Glucocorticoid insufficiency, Achalasia, Alacrima with autonomic and motor neuropathy

We report the case of a patient with adrenal disease with achalasia and alacrima, which appear to be part of a widespread defect in adrenal and nervous system function. A 21-year-old white woman at age 6 had had hypoglycaemia, hyperpigmentation, low plasma cortisol level (30 nmol/L; normal, 200 to 600), and a lack of cortisol response to cosyntropin. Alacrima had been noted since infancy but there were no other abnormal neurologic features. A roentgenogram of the chest at age 9 showed bilateral pulmonary opacities presumed due to aspiration; these have persisted. Nocturnal cough, vomiting of undigested food, and recurrent chest..

Oestrogen replacement therapy may improve memory functioning in the absence of APOE e4

There is currently intense controversy regarding the use of hormone replacement therapy (HRT) in postmenopausal women, in relation to its therapeutic efficacy in Alzheimer's disease (AD). It has been suggested that the benefits of HRT may be modified by apolipoprotein E (APOE) genotype (the major genetic risk factor for AD). Here we report the findings of the first study designed to systematically explore the interaction of (a) oestrogen replacement therapy (ERT) and (b) possession of an ε4 allele of APOE on specific elements of episodic learning and memory that are commonly used indices of age-related cognitive decline. This data represents a cross-sectional analysis of the interaction of ERT and APOE genotype on learning and memory in a cohort of 181 healthy postmenopausal women [ERT users (n = 101, mean age 65.40 ± 6.34); ERT non-users (n = 80, mean age 67.03 ± 6.80)] residing in Perth, Western Australia. The highest level of learning (trials 2-5; P < 0.05) and memory (e.g. total number of items recalled; P < 0.05) performance was observed in women taking ERT who were not carriers of the APOE ε4 allele. APOEε4 carriers receiving ERT performed no better on episodic memory testing than APOE ε4 carriers who were not receiving ERT. These cognitive differences related to genetic profile, were noted on both recall and recognition (P = 0.005) tests of memory. The findings have significance for evaluating whether and when ERT may be clinically indicated. Specifically, ERT may benefit the cognitive functioning of women not carrying the APOE ε4 allele

Polymorphism of the follistatin gene in polycystic ovary syndrome

Follistatin has been reported as a candidate gene for polycystic ovary syndrome (PCOS) from linkage and association studies. Acting to regulate the development of ovarian follicles and as an antagonist to aromatase activity, alterations in follistatin function or expression may result in key features of PCOS such as reduced serum FSH, impaired ovarian follicle development and augmented ovarian androgen production. We investigated polymorphisms in the FST gene to determine if genetic variation is associated with susceptibility to PCOS or key phenotypic features of PCOS patients in a case-control association study. One hundred and seventy-three PCOS patients of Caucasian descent (mean age 30.0 ± 4.8 years), conforming to the NIH diagnostic criteria, were recruited from a clinical practice database and 107 normal ovulating women (mean age 38.8 ± 13.4 years) were recruited from the general community as control subjects. Morphometric data, biochemistry and genomic DNA were collected from study subjects and genotyping was performed on seven Single nucleotide polymorphisms (SNPs) in the FST gene region. Allele frequencies of the SNPs were rs1423560 G/C (0.99/0.01), rs3797297 C/A (0.80/0.20), rs11745088 C/G (0.98/0.02), rs3203788 A/T (0.98/0.02) and rs1062809 G/C (1.00/-), rs1127760 A/T (0.98/0.02) and rs1127761 A/T (0.98/0.02), and these were not significantly different between the PCOS and control groups (P < 0.05). Statistical analysis revealed significant associations between the SNP rs3797297 and sex hormone-binding globulin (P = 0.04) and free androgen index (FAI) (P < 0.01). We conclude that FST is not a susceptibility locus for PCOS; however, the SNP rs3797297 from FST gene was associated with androgenic markers for PCOS and may be of importance in the hyperandrogenaemia of the disease

Polymorphism in postinsulin receptor signaling pathway is not associated with polycystic ovary syndrome

Objective: To investigate polymorphisms in postinsulin receptor signaling. To investigate PIK3R1, SLC2A4, SLC2A4RG, and MEF2A to determine whether these genes are associated with susceptibility to polycystic ovary syndrome (PCOS) or key phenotypic features of insulin resistance in subjects with PCOS. Design: Case-control study. Setting: Participants with PCOS were recruited from a clinical practice database, and controls from the general community. Patient(s): One hundred seventy-three patients with PCOS conforming to the National Institutes of Health (NIH) diagnostic criteria, all of Caucasian descent; 107 normally ovulating women of white descent from the general community. Intervention(s): Drawing of blood for DNA extraction. Main Outcome Measure(s): Frequency of PIK3R1, SLC2A4, SLC2A4RG, and MEF2A polymorphisms in case and control subjects. Result(s): No significant difference between the frequency of the polymorphisms in case and control women was identified. No single nucleotide polymorphism studied in any of these four genes was associated with the PCOS phenotype. Conclusion(s): Polymorphisms in the PIK3R1, SLC2A4, SLC2A4RG, and MEF2A genes are not associated with key PCOS phenotypes

