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Aims/hypothesis: The main disadvantage of intensive treatment in the Diabetes Control and Complications Trial (DCCT) was an increased risk of hypoglycaemia that was not explained by the difference in HbA(1c) values alone. This study re-analysed DCCT data to establish whether mean blood glucose (MBG) and/or glucose variability add to the predictive value of HbA(1c) for hypoglycaemia risk in type 1 diabetes., Methods: The times to first and subsequent severe hypoglycaemic events were compared with MBG, HbA(1c) and within-day SD of blood glucose using Cox regression after adjusting for other known risk factors for hypoglycaemia., Results: On its own, the incidence of time to first hypoglycaemic event increased 1.05-fold for each 1 mmol/l decrease in MBG and 1.07-fold for every 1 mmol/l increase in glucose SD. MBG and SD of blood glucose also both added to the ability of HbA(1c) to predict repeated hypoglycaemic events: after adjusting for HbA(1c), a 1 mmol/l increase in SD was associated with a 1.09-fold increased risk of a first event, increasing to a 1.12-fold risk of a fifth event. A 1 mmol/l fall in MBG added a constant 1.02-1.03-fold risk of repeated events. Daytime events were predicted more accurately than nocturnal episodes., Conclusions/interpretation: This study has established that HbA(1c), MBG and glucose variability measurements each have an independent role in determining an individual's risk of hypoglycaemia in type 1 diabetes. All three aspects of glycaemic assessment should thus be considered in patients in whom hypoglycaemia is a real or potential problem.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women that has received an immense amount of attention in the recent years due to the possible associated risk of cardiovascular disease. Women with PCOS demonstrate an adverse cardiovascular profile characteristic of the cardiometabolic syndrome and an established risk of progression to type 2 diabetes. Despite the presence of cardiovascular risk factors and increased surrogate markers of cardiovascular disease, it is unclear if they develop accelerated atherosclerosis. This article summarized the recent development and findings of cardiovascular risk in women with PCOS, and finally the therapeutic options will be discussed.

Angiogenesis is critical for the growth and metastatic spread of tumours. Vascular endothelial growth factor (VEGF) is the most potent inducer of neovasculature, and its increased expression has been related to a worse clinical outcome in many diseases. The purpose of this study was to evaluate the relation between VEGF, its receptors (VEGFR-1 and VEGFR-2) and microvessel density (MVD) in thyroid diseases. Immunostaining for VEGF and VEGF receptors was performed in 66 specimens of thyroid tissue, comprising 17 multinodular goitre (MNG), 14 Graves' disease, 10 follicular adenoma, 8 Hashimoto's thyroiditis, 7 papillary carcinoma and 10 normal thyroid specimens. Thyrocyte positivity for VEGF and VEGF receptors was scored 0-3. Immunohistochemistry for CD31, and CD34 on the same sections was performed to evaluate MVD. Immunohistochemical staining of VEGF in thyrocytes was positive in 92% of all the thyroid tissues studied. Using an immunostaining intensity cut off of 2, increased thyrocyte staining was seen in follicular adenoma specimens, MNG and normal thyroids compared with Hashimoto's thyroiditis and Graves' disease (P < 0.05). Similarly, VEGF thyrocyte expression in Graves' disease was less than other pathologies (P < 0.05). VEGFR-1 expression and the average MVD score did not differ between the different thyroid pathologies. VEGF expression was lower in autoimmune pathologies compared to autonomous growth processes. Conversely, both VEGFR-1 and VEGFR-2 were widely expressed in benign and neoplastic thyroid disease, suggesting that the up-regulation of VEGF and not its receptors occurs as tissue becomes autonomous. There was no clear relationship between MVD measurement and thyroid pathology.

Objective: Turner syndrome has well-recognized cardiovascular complications that appear in up to 40% of the patients and are more common in monosomy X. Left-sided obstructive lesions are relatively more frequent and predispose to aortic root dilatation and life-threatening aortic dissection. However, bicuspid aortic valves, hypertension, coarctation and aortic stenosis are also at risk of aortic dissection. Currently there is no clear guideline regarding the best single test for detection or monitoring aortic disease progression., Design: Routine thoracic aortic magnetic resonance imaging (MRI) was introduced to the dedicated Turner syndrome clinic, with repeated MRI examination every 2 years to detect or assess progression of aortic lesions., Results: Seven out of a total of 17 patients developed aortic anomalies during the course of surveillance, which included coarctation as well as aortic dilatation. None of these patients had any cardiovascular symptoms and the vascular abnormalities were detected on MRI at presentation or during the course of their follow-up. In patients with previously normal aortic imaging, the time interval for the lesion to be detectable varied between 2 and 6 years. In one patient there was progression of an established lesion over the 2-year period., Conclusion: In the few patients presented here, regular imaging at first consultation followed by every 2 years would appear to be warranted, although the exact frequency of imaging and by what modality still need to be ascertained definitively.

