Peter J. Wood

Determinants of bone loss in elderly men and women: a prospective population-based study.

Abstract: While several studies have described the rate and pattern of involutional bone loss in women, far less information is available for men. Furthermore, the roles of lifestyle and body build in determining bone loss rate in both sexes have been largely extrapolated from cross-sectional studies. We addressed this issue in a population-based longitudinal study which sought to ascertain rates of bone loss at the femoral neck and lumbar spine in a cohort of men and women aged 60–75 years at baseline, and to relate this loss to anthropometric and lifestyle variables. We additionally investigated the capacity of biochemical markers of bone turnover to predict bone loss rates in these subjects. Women lost bone at all sites; this ranged from 0.20%/year at the lumbar spine to 1.43%/year at the femoral trochanteric region. By contrast, men lost only 0.20%/year at the trochanteric region, and gained at the lumbar spine (0.33%/year) and at Ward’s triangle (0.27%/year) over the 4-year period. Anthropometric measurements were associated with bone loss in both sexes; lower baseline body mass index (BMI) and a greater rate of loss of adiposity over the follow-up period were both associated with greater bone loss at all proximal femoral sites. These attained statistical significance after Bonferroni correction at the total proximal femur among both men (r= 0.29), p<0.01) and women (r= 0.31, p<0.05). Lifestyle factors associated with lower rates of bone loss (after adjustment for BMI) included alcohol consumption at the femoral neck among women (p= 0.007) and physical activity at the lumbar spine among men (p = 0.05). Serum parathyroid hormone, 25-hydroxyvitamin D and biochemical markers of bone turnover did not predict bone loss after adjustment for adiposity.

In humans, early cortisol biosynthesis provides a mechanism to safeguard female sexual development

In humans, sexual differentiation of the external genitalia is established at 7-12 weeks post conception (wpc). During this period, maintaining the appropriate intrauterine hormone environment is critical. In contrast to other species, this regulation extends to the human fetal adrenal cortex, as evidenced by the virilization that is associated with various forms of congenital adrenal hyperplasia. The mechanism underlying these clinical findings has remained elusive. Here we show that the human fetal adrenal cortex synthesized cortisol much earlier than previously documented, an effect associated with transient expression of the orphan nuclear receptor nerve growth factor IB-like (NGFI-B) and its regulatory target, the steroidogenic enzyme type 2 3beta-hydroxysteroid dehydrogenase (HSD3B2). This cortisol biosynthesis was maximal at 8-9 wpc under the regulation of ACTH. Negative feedback was apparent at the anterior pituitary corticotrophs. ACTH also stimulated the adrenal gland to secrete androstenedione and testosterone. In concert, these data promote a distinctive mechanism for normal human development whereby cortisol production, determined by transient NGFI-B and HSD3B2 expression, provides feedback at the anterior pituitary to modulate androgen biosynthesis and safeguard normal female sexual differentiation.

Size at birth, gestational age and cortisol secretion in adult life: foetal programming of both hyper‐ and hypocortisolism?

objective Recent studies have suggested that lifelong programming of the hypothalamic–pituitary–adrenal (HPA) axis in utero is an important mechanism in explaining the link between small size at birth and adult cardiovascular disease. However, direct evidence from human birth cohorts has so far been contradictory. We set out to study reasons for this discrepancy by examining the relationship between adult HPA axis function and birthweight and body proportions at birth in a group of elderly subjects with detailed birth records.

Variation in Detection of VEGF in Maternal Serum by Immunoassay and the Possible Influence of Binding Proteins

Using radioimmunoassay (RIA) and a polyclonal antibody we have shown that maternal serum vascular endothelial growth factor (VEGF) is elevated during pregnancy. In contrast, a commercial VEGF ELISA utilizing a sandwich two-site immunoassay was unable to detect VEGF in 19 of the 20 maternal serum samples analysed. In addition, the recovery of exogenous VEGF added to the pregnancy samples was low or not recordable with the ELISA. Using RIA, 82–101% of the added VEGF was recovered. These differing results could be explained by the formation of VEGF-protein complexes that are detectable using RIA but undetectable with the ELISA. Our data imply that there is a substantial increase in circulating VEGF binding proteins during pregnancy. The increase in VEGF and its binding proteins during pregnancy may reflect important physiological events in the mother and feto-placental unit.