Polymorphism in HSD17B6 is associated with key features of polycystic ovary syndrome

Objective: To investigate polymorphisms in androgen metabolism regulators that are implicated in the etiology of polycystic ovary syndrome (PCOS) in vitro; to investigate HSD17B6 and GATA6 to determine whether these genes are associated with susceptibility to PCOS or key phenotypic features of patients with PCOS. Design: Case-control association study. Setting: Participants with PCOS were recruited from a clinical-practice database, and controls, from the general community. Patient(s): One hundred seventy-three patients with PCOS and who were of Caucasian descent and conformed to the National Institutes of Health (NIH) diagnostic criteria; 107 normally ovulating women of Caucasian descent from the general community. Intervention(s): Drawing of blood for DNA extraction. Main Outcome Measure(s): Frequency of HSD17B6 and GATA6 polymorphisms in cases and controls. Association of single-nucleotide polymorphisms from HSD17B6 in subjects with PCOS with key phenotypes of PCOS: androgen status, insulin resistance, and body mass index. Result(s): Allele distribution for the single-nucleotide polymorphism rs898611 in HSD17B6 was significantly different between PCOS and control subjects (P=.03). Presence of the polymorphic allele was associated with reduced fasting glucose-insulin ratio (P=.02) and increased homeostasis model assessment (P<.01) and body mass index (P<.001) as well as with reduced T (P=.03) in the PCOS group. No association was seen between GATA6 and any of the variables studied. Conclusion(s): These data suggest that polymorphisms in the HSD17B6 gene are associated with PCOS and key clinical phenotypes of the disorder

Clinical, biochemical, hematologic, and radiographic responses in Paget's disease following intravenous pamidronate disodium: A 2-year study

An intravenous dosage schedule using pamidronate disodium, based on biochemical severity, was used to treat 71 patients with Paget's disease who had had no previous bisphosphonate treatment. Disease severity was stratified by fasting hydroxyproline excretion (Hyp(E)): Group (Gp) I (mild disease; Hyp(E) < 5.0 μmol/LGF) received a total dose of 120 mg; Gp II (moderate; Hyp(E), 5.00-9.99) received 180 mg; and Gp III (severe; Hyp(E) ≤ 10) received 240 mg. Within each group patients were randomly allocated to receive daily 30 mg or 60 mg infusions. Observations for 2 years included pain scores, indices of bone turnover, and radiology of lytic lesions. There was no difference in biochemical responses, or in the percentage of patients with early fever, between the 30 mg and 60 mg daily subgroups; for convenience, 60 mg infusions are recommended. Neutrophils and total white cell counts were both significantly below baseline 4 days after the first infusion; lymphocytes were significantly reduced by day 2; and all three measures had returned to within the reference range by day 6. Remission was assessed at 6 months, when both plasma alkaline phosphatase (ALP) and Hyp(E), had reached stable nadirs. Increasing severity was associated with increasing resistance to suppression of Hyp(E) at 6 months to within the reference range: Gp I, 87%; Gp II, 44%; and Gp III, O% (p < 0.0001 by chi-square test). Biochemical relapse at 2 years (defined as ALP 50% above the 6 month level) was also dependent on initial disease severity (Gp I, 6%; GpII, 39%; Gp III, 62%;p < 0.0005 by chi-square test). There was no association between time to relapse and either initial dose or log dose. Radiologic lytic lesions (in 22 patients) were all in remission at 3 months; however, relapse rates at 2 years appeared to be severity-dependent: Gp I, 13%; Gp II, 43%; and Gp III, 57% (n.s. by chi-square test). Remission rates based on a fall to < 50% of pretreatment of either Hyp(E) or ALP were more in accord with lytic lesion remission rates than were rates based on Hyp(E) falling to within the reference range. Pamidronate produced a significant reduction from baseline in Pagetic bone, Pagetic joint, and unrelated musculoskeletal pain in the first 6 months (p < 0.0001). From 0 months to 2 years the maintenance of improvement in bone pain (p < 0.005) and joint pain (p < 0.05) was significantly better than in unrelated pain. Pamidronate is a safe, well-tolerated, and effective treatment for Paget's disease. In spite of larger dosage in severe disease, increasing severity was associated with resistance to normalization of biochemistry and a higher incidence of biochemical and radiological relapse at 2 years. Our current dosage recommendation would be for two 60 mg infusions for mild disease (Gp I); and four 60 mg infusions for moderate disease (Gp II). Severe disease (Gp III) remains a challenge; regardless of dosage, the majority of patients will be in relapse 2 years after a single course of treatment

