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Short-term oral oestrogen therapy dissociates the growth hormone/IGF-I axis without altering energy metabolism in premenopausal women(2009) O'Sullivan, Anthony; Huang, DeniseJournal ArticleObjective: Oral oestrogen has been shown to dissociate the growth hormone (GH)/insulin-like growth factor (IGF)-I axis and alter energy metabolism in postmenopausal women. This study was designed to determine whether these metabolic changes occur with short-term oral oestrogen in premenopausal women. Study design: A double-blind placebo controlled randomised-crossover design study was performed in 12 premenopausal women. Investigations were performed after either 5 days of oral 17β-oestradiol valerate 2 mg twice daily or placebo. Outcomes included body composition measured by bio-impedance, energy metabolism measured by indirect calorimetry and blood sampling. Results: Oral oestrogen significantly suppressed IGF-I levels and increased fasting GH levels. No significant changes in energy metabolism or body composition were detected. Conclusions:Short-term oral oestrogen suppresses IGF-I and elevates GH levels in premenopausal women. No effects were seen on body composition and energy metabolism. Further research is required to determine whether metabolic effects of oral oestrogen may become apparent if longer courses of treatment were administered to premenopausal women.
(2001) Martin, Allison; O'Sullivan, Anthony; Brown, MarkJournal ArticleObjective To determine whether the insulin resistance syndrome and altered body composition are features of hypertensive pregnancy.Design Women were recruited in the third trimester of pregnancy from the antenatal clinic, day assessment unit, and maternity ward of St George Hospital, Sydney.Population Women with pre-eclampsia (n=12), gestational hypertension (n=12), essential hypertension in pregnancy (n=11), and normotensive pregnancy (n=10).Methods Energy metabolism was assessed by indirect calorimetry to measure basal metabolic rate and diet-induced thermogenesis. Body composition was measured as lean body mass, total body water and fat mass by bio-electrical impedance. Blood was collected for measurement of glucose, insulin and lipid profiles. Insulin resistance was indirectly assessed by the insulin and glucose concentrations and diet-induced thermogenesis.Results Women with essential hypertension and gestational hypertension were heavier than women with normotensive pregnancies both pre-pregnancy and in the third trimester, whereas women with pre-eclampsia were similar to those with normotensive pregnancy. Women with essential hypertension were otherwise similar to normotensive pregnancy but women with gestational hypertension had a reduced diet-induced thermogenesis and almost double insulin levels. Women with pre-eclampsia had a similar body composition and insulin levels but reduced basal metabolic rate, diet-induced thermogenesis and glucose levels compared with normotensive pregnancy.Conclusions Women who develop gestational hypertension, but not pre-eclampsia, are more likely to be overweight. Women with essential hypertension are similar to women with normotensive pregnancy throughout pregnancy. Both gestational hypertension and pre-eclampsia appear to be associated with some degree of insulin resistance, greater than that occurring in normal pregnancy.
(2009) Shen, Bojiang; Bhargav, Divya; Wei, Ai-Qun; Williams, Lisa; Diwan, AshishJournal ArticleBone morphogenetic protein-13 (BMP-13) plays an important role in skeletal development. In the light of a recent report that mutations in the BMP-13 gene are associated with spine vertebral fusion in Klippel-Feil syndrome, we hypothesized that BMP-13 signaling is crucial for regulating embryonic endochondral ossification. In this study, we found that BMP-13 inhibited the osteogenic differentiation of human bone marrow multipotent mesenchymal stromal cells (BM MSCs) in vitro. The endogenous BMP-13 gene expression in MSCs was examined under expansion conditions. The MSCs were then induced to differentiate into osteoblasts in osteo-inductive medium containing exogenous BMP-13. Gene expression was analysed by real-time PCR. Alkaline phosphatase (ALP) expression and activity, proteoglycan (PG) synthesis and matrix mineralization were assessed by cytological staining or ALP assay. Results showed that endogenous BMP-13 mRNA expression was higher than BMP-2 or -7 during MSC growth. BMP-13 supplementation strongly inhibited matrix mineralization and ALP activity of osteogenic differentiated MSCs, yet increased PG synthesis under the same conditions. In conclusion, BMP-13 inhibited osteogenic differentiation of MSCs, implying that functional mutations or deficiency of BMP-13 may allow excess bone formation. Our finding provides an insight into the molecular mechanisms and the therapeutic potential of BMP-13 in restricting pathological bone formation.
