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Biomedical subjects

J Newell-Price

Publications and source records attributed to J Newell-Price.

At least 19 recordsLinked to original sources
PubMed2006

Circadian hydrocortisone infusions in patients with adrenal insufficiency and congenital adrenal hyperplasia.

OBJECTIVE: Conventional hydrocortisone therapy in adrenal insufficiency cannot provide physiological replacement. We have explored the potential of circadian delivery of hydrocortisone as proof of concept for such therapy delivered in modified-release tablet formulation. METHODS: We investigated whether the circadian intravenous infusion of hydrocortisone could improve control of ACTH and androgen levels. Two healthy subjects, two patients with Addison's disease and two patients with congenital adrenal hyperplasia (CAH) were studied. RESULTS: In patients on thrice daily oral hydrocortisone, peak serum cortisol levels were higher than in normal subjects and overnight levels were very low. Patients had very high plasma ACTH levels before their morning dose of hydrocortisone, both at the beginning and at the end of their conventional oral therapy: mean +/- SEM 311.8 +/- 123.2 and 311.2 +/- 85.4 ng/l, respectively. In the patients with CAH, serum 17-hydroxyprogesterone levels were also elevated: 550 and 642 nmol/l at the beginning and 550 and 777 nmol/l at the end of conventional treatment, respectively. The overall 24-h mean cortisol levels were similar for conventional oral hydrocortisone and the circadian infusion. At 0700 h, ACTH levels were much higher on conventional treatment than after circadian infusion: mean +/- SEM 311.2 +/- 85.4 vs. 70.5 +/- 45.0 ng/l, respectively (P < 0.05). The same pattern was observed in 17-hydroxyprogesterone levels, which were 550 and 777 nmol/l after conventional treatment and 3 and 64 nmol/l after circadian infusion. CONCLUSIONS: In patients with poor biochemical control of Addison's disease and CAH, a 24-h circadian infusion of hydrocortisone can decrease morning ACTH and 17-hydroxyprogesterone levels to near normal.

17-alpha-Hydroxyprogesterone↗
PubMed2004

Endocrine emergencies.

Diabetic and endocrine emergencies are traditionally treated by the acute medical admitting team or accident and emergency department staff. Most will see diabetic emergencies on a regular basis, as they are common and both type 1 and type 2 disease are increasing in prevalence. Diabetic emergencies are usually easily treated and the patients discharged. However, it is vital not to become complacent as these disorders can lead to death. It is particularly important to follow local guidance and to involve the diabetes team both during and after each episode. Recently it has become clear that about 30% of patients admitted with acute coronary syndrome (including infarction) have either diabetes or "stress hyperglycaemia"; evidence suggests that these patients should be treated not only as a cardiac emergency but also as a diabetic one. Thus, every patient with acute coronary syndrome or acute myocardial infarction needs diabetes to be excluded. The other endocrine emergencies are less common, but in some ways more important simply because of their rarity. A high level of suspicion is often required to make a diagnosis, although some, such as myxoedema coma, are usually obvious. Treatment must be started before the diagnosis can be confirmed. Guidance on making the diagnosis and initiating treatment should be made available on the local NHS intranet for non-endocrinologists to access; and where possible expert advice made available by telephone. The basic management steps in the common diabetic and endocrine emergencies are outlined; this is not a complete list, but rather an insight for those involved in non-selected emergency admissions.

Emergencies↗
PubMed2003

Patients with chronic pain and abnormal pituitary function require investigation.

Misuse of opioids is associated with abnormalities of pituitary function. Patients with chronic pain frequently complain of fatigue and undergo endocrine testing. To test whether oral opioid treatment causes abnormal pituitary function we prospectively assessed pituitary function in 37 patients with chronic pain who were receiving either oral opioid analgesia or non-opioid analgesia. Oral opioid treatment was not associated with abnormal pituitary function although a few patients had abnormal results mainly related to obesity. Our results suggest that patients with chronic pain who have abnormal endocrine results should have a complete assessment, since abnormal test results cannot be attributed to their analgesia.

