Steven Soule

Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis.

CONTEXT The diagnostic value of tests for detecting hypothalamic-pituitary adrenal insufficiency (HPAI) is controversial. OBJECTIVE Our objective was to compare standard-dose and low-dose corticotropin tests for diagnosing HPAI. DATA SOURCES We searched the PubMed database from 1966-2006 for studies reporting diagnostic value of standard-dose or low-dose corticotropin tests, with patient-level data obtained from original investigators. STUDY SELECTION Eligible studies had more than 10 patients. All subjects were evaluated because of suspicion for chronic HPAI, and patient-level data were available. We excluded studies with no accepted reference standard for HPAI (insulin hypoglycemia or metyrapone test) if test subjects were in the intensive care unit or if only normal healthy subjects were used as controls. DATA EXTRACTION We constructed receiver operator characteristic (ROC) curves using patient-level data from each study and then merged results to create summary ROC curves, adjusting for study size and cortisol assay method. Diagnostic value of tests was measured by calculating area under the ROC curve (AUC) and likelihood ratios. DATA SYNTHESIS Patient-level data from 13 of 23 studies (57%; 679 subjects) were included in the metaanalysis. The AUC were as follows: low-dose corticotropin test, 0.92 (95% confidence interval 0.89-0.94), and standard-dose corticotropin test, 0.79 (95% confidence interval 0.74-0.84). Among patients with paired data (seven studies, 254 subjects), diagnostic value of low-dose corticotropin test was superior to standard-dose test (AUC 0.94 and 0.85, respectively; P<0.001). CONCLUSIONS Low-dose corticotropin test was superior to standard-dose test for diagnosing chronic HPAI, although it has technical limitations.

Recommended evaluation of adrenal incidentalomas is costly, has high false-positive rates and confers a risk of fatal cancer that is similar to the risk of the adrenal lesion becoming malignant; time for a rethink?

OBJECTIVE To assess the performance of current clinical recommendations for the evaluation of an adrenal incidentaloma. DESIGN AND METHODS LITERATURE REVIEW: Electronic databases (Pubmed, Ovid and citation searches from key articles) from 1980 to 2008 were searched. Eligible studies were those deemed most applicable to the clinical scenario of a patient referred to an endocrinologist for assessment of an incidentally detected adrenal mass. Surgical series, histopathological series and oncological series were reviewed and most were excluded. RESULTS The prevalence of functional and malignant lesions presenting as adrenal incidentaloma was similar to that quoted in most reviews, other than a lower incidence of adrenal carcinoma (1.9 vs 4.7%) and metastases (0.7 vs 2.3%). The development of functionality or malignancy during follow-up was rare (<1% becoming functional and 0.2% becoming malignant). During follow-up, false-positive rates of the recommended investigations are typically 50 times greater than true positive rates. The average recommended computed tomography (CT) scan follow-up exposes each patient to 23 mSv of ionising radiation, equating to a 1 in 430 to 2170 chance of causing fatal cancer. This is similar to the chance of developing adrenal malignancy during 3-year follow-up of adrenal incidentaloma. CONCLUSION Current recommendations for evaluation of adrenal incidentaloma are likely to result in significant costs, both financial and emotional, due to high false-positive rates. The dose of radiation involved in currently recommended CT scan follow-up confers a risk of fatal cancer that is similar to the risk of the adrenal becoming malignant. This argues for a review of current guidelines.

Macroprolactinaemia: Contribution to Hyperprolactinaemia in a District General Hospital and Evaluation of a Screening Test Based on Precipitation with Polyethylene Glycol

For a period of 12 months all samples submitted for serum prolactin (PRL) assay and with PRL>700mU/L were examined by gel filtration chromatography. In 17 (25%) of 69 samples we found macroprolactin. The Delfia and Immuno 1 immunoassay systems gave similar PRL results with samples containing macroprolactin whereas the ACS 180 system gave lower results. With the Delfia and Immuno 1 systems samples containing substantial quantities of macroprolactin showed low recovery of PRL after precipitation with polyethylene glycol 6000 (PEG 6000) and this technique can be used as a screening test for macroprolactinaemia. We conclude that macroprolactinaemia is a common phenomenon and, in assays which detect this species, is a common cause of hyperprolactinaemia. Macroprolactinaemia may contribute to the difficulty in establishing an upper limit of the reference range for serum PRL. In our experience, patients with macroprolactinaemia do not exhibit features of the hyperprolactinaemia syndrome and it is important to recognize macroprolactin as the cause of hyperprolactinaemia to avoid unnecessary investigation and treatment.

