a complex tumour syndrome such as multiple endocrine neoplasia type 1 (MEN 1) or type 2 (MEN 2), or the hereditary hyperparathyroidism-jaw tumour syndrome (HPT-JT). Familial isolated hyperparathyroidism (FIHP) is an autosomal dominant disorder characterised by u...

2-Methoxyoestradiol (2-MeOE2) is a human endogenous metabolite of oestradiol which is known to inhibit the proliferation of breast cancer cells. Sulphamoylation of 2-MeOE2 greatly enhances its ability to inhibit breast cancer cell proliferation and induce apoptosis. To establish whether 2-MeOE2 and its mono- and bis-sulphamoylated derivatives would also be an effective treatment for other endocrine cancers, we have investigated their effects, and those of 2-ethyloestradiol (2-...

Hypercalcaemia is a prevalent complication in malignancies as a consequence of tumor secretion of parathyroid hormone related peptide (PTHrP). This complication is also associated with ovarian dysgerminomas but is much less common than for other tumours. To investigate this further we have studied 10 cases of dysgerminoma, assessing biochemical parameters and analysing mRNA and protein expression in tissue biopsies. Pathological reports show raised serum calcium and 1,25(OH)<s...

Parathyroid tumours occurring in association with ossifying fibromas of the jaw are the hallmarks of the hyperparathyroidism-jaw tumour (HPT-JT) syndrome, which is inherited as an autosomal dominant trait. The HPT-JT gene, which is located on chromosome 1q25, consists of 17 exons and encodes a 531 amino acid protein named PARAFIBROMIN (Nature Genetics, in press). The observation of loss of heterozygosity (LOH) involving 1q25 in HPT-JT parathyroid tumours and the detection of i...

Carcinoid tumours are neuroendocrine tumours that may arise as isolated non-familial cancers or in association with multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant disorder characterised by the combined occurrence of tumours of the parathyroids, the anterior pituitary and the pancreatic islets. The molecular mechanisms underlying carcinoid tumourogenesis have not been fully defined and in order to further characterise these, we undertook 2 approaches...

The hyperparathyroidism-jaw tumour (HPT-JT) syndrome is an autosomal dominant disease characterised by the occurrence of parathyroid tumours, which are often carcinomas, and fibro-osseous tumours of the jaw bones. The HPT-JT gene is on chromosome 1q25 and consists of 17 exons that encode a 531 amino-acid protein, designated PARAFIBROMIN (Nature Genetics, in press). Thirteen heterozygous germline mutations that result in truncated or inactivated forms of PARAFIBROMIN have been ...

Background/Aims: Prognosis in midgut carcinoid tumours (MGCs) is difficult to predict. Studies of traditional clinical parameters give conflicting results. This is a large retrospective survival analysis of both clinical and biochemical data collected at diagnosis before treatment.Methods: Sequential cases of MGCs were identified using a database in Belfast from 1978. Clinical notes and pre-treatment plasma Neurokinin A (NKA) concentrations, were reviewed for each patient ...

The capacity of the adrenal to produce cortisol is controlled in part by the transcription of 21 hydroxylase(CYP21) and production of androgens by 17 hydroxylase/17-20 lyase(CYP17) in response to secretogoues including ACTH, angiotensin-II(A-II) and forskolin. Both mRNA and protein expression of CYP21 was upregulated in the presence of forskolin and A-II alone and in combination in vitro H-295 adrenocortical cells, as detected by northern and western blotting. Whereas, ...

One third of pituitary adenomas surgically removed are invasive, the presence of which increases the patients' risk of morbidity and mortality. IL6 has been shown to have conflicting effects on growth of human pituitary adenoma cells in culture but may act not only with mitogenic effects but on facilitating tumour invasion into surrounding tissue. We have previously shown IL6 mRNA expression correlates with invasive status and tumour volume(1). IL6 and IL1 are known to stimula...