Radioiodine and thionamide treatment are the most frequently used treatment modalities for thyrotoxicosis in Europe and North America with surgery being reserved for selected cases. * In our clinic patients were offered all three modalities via simultaneous interview with an endocrinologist and a surgeon, with international risk benefit data for radioiodine and thionamide therapy, and local risk benefit data for total thyroidectomy provided. * When given the choice, at least 15% of patients opted for total thyroidectomy over the other modalities. * In our series of 100 consecutive surgical patients there was a 4% malignancy rate. * Total thyroidectomy should be offered equally, with radioiodine and thionamide treatment, as a first line treatment modality in the management of thyrotoxicosis.

Both northern and southern Sudan are deploying artemisinin-based combinations against uncomplicated Plasmodium falciparum malaria (artesunate+sulfadoxine-pyrimethamine [AS+SP] in the north, artesunate+amodiaquine [AS+AQ] in the south). In 2003, we tested the efficacy of 3 day AS+SP and AS+AQ regimens in vivo in the isolated, seasonally endemic Nuba Mountains region (the first study of AS combinations in southern Sudan). We also analysed pre-treatment blood samples for mutations at the P. falciparum chloroquine transporter (Pfcrt) gene (associated with CQ resistance), and at the dihydrofolate reductase (Dhfr) gene (associated with pyrimethamine resistance). Among 161 randomized children under 5 years, PCR-corrected cure rates after 28 days were 91.2% (52/57, 95% CI 80.7-97.1) for AS+SP and 92.7% (51/55, 95% CI 82.4-98.0) for AS+AQ, with equally rapid parasite and fever clearance. The Pfcrt K76T mutation occurred in 90.0% (144/160) of infections, suggesting CQ would work poorly in this region. Overall, 82.5% (132/160) carried mutations at Dhfr (N51I, C59R or S108N, but not I164L), but triple mutants (more predictive of in vivo SP failure) were rare (3.1%). CQ use should be rapidly discontinued in this region. SP resistance may propagate rapidly, and AS+AQ is likely to be a better long-term option, provided AQ use is limited to the combination.

The objective of this study was to evaluate and compare the effect of treatment with orlistat vs. metformin on the hormonal and biochemical features of patients with polycystic ovarian syndrome (PCOS). Twenty-one Caucasian women with PCOS [mean (+/-SEM) age 27 +/- 0.9 yr and body mass index 36.7 +/- 3.3 kg/m(2)] participated in this prospective, randomized, open-labeled study. All subjects had an 8-wk run-in period of dietary modification and then randomized to receive either metformin (500 mg three times daily) or orlistat (120 mg three times daily) for 3 months. Weight, blood pressure, and fasting blood samples were taken at screening, randomization, and on completion. Insulin resistance (IR) was calculated using the homeostasis model of assessment (HOMA)-IR method [HOMA-IR = (insulin x glucose)/22.5]. The results are expressed as mean +/- SEM. When compared with baseline, treatment with both orlistat [93.5 +/- 11.5 ng/dl (3.24 +/- 0.4 nmol/liter) vs. 114.5 +/- 11.5 ng/dl (3.97 +/- 0.4 nmol/liter), P = 0.039] and metformin [97.2 +/- 11.5 ng/dl (3.37 +/- 0.4 nmol/liter) vs. 120.0 +/- 8.7 ng/dl (4.16 +/- 0.3 nmol/liter), P = 0.048] produced a significant reduction in total testosterone. Treatment with orlistat produced a 4.69% reduction in weight (99.0 +/- 6.0 vs. 94.6 +/- 6.1 kg, P = 0.002), and this reduction was more significant than the reduction produced by metformin (4.69 vs. 1.02%, P = 0.006). There was no significant reduction seen after either treatment group for fasting insulin, HOMA-IR, SHBG, or any of the lipid parameters studied. In this study, orlistat produced a significant reduction in weight and total testosterone. The reduction in total testosterone was similar to that seen after treatment with metformin. Therefore, orlistat may prove to be a useful adjunct in the treatment of PCOS.

Somatostatins are neuropeptides that have a downregulatory effect on various physiological processes. Their use in the management of certain endocrine tumours is well recognized. Their use in thyroid cancer is not established, although there is some evidence to suggest that they have a role in advanced metastatic disease. We report a case of a patient with advanced metastatic follicular thyroid cancer which demonstrated strong octreotide uptake with reduced avidity for I(131). Treatment with the somatostatin analogue octreotide, however, failed to achieve a significant response. We feel this case is important as it suggests that although octreotide provides a useful further imaging modality in differentiated thyroid cancer, it has no therapeutic role.

The role of chemotherapy in squamous cell carcinoma of the larynx has not been clearly defined. Whilst toxic chemotherapy regimes may confer a marginal improvement in survival, surgery and radiotherapy remain the mainstay of treatment. Somatostatin is a naturally occurring peptide, which exerts antiproliferative and antiangiogenic effects via five membrane-bound receptor subtypes. The expression of somatostatin receptor subtypes (SSTRs) 1 and 2 was studied in benign, pre-malignant and malignant laryngeal specimens. Epithelial expression of SSTR1 was detected in 4/6 (67%) Reinke's oedema, 5/6 (83%) pre-malignant and 8/12 (67%) malignant specimens, with virtually no stromal or vascular expression. High levels of epithelial SSTR2 expression were noted in all Reinke's oedema specimens, compared with low-to-moderate levels in only 2/6 (33%) pre-malignant and 3/12 (25%) malignant specimens (P < 0.01). This 'loss' of epithelial SSTR2 expression may provide a growth advantage in pre-malignant and malignant laryngeal lesions. Vascular expression of SSTR2 was ubiquitous in all groups, with scant stromal expression. Overall, most (>80%) pre-malignant and malignant laryngeal specimens expressed at least one of the two SSTR subtypes studied. Somatostatin analogues may have a therapeutic role in squamous cell carcinoma of the larynx.

