SummaryPPARγ is essential for adipogenesis and metabolic homeostasis. We describe mutations in the DNA and ligand binding domains of human PPARγ in lipodystrophic, severe insulin resistance. These receptor mutants lack DNA binding and transcriptional activity but can translocate to the nucleus, interact with PPARγ coactivators and inhibit coexpressed wild-type receptor. Expression of PPARγ target genes is markedly attenuated in mutation-containing versus receptor haploinsufficent primary cells, indicating that such dominant-negative inhibition operates in vivo. Our observations suggest that these mutants restrict wild-type PPARγ action via a non-DNA binding, transcriptional interference mechanism, which may involve sequestration of functionally limiting coactivators.

Summary OBJECTIVE The 1 µg ACTH stimulation test has been introduced to improve the sensitivity of ACTH as a test of the integrity of hypothalamic–pituitary–adrenal axis (HPAA). This study aims to compare the sensitivity, specificity and diagnostic accuracy of the ‘low‐dose’ 1 µg ACTH (LDACTH) test and the ‘standard dose’ 250 µg ACTH (SDACTH) test, with the overnight metyrapone test (OMT) which assesses the entire HPAA. DESIGN A prospective evaluation of the performance of SDACTH and LDACTH screening tests in a diverse cohort of patients with possible adrenal insufficiency as routinely encountered in clinical practice using the OMT as the reference method. PATIENTS A total of 51 patients (26 with asthma on inhaled glucocorticoid, nine with hypopitutarism, three with hypothyroidism, one with hyponatraemia, one with Crohn’s disease, one with encephalitis and 10 with non‐specific symptoms) each underwent SDACTH, LDACTH and OMT tests in random sequence at least 1 week apart. MEASUREMENTS Blood was sampled for plasma cortisol levels at 0 and 30 min after intravenous administration of 1 µg and 250 µg of ACTH. Metyrapone 30 mg/kg body weight was taken orally at midnight, and plasma samples were taken for measurement of 11‐deoxycortisol and cortisol next morning between 08·00 and 09·00 h. The OMT was deemed to be abnormal when both 11‐deoxycortisol and cortisol levels were less than 200 nmol/l. RESULTS The sensitivity and specificity at an empirical ‘normal’ plasma cortisol threshold value of 500 nmol/l were 67% and 100% for the SDACTH test, and 73% and 81% for the LDACTH test, respectively. As the plasma cortisol cut‐off value was increased to 550 nmol/l and 600 nmol/l, the sensitivity of the SDACTH test was 67% and 80% and specificity was 97% and 92%, respectively. The sensitivity of the LDACTH test increased from 93% at plasma cortisol cut‐off value of 550 nmol/l to 100% at plasma cortisol cut‐off value of 600 nmol/l. However, the specificity of the LDACTH test fell from 72% to 56% as the plasma cortisol cut‐off value was increased from 550 nmol/l to 600 nmol/l. A receiver operating characteristic curve demonstrated that the specificity of the SDACTH test was higher than the specificity of the LDACTH test at any given level of sensitivity. CONCLUSIONS Both the LDACTH and SDACTH tests fail to achieve acceptable levels of sensitivity and specificity to be useful as screening tests for secondary adrenal insufficiency. In this context the OMT can be safely used to assess the integrity of the entire HPAA.

No abstract

ObjectivesThis study aimed to investigate the hypothalamic-pituitary-gonadal axis in a sample of male patients undertaking intrathecal opioid delivery for the management of chronic non-malignant pain and the presence of osteopaenia and/or osteoporosis in those diagnosed with hypogonadism.DesignObservational study using health data routinely collected for non-research purposes.SettingDepartment of Pain Management, Russells Hall Hospital, Dudley, UK.PatientsTwenty consecutive male patients attending follow-up clinics for intrathecal opioid therapy had the gonadal axis evaluated by measuring their serum luteinising hormone, follicle stimulating hormone, total testosterone, sex hormone binding globulin and calculating the free testosterone level. Bone mineral density was measured by DEXA scanning in those patients diagnosed with hypogonadism.ResultsBased on the calculated free testosterone concentrations, 17 (85%) patients had biochemical hypogonadism with 15 patients (75%) having free testosterone <180 pmol/L and 2 patients (10%) between 180 and 250 pmol/L. Bone mineral density was assessed in 14 of the 17 patients after the exclusion of 3 patients. Osteoporosis (defined as a T score ≤−2.5 SD) was detected in three patients (21.4%) and osteopaenia (defined as a T score between −1.0 and −2.5 SD) was observed in seven patients (50%). Five of the 14 patients (35.7%) were at or above the intervention threshold for hip fracture.ConclusionsThis study suggests an association between hypogonadism and low bone mass density in patients undertaking intrathecal opioid delivery for the management of chronic non-malignant pain. Surveillance of hypogonadism and the bone mineral density levels followed by appropriate treatment may be of paramount importance to reduce the risk of osteoporosis development and prevention of fractures in this group of patients.

Osteoporosis is more common in chronic alcoholics than in age-matched controls. Possible aetiological factors are: malabsorption of calcium and vitamin D; liver disease and abnormal parathyroid function. The possibility that alcohol may directly affect osteoblastic function has, however, received little attention. We measured plasma osteocalcin, a protein synthesised specifically by osteoblasts, in chronic alcoholics. Our data show that these have low plasma osteocalcin but normal calcium, magnesium and parathormone, which suggest that alcohol may be directly toxic to osteoblasts.