Thyroglobulin is generally a reliable marker of recurrent disease in patients with well differentiated thyroid carcinoma. However, some patients have recurrent disease but no increase in serum thyroglobulin. In order to try to identify patients who might recur with no such sign of the disease, we preoperatively assessed thyroglobulin levels in 185 consecutive patients scheduled for primary treatment for well differentiated thyroid carcinoma from June 1997 to May 2002 at the He...

Aims: Previous studies of acromegaly have suggested a prevalence of 60 per million and an incidence of 3-4 per million per year. We have performed a population-based survey to ascertain prevalence and incidence of acromegaly, and biochemical outcomes to treatment. Methods: We have reviewed case notes of all patients with acromegaly under the care of the endocrine unit (referral population of 700,000). Growth hormone (GH) and IGF-1 levels at follow-up were examined. Results: Th...

Background: Vitamin D prevents proliferation, promotes differentiation and induces apoptosis of colonic cells. A reduced dietary intake is associated with an increased risk of colorectal cancer (CRC). Recently, we have shown that 25-hydroxyvitamin D-1-alpha hydroxylase (1aOHase) mRNA, which converts vitamin D to its active metabolite, is upregulated in CRC. However, this was based on small number of samples and data on vitamin D receptor (VDR) expression in CRC are inconsisten...

Increased mortality in patients with acromegaly has been confirmed in a number of retrospective studies, but causative factors and relationship to serum IGF1 remain uncertain. The West Midlands Acromegaly database contains details of 419 patients (178 males). Serum IGF1 data from the Regional Endocrine Laboratory was available for 338 patients (81%). At diagnosis mean age was 47 years (range 12-84) and mean GH was 70plus/minus5.4 milliunits per litre. 61% were treated by surge...

Epidemiological data suggests a correlation between phytoestrogen consumption and a reduced incidence of breast cancer. Current in vitro data is ambiguous, suggesting differential proliferative effects of phytoestrogens depending on ER expression status and exogenous estradiol levels. This study aims to characterise the growth inhibitory effects of the isoflavones genistein and daidzein using a panel of human breast cancer cell lines.Flow cytometry revealed low leve...

To dissect mechanisms which result in 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) insensitivity we have compared the antiproliferative actions of 1,25(OH)2D3 in a range of malignant breast cell lines (ZR-75-1, T-47D, MCF-7, MCF-7Res and MDA-MB-231) and the non-malignant breast epithelial cells MCF-12A cells. All the malignant cell lines displayed greater resistance than MCF-12A cells to 1,25(OH)2D3. For ex...

The demonstration in extrathyroidal tissues of the sodium iodide symporter (NIS) has raised the possibility that 131I, commonly used as a therapeutic ablative agent in hyperthyroidism and thyroid cancer, might be applied in the treatment of tumours in other NIS expressing tissues such as human breast cancer. As thyroidal uptake of 131I is known to be inversely proportional to circulating stable I- concentration, the aim of this study was to determine how I- would effect such u...

The ACTH receptor (ACTH-R) is the second member of the melanocortin receptor family that includes five seven-transmembrane G protein-coupled receptors, and has been shown to be predominantly expressed in the adrenal cortex. It has been postulated that ACTH may regulate its own secretion through ultra-short loop feedback within the pituitary, and as ACTH-secreting adenomas are characterised by resistance to glucocorticoid feedback, they may also have dysregulated ACTH feedback....

Ghrelin is a brain-gut peptide originally identified in the stomach. It binds to and stimulates the growth hormone secretagogue receptor type 1a (GHS-R). The presence of ghrelin in hypothalamic tissue was studied. It has been previously established that neither the synthetic GHSs, nor the endogenous hormone ghrelin, is specific for GH stimulation: they generally also stimulate the HPA axis as well as prolactin release. Since there is no direct stimulatory effect on ACTH releas...

PTTG has been implicated in the pathogenesis of pituitary, thyroid and other tumours. PBF was recently identified as a protein which interacts specifically with PTTG both in vitro and in vivo. PBF facilitates PTTG's nuclear localisation, and mediates its ability to transactivate basic fibroblast growth factor (FGF-2). We investigated PBF expression and function in vitro, and examined its relationship to PTTG action. Transient transfection of wild type PTTG induced a significan...