This study was designed to assess the biological variability of total testosterone and SHBG in polycystic ovarian syndrome (PCOS) and to determine the use of SHBG as a surrogate marker of insulin resistance in PCOS. Fasting blood samples were collected at 4-d intervals on 10 consecutive occasions from 12 PCOS patients and 11 age- and weight-matched controls. Duplicate samples were analyzed for SHBG, testosterone, and insulin in a single batch, and insulin resistance was calculated by the homeostasis model assessment method (HOMA-IR). The PCOS group had higher testosterone (mean +/- SD, 3.9 +/- 0.8 vs. 3.2 +/- 1.3 nmol/liter; P = 0.001), lower SHBG (28.6 +/- 17.1 vs. 57.6 +/- 30.2 nmol/liter; P = 0.001), and greater HOMA-IR (5.85 +/- 5.3 vs. 1.67 +/- 0.63 U; P = 0.001) than the controls. In contrast to HOMA-IR (1.09 vs. 0.48 U; P = 0.001), the intraindividual variation in SHBG was lower in the PCOS group (mean, 3.4 vs. 6.3 nmol/liter; P = 0.041). The index of individuality for SHBG and testosterone in PCOS was 0.49 and 0.69, respectively. This study shows that for patients with PCOS, SHBG is an integrated marker of insulin resistance that may be of use to identify insulin-resistant individuals for targeted treatment with insulin-sensitizing agents. However, SHBG and testosterone concentrations measured in isolation are inherently unsuitable for use as tests to detect hyperandrogenemia.

Conventional surgery and radiotherapy for acromegaly have limitations. There are few data on the use of the somatostatin analog octreotide (Oct) as primary medical therapy. An open prospective study of 27 patients with newly diagnosed acromegaly was conducted in nine endocrine centers in the United Kingdom. Twenty patients had macroadenomas, and 7 had microadenomas. For the first 24 wk (phase 1), patients received sc Oct in an initial dose of 100 microg, 3 times daily, increased to 200 micro g three times daily after 4 wk in the 13 patients whose mean serum GH remained greater than 5 mU/liter (2 microg/liter). Five-point GH profiles were performed at 0, 4, 12, and 24 wk, and high resolution pituitary imaging using a standard protocol was performed at 0, 12, and 24 wk (magnetic resonance imaging in 25 patients and computed tomography in 2). Tumor dimensions and volumes were calculated by a central, reporting neuroradiologist, and the results were audited by a second, independent neuroradiologist. After 24 wk, 15 patients proceeded to phase 2 of the study with a direct switch to monthly injections of the depot formulation of Oct, Sandostatin long-acting release (Oct-LAR). Further GH profiles were performed at 36 and 48 wk, and pituitary imaging was performed at 48 wk. The median pretreatment serum GH concentration was 30.7 mU/liter (range, 6.7-141.4). During sc Oct, serum GH fell to less than 5 mU/liter in 9 patients (38%), and IGF-I fell to normal in 8 patients (33%). All 27 tumors shrank during sc Oct; for microadenomas the median tumor volume reduction was 49% (range, 12-73), and for macroadenomas it was 43% (range, 6-92). After 24 wk of Oct-LAR (end of phase 2), the GH level was less than 5 mU/liter in 11 of 14 patients (79%), and IGF-I was normal in 8 of 15 patients (53%). In the 15 patients given Oct-LAR (10 macroadenomas), wk 48 scans showed a further overall median tumor volume reduction of 24%. At the end of the study 79% of patients had mean serum GH levels below 5 mU/liter, 53% had normal IGF-I levels, and 73% showed greater than 30% tumor shrinkage. Twenty-nine percent of patients achieved all 3 targets, but no patient with pretreatment GH levels above 50 mU/liter did so at any stage of the study. Primary medical therapy with Oct offers the prospect of normalization of GH/IGF-I levels together with substantial tumor shrinkage in a significant subset of acromegalic patients. This is most likely to occur in patients with pretreatment GH levels less than 50 mU/liter (20 microg/liter).

Increased insulin resistance (IR) is a cardinal feature of overweight patients with polycystic ovarian syndrome (PCOS). However, there are no data on the variability of IR for subjects with PCOS. The biological variation of IR (homeostasis model assessment model) was assessed by measuring IR at 4-d intervals on 10 consecutive occasions in 12 overweight PCOS patients (median age, 28 yr; range, 18-31 yr) and 11 weight-matched control women having regular menses and without PCOS (median age, 30 yr; range, 19-33 yr). The distribution of IR was log Gaussian in PCOS and Gaussian distribution in the control group. The IR in PCOS subjects was significantly greater than in the controls [mean (range), 5.85 U (1-42.1) vs. 1.67 U (0.48-3.49); P = 0.001]. After accounting for analytical variation, the mean intraindividual variance was also substantially greater in PCOS patients than in controls (mean, 1.19 vs. 0.23). As a consequence, at any level of IR, a subsequent sample must rise by more than 322% or fall by more than 31% to be considered significantly different from the first. IR, measured using the homeostasis model assessment model, is significantly greater and more variable for overweight patients with PCOS. Therefore, this inherent variability needs to be accounted for in studies of IR in PCOS.