FGF23 Elevation and Hypophosphatemia after Intravenous Iron Polymaltose: A Prospective Study

CONTEXT Parenteral iron administration has been associated with hypophosphatemia. Fibroblast growth factor 23 (FGF23) has a physiological role in phosphate homeostasis via suppression of 25-hydroxyvitamin D [25(OH)D] activation and promotion of phosphaturia. We recently reported a case of iron-induced hypophosphatemic osteomalacia associated with marked FGF23 elevation. OBJECTIVE Our objective was to prospectively investigate the effect of parenteral iron polymaltose on phosphate homeostasis and to determine whether any observed change was related to alterations in circulating FGF23. DESIGN, SETTING, AND PARTICIPANTS Eight medical outpatients prescribed iv iron polymaltose were recruited. Plasma phosphate, 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], PTH, FGF23, and urinary tubular reabsorption of phosphate were measured prior to iron administration and then weekly for a minimum of 3 wk. RESULTS Plasma phosphate fell from 3.4 +/- 0.6 mg/dl at baseline to 1.8 +/- 0.6 mg/dl at wk 1 (P < 0.0001) associated with a fall in percentage tubular reabsorption of phosphate (90 +/- 4.8 to 68 +/- 13; P < 0.001) and 1,25(OH)(2)D (54 +/- 25 to 9 +/- 8 pg/ml; P < 0.001). These indices remained significantly suppressed at wk 2 and 3. 25(OH)D levels were unchanged. FGF23 increased significantly from 43.5 pg/ml at baseline to 177 pg/ml at wk 1 (P < 0.001) with levels correlating with both serum phosphate (R = -0.74; P <0.05) and 1,25(OH)(2)D (R = -0.71; P < 0.05). CONCLUSION Parenteral iron suppresses renal tubular phosphate reabsorption and 1alpha-hydroxylation of vitamin D resulting in hypophosphatemia. Our data suggest that this is mediated by an increase in FGF23.

Effect of laparoscopic ovarian electrocautery on ovarian response and outcome of treatment with gonadotropins in clomiphene citrate-resistant patients with polycystic ovary syndrome

OBJECTIVE To evaluate the effect of ovarian electrocautery on the ovarian response to gonadotropic stimulation and pregnancy rate (PR) in clomiphene citrate (CC)-resistant women with polycystic ovary syndrome (PCOS) and high basal serum LH levels. DESIGN Retrospective study. SETTING Outpatient infertility clinic in a tertiary referral center. SUBJECTS Twenty-two women with PCOS, high basal serum LH concentrations, and CC resistance who underwent laparoscopic ovarian electrocautery. Treatment with gonadotropin was scheduled after failure to ovulate spontaneously or conceive after electrocautery. Data from gonadotropin-stimulated cycles were compared with data from treatment cycles in the same patients before ovarian electrocautery. MAIN OUTCOME MEASURES Number of ampules, duration of induction phase, daily effective dose, PR, and pregnancy outcome. RESULTS Markedly reduced basal serum LH concentrations and normal menstrual cyclicity in 41% of patients were recorded after laparoscopic ovarian electrocautery. Comparison of gonadotropin-stimulated cycles before and after electrocautery revealed significantly higher rates of ovulation and pregnancy after electrocautery as well as significant reduction in the number of ampules, daily effective dose, and duration of the induction phase with hMG and in daily effective dose with FSH. CONCLUSIONS Our results indicate an increased ovarian sensitivity to gonadotropins after laparoscopic ovarian electrocautery. A preference for laparoscopic ovarian electrocautery over medical treatment in all or selected groups of CC-resistant PCOS patients is suggested.

Osteopenia as a feature of the androgen insensitivity syndrome

OBJECTIVE The syndrome of androgen insensitivity, a paradigm of a hormone resistance syndrome, manifests as failure of masculinization despite normal or high concentrations of serum testosterone. The defect in these 46 XY patients resides in the androgen receptor gene, with consequent defective androgen action and abnormal sexual differentiation. We sought to evaluate whether the adverse sequelae of androgen resistance may extend to skeletal tissue by measuring bone mineral density In SIX patients with androgen Insensitivity.