Cortisol and the metabolic syndrome in South Asians

objective The cardiovascular risk factors which comprise the metabolic syndrome are associated with increased hypothalamic–pituitary–adrenal axis (HPAA) activity in some Caucasian populations. South Asians have high rates of cardiovascular disease and its risk factors. We have investigated the relationships between HPAA activity, adiposity and the metabolic syndrome in a South Asian population.

Salivary steroid assays – research or routine?

Salivary concentrations of unconjugated steroids reflect those for free steroids in serum although concentrations may differ because of salivary gland metabolism. Samples for salivary steroid analysis are stable for up to 7 days at room temperature, one month or more at 4°C and three months or more at −20°C. When assessed against strict criteria, the evidence shows that salivary cortisol in evening samples or following dexamethasone suppression provides a reliable and effective screen for Cushings syndrome. Sequential salivary cortisol measurements are also extremely helpful for the investigation of suspected cyclical Cushings syndrome. There is potential for the identification of adrenal insufficiency when used with Synacthen stimulation. Salivary 17-hydroxyprogesterone and androstenedione assays are valued as non-invasive tests for the home-monitoring of hydrocortisone replacement therapy in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The diagnostic value of salivary oestradiol, progesterone, testosterone, dehydroepiandrosterone and aldosterone testing is compromised by rapid fluctuations in salivary concentrations of these steroids. Multiple samples are required to obtain reliable information, and at present the introduction of these assays into routine laboratory testing is not justified.

An in vivo study of the cortisol-cortisone shuttle in subcutaneous abdominal adipose tissue

Previous in vitro studies have demonstrated significant 11‐beta hydroxysteroid dehydrogenase (11 β‐HSD) oxo‐reductase activity in visceral, but not subcutaneous adipose stromal cells. We have conducted an in vivo study of the cortisol–cortisone shuttle in subcutaneous abdominal adipose tissue.

Size at birth, the metabolic syndrome and 24‐h salivary cortisol profile

objective  Individual variation in hypothalamic–pituitary–adrenal axis (HPAA) function has been suggested to be important in linking small size at birth with adult cardiovascular disease and its risk factors, in particular the metabolic syndrome. Human studies have, however, so far only been performed in clinic settings, and their results have not been consistent. Our aim was to assess whether HPAA activity in everyday living circumstances is related to the metabolic syndrome and size at birth.

Serum IGF-I and IGF binding proteins 2 and 3 as potential markers of doping with human GH.

IGF‐I and IGF binding protein (IGFBP)‐3 levels in man are positively regulated by GH status; in contrast, evidence suggests an inverse relationship between GH status and IGFBP‐2. We investigated the effects of somatropin administration on the serum concentrations of these analytes, together with serum and urinary concentrations of GH, to evaluate their potential as markers in the development of a test for detecting doping with GH in sports competitors.

Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome.

OBJECTIVE Enhancement of negative feedback control of the HPA axis in patients with chronic fatigue syndrome (CFS) has been reported using the low dose dexamethasone suppression test. We have developed the use of prednisolone (5mg) as a more physiologically appropriate alternative to dexamethasone in the investigation of mild degrees of glucocorticoid resistance or supersensitivity. The objective of the study was to use this test to look for alterations in negative feedback control of the HPA axis in CFS patients. METHODS Fifteen patients with CFS were recruited after fulfilling strict criteria including the absence of comorbid psychiatric diagnosis. They collected urine between 0900 and 1800h and saliva at 0900h pre-prednisolone. At midnight, they took prednisolone (5mg) orally and then collected urine and saliva at the same intervals the following day. RESULTS Salivary cortisol was lower in CFS subjects pre-prednisolone than controls. Urinary cortisol metabolites were lower in CFS subjects pre-prednisolone, but did not reach significance. Both measures were significantly lower in CFS subjects post-dose. Mean percentage suppression of both salivary cortisol and urinary cortisol metabolites was significantly higher in CFS compared to controls. CONCLUSION There is enhanced sensitivity of the HPA axis to negative feedback in CFS as demonstrated using the prednisolone suppression test. This provides further evidence of alterations in the control of the HPA axis in patients with established CFS.