Somatostatins are neuropeptides that exert a downregulatory effect on various physiological processes. Somatostatin analogues are used in the imaging and management of various tumour types. Their role in thyroid cancer has not as yet been fully elucidated. A systematic review of the literature using the keywords thyroid, cancer and somatostatin revealed 263 references. This paper summarizes the current knowledge of the role of somatostatins in thyroid cancer and assesses their future potential.

Background: Pseudoporphyria has been attributed to both medication usage and chronic hemodialysis. Histologically, it is identical to porphyria cutanea tarda. It is most commonly seen as localized bullae on sun-exposed skin, often on the dorsum of the hands and fingers., Objectives: We describe a 31-year-old man with rapidly evolving bullae which became denuded, clinically suggestive of toxic epidermal necrolysis. Pseudoporphyria was proven histologically. However, our patient's eruption was not localized as small bullae but was widespread, with large bullae evolving into large, cutaneous, denuded erosions., Conclusions: We describe a previously unreported, generalized variant of pseudoporphyria that resembles toxic epidermal necrolysis. We provide a review of pseudoporphyria and compare our variant to toxic epidermal necrolysis and mimicking disorders.

A 44-year-old woman presented to her GP with excessive tiredness. She had positive thyroid microsomal and thyroglobulin autoantibodies and was found to have an elevated serum thyroid-stimulating hormone (TSH) concentration of 8.37 (normal = 0.15-3.5)mU/L and a low normal total thyroxine (T4) of 86 (reference range 60-145)nmol/L. She was rendered symptom free on a dose of 150 microg of thyroxine per day. However, her TSH failed to return to normal, and following a further increase in her thyroxine dose she was referred to the endocrine clinic for further assessment. Her TSH at this stage was 14mU/L, free T4 (fT4) 28 (normal = 10-27)pmol/L and free T3 (fF3) 10 (normal = 4.3-7.6)pmol/L. She denied any problems with adherence to her medication. Her serum prolactin was elevated at 861 (normal = 60-390)mU/L. A pituitary tumour was suspected and an MRI scan showed a macroadenoma of the right lobe of the pituitary, extending into the suprasellar cistern. The tumour was resected trans-sphenoidally. Electron microscopy showed a dual population of neoplastic cells compatible with a thyrotroph cell and prolactin-secreting adenoma. Immunocytochemistry and cell culture studies confirmed the secretion of TSH, prolactin and alpha-subunit. Postoperative combined anterior pituitary function tests did not demonstrate any deficiency of anterior pituitary hormones. A repeat MRI scan showed no significant residual tumour; however, her serum TSH and prolactin levels remained high and she was given a course of pituitary irradiation. This case illustrates the difficulty of diagnosing a TSHoma when it coexists with autoimmune hypothyroidism. We believe the combination of pathologies reported here is unique.

We have examined messenger RNA (mRNA) expression of estrogen receptor (ER) alpha, wild-type ERbeta (mRNA and protein), and ERbeta exon 5 deletion variants (ERbeta delta5) in samples of normal human mammary gland obtained from 37 premenopausal subjects undergoing reduction mammoplasty. Comparing individual expression, ERbetaP mRNA predominated, expressed in 34 of 37 samples (91%), whereas ERalpha was found in 21 of 37 cases (57%). Receptor combinations were then analyzed and compared. Most samples either coexpressed ERalpha with ERbeta (54%) or expressed just ERbeta (38%). Immunohistochemical analysis revealed that ERbeta mRNA expression mirrored that of protein. Immunoreactivity was observed in the nucleus with additional evidence of cytoplasmic staining in those epithelial cells lining the breast ducts. Sporadic immunoreactivity was also detected in stromal cells. Expression of wild type and ERbeta delta5 was analyzed, and their association with ERalpha was compared. Most samples coexpressed wild-type ERbeta and the splice variant (62%; P = 0.05), with 30% exclusively expressing wild-type ERbeta. Although samples coexpressing wild type and variant ERbeta showed no statistical association with ERalpha, those samples expressing only wild-type ERP, showed a trend toward associations with ERalpha (P = 0.07). In conclusion, our data would support a role for ERbeta in the normal human mammary gland, where we propose it may be the dominant receptor.