(2009) O'Sullivan, Anthony; Brillante, D; Johnstone, M; Howes, LJournal ArticleBackground The haemodynamic effects of intravenous infusion of the non-selective nitric oxide synthase (NOS) l-omega monomethyl arginine (l-NMMA) have previously been characterized in humans. Its effect of reducing cardiac index (CI) is an important reason for the increase in mortality in patients with septic shock receiving l-NMMA in a pivotal outcome trial for this indication. The mechanism for the reduction in CI however, is uncertain. Methods In this study, we investigated the haemodynamic and arterial stiffness response to a bolus intravenous infusion of l-NMMA (3 mg kg−1 over 5 min) in 26 healthy human volunteers to clarify the likely cause of l-NMMA induced negative inotropic and chronotropic effects. Digital photoplethysmography (MicroMedical Pulse Trace) was used to derive two measures of arterial stiffness: stiffness index, a measure of large arterial stiffness, and reflection index (RI), a measure of small- to medium-sized arterial stiffness. Haemodynamic measurements of systolic blood pressure, diastolic blood pressure, heart rate, systemic vascular resistance index (SVRI), stroke index and CI were made using a bioimpedance monitor (BioZ Cardiodynamics). Results We found that changes in CI during l-NMMA are closely related to changes in RI and SVRI. Conclusion The negative inotropic effect of l-NMMA may be a result of an increase in coronary vascular resistance and a resultant decrease in myocardial perfusion. The reduction in CI may also result from a direct reduction of the normal positive inotropic effect of NO by l-NMMA which is closely correlated with its effects on SVRI.
(2001) Martin, Allison; Brown, Mark; O'Sullivan, AnthonyJournal ArticleSummary: The objective of the study was to measure energy metabolism and body composition during pregnancy and postpartum, compared to non-pregnant women, using non-invasive techniques. A longitudinal study of eight normotensive pregnant women was carried out at 19 ± 1 and 36 ± 1 weeks gestation, and postpartum. A cross-sectional study was also performed comparing postpartum to 12 nonpregnant women. Indirect calorimetry was performed while fasting to measure basal metabolic rate (BMR) and postprandially to measure diet-induced thermogenesis (DIT). Body composition consists of fat mass, lean body mass (LBM), and total body water (TBW) and was measured by bio-electrical impedance. Insulin resistance was indirectly assessed by glucose and insulin concentration and DIT. Weight gain in pregnancy was predominantly fat mass (p < 0.01), but LBM and TBW also increased (p < 0.01). Weight loss postpartum was comprised of fat mass, LBM and TBW (p < 0.01). BMR, glucose and insulin increased in pregnancy and decreased postpartum (p < 0.05), but DIT was unchanged. The BMR was not correlated with weight gain. Apart from fat mass, postpartum and non-pregnant women were similar. The insulin resistance increased insulin and glucose levels but not DIT. Fat mass was the major component of weight gain during pregnancy and there was an increase in BMR, glucose and insulin but no change in DIT. BMR decreased to normal but fat mass remained elevated 16 weeks post-partum.
(2001) O'Sullivan, Anthony; Martin, Allison; Brown, MarkJournal ArticleThere is a sexual dimorphism in body fat in humans. Adipose tissue increases with puberty and early pregnancy in women, suggesting gonadal steroids can influence body fat. Previously, we have observed that oral estrogen, compared with transdermal estrogen, reduced postprandial lipid oxidation and increased body fat, possibly due to suppressed hepatic lipid oxidation. If estrogen effects lipid oxidation, we predicted that subjects with significantly different endogenous estrogen production would oxidize lipids at different rates. The aim of this study was to compare energy metabolism in 12 pregnant (19 wk gestation, 29 ± 1 yr, 1.66 ± 0.02 m, 73.5 ± 2.4 kg), 11 nonpregnant premenopausal (29 ± 2 yr, 1.68 ± 0.02 m, 63.1 ± 1.8 kg), and 28 postmenopausal (58 ± 1 yr, 1.62 ± 0.01 m, 69.9 ± 1.0 kg) women who were not receiving estrogen, and to relate these findings to endogenous estrogen concentrations. All women underwent indirect calorimetry under identical situations in the basal and postprandial state following a standard mixed meal. Basal (5998 ± 184 vs. 5712 ± 184 vs. 5800 ± 121 kJ·24 h, respectively) and postprandial energy expenditure (7172 ± 239 vs. 6964 ± 210 vs. 6955 ± 147 kJ·24 h) was similar among groups. However, basal lipid oxidation was reduced in pregnant (45.3 ± 6.1 mg/min, P < 0.05) and nonpregnant women (44.5 ± 6.3 mg/min, P < 0.05) compared with postmenopausal women (58.4 ± 2.9 mg/min). Postprandial lipid oxidation differed among groups, being least in pregnant women (8.8 ± 6.2 mg/min) compared with nonpregnant (28.9 ± 6.4 mg/min, P < 0.04) and postmenopausal (48.1 ± 4.0 mg/min, P = 0.0001) women. There was a significant reciprocal increase in postprandial carbohydrate oxidation. Mean postprandial glucose levels were slightly but nonsignificantly higher in pregnant women. Insulin levels were significantly higher in postmenopausal compared nonpregnant, but not pregnant, women. In a multiple regression analysis, serum estradiol (log transformed) correlated negatively with postprandial lipid oxidation (r = -0.66, P = 0.0001) and positively with postprandial nonesterified free fatty acid levels, whereas no correlation was found with postprandial insulin, glucose, fat free mass, and fat mass. In summary, postprandial lipid oxidation is reduced in pregnancy compared with that in healthy nonpregnant women, who in turn have lower postprandial lipid oxidation than postmenopausal women. This implies that the premenopausal years and early pregnancy are states of efficient fat storage, possibly mediated through reduced lipid oxidation due to estrogen, therefore increasing body fat for reproduction, thus supporting the notion that fat mass can be regulated.