Mediation analysis of the testosterone treatment effect to prevent type 2 diabetes in the Testosterone for Prevention of Type 2 Diabetes Mellitus trial

OBJECTIVE: To determine if testosterone treatment effect on glycaemia is mediated through changes in total fat mass, abdominal fat mass, skeletal muscle mass, non-dominant handgrip, oestradiol (E2), and sex hormone-binding globulin (SHBG). DESIGN: Mediation analysis of a randomised placebo-controlled trial of testosterone. METHODS: Six Australian tertiary care centres recruited 1007 males, aged 50-74 years, with waist circumference ≥ 95 cm, serum total testosterone ≤ 14 nmol/L (immunoassay) and either impaired glucose tolerance or newly diagnosed type 2 diabetes on an oral glucose tolerance test (OGTT). Participants were enrolled in a lifestyle program and randomised 1:1 to 3 monthly injections of 1000 mg testosterone undecanoate or placebo for 2 years. Complete data were available for 709 participants (70%). Mediation analyses for the primary outcomes of type 2 diabetes at 2-years (OGTT ≥ 11.1 mmol/L and change in 2-hour glucose from baseline), incorporating potential mediators: changes in fat mass, % abdominal fat, skeletal muscle mass, non-dominant hand-grip strength, E2, and SHBG was performed. RESULTS: For type 2 diabetes at 2-years, the unadjusted OR for treatment was 0.53 (95% CI:0.35-0.79), which became 0.48 (95% CI:0.30-0.76) after adjustment for covariates. Including potential mediators attenuated the treatment effect (OR 0.77; 95% CI:0.44-1.35; direct effect) with 65% mediated. Only fat mass remained prognostic in the full model (OR: 1.23; 95% CI: 1.09-1.39; p < 0.001). CONCLUSION: At least part of the testosterone treatment effect was found to be mediated by changes in fat mass, abdominal fat, skeletal muscle mass, grip strength, SHBG, and E2, but predominantly by changes in fat mass.Kristy P. Robledo, Ian C. Marschner, David J. Handelsman, Karen Bracken, Bronwyn G.A. Stuckey, Bu B. Yeap, Warrick Inder, Mathis Grossmann, David Jesudason, Carolyn A. Allan, and Gary Witter

Efficacy and safety of beloranib for weight loss in obese adults: a randomized controlled trial

Aim: To assess the efficacy, safety and tolerability of beloranib treatment for obesity. Methods: This phase II, double-blind, randomized study investigated the effects of beloranib suspension (0.6, 1.2 and 2.4mg) or placebo, administered subcutaneously, for 12weeks in 147 participants (primarily white women) with obesity. No diet or exercise advice was administered. Results: At week 12, beloranib resulted in dose-dependent progressive weight loss of -5.5±0.5, -6.9±0.6 and -10.9±1.1kg for the 0.6, 1.2 and 2.4mg beloranib doses, respectively, compared with -0.4±0.4kg with placebo (all

Effect of Testosterone treatment on bone microarchitecture and bone mineral density in men: a two-year RCT

CONTEXT: Testosterone treatment increases bone mineral density (BMD) in hypogonadal men. Effects on bone microarchitecture, a determinant of fracture risk, are unknown. OBJECTIVE: Determine the effect of testosterone treatment on bone microarchitecture using high resolution-peripheral quantitative computed tomography (HR-pQCT). DESIGN, SETTING, PARTICIPANTS: Men>50 years were recruited from six Australian centres. INTERVENTIONS: Injectable testosterone undecanoate or placebo over 2 years on the background of a community-based lifestyle program. MAIN OUTCOMES: Primary endpoint was cortical volumetric BMD (vBMD) at the distal tibia, measured using HR-pQCT in 177 men (one centre). Secondary endpoints included other HR-pQCT parameters and bone remodelling markers. Areal BMD (aBMD) was measured by dual energy X-ray absorptiometry (DXA) in 601 men (five centres). Using a linear mixed model for repeated measures, the mean adjusted differences (MAD) [95% CI] at 12 and 24 months between groups are reported as treatment effect. RESULTS: Over 24 months, testosterone treatment, compared to placebo, increased tibial cortical vBMD), 9.33mgHA/cm 3[3.96;14.71],p50 years, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.Mark Ng Tang Fui, Rudolf Hoermann, Karen Bracken, David J Handelsman, Warrick J Inder, Bronwyn G A Stuckey ... et al