Objective: The management of CSF rhinorrhoea following dopamine agonist (DA) treatment for invasive prolactinomas is difficult and there is no clear consensus for its treatment. Our objective was therefore to investigate the different treatments for this condition., Design and Patients: We examined the case notes of five patients with invasive prolactinomas and CSF rhinorrhoea following DA treatment. The different ways in which this complication had been managed is detailed along with a review of the literature., Results: Five patients aged 24-67 years (3 male) with massive invasive prolactinomas (serum prolactin 95000-500000 mU/l) eroding the skull base were treated with dopamine agonists (3 bromocriptine, 1 cabergoline and 1 both). CSF rhinorrhoea developed in all patients between 1 week and 4 months after commencing dopamine agonist treatment. In two patients (cases 1 and 4), CSF rhinorrhoea ceased within a few days of stopping bromocriptine but restarted when treatment was resumed. One of these (case 4), a 67-year-old woman had no further treatment and CSF leakage stopped completely. She died of unrelated medical problems 3 years later. In one patient staphylococcus aureus meningitis and pneumocephalus developed as a complication of CSF rhinorrhoea. Three patients had endoscopic nasal surgery to repair the fistula using muscle grafts, and to decompress the pituitary tumour, with success in two. One patient had intracranial surgery and dural repair, which was successful in sealing the leak., Conclusions: We suggest that surgery as soon as is feasible is the treatment of choice for the repair of a CSF leak following dopamine agonist treatment. An additional strategy is the withdrawal of dopamine agonist to allow tumour re-growth to stop the leak.

Tamoxifen is currently the first-line therapy for treatment of hormone-dependent breast cancer. However, despite initial benefits, most patients eventually relapse. Two groups of patients were identified: (a) a tamoxifen-sensitive group (n = 8); and (b) a tamoxifen-resistant group (n = 9). Using reverse transcription-PCR, the relative expression of mRNA for both estrogen receptor (ER) beta and transforming growth factor beta1 was determined in each patient group and quantified against a known reference standard. ER-beta mRNA was significantly up-regulated in the tamoxifen-resistant group as compared with the tamoxifen-sensitive group (P = 0.001 by Fisher's exact test), and, consistent with previous findings, transforming growth factor beta1 was also up-regulated in the tamoxifen-resistant cohort (P = 0.02). The importance of ER-beta in tamoxifen resistance was validated using tamoxifen-sensitive and -resistant cell lines, in which it was demonstrated that ER-beta mRNA was significantly up-regulated in the resistant cells. These results lend further support to a role for ER-beta as a poor prognostic factor in breast cancer.

17Beta-hydroxysteroid dehydrogenase (17betaHSD) isoforms reversibly catalyze the final step in the formation of estradiol (E2) from estrone (E1) and the formation of testosterone from androstenedione. We have investigated 17betaHSD type 1, 2, 3, and 4 gene expression and 17betaHSD estrogenic activity in human anterior pituitary adenomas. 17BetaHSD messenger ribonucleic acid (mRNA) expression was studied by RT-PCR in 42 pituitary tumors and 3 normal pituitaries, 17betaHSD activity was studied in 11 tumors and 17betaHSD type 1 was immunolocalized in vitro in 6 tumors. 17BetaHSD type 1 gene expression was detected in 34 of 42 adenomas in all tumor subtypes; 17betaHSD type 2 mRNA was detected in 18 of 42 adenomas, but not in prolactinomas; 17betaHSD type 3 mRNA was detected in 12 of 42 adenomas, but not in corticotropinomas; 17betaHSD type 4 was expressed in 20 of 42 adenomas by all adenoma subtypes. Reversible 17betaHSD activity was found in 9 of 11 adenomas, and 17betaHSD type 1 immunopositivity was cytoplasmically distributed in all 6 adenomas in vitro. All 4 17betaHSD isoforms are variably expressed in human anterior pituitary adenomas, which also show 17betaHSD enzyme activity, suggesting that 17betaHSD may play an important role in regulating the local cellular levels of estradiol.

The cloning of a second estrogen receptor (ER), ER beta, has prompted a reevaluation of the role of ERs in breast cancer. The aim of this study was to determine the expression of both ER isoforms in normal (n = 23) and malignant (n = 60) human breast tissue by reverse transcription-PCR and correlate this information with known prognostic factors including tumor grade and node status. In normal breast tissue, expression of ER beta predominated, with 22% of samples exclusively expressing ER beta; this was not observed in any of the breast tumor samples investigated. Most breast tumors expressed ER alpha, either alone or in combination with ER beta. Interestingly, those tumors that coexpressed ER alpha and ER beta were node positive (P = 0.02; Fisher's exact test) and tended to be of higher grade. Because antiestrogens are agonists when signaling through the AP1 element, overexpression of ER beta in tumors expressing both ER subtypes may explain the failure of antiestrogen therapy in some breast cancer patients. Thus, ER beta may be a useful prognostic factor in patients with breast cancer.

Unlabelled: Cell density effects were investigated on tumorous hormonal secretion from 10 pituitary adenomas: 3 somatotrophinomas secreting GH and PRL; 7 gonadotrophinomas, 3 co-secreted both FSH and LH, all 7 secreted LH. Enzymatically dispersed tissue was plated out in 24-well plates at 5 x 10(5), 10(5), 5 x 10(4) and 10(4) cells/well in serum-free media. Media were collected weekly for 2 weeks., Results: In 3 of 3 somatotrophinomas, GH and PRL secretion was higher (p < 0.05) at both week 1 and 2 from 10(4) cells/well, but similar at other cell densities. In all 3 gonadotrophinomas, the FSH secretory rate was highest at 5 x 10(5) cells/well which fell as cell density decreased. Conversely, in 7 of 7 gonadotrophinomas the LH secretory rate was highest at 10(4) cells/well (p < 0.01) which fell as cell density increased., Conclusion: These data suggest that paracrine factors may modulate tumorous GH, PRL, FSH and LH secretion, and show that FSH and LH secretion vary inversely as cell density increases.