Background: Sporadic colorectal carcinoma (CRC) is more common on the left side of the colon. Acromegaly confers an increased risk of developing CRC but with an increase of right sided disease. IGFBP-3 both regulates tissue exposure to IGF-I and also exerts cellular IGF-l independent pro-apoptotic effects. Whether variation in regional IGFBP-3 expression in the colon may explain the observed pattern of disease in both normal and acromegalic patients is unknown.Aim: 1) To c...

Background:The growth hormone/insulin-like growth factor-I (GH/IGF-I) axis has been increasingly implicated in the development of breast cancer. Previously we have demonstrated the local expression of IGF-I in normal and malignant breast tissue. However the correlation of this local expression with clinical factors has not fully been investigated.Aims: (i) To quantify the mRNA levels of IGF-I in normal and malignant breast tissue and (ii) to identify any correlation betwee...

Background:Recent studies have linked low serum levels of IGFBP-3 with an increased risk of developing breast cancer.In addition to modulating IGF-I bioactivity, IGFBP-3 also exerts IGF-I independent pro-apoptotic effects. Our previous work has demonstrated that IGFBP-3 mRNA expression is significantly down regulated in breast tumours compared to normal breast tissue. It is uncertain, however, how this pattern of expression relates to the pathological and prognostic features o...

Expression of the Sodium Iodide symporter (NIS) in the breast was thought to be restricted to lactation but recently have been shown in breast cancer and benign breast disease. CpG island methylation of the promoter region of NIS is known to decrease iodide uptake in the thyroid. No such information has been documented in the breast. The aim of this study was to investigate the effect of demethylating agents on iodide uptake in breast cancer cell lines MCF-7 (oestrogen (E) and...

Hyperprolactinaemia in the presence of pituitary tumour can occur from tumour secretion or from stalk compression causing loss of dopaminergic inhibition. It is generally accepted that, in the presence of a large pituitary mass, a serum prolactin level up to 3000mU/l indicates stalk compression rather than a prolactinoma; the clinical diagnosis of prolactinoma depends on the degree of hyperprolactinaemia in the context of pituitary tumour size. Our aim was to examine more form...

Introduction. Lipocortin-1 (annexin-1 and p35) is a 37-kDa Ca2+-dependant membrane-binding protein that hasanti-inflammatory, anti-mitotic and anti-proliferative properties.With these properties in mind it was hypothesised that lipocortin-1 may have an important role in the endometrium. Therefore, the aim ofthis study was to determine the distribution of lipocortin-1 in normal and abnormal endometrial tissue.Methods. Formalin fixed paraffin embedded sect...

ER-alpha and ER-beta function as transcription factors to modulate expression of target genes. Both interact with nuclear regulatory proteins to enhance or inhibit transcription. We hypothesized that these co-regulators are expressed in breast cancer tissue and may be differentially regulated by estrogen and tamoxifen.ER-alpha, ER-beta, the co-activator SRC-1, and the co-repressor SMRT were localized within breast tissue by immunohistochemistry, and the spatial co-expressi...

We have evaluated the effectiveness of radiotherapy in three patients with recurrent symptomatic hypophysitis following surgical decompression.Case 1(54 F); presented with diabetes insipidus, hypopituitarism and a large hypophyseal mass. Following trans-sphenoidal surgery (TSS), a diagnosis of xanthomatous hypophysitis was made. Two years later severe headaches returned, and despite a second trans-sphenoidal procedure, visual acuity further deteriorated in the left eye...

Glucocorticoids (GCs) mediate many of their physiological effects through inhibition of cell proliferation. More contentious is the antiproliferative action of GCs and their possible tumour-modifying effects in neoplastic tissues. However, in recent studies we have shown that 'prereceptor' metabolism of GCs by the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) is a pivotal determinant of cell proliferation and tumour formation. Two isozymes of 11beta-HSD interconvert ...