Analgesics, Opioid↗
PubMed2003

Diagnosis and complications of Cushing's syndrome: a consensus statement.

In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized.

Cardiovascular Diseases↗
PubMed2003

Proopiomelanocortin gene expression and DNA methylation: implications for Cushing's syndrome and beyond.

Proopiomelanocortin gene (POMC) is recognised as playing an important role in the regulation of the hypothalamo-pituitary-adrenal axis, adrenal development and obesity. POMC is activated in ACTH-dependent Cushing's syndrome. The syndrome may occur when the highly tIssue-specific 5' promoter of human POMC is activated in pituitary and non-pituitary sites. Whilst the factors involved in transcription in the corticotrophs of the anterior pituitary gland are becoming well delineated, the mechanism of activation in non-pituitary sites is not fully understood. This promoter is embedded within a defined CpG island, and, in contrast to somatically expressed CpG island promoters reported to date, is methylated in normal non-expressing tIssues, but is specifically unmethylated in expressing tIssues, tumours and the POMC-expressing DMS-79 small-cell lung cancer cell line. Methylation in vitro is sufficient for silencing of expression. In particular, methylation near the response element for the tIssue-specific POMC activator PTX1, diminishes POMC expression. Sites outside the PTX1 response element may be important for binding, and this may have implications for pituitary development. DMS-79 cells lack POMC-demethylating activity, implying that the methylation and expression patterns are likely to be set early or prior to neoplastic transformation, and that targeted de novo methylation might be a potential therapeutic strategy. It is conceivable that in POMC neurons of the hypothalamus the POMC promoter is subject to a variable density of methylation with clear implications for the signalling of satiety and obesity.

ACTH Syndrome, Ectopic↗
PubMed2002

Optimal response criteria for the human CRH test in the differential diagnosis of ACTH-dependent Cushing's syndrome.

The CRH test is in widespread use for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). Despite the greater availability worldwide of human-sequence CRH (hCRH), there are no large series reporting the response criteria that best discriminate between Cushing's disease (CD) and the ectopic ACTH syndrome (EC) when using hCRH, rather than ovine-sequence CRH. We have, therefore, analyzed retrospectively the serum cortisol and plasma ACTH responses to hCRH in patients with ACTH-dependent CS, to develop response criteria that best discriminate between CD and EC. One hundred fifteen consecutive patients with proven ACTH-dependent CS were studied: 101 with CD (78 females; mean age, 40 yr; range, 10-73) and 14 with EC (7 females; mean age, 46 yr; range, 32-69). The response to hCRH was also studied in 30 normal volunteers (NVs; mean age, 29 yr; range, 20-44) with no clinical evidence of CS, and the results were compared. Following basal sampling at -15 and 0 min, hCRH (100 microg iv) was administered via an indwelling forearm cannula at 0900 h and serum cortisol and ACTH were measured at 15-min intervals for 2 h. The mean basal, peak, incremental, and percentage change in the serum cortisol and ACTH at all time points, and combination of time points, were calculated and analyzed to establish the best criteria to discriminate between CD and EC, and also between CD and NVs. The mean serum cortisol concentration in samples obtained at 15 and 30 min after CRH increased by at least 14% above the mean basal in 85 of 100 patients with CD, but in none with EC, giving a sensitivity of 85% at a specificity set at 100%. In contrast, the best plasma ACTH response of a rise of 105%, calculated from the maximal rise, gave only 70% sensitivity at 100% specificity. In the NVs, the maximum cortisol at the mean 15+30 min time point was 615 nmol/liter. Using the 15 and 30 min time points as the reference point, 71 of 100 patients with CD had a rise of serum cortisol greater than 14% and also showed an absolute cortisol level more than 615 nmol/liter. Serum cortisol responses to hCRH can be used to suggest the diagnosis of CD in the majority of patients with this condition, but it should only be used in conjunction with other biochemical and imaging modalities in establishing this important diagnosis. The measurement of plasma ACTH was less helpful in making this distinction, although it may have additional value in excluding ACTH-independent causes of CS. Although we believe that bilateral inferior petrosal sinus sampling remains the single most useful test in discriminating CD from EC in patients with ACTH-dependent CS, hCRH offers rapid diagnostic information and is a useful adjunctive test in establishing the presence of a possible ectopic source.

ACTH Syndrome, Ectopic↗
PubMed2002

Biochemical and imaging evaluation of Cushing's syndrome.

The diagnosis and differential diagnosis of Cushing's syndrome remains a considerable challenge in clinical endocrinology. Investigation is a two-step process, involving first diagnosis followed by differential diagnosis. Traditionally diagnosis has relied upon urinary free cortisol (UFC) collection, low-dose dexamethasone-testing, and assessment of midnight cortisol. More recently, differentiation between mild disease and pseudo-Cushing's states has been achieved using dexamethasone-suppressed corticotropin releasing hormone (CRH) and desmopressin tests. Refinements of tests used for differential diagnosis have been made including optimized response criteria for ovine and human sequence CRH tests, desmopressin tests, GHBP-testing and testing with combinations of peptides. Despite improvements in these non-invasive tests use of inferior petrosal or cavernous sinus sampling is frequently required. Imaging is guided by biochemical assessment. MRI is the investigation of choice for Cushing's disease, but is often negative. Scintigraphic investigation using radionucleotide-labeled agonists for receptors commonly expressed by neuroendocrine tumors the investigation of occult ACTH-dependent disease remains disappointing. In this review we critically analyze the tests used for this most challenging of clinical conditions.

ACTH Syndrome, Ectopic↗
PubMed2001

The CpG island promoter of the human proopiomelanocortin gene is methylated in nonexpressing normal tissue and tumors and represses expression.

Ectopic secretion of ACTH, from sites such as small cell lung cancer (SCLC), results in severe Cushing's syndrome. ACTH is cleaved from POMC. The syndrome may occur when the highly tissue-specific promoter of the human POMC gene (POMC) is activated. The mechanism of activation is not fully understood. This promoter is embedded within a defined CpG island, and CpG islands are usually considered to be unmethylated in all tissues. We demonstrate that much of this CpG island is methylated in normal nonexpressing tissues, in contrast to somatically expressed CpG island promoters reported to date, and is specifically unmethylated in expressing tissues, tumors, and the POMC-expressing DMS-79 SCLC cell line. A narrow 100-bp region is free of methylation in all tissues. E2F factors binding to the upstream domain IV region of the promoter have been shown to be involved in the expression of POMC in SCLC. We show that these sites are methylated in normal nonexpressing tissues, which will prevent binding of E2F, but are unmethylated in expressing tissue. Methylation in vitro is sufficient for silencing of expression, which is not reversed by treatment with Trichostatin A, suggesting that inhibition of expression may be mediated by means other than recruitment of histone deacetylase activity. The DMS-79 cells lack POMC demethylating activity, implying that the methylation and expression patterns are likely to be set early or before neoplastic transformation, and that targeted de novo methylation might be a potential therapeutic strategy.

Adenoma↗
PubMed2001

The differential diagnosis of Cushing's syndrome.

The diagnosis of Cushing's syndrome remains one of the most challenging tasks in clinical neuroendocrinology. The diagnostic procedure can be divided into two distinct steps: diagnosis of the neuroendocrine disorder and differential diagnosis of the precise aetiology. The goal of the first laboratory tests is to obtain biochemical proof of Cushing's syndrome. Patients with Cushing's syndrome are relatively insensitive to glucocorticoid feedback and exhibit an oversecretion of cortisol devoid of a circadian cycle. In our experience, a low-dose dexamethasone suppression test provides the most reliable confirmation of steroid resistance, a cortisol level of<50 nmol/l at 9 a.m. having 98% sensitivity. A cortisol level below 50 nmol/l at midnight rules out active Cushing's syndrome with, in our experience, 100% sensitivity and a specificity depending on numerous other variables. A very high level of free urinary corticol can be a useful sign. After having established the diagnosis of Cushing's syndrome, a persistently low level of ACTH (<10 pg/ml), or preferentially an undetectable level unresponsive to CRH (100 microgram iv), is suggestive of an ACTH-independent disorder, and consequently of primary adrenal disease. The precise location of the lesion can identified with CT or MRI imaging, generally prior to surgical cure. If the ACTH level is detectable, patients with pituitary Cushing's syndrome, or Cushing's disease, should be differentiated from those with ectopic ACTH secretion. The secreting tumour may be difficult to localise and diagnosis is never 100% sure with dynamic tests. Catheterisation of the petrosal sinus with CRH stimulation provides the best sensitivity for differentiating the two aetiologies. We consider a central to peripheral gradient of>3 to confirm the pituitary origin of the disorder with a 98% sensitivity. Chest or abdominal CT can be helpful to identify an ectopic tumour but very small tumours may go undetected. MRI can detect 60 or 70% of all pituitary adenomas but is virtually non-contributive to the diagnosis of Cushing's disease in children.

Adenoma↗
PubMed1999

The diagnosis and differential diagnosis of Cushing's syndrome.

Cushing's syndrome is defined as the symptoms and signs of glucocorticoid excess, but the precise diagnosis may be difficult to establish and harder to localise. The clinicial, biochemical and imaging features of the syndrome are discussed in the light of our own extensive experience and the published literature. We describe the optimal diagnostic routines currently recommended in major centres, and analyse the sensitivities and specialities of the various tests employed. Only by means of establishing a precise diagnosis can the disorder be successfully treated.

Adrenocorticotropic Hormone↗
PubMed1999

Computed tomography appearance of the thymus and anterior mediastinum in active Cushing's syndrome.

Computed tomography (CT) evaluation of the thymus and anterior mediastinum is an important aspect of the investigation of patients with ACTH-dependent Cushing's syndrome in order to exclude an ACTH-secreting carcinoid tumor. We have reviewed the CT imaging of the thymus and anterior mediastinum in a series of 85 patients (55 females; median age 41, range 7-77 yr) with active Cushing's syndrome as there are few data on the range of appearances in hypercortisolemic states. One patient had a thymic carcinoid tumor (24 x 18 mm). Of the others, 28/84 (33%) patients showed thymic remnant tissue, consisting of either nodule(s) at least 5 mm diameter (n = 21, mean diameters 12.5 +/- 5 x 9.6 +/- 4 mm), or triangular bilobed glands (n = 7, mean thickness of the body, right and left limbs 25 +/- 7, 14 +/- 3, and 12 +/- 5 mm). Thymic involution appeared in 56/84 (67%) patients, ranging from small nodule(s) of less than 5mm diameter to linear soft tissue strands and complete fatty replacement. Patients with thymic remnant tissue were younger than those with thymic involution (P < 0.05). The thymic carcinoid tumor could be distinguished from remnant tissue on the basis of age and size. The presence of anterior mediastinal nodule(s) in hypercortisolemia need not imply the presence of a thymic carcinoid tumor, although in older patients this should arouse suspicion.

ACTH Syndrome, Ectopic↗
PubMed1999

Desmopressin normalizes the blunted adrenocorticotropin response to corticotropin-releasing hormone in melancholic depression: evidence of enhanced vasopressinergic responsivity.

Major depression is associated with significant disturbance in hypothalamic-pituitary-adrenal axis functioning, including blunted release of ACTH in response to CRH infusion. Eight melancholic depressives and eight matched healthy comparison subjects underwent, in random order, the following challenges: placebo, CRH, CRH + DDAVP. Blood for ACTH and cortisol estimation was drawn at -15, 0, 15, 30, 45, 60, 90, and 120 min. A blunted release of ACTH, in response to CRH challenge, was observed in depression (P < 0.01), whereas maximal cortisol responses in both groups were similar, despite elevated baseline levels in depression (P < 0.05). The combined CRH/DDAVP infusion produced similar ACTH and cortisol release in both groups. These results suggest that melancholic depression is associated with enhanced pituitary vasopressinergic responsivity.

Adrenocorticotropic Hormone↗
PubMed1997

A combined test using desmopressin and corticotropin-releasing hormone in the differential diagnosis of Cushing's syndrome.

To assess the ability of desmopressin to differentiate between pituitary and ectopic ACTH-dependent Cushing's syndrome and to determine whether diagnostic accuracy could be improved by administering it together with human sequence CRH, we examined its effects on cortisol and ACTH secretion when given alone or in combination with CRH in patients with Cushing's syndrome of varied etiology and compared these data to the results of a standard CRH test in the same individuals. Each patient was studied on three occasions, in random order, separated by at least 48 h. At 0900 h, via an indwelling forearm cannula, 10 micrograms desmopressin, 100 micrograms CRH, or a combination of the two were given as an iv bolus; thereafter, blood was drawn every 15 min for 2 h. The responses to the individual agents were determined according to the timing and calculation criteria suggested by Nieman et al. (1993). A total of 25 patients with Cushing's syndrome were studied: 17 patients with pituitary-dependent Cushing's syndrome, Cushing's disease (CD); 5 patients with occult ectopic ACTH secretion (EC); and 3 patients with primary adrenal (ACTH-independent) Cushing's syndrome. In this series, the best discrimination among ACTH-dependent patient groups was achieved using the combined test. Using the responses of plasma cortisol, all 17 patients with CD showed a rise greater than any of the 5 patients with EC, whereas 1 patient with CD showed a plasma ACTH response within the range seen in the patients with EC. Plasma cortisol responses to desmopressin alone were seen in 14 of 17 patients with CD and 1 of 5 patients with EC and, after CRH alone, in 15 of 17 patients with CD but in no patient with EC. In contrast, plasma ACTH responses after CRH alone were seen in 14 of 17 patients with CD and 2 of 5 patients with EC and, after desmopressin alone, in 12 of 17 with CD and 3 of 5 with EC, thus indicating overlapping responses between the groups and poorer discrimination. No responses were seen in the ACTH-independent group. These data indicate that desmopressin causes the secretion of ACTH and cortisol in patients with ACTH-dependent Cushing's syndrome, and that in combination with CRH, it may provide an improvement over the standard CRH test in the differential diagnosis of ACTH-dependent Cushing's syndrome. Furthermore, these data suggest that there may be abnormalities in vasopressin receptor function or number in ACTH-secreting tumors.

ACTH Syndrome, Ectopic↗
PubMed1996

Adrenal incidentaloma: subclinical Cushing's syndrome.

Adrenal incidentalomas present a significant differential diagnostic challenge. All patients with an incidentally discovered adrenal lesion should be carefully considered and re-evaluated to exclude extra-adrenal malignancy. Tumours with hypersecretory syndromes require excision, whilst those tumours more than 6 cm in size, particularly if they exhibit other features of malignancy on computed tomography (CT), magnetic resonance imaging (MRI) or scintigraphy, should also be excised. In all cases screening for phaeochromocytomas should be performed, and in the context of hypertension and spontaneous hypokalaemia, a primary aldosterone-secreting tumour requires exclusion. However, the natural history and treatment regimens for those individuals demonstrating 'subclinical Cushing's syndrome' is far from clear. Size, as determined by CT or MR scanning, does not in itself reliably distinguish benign from malignant disease. Scintigraphy may be a useful adjunct, with discordant patterns suggesting malignant disease. Fine needle aspiration should not routinely be used but may be useful in cases of doubt about other extra adrenal malignancy.

Adenoma↗
PubMed1996

Angiotensinogen in human essential hypertension.

The candidacy of angiotensinogen for a role in the genetic basis of hypertension is supported by the observation that plasma angiotensinogen levels track with raised blood pressure through families. In addition, transgenic mice with overexpression of a rat angiotensinogen gene develop hypertension, and knockout mice with a disrupted gene and absent angiotensinogen production develop low blood pressure. There are now two studies in populations of white European origin and one in African Caribbeans providing support for a role of the angiotensinogen gene locus in human essential hypertension.

Angiotensinogen↗