A method to determine whether dispersed human anterior pituitary adenoma cells proliferate in mixed culture was developed. Fifteen pituitary adenomas were dispersed enzymatically to single cells, following which twelve were double immunostained after eight days. Proliferating cells were identified immunologically following one hour of bromo-deoxyuridine incorporation. Adenoma cells were subsequently identified with an anti-neuron-specific enolase antibody system. A time course of bromo-deoxyuridine labelling was performed on three nonfunctional adenomas over a four day period, with bromo-deoxyuridine being added to cultures at one hour, 24 hours and four days prior to immunostaining. Double immunolabelled cells were unambiguously identified by a dark brown nucleus surrounded by red cytoplasm. Eight out of 12 pituitary adenomas (two prolactinomas, three nonfunctional, three growth hormone secreting) showed an increased bromo-deoxyuridine labelling index (range 0.1%-1.4%). Bromo-deoxyuridine incorporation over four days showed an increase in bromo-deoxyuridine from 0.02%, 0.03% and 3.3% at one hour to 10.1%, 1.3% and 5.0% at four days, respectively, but evidence of mitosis was scant. This study shows that pituitary adenomas may proliferate in vitro and that this double immunostaining method may be used as an in vitro proliferation assay in a mixed cell population.

The authors compared detection methods for cell proliferation in human anterior pituitary adenomas using histological sections and dispersed cell culture. After tumor cells had been grown for 4 days in dispersed culture, bromodeoxyuridine (BUdR), proliferating cell nuclear antigen (PCNA), and Ki-67 were compared by double immunostaining and contrasted with single staining of PCNA and Ki-67 indices in the corresponding histological sections from 12 human pituitary adenomas. In vitro, the BUdR labeling index was positive in six of 12 tumors (range < 0.1-5.1%), 10 of 12 tumors were PCNA-positive (range < 0.1-100%), and Ki-67 was positive in 10 of 12 adenomas (range < 0.1-8%). In vitro, BUdR and Ki-67 gave similar proliferative indices for 10 of 12 adenomas. In vivo, the PCNA labeling index was positive in 12 of 12 adenomas (range 0.9-95%) and Ki-67 was positive in 11 of 12 adenomas (range < 0.1-2%). Tumors with a labeling index less than 0.1% were considered to be negative for proliferation. High PCNA values were found in vitro and in vivo, whereas Ki-67 labeling indices were similar in vitro and in vivo for nine of 12 adenomas. It is concluded that Ki-67 proliferative indices in vivo reflect those found in vitro, at least after 4 days in dispersed culture, but that PCNA overestimates pituitary adenoma proliferation in histological sections as well as in dispersed culture.

Human anterior pituitary adenomas proliferate and express the p53 tumour suppressor gene protein, but it is not known if apoptosis (programmed cell death) occurs. Therefore, the detection of apoptosis was undertaken in tumorous human anterior pituitary tissue and compared with p53 protein expression, tumour type and tumour size. Apoptosis (detected by the in situ end labelling technique) and p53 suppressor gene protein (detected by DO.1-antibody immunocytochemistry) were determined in formalin-fixed and paraffin-embedded tissue from 37 human pituitary adenomas (2 macroprolactinomas, 9 somatotrophinomas and 26 non-functioning adenomas). Two normal anterior pituitaries were also included in this study. Pre-operative tumour size was scored 1 to 4 from magnetic resonance imaging radiology. Apoptosis was found in 7 of 29 tumours (24%), 11% of somatotrophinomas and 33% of non-functioning adenomas, although this difference was not significant. The p53 tumour suppressor protein was found in 7 of 31 tumours (23%), 33% of somatotrophinomas and 19% of non-functioning adenomas. Apoptosis and p53 protein expression were not found in normal anterior pituitary. In conclusion, apoptosis occurs in human anterior pituitary adenomas, but no significant association was found between apoptosis and p53 protein expression, tumour type or tumour size.