While primary hyperparathyroidism is most commonly due to a parathyroid adenoma, very occasionally it may be secondary to a parathyroid carcinoma. A substantial minority of parathyroid adenomas are due to mutations or transpositions in genes in involved in the regulation of the cell cycle. In particular, at the cell cycle checkpoint which regulates exit from G1 phase, there is an interaction between the cyclins and cyclin-dependent kinases (CDKs); specifically, cyclin D intera...

Her-2/neu over-expression is associated with elevated tumorigenicity and enhanced metastatic potential. Recently a DNA motif containing the consensus binding site of PEA3, a member of the ets transcription factor family has been identified on the Her-2/neu promoter. Activation of the PEA3 response element has been proposed to be involved in the transcriptional squelching of Her-2/neu.Methods: Using RT-PCR we have determined PEA3 mRNA expression in human breast tissue and l...

Fifty patients (male:female 23:27) with a phaeochromocytoma or paraganglionoma have been seen within the Oxford hospitals since 1985. Further information has been located on 48. Patients had a median age of 42.6 years (range 19.4-74.6) and a median follow up of 13.9 months postoperatively (range 0.6-146.3). The adenoma was unilateral in 44 cases (88%, left 20, right 22) and bilateral in 4 cases (8% 2 Von Hippel-Lindau disease (VHL) 1 Neurofibromatosis type 1 (NF1) 1 Sporadic)....

Disorders of calcium metabolism may occur as hereditary traits eg. the Multiple Endocrine Neoplasia type 1 (MEN1) or type 2 (MEN2) syndromes, Familial isolated hyperparathyroidism (FIHP), neonatal severe primary hyperparathyroidism (NSHPT), Familial benign hypocalciuric hypercalcaemia (FBHH), the autoimmune poly- endocrinopathy-candidiasis-ectodermal-dystrophy (APECED) and DiGeorge syndromes, isolated hypoparathyroidism and the autosomal dominant hypocalcaemic hypercalciuria (...

Somatostatin (sst) modulates exocrine and endocrine secretions, cellular proliferation and apoptosis, via a series of 5 G-protein linked transmembrane receptors (sstrs 1-5). Sstrs 2 and 5 have been reported on vasculature but their role remains obscure. Here, we report the expression of sstrs in endothelial cells in vitro, during both proliferative and quiescent states to determine whether these receptors may change dynamically. Endothelial cells were harvested from ten...

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Introduction: TSH secreting pituitary adenomas (TSHomas) are often large and locally invasive. Following trans-sphenoidal surgery (TSS) patients frequently require adjuvant treatment with either anti-thyroid medication or somatostatin analogue therapy.Objective: To evaluate the value of a single subcutaneous octreotide test dose in predicting the the response to long term treatment in 5 patients with TSHomas.Methods: Five consecutive patients presenting 2000-02 were ev...

From a group of 41 patients with acromegaly, the majority of whom had pituitary surgery as primary therapy, we have compared growth hormone responses to a test dose of octreotide across 8 hours with a 3 year random growth hormone in 22 patients who at the 3 year assessment were receiving at least 600mcg octreotide daily subcutaneously or 20mg LAR monthly intramuscularly and in 2 other patients who had achieved 3 year GH of <5 mU/l on smaller doses. Seven patients had a basa...

Vascular Endothelial Growth Factor (VEGF) is an important growth factor, simulating the process of angiogenesis which is required for tumour progression. It mainly acts through 2 receptors VEGF-R1 and VEGF-R2. Whilst the presence of VEGF has been shown in pituitary adenomas, no study has undertaken the quantification of the expression of VEGF121, VEGF165, VEGF-R1 and VEGF-R2, and whether their expression may correlate.METHODS. We have used the technique of quantitative RT-...

Introduction: Cyclooxygenase-2 (COX-2), an inducible enzyme in prostaglandin synthesis, plays a major role in the pathogenesis of sporadic colorectal carcinoma (CRC). COX-2 inhibitors reduce the mortality from sporadic CRC. Acromegaly is associated with an increased risk of CRC, with a preponderance of right sided disease, but COX-2 protein is reduced or absent in acromegalic normal and malignant colonic mucosa. The mechanisms responsible for this are unknown.Aims: (i) To ...