Characterisation of proghrelin peptides in mammalian tissue and plasma

Ghrelin is a 28 amino acid stomach peptide, derived from proghrelin(1-94), that stimulates GH release, appetite and adipose deposition. Recently, a peptide derived from proghrelin(53-75) -- also known as obestatin -- has been reported to be a physiological antagonist of ghrelin in the rat. Using four specific RIAs, we provide the first characterisation of proghrelin(1-94) peptides in human plasma, their modulation by metabolic manipulation and their distribution in mammalian tissues. ghrelin(1-28) immunoreactivity (IR) in human plasma and rat plasma/stomach consisted of major des-octanoyl and minor octanoylated forms, as determined by HPLC/RIA. Human plasma ghrelin(1-28) IR was significantly suppressed by food intake, oral glucose and 1 mg s.c. glucagon administration. ghrelin(1-28) IR and proghrelin(29-94) IR peptide distributions in the rat indicated that the stomach and gastrointestinal tract contain the highest amounts of the peptides. Human and rat plasma and rat stomach extracts contained a major IR peak of proghrelin(29-94)-like peptide as determined by HPLC/RIA, whereas no obestatin IR was observed. Human plasma proghrelin(29-94)-like IR positively correlated with ghrelin(1-28) IR, was significantly suppressed by food intake and oral glucose and shared with ghrelin(1-28) IR a negative correlation with body mass index. We found no evidence for the existence of obestatin as a unique, endogenous peptide. Rather, our data suggest that circulating and stored peptides derived from the carboxyl terminal of proghrelin (C-ghrelin) are consistent in length with proghrelin(29-94) and respond to metabolic manipulation, at least in man, in similar fashion to ghrelin(1-28).

A new mutation, R563Q, of the beta subunit of the epithelial sodium channel associated with low-renin, low-aldosterone hypertension.

Objective To determine the relationship between R563Q, a mutation of the renal epithelial sodium channel, and hypertension. Methods Hypertensive patients with low renin and aldosterone, hypokalemia or resistant hypertension were selected for DNA analysis. Genomic DNA encoding the C-terminal domain of the epithelial sodium channel beta subunit from hypertensives and controls was amplified by polymerase chain reaction and screened for the R563Q mutation by digestion with Sfc1 restriction enzyme, or sequenced. Results A previously undescribed mutation, R563Q, of the beta epithelial sodium channel was found in 10 of 139 black hypertensives, but was not present in any of 103 black normotensives, a significant (P = 0.0058) difference in frequency. The frequency of the mutation in the subgroup of black low-renin, low-aldosterone hypertensives (four of 14) was significantly (P = 0.0001) greater than in normotensives, and was also greater (P = 0.041) than in normal-high renin hypertensives, suggesting that R563Q is an activating mutation of the epithelial sodium channel. R563Q was also found in seven out of 250 mixed ancestry hypertensives, and was significantly (P = 0.017) associated with low-renin, low-aldosterone hypertension in this population group. The mutation was found in one of 100 mixed ancestry normotensives but not in any of 136 white hypertensives. Of the 18 R563Q patients, 11 had severe hypertension, leading to renal failure in two cases, while only two had hypokalaemia. Conclusions R563Q, a new variant of the beta epithelial sodium channel, is associated with low-renin, low-aldosterone hypertension, in South African black and mixed-ancestry patients. Only a minority of individuals with the R563Q allelle fully express the Liddles syndrome phenotype.

Failure of the short ACTH test to unequivocally diagnose long-standing symptomatic secondary hypoadrenalism

Recent guidelines propose that secondary hypoadrenalism can be reliably diagnosed, in the absence of acute ACTH deficiency or glucocorticoid use, by means of the short ACTH test (Synacthen). We report a patient who maintained a normal response to exogenous ACTH stimulation despite symptomatic chronic ACTH deficiency proven by the insulin tolerance and overnight metyrapone tests. It is suggested that partial ACTH deficiency may prevent involution of the adrenal cortex and preserve the cortisol response to ACTH stimulation. A normal cortisol response in the short ACTH test does not therefore exclude the possibility of clinically relevant ACTH deficiency.

Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia

Iron-induced renal phosphate wasting, hypophosphataemia and osteomalacia have previously been reported in a small number of Japanese patients receiving parenteral iron sucrose. We report the case history of a European male who, as a result of regular intravenous iron polymaltose, developed prolonged hypophosphataemia complicated by widespread insufficiency fractures. The pathogenesis of this complication remains unknown however our novel finding of a marked elevation in fibroblast growth factor 23 (FGF23), which normalized after ceasing parenteral iron, suggests an important and previously unreported effect of iron on FGF23 homeostasis.