Objective: There is increasing evidence for the role of cytokines in pituitary differentiated function and tumorigenesis, but the spectrum of cytokines found in the pituitary is unknown. Therefore profiles of cytokine expression were determined in different human anterior pituitary adenoma sub-types., Design: The reverse transcriptase-linked polymerase chain reaction (PCR) was used to identify the presence of cytokine mRNA within human pituitary adenomas., Patients: Seventeen pituitary adenoma biopsies removed at transsphenoidal surgery were examined: 4 somatotrophinomas, 7 non-functional adenomas, 4 prolactinomas, one case of Cushing's disease and one case of Nelson's syndrome., Measurements: RNA was extracted from each adenoma biopsy and reverse transcribed into cDNA. This was specifically amplified in a PCR using oligonucleotide primers complementary to each cytokine. The cytokines investigated were interleukin (IL)-I alpha, IL-I beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, tumour necrosis factor (TNF)-alpha, TNF-beta and transforming growth factor (TGF)-beta 1, beta 2 and beta 3. The products of each PCR were visualized using agarose gel electrophoresis., Results: All 17 adenomas expressed IL-8 transcripts, but no expression of IL-2, IL-5 or IL-7 was found. IL-6 was expressed in all 4 somatotrophinomas, 3 of 7 non-functional tumours, 2 of 4 prolactinomas and in the single case of Nelson's syndrome. At least one of the 3 isoforms of TGF-beta was found in all but 2 tumours; one prolactinoma and one non-functional adenoma. IL-1 alpha, IL-beta, IL-4, TNF-alpha and TNF-beta were expressed sporadically by individual adenomas., Conclusion: These data suggest that whilst IL-8 may be important, the local expression of the cytokines IL-2, IL-5 and IL-7 is not important in human anterior pituitary tumorigenesis.

A female aged 53 years was found to have a suprasellar lesion, which was shown to be a Rathke's cyst after removal by transsphenoidal surgery. She presented 16 days postoperatively, and following two grand mal seizures was found to be profoundly hyponatraemic (sodium 101 nmol/l). She was initially thought to have the syndrome of inappropriate antidiuretic hormone and was treated accordingly, but central venous pressure measurement revealed the hypovolaemia of cerebral salt wasting syndrome. The patient subsequently developed severe neurological sequelae after the correction of her hyponatraemia, following the development of extrapontine myelinolysis. Cerebral salt wasting syndrome is a rare cause of hyponatraemia following pituitary transsphenoidal surgery, which may mimic the syndrome of inappropriate antidiuretic hormone secretion. This case emphasizes the poor prognosis that may result from the rapid correction of profound hyponatraemia.

Objective: The human pituitary gland is affected selectively by conditions associated with iron deposition, but the mechanisms for this are unknown. In this study we have determined whether the transferrin receptor, which mediates iron uptake by cells, could be detected immunocytochemically in human pituitary adenomas in vitro., Patients: Data were derived from 35 patients undergoing transsphenoidal surgery and included 13 with clinically non-functioning adenomas, 15 with acromegaly, 4 prolactinomas, 2 patients with Cushing's disease and one patient with Nelson's syndrome., Measurements: Transferrin receptor immunopositivity was determined for each adenoma in dispersed cell culture using a specific monoclonal antibody., Results: Eight of 13 clinically functionless adenomas showed immunopositive transferrin receptor expression, whilst adenomas from 15 patients with acromegaly, 4 prolactinomas, 2 Cushing's syndrome and one patient with Nelson's syndrome were negative. The eight transferrin receptor positive tumours were gonadotrophinomas and accounted for eight of the nine tumours which secreted and immunostained for FSH; all eight also secreted and immunostained for LH., Conclusions: These findings may reflect a special requirement for iron by gonadotrophin secreting cells in comparison to other pituitary cell types and this could underlie the reasons why in the normal pituitary these cells are especially susceptible to malfunction in iron overload syndromes such as genetic haemochromatosis and beta-thalassaemia.

Background: Quinagolide (CV 205 502) is a dopamine D2-receptor agonist which has proved effective in the treatment of prolactinomas, reducing both serum PRL and tumour size. Some of its D2-receptor effects are mediated via alpha-adrenoceptors, which have a major influence on the control of vascular tone. The aim of this study was to examine the influence of quinagolide on in-vivo dorsal hand vein vascular responses to noradrenaline in patients with a prolactinoma., Design and Patients: Seven female patients with prolactinomas (age 37 (28-46) years), intolerant of bromocriptine, were studied before and after 3 months treatment with quinagolide (0.75-1.5 mg/day). Patients were otherwise disease free, were taking no other medication, and had been on no other medication (including bromocriptine) for at least 3 months prior to enrollment into the study., Measurements: Vascular responses to locally infused noradrenaline were measured in dorsal hand veins using an established technique. PRL, oestradiol, FSH, LH, blood pressure and body mass index were also measured before and after 3 months treatment., Results: Quinagolide significantly reduced PRL in all 7 patients (1795 (696-4680) (mean (range)) vs 488 (290-868) mU/l, P = 0.001), with no effect on the other parameters, including mean arterial pressure (88 (2) vs 87 (4) mmHg, P = 0.6). Vascular reactivity to noradrenaline was significantly increased after 3 months therapy: log10 dose estimated to cause 50% vasoconstriction (ED50) 1.37 (0.12) vs 0.85 (0.12) ng/min (P = 0.003; a lower ED50 indicates less noradrenaline is required to constrict the vein by 50%)., Conclusions: Vasoconstrictor responses to noradrenaline were increased in all patients after 3 months treatment with quinagolide. Peripheral veins carry alpha-adrenoceptors analogous to those of systemic resistance vessels. If this increased vasoconstrictor response in patients with prolactinomas was occurring in hypophyseal vessels, it would lead to reduced tumour blood supply. Quinagolide may therefore reduce tumour blood flow, which may be one factor responsible for its effectiveness in these patients.

A 31 year old female presented with primary infertility and gave a two year history of amenorrhea without symptoms or signs of endocrine dysfunction. Examination was normal and investigation showed low oestradiol and progesterone levels with decreased LH pulsatility. The cortisol responses were impaired following hypoglycaemic stress and a short synacthen test, but the cortisol response to a prolonged synacthen test was normal. An inadequate ACTH response to CRF testing confirmed the diagnosis of isolated ACTH deficiency. Hydrocortisone therapy was followed by an ovulatory menstrual cycle. Amenorrhea again ensued following the reduction of the steroid dose and normal menses resumed on normal steroid replacement therapy. Six hourly gonadotrophin pulsatility showed a significant increase in both pulse amplitude and mean LH and FSH levels following steroid treatment. Isolated ACTH deficiency is a rare but treatable cause of hypogonadism and infertility, and this case gives further insight on the role of cortisol on the hypothalamo-pituitary gonadal axis.

A 15-year-old girl presented de novo in diabetic ketoacidosis having been comatose for 24 h (day 1). A CT scan and lumbar puncture performed on admission were normal and her conscious level slowly improved over several days. On day 7 she had central neurological signs of bilateral knee clonus and an extensor plantar response. In addition, she had developed lower motor neurological signs of an ulnar nerve palsy of the left forearm, and ulnar, median, and radial nerve palsies of the right forearm. Magnetic resonance imaging (MRI), performed on day 12, showed multiple small cerebral haematomata with appearances at least several days of age. The scattered lesions were localized particularly to the parieto-occipital region, with sparing of the basal ganglia and without cerebral oedema, a novel feature not previously described in juvenile ketoacidosis. Four months later there was minimal residual disability of her right arm. The clinical findings together with the MRI images suggested that the peripheral nerve and central lesions were temporally related, suggesting a common aetiology. However, it is likely that MRI showed cerebral lesions which may have been missed by the conventional CT scanning performed initially.

Pituitary apoplexy has been reported as a rare complication of combined tests and of TRH administration in prolactinomas. A 54-year-old man with a pituitary macroadenoma had a single injection of 100 micrograms GnRH. Twenty minutes later he complained of increasing headache and vomited. These symptoms settled spontaneously and were attributed to the pharmacological effects of GnRH. Five hours later he was found to be blind and disorientated without spontaneous complaint. Emergency CT showed a large adenoma with central necrosis, consistent with pituitary apoplexy. An urgent surgical decompression was carried out and necrotic haemorrhagic debris removed. Baseline bloods revealed non-pulsatile FSH of 40 U/l with LH 0.3 U/l with no hormonal response to GnRH administration, but the sequence of events strongly suggests a causal relationship between this and pituitary apoplexy. To our knowledge this is the first time that GnRH administration has been associated with pituitary apoplexy of a glycoprotein secreting pituitary adenoma.

This study was designed to compare the clinical efficacy and safety of oral clonidine and oral labetalol in the treatment of severe hypertension in an emergency department setting. Thirty-six patients with severely elevated blood pressure (mean baseline blood pressure 199/132 mm Hg) without acute end-organ dysfunction were treated with either oral labetalol or oral clonidine in a randomized double-blind prospective study. Labetalol was administered as an initial dose of 200 mg, followed by hourly 200 mg doses up to 1,200 mg. Clonidine was administered as an initial dose of 0.2 mg, followed by hourly 0.1 mg doses up to 0.7 mg. Labetalol reduced diastolic blood pressure in 94% of the patients within 6 hours, with a mean reduction in blood pressure of 54/37 mm Hg. Clonidine reduced diastolic blood pressure in 83% of the patients within 6 hours, with a mean reduction in blood pressure of 57/32 mm Hg. The authors conclude that oral labetalol was comparable to clonidine in efficacy, had a similar incidence of side effects, and offered the clinician a useful alternative for the treatment of severe hypertension in an emergency department setting. Further studies are indicated to determine appropriate dosing regimens for oral labetalol in the acute treatment of severe hypertension.

Severe hypothermia with cardiopulmonary arrest often requires prolonged resuscitation while rewarming procedures are implemented. A 63-year-old male in cardiopulmonary arrest with a core body temperature of 23.7 C was resuscitated successfully after core rewarming by means of a two-chest-tube continuous thoracostomy lavage procedure. This lavage procedure resulted in effective and rapid rewarming after other conventional rewarming methods had failed.

Carbamazepine-induced skin eruptions are common but lichenoid skin rashes associated with this drug are not well documented. We report here a patient with a lichenoid drug eruption secondary to carbamazepine.

Arthritis associated with leprosy is underreported. In Egypt 66 patients from a leprosy colony were studied, 20 of whom had arthropathy. This was characterised by an inflammatory symmetrical peripheral polyarthritis. The wrist, metacarpal and proximal interphalangeal joints of the hands, the knees, and the metatarsophalangeal joints of the feet were affected with associated morning stiffness. The arthritis was erosive in 11 out of 20 patients, had no features of the arthritis associated with erythema nodosum leprosum reactions, but symptomatically responded to antileprosy treatment. This arthritis would seem to be a previously unrecognised feature of leprosy.