Aims: The majority of patients with Cushing's disease have pituitary microadenomas and preoperative localization can be helpful during transphenoidal surgery. Inferior petrosal sinus sampling (IPSS) of ACTH and responses to CRH may show higher levels on the side ipsilateral to the tumour, although this remains controversial. A few small studies suggested a prolactin response to CRH during IPSS. We assessed whether prolactin responses to CRH can help lateralize the microadenoma...

NICTH is a well-recognised syndrome associated with overproduction of pro-IGF-II, usually secreted by large mesenchymal tumours. The determination of pro-IGF-II is currently laborious and cumbersome. The aim of the present study was to therefore establish a quick method for determining serum pro-IGF-II. Serum samples from 13 patients with NICTH were obtained after informed consent and these samples were studied and compared to sex- and age-matched controls. Serum concentration...

A new role for the endocrine nurse within a multidisciplinary approach to neuro-endocrine tumours.Historically patients with neuroendocrine tumours have been looked after either by the gastrointestinal team, the oncologists or the endocrinologists. Here, we demonstrate the need for a multidisciplinary approach to managing these rare tumours and a new role for the endocrine nurse.Our newly evolved, multi-disciplinary neuroendocrine tumour (NET) clinic comprises an endoc...

Aim: To analyse outcome of transsphenoidal surgery for acromegaly in Wales using stringent remission criteria.Method: We retrospectively analysed 90 patients who underwent transsphenoidal surgery (performed by 3 surgeons) as initial therapy for acromegaly in our centre between January 1980 and December 2001. A combination of modern, evidence-based remission criteria including mean day curve GH < 5 mU/l and /or a nadir GH < 2 mU/l after an oral glucose tolerance test ...

Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome featuring cardiac, endocrine, cutaneous and neural tumours, as well as a variety of pigmented lesions of the skin and mucosa. Pituitary GH-secreting tumours are found in approximately 10% of patients with CNC. One of the genes responsible for CNC, the PRKAR1A gene, located on human chromosome 17q22-24, has recently been cloned. This represents a putative tumour suppressor gene, coding for the type 1alpha...

A 52 year old man presented with a 4 week history of heartburn and epigastric pain. On examination 6 centimetres of irregular heptomegaly were palpable extending across to the epigastrium. Ultrasound of the abdomen demonstrated multiple liver metastases. Percutaneous liver biopsy was consistent with a neuroendocrine tumour (NET) with positive staining for CAM 5.2, chromogranin, PGP 9.5 and S100 but negative for alpha fetoprotein and CEA. Gamma glutamyl transpepitdase was eleva...

BACKGROUND: An audit of facilities and medical and surgical care based on the 1997 Royal College of Physicians and Society for Endocrinology guidelines for the management of pituitary tumours was carried out in the South West in 2001. We present the results for patients referred to one specialist pituitary surgeon in Plymouth.METHODS: 1. A questionnaire was sent to each endocrinology department covering staff resources, facilities for investigations and the process of care...

Lymphocytic adenohypophysitis (LA) is a rare inflammatory disorder of the pituitary, probably auto-immune in origin, usually affecting young pregnant women. Clinical features resemble a pituitary adenoma but differing in the hierarchy of endocrine loss, preferentially destroying ACTH and TSH secreting cells. A useful diagnostic feature is pituitary enhancement with gadolinium on MRI.A 39-year old female, with treated hypothyroidism, was referred to endocrinology out-patien...

A 72-year-old man presented with a two-year history of hot sweats, impotence and mood swings. He had a past medical history of polymyalgia rheumatica, osteoporosis and mild hypercalcaemia.On examination he was sweating excessively, had testicular atrophy and mild hypertension. Blood tests revealed a raised LH, FSH and a low testosterone consistent with primary hypogonadism. Hypercalcaemic screen was negative. He was started on androgen replacement therapy as